PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.

“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.

Bruce Jancin/Frontline Medical News

[email protected]

PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.

“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.

Bruce Jancin/Frontline Medical News

[email protected]

PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.

“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.

Bruce Jancin/Frontline Medical News

[email protected]

NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.

But when a patient with follicular lymphoma experiences early disease progression on bendamustine, what should the next treatment be? Autologous stem cell transplantation (ASCT)? Novel therapies? That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
 

Dr. Casulo: ASCT

“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.

“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.

Dr. Link: Novel agents

“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.

“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.

NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.

But when a patient with follicular lymphoma experiences early disease progression on bendamustine, what should the next treatment be? Autologous stem cell transplantation (ASCT)? Novel therapies? That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
 

Dr. Casulo: ASCT

“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.

“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.

Dr. Link: Novel agents

“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.

“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.

NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.

But when a patient with follicular lymphoma experiences early disease progression on bendamustine, what should the next treatment be? Autologous stem cell transplantation (ASCT)? Novel therapies? That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
 

Dr. Casulo: ASCT

“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.

“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.

Dr. Link: Novel agents

“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.

“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.

Categorizing hair loss in children depends on many factors, but it is important to rule out an infectious etiology as early as possible, according to Sheila Fallon Friedlander, MD.

“What can Tinea capitis look like? Anything,” she said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.

Although T. capitis most often presents in children aged 3-7 years as a pattern of localized hair loss, often with scaling, sometimes with nodules, other possibilities include pustules, boggy masses, and diffuse hair loss, said Dr. Friedlander, professor of pediatrics and dermatology at the University of California, San Diego.

Sometimes the hair loss may be so subtle that families come in complaining of “dandruff” rather than hair loss, she noted. Evaluating the patient for the presence of cervical or occipital lymph nodes is crucial; big nodes are usually a tip-off that infection is present.

The optimal treatment plan for T. capitis depends on the source, Dr. Friedlander explained. If M. canis is the cause, “griseofulvin is the drug of choice,” along with a twice-weekly sporicidal shampoo, she said.

Other treatment options include terbinafine, itraconazole, and fluconazole, and each have their pros and cons, she said. Terbinafine – which persists for months in the skin, nails, and hair – is the least expensive, and is her first choice for infections caused by T. tonsurans.

Itraconazole is available as a liquid, but costs more, causes diarrhea, and comes with a boxed warning about the potential for cardiac complications; fluconazole is the most expensive, but may be used in infants, she added.

Other high-risk groups for T. capitis include female caretakers of high-risk individuals, such as “grandma”; wrestlers; and Buddhist monks, she said. “Short hair, sharing combs, and unclean barbers” contributed to a documented increased risk of T. capitis according to a recently published study of 60 Buddhist monks whose average age was 11.6 years, she added. (Pediatr Dermatol. 2017 May;34[3]:371-3).

Dr. Friedlander had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by Frontline Medical Communications.

Categorizing hair loss in children depends on many factors, but it is important to rule out an infectious etiology as early as possible, according to Sheila Fallon Friedlander, MD.

“What can Tinea capitis look like? Anything,” she said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.

Although T. capitis most often presents in children aged 3-7 years as a pattern of localized hair loss, often with scaling, sometimes with nodules, other possibilities include pustules, boggy masses, and diffuse hair loss, said Dr. Friedlander, professor of pediatrics and dermatology at the University of California, San Diego.

Sometimes the hair loss may be so subtle that families come in complaining of “dandruff” rather than hair loss, she noted. Evaluating the patient for the presence of cervical or occipital lymph nodes is crucial; big nodes are usually a tip-off that infection is present.

The optimal treatment plan for T. capitis depends on the source, Dr. Friedlander explained. If M. canis is the cause, “griseofulvin is the drug of choice,” along with a twice-weekly sporicidal shampoo, she said.

Other treatment options include terbinafine, itraconazole, and fluconazole, and each have their pros and cons, she said. Terbinafine – which persists for months in the skin, nails, and hair – is the least expensive, and is her first choice for infections caused by T. tonsurans.

Itraconazole is available as a liquid, but costs more, causes diarrhea, and comes with a boxed warning about the potential for cardiac complications; fluconazole is the most expensive, but may be used in infants, she added.

Other high-risk groups for T. capitis include female caretakers of high-risk individuals, such as “grandma”; wrestlers; and Buddhist monks, she said. “Short hair, sharing combs, and unclean barbers” contributed to a documented increased risk of T. capitis according to a recently published study of 60 Buddhist monks whose average age was 11.6 years, she added. (Pediatr Dermatol. 2017 May;34[3]:371-3).

Dr. Friedlander had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by Frontline Medical Communications.

Categorizing hair loss in children depends on many factors, but it is important to rule out an infectious etiology as early as possible, according to Sheila Fallon Friedlander, MD.

“What can Tinea capitis look like? Anything,” she said in a presentation at Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar.

Although T. capitis most often presents in children aged 3-7 years as a pattern of localized hair loss, often with scaling, sometimes with nodules, other possibilities include pustules, boggy masses, and diffuse hair loss, said Dr. Friedlander, professor of pediatrics and dermatology at the University of California, San Diego.

Sometimes the hair loss may be so subtle that families come in complaining of “dandruff” rather than hair loss, she noted. Evaluating the patient for the presence of cervical or occipital lymph nodes is crucial; big nodes are usually a tip-off that infection is present.

The optimal treatment plan for T. capitis depends on the source, Dr. Friedlander explained. If M. canis is the cause, “griseofulvin is the drug of choice,” along with a twice-weekly sporicidal shampoo, she said.

Other treatment options include terbinafine, itraconazole, and fluconazole, and each have their pros and cons, she said. Terbinafine – which persists for months in the skin, nails, and hair – is the least expensive, and is her first choice for infections caused by T. tonsurans.

Itraconazole is available as a liquid, but costs more, causes diarrhea, and comes with a boxed warning about the potential for cardiac complications; fluconazole is the most expensive, but may be used in infants, she added.

Other high-risk groups for T. capitis include female caretakers of high-risk individuals, such as “grandma”; wrestlers; and Buddhist monks, she said. “Short hair, sharing combs, and unclean barbers” contributed to a documented increased risk of T. capitis according to a recently published study of 60 Buddhist monks whose average age was 11.6 years, she added. (Pediatr Dermatol. 2017 May;34[3]:371-3).

Dr. Friedlander had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by Frontline Medical Communications.

Editor’s note: Each month, the Society of Hospital Medicine puts the spotlight on some of our most active members who are making substantial contributions to hospital medicine. Log on to www.hospitalmedicine.org/getinvolved for more information on how you can lend your expertise to help SHM improve the care of hospitalized patients.

This month, The Hospitalist spotlights Lorraine Britting, ANP, SFHM, clinical director of advanced practice in cardiology medicine at Beth Israel Deaconess Medical Center, Boston. Ms. Britting has been an SHM member for over 10 years, has served on various SHM committees, and was one of the first nurse practitioners to earn the Senior Fellow in Hospital Medicine designation.

How did you become a hospital medicine nurse practitioner, and when did you join SHM?

I was a nurse working in a CCU and MICU for 19 years when I graduated from a master’s program as a nurse practitioner (NP) in adult care. I thought I was going to work in the outpatient side after graduation, but my experience was much more suited to hospital medicine.

My first job in 2004 was as a hospitalist in a very small community hospital affiliated with Beth Israel Deaconess Medical Center. I was the first NP to work as an inpatient provider there, which was challenging, but I had the opportunity to wear many hats and be involved with numerous quality initiatives that helped me grow as a provider and a leader. I was working as the clinical manager of three hospitalist programs under the director by the time I left. I now work in inpatient cardiology and am the director of advanced practice providers (APPs) for cardiology medicine. I joined SHM in 2005 when it was a small but rapidly growing society, and I started work on the NP/PA Committee. I was also involved in the Hospital Quality and Patient Safety Committee for 6 years and worked as a peer reviewer for the Journal of Hospital Medicine.
 

Describe your role on the Membership Committee. What is the committee currently working on?

I am finishing my 3rd year on the committee. In the last few months, we have been focusing on member engagement. We have collected information on why members choose to join SHM and what deters potential members from joining SHM and we are developing strategies to build and retain our membership. The Membership Committee also reviews Fellows applications and discusses modifications of requirements each year.

As an NP, I have unique insight into motivations for why other APPs would join SHM and which membership benefits are most valuable. I find that many APPs join SHM because they feel that SHM treats them as equals, not junior members, as in some other physician organizations.
 

What does the Senior Fellow in Hospital Medicine designation mean to you?

I am grateful that SHM allows all members to be a part of the Fellows program, and I was honored to be one of the first NPs to become a Senior Fellow. Many medical societies allow APPs to join but do not offer the opportunity to become Fellows.

The Senior Fellowship application was a rigorous process and required experience in multiple areas, including quality projects, hospital committees, SHM Annual Conference attendance, and other clinical and nonclinical work that advances the profession.
 

As a nurse practitioner, which SHM resources do you find most valuable?

As a specialist NP, it’s easy for me to be current in cardiology but harder to keep current in general medicine. I find the clinical information very helpful to keep me up to date on hospital medicine. The Journal of Hospital Medicine and The Hospitalist are must reads, and the Annual Conference is, of course, very informative. I also enjoy the conversations on the Hospital Medicine Exchange and feel that the Choosing Wisely campaign is an excellent contribution to the goal of cost containment in everyday practice.

One of the best features of SHM is that I can meet other clinicians from around the country and around the world who have innovations or novel ideas that I can bring back to my institution.
 

What advice do you have for nurse practitioners as their role in hospital medicine continues to evolve?

I say to my staff that they should always say yes. Yes to continuing education, yes to opportunities for growth and advancement, yes to promotions, yes to research, etc. Careers develop in nonlinear ways, and you have to follow the opportunities as they come.

Ms. Steele is the marketing communications specialist at the Society of Hospital Medicine.

Editor’s note: Each month, the Society of Hospital Medicine puts the spotlight on some of our most active members who are making substantial contributions to hospital medicine. Log on to www.hospitalmedicine.org/getinvolved for more information on how you can lend your expertise to help SHM improve the care of hospitalized patients.

This month, The Hospitalist spotlights Lorraine Britting, ANP, SFHM, clinical director of advanced practice in cardiology medicine at Beth Israel Deaconess Medical Center, Boston. Ms. Britting has been an SHM member for over 10 years, has served on various SHM committees, and was one of the first nurse practitioners to earn the Senior Fellow in Hospital Medicine designation.

How did you become a hospital medicine nurse practitioner, and when did you join SHM?

I was a nurse working in a CCU and MICU for 19 years when I graduated from a master’s program as a nurse practitioner (NP) in adult care. I thought I was going to work in the outpatient side after graduation, but my experience was much more suited to hospital medicine.

My first job in 2004 was as a hospitalist in a very small community hospital affiliated with Beth Israel Deaconess Medical Center. I was the first NP to work as an inpatient provider there, which was challenging, but I had the opportunity to wear many hats and be involved with numerous quality initiatives that helped me grow as a provider and a leader. I was working as the clinical manager of three hospitalist programs under the director by the time I left. I now work in inpatient cardiology and am the director of advanced practice providers (APPs) for cardiology medicine. I joined SHM in 2005 when it was a small but rapidly growing society, and I started work on the NP/PA Committee. I was also involved in the Hospital Quality and Patient Safety Committee for 6 years and worked as a peer reviewer for the Journal of Hospital Medicine.
 

Describe your role on the Membership Committee. What is the committee currently working on?

I am finishing my 3rd year on the committee. In the last few months, we have been focusing on member engagement. We have collected information on why members choose to join SHM and what deters potential members from joining SHM and we are developing strategies to build and retain our membership. The Membership Committee also reviews Fellows applications and discusses modifications of requirements each year.

As an NP, I have unique insight into motivations for why other APPs would join SHM and which membership benefits are most valuable. I find that many APPs join SHM because they feel that SHM treats them as equals, not junior members, as in some other physician organizations.
 

What does the Senior Fellow in Hospital Medicine designation mean to you?

I am grateful that SHM allows all members to be a part of the Fellows program, and I was honored to be one of the first NPs to become a Senior Fellow. Many medical societies allow APPs to join but do not offer the opportunity to become Fellows.

The Senior Fellowship application was a rigorous process and required experience in multiple areas, including quality projects, hospital committees, SHM Annual Conference attendance, and other clinical and nonclinical work that advances the profession.
 

As a nurse practitioner, which SHM resources do you find most valuable?

As a specialist NP, it’s easy for me to be current in cardiology but harder to keep current in general medicine. I find the clinical information very helpful to keep me up to date on hospital medicine. The Journal of Hospital Medicine and The Hospitalist are must reads, and the Annual Conference is, of course, very informative. I also enjoy the conversations on the Hospital Medicine Exchange and feel that the Choosing Wisely campaign is an excellent contribution to the goal of cost containment in everyday practice.

One of the best features of SHM is that I can meet other clinicians from around the country and around the world who have innovations or novel ideas that I can bring back to my institution.
 

What advice do you have for nurse practitioners as their role in hospital medicine continues to evolve?

I say to my staff that they should always say yes. Yes to continuing education, yes to opportunities for growth and advancement, yes to promotions, yes to research, etc. Careers develop in nonlinear ways, and you have to follow the opportunities as they come.

Ms. Steele is the marketing communications specialist at the Society of Hospital Medicine.

Editor’s note: Each month, the Society of Hospital Medicine puts the spotlight on some of our most active members who are making substantial contributions to hospital medicine. Log on to www.hospitalmedicine.org/getinvolved for more information on how you can lend your expertise to help SHM improve the care of hospitalized patients.

This month, The Hospitalist spotlights Lorraine Britting, ANP, SFHM, clinical director of advanced practice in cardiology medicine at Beth Israel Deaconess Medical Center, Boston. Ms. Britting has been an SHM member for over 10 years, has served on various SHM committees, and was one of the first nurse practitioners to earn the Senior Fellow in Hospital Medicine designation.

How did you become a hospital medicine nurse practitioner, and when did you join SHM?

I was a nurse working in a CCU and MICU for 19 years when I graduated from a master’s program as a nurse practitioner (NP) in adult care. I thought I was going to work in the outpatient side after graduation, but my experience was much more suited to hospital medicine.

My first job in 2004 was as a hospitalist in a very small community hospital affiliated with Beth Israel Deaconess Medical Center. I was the first NP to work as an inpatient provider there, which was challenging, but I had the opportunity to wear many hats and be involved with numerous quality initiatives that helped me grow as a provider and a leader. I was working as the clinical manager of three hospitalist programs under the director by the time I left. I now work in inpatient cardiology and am the director of advanced practice providers (APPs) for cardiology medicine. I joined SHM in 2005 when it was a small but rapidly growing society, and I started work on the NP/PA Committee. I was also involved in the Hospital Quality and Patient Safety Committee for 6 years and worked as a peer reviewer for the Journal of Hospital Medicine.
 

Describe your role on the Membership Committee. What is the committee currently working on?

I am finishing my 3rd year on the committee. In the last few months, we have been focusing on member engagement. We have collected information on why members choose to join SHM and what deters potential members from joining SHM and we are developing strategies to build and retain our membership. The Membership Committee also reviews Fellows applications and discusses modifications of requirements each year.

As an NP, I have unique insight into motivations for why other APPs would join SHM and which membership benefits are most valuable. I find that many APPs join SHM because they feel that SHM treats them as equals, not junior members, as in some other physician organizations.
 

What does the Senior Fellow in Hospital Medicine designation mean to you?

I am grateful that SHM allows all members to be a part of the Fellows program, and I was honored to be one of the first NPs to become a Senior Fellow. Many medical societies allow APPs to join but do not offer the opportunity to become Fellows.

The Senior Fellowship application was a rigorous process and required experience in multiple areas, including quality projects, hospital committees, SHM Annual Conference attendance, and other clinical and nonclinical work that advances the profession.
 

As a nurse practitioner, which SHM resources do you find most valuable?

As a specialist NP, it’s easy for me to be current in cardiology but harder to keep current in general medicine. I find the clinical information very helpful to keep me up to date on hospital medicine. The Journal of Hospital Medicine and The Hospitalist are must reads, and the Annual Conference is, of course, very informative. I also enjoy the conversations on the Hospital Medicine Exchange and feel that the Choosing Wisely campaign is an excellent contribution to the goal of cost containment in everyday practice.

One of the best features of SHM is that I can meet other clinicians from around the country and around the world who have innovations or novel ideas that I can bring back to my institution.
 

What advice do you have for nurse practitioners as their role in hospital medicine continues to evolve?

I say to my staff that they should always say yes. Yes to continuing education, yes to opportunities for growth and advancement, yes to promotions, yes to research, etc. Careers develop in nonlinear ways, and you have to follow the opportunities as they come.

Ms. Steele is the marketing communications specialist at the Society of Hospital Medicine.

The FP diagnosed skin tags (acrochordons) on her eyelids and explained that they were not dangerous. Removal options include cryotherapy, snip excisions, and electrosurgery.

The safest method of cryotherapy in a case like this is to use Cryo Tweezers. (See a video on how to perform cryosurgery here.) Using a cryo-spray in this area could result in the treatment getting into the eye.

Cryo Tweezers can apply cold to the skin tags without risking damage to the eye. The Cryo Tweezers are made cold by dipping them into liquid nitrogen. Then, each skin tag is grasped while gently pulling it away from the orbit. The skin tag is held between the 2 ends of the tweezer until it turns white. This method is very safe and causes very little discomfort to the patient.

Snip excisions on the eyelid are challenging for a number of reasons, including the fact that aluminum chloride or other chemical hemostatic agents are not safe for the eye. Electrosurgery can be performed with a loop electrode but only after the skin tags are numbed by injecting a local anesthetic into the eyelids. While it is possible for this to be performed safely, it is more challenging than using the Cryo Tweezers, which do not require a local anesthetic.

The patient in this case chose Cryo Tweezers for treatment and tolerated it well. The FP also documented that the patient believed the skin tags were affecting her vision in an effort to increase the likelihood that her insurance would cover the procedure. At a follow-up appointment 2 months later for the patient’s diabetes, the skin tags on her eyelids had resolved.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith AM. Skin tags. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 922-925.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP diagnosed skin tags (acrochordons) on her eyelids and explained that they were not dangerous. Removal options include cryotherapy, snip excisions, and electrosurgery.

The safest method of cryotherapy in a case like this is to use Cryo Tweezers. (See a video on how to perform cryosurgery here.) Using a cryo-spray in this area could result in the treatment getting into the eye.

Cryo Tweezers can apply cold to the skin tags without risking damage to the eye. The Cryo Tweezers are made cold by dipping them into liquid nitrogen. Then, each skin tag is grasped while gently pulling it away from the orbit. The skin tag is held between the 2 ends of the tweezer until it turns white. This method is very safe and causes very little discomfort to the patient.

Snip excisions on the eyelid are challenging for a number of reasons, including the fact that aluminum chloride or other chemical hemostatic agents are not safe for the eye. Electrosurgery can be performed with a loop electrode but only after the skin tags are numbed by injecting a local anesthetic into the eyelids. While it is possible for this to be performed safely, it is more challenging than using the Cryo Tweezers, which do not require a local anesthetic.

The patient in this case chose Cryo Tweezers for treatment and tolerated it well. The FP also documented that the patient believed the skin tags were affecting her vision in an effort to increase the likelihood that her insurance would cover the procedure. At a follow-up appointment 2 months later for the patient’s diabetes, the skin tags on her eyelids had resolved.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith AM. Skin tags. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 922-925.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP diagnosed skin tags (acrochordons) on her eyelids and explained that they were not dangerous. Removal options include cryotherapy, snip excisions, and electrosurgery.

The safest method of cryotherapy in a case like this is to use Cryo Tweezers. (See a video on how to perform cryosurgery here.) Using a cryo-spray in this area could result in the treatment getting into the eye.

Cryo Tweezers can apply cold to the skin tags without risking damage to the eye. The Cryo Tweezers are made cold by dipping them into liquid nitrogen. Then, each skin tag is grasped while gently pulling it away from the orbit. The skin tag is held between the 2 ends of the tweezer until it turns white. This method is very safe and causes very little discomfort to the patient.

Snip excisions on the eyelid are challenging for a number of reasons, including the fact that aluminum chloride or other chemical hemostatic agents are not safe for the eye. Electrosurgery can be performed with a loop electrode but only after the skin tags are numbed by injecting a local anesthetic into the eyelids. While it is possible for this to be performed safely, it is more challenging than using the Cryo Tweezers, which do not require a local anesthetic.

The patient in this case chose Cryo Tweezers for treatment and tolerated it well. The FP also documented that the patient believed the skin tags were affecting her vision in an effort to increase the likelihood that her insurance would cover the procedure. At a follow-up appointment 2 months later for the patient’s diabetes, the skin tags on her eyelids had resolved.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith AM. Skin tags. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 922-925.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

To the Editor:

The combination of menthol and methyl salicylate found in a variety of over-the-counter (OTC) creams in conjunction with a heat source such as a heating pad used for musculoskeletal symptoms can be a dire combination due to increased systemic absorption with associated toxicity and localized effects ranging from contact dermatitis or irritation to burn or necrosis.^1-6 We present a case of localized burn due a combination of topical methyl salicylate and heating pad use. We also discuss 2 commonly encountered side effects in the literature—localized burns and systemic toxicity associated with percutaneous absorption—and provide specific considerations related to the geriatric and pediatric populations.

A 62-year-old woman with a history of eczematous dermatitis and osteoarthritis with pain of the left shoulder presented to the dermatology clinic with painful skin-related changes on the left arm of 1 week’s duration. She was prescribed acetaminophen and ibuprofen. However, she self-medicated the left shoulder pain with 2 OTC products containing topical menthol and/or methyl salicylate in combination with a heating pad and likely fell asleep with this combination therapy applied. She noticed the burn the next morning. On examination, the left arm exhibited a geometric, irregularly shaped, erythematous, scaly plaque with a sharp transverse linear demarcation proximally and numerous erythematous linear scaly plaques oriented in an axial orientation with less-defined borders distally (Figure). The patient was diagnosed with burn secondary to combination of topical methyl salicylate and heating pad use. The patient was advised to discontinue the topical medication and to use caution with the heating pad in the future. She was prescribed pramoxine-hydrocortisone lotion to be applied to the affected area twice daily up to 5 days weekly until resolution. Subsequent evaluations revealed progressive improvement with only mild postinflammatory hyperpigmentation noted at 6 months after the burn.

The US Food and Drug Administration (FDA) released statements in 2012 regarding concern for burns related to use of OTC musculoskeletal pain relievers, with 43 cases of burns reported due to methyl salicylate and menthol from 2004 to 2010. Most of the second- and third-degree burns occurred following topical applications of products containing either menthol monotherapy or a combination of methyl salicylate and menthol.^1,2 In 2006, the FDA had already ordered 5 firms to stop compounding topical pain relief formulations containing these ingredients, with concerns that it puts patients at increased risk because the compounded formulations had not received FDA approval.³ Despite package warnings, patients may not be aware of the concerning side effects and risks associated with use of OTC creams, especially in combination with occlusion or heating pad use. Our case highlights the importance of ongoing patient education and physician counseling when encountering patients with arthritis or musculoskeletal pain who may often try various OTC self-treatments for pain relief.⁷

In 2012, the FDA reports stated that the cases of mild to serious burns were associated with methyl salicylate and menthol usage, in some cases 24 hours after first usage. Typically, these effects occur when concentrations are more than either 3% menthol alone or a combination of more than 3% menthol and more than 10% methyl salicylate.^1,2 In our case, the patient had been using 2 different OTC products that may have contained as much as 11% menthol and/or 30% methyl salicylate. Electronic resources are available that disclose safety instructions including not to occlude the site, not to use on wounds, and not to be used in conjunction with a heating pad.^8,9 Skin breakdown and vasodilation are more likely to occur in a setting of heat and occlusion, which allows for more absorption and localized side effects.^4,10 Localized reactions may range from contact dermatitis⁴ to muscle necrosis.⁵

The most noteworthy case of localized destruction described a 62-year-old man who had applied topical methyl salicylate and menthol to the forearms, calves, and thighs, then intermittently used a heating pad for 15 to 20 minutes (total duration).⁵ He subsequently developed erythema and numerous 7.62- to 10.16-cm bullae, which was thought to be consistent with contact dermatitis. Three days later, he was found to have full-thickness cutaneous, fascial, and muscle necrosis in a linear pattern. He was hospitalized for approximately 1 year and treated with extensive debridement and a skin graft. His serum creatinine level increased from 0.7 mg per 100 mL to 2.7 mg per 100 mL (reference range, 0.6–1.2 mg/dL) with evidence of toxic nephrosis and persistent interstitial nephritis, demonstrating the severity of localized destruction that may result when combining these products with direct heat and potential subsequent systemic consequences of this combination.⁵

The systemic absorption of OTC formulations also has been studied. Morra et al¹⁰ studied 12 volunteers (6 women, 6 men) who applied either 5 g of methyl salicylate ointment 12.5% twice daily for 4 days to an area on the thigh (approximately equal to 567 mg salicylate) or trolamine cream 10% twice for 1 day. The participants underwent a break for 7 days and then switched to the alternate treatment. They found that 0.31 to 0.91 mg/L methyl salicylate was detected in the serum 1 hour after applying the ointment consisting of methyl salicylate, and 2 to 6 mg/L methyl salicylate was detected on day 4. Therapeutic serum salicylate levels are 150 to 300 mg/L. They found that approximately 22% of the methyl salicylate also was found in urine samples on day 4. Although these figures may appear small, this study was prompted when a 62-year-old man presented to the emergency department with symptoms of salicylate toxicity and a serum concentration of 518 mg/L from twice-daily use of an OTC formulation containing methyl salicylate over the course of multiple weeks.¹⁰ Additionally, those who have aspirin hypersensitivity should be cautious when using such products due to the risk for reported angioedema.⁴

Providers must exercise extreme caution while caring for geriatric patients, especially if patients are taking warfarin. The combined effects of warfarin and methyl salicylate have previously caused cutaneous purpura, gastrointestinal bleeding, and elevated international normalized ratio values.^4,10 Older individuals also have increased skin fragility, allowing microtraumatic insult to easily develop. This fragility, along with an overall decreased intactness of the skin barrier, may lead to increased skin absorption. Furthermore, the addition of applying any heat source places the geriatric patient at greater risk for adverse events.¹⁰

In considering the limits of age, the pediatric population also has been studied regarding salicylate toxicity. Most commonly, oral ingestion has caused fatalities, as oil of wintergreen has been cited as extremely dangerous for children if swallowed; doses as small as a teaspoon (5 mL: 7000 mg salicylate) have resulted in fatalities.^4,6 Although the consumption of a large amount of a cream- or ointment-based product is unlikely due to the consistency of the medication,⁶ the thought does merit consideration in the inquisitive toddler age group. For a 15-kg toddler, 150 mg/kg of aspirin or 2250 mg of aspirin, is considered the toxic level, which upon conversion to methyl salicylate levels using a 1.4 factor equates to 1607 mg of methyl salicylate to reach toxicity.⁶ If using a product with methyl salicylate 30% composition, 1 g of the product contains 300 mg of methyl salicylate; therefore if the toddler consumed approximately 5.3 g of the product (1607 mg methyl salicylate [toxic level] divided by 300 mg methyl salicylate per 1 g of product), he/she would reach toxic levels.^6,11 To put this into perspective, a 2-oz tube contains 57 g (approximately 10 times the toxic dose) of the product.⁸ Thus, although there is less concern overall for consumption of cream- or ointment-based methyl salicylate, there still is potential for harm if a small child were to ingest such a product containing higher percentages of methyl salicylate.⁶

There also have been reports of pediatric toxicity related to percutaneous absorption, even leading to pediatric fatality.^4,6 In particular, there was a case of a young boy hospitalized with ichthyosis who received escalating doses of percutaneous salicylate, which resulted in toxicity; when therapy was discontinued, he experienced full recovery.¹² In 2007, a 17-year-old adolescent girl died from methyl salicylate toxicity after numerous applications of salicylate-containing products in conjunction with medicated pads.⁷

Although the FDA has drawn attention and encouraged caution with use of OTC topical musculoskeletal pain relievers, the importance of ensuring patients are fully aware of potential burns, permanent skin or muscle damage, and even death if used inappropriately cannot be overstated. The FDA consumer health information website has 2 patient-directed handouts^2,3 that may be useful to post in patient waiting areas to increase overall understanding of the risks associated with OTC products containing methyl salicylate and menthol ingredients. Fortunately, our patient suffered only mild postinflammatory hyperpigmentation without substantial sustained consequences.

To the Editor:

The combination of menthol and methyl salicylate found in a variety of over-the-counter (OTC) creams in conjunction with a heat source such as a heating pad used for musculoskeletal symptoms can be a dire combination due to increased systemic absorption with associated toxicity and localized effects ranging from contact dermatitis or irritation to burn or necrosis.^1-6 We present a case of localized burn due a combination of topical methyl salicylate and heating pad use. We also discuss 2 commonly encountered side effects in the literature—localized burns and systemic toxicity associated with percutaneous absorption—and provide specific considerations related to the geriatric and pediatric populations.

A 62-year-old woman with a history of eczematous dermatitis and osteoarthritis with pain of the left shoulder presented to the dermatology clinic with painful skin-related changes on the left arm of 1 week’s duration. She was prescribed acetaminophen and ibuprofen. However, she self-medicated the left shoulder pain with 2 OTC products containing topical menthol and/or methyl salicylate in combination with a heating pad and likely fell asleep with this combination therapy applied. She noticed the burn the next morning. On examination, the left arm exhibited a geometric, irregularly shaped, erythematous, scaly plaque with a sharp transverse linear demarcation proximally and numerous erythematous linear scaly plaques oriented in an axial orientation with less-defined borders distally (Figure). The patient was diagnosed with burn secondary to combination of topical methyl salicylate and heating pad use. The patient was advised to discontinue the topical medication and to use caution with the heating pad in the future. She was prescribed pramoxine-hydrocortisone lotion to be applied to the affected area twice daily up to 5 days weekly until resolution. Subsequent evaluations revealed progressive improvement with only mild postinflammatory hyperpigmentation noted at 6 months after the burn.

The US Food and Drug Administration (FDA) released statements in 2012 regarding concern for burns related to use of OTC musculoskeletal pain relievers, with 43 cases of burns reported due to methyl salicylate and menthol from 2004 to 2010. Most of the second- and third-degree burns occurred following topical applications of products containing either menthol monotherapy or a combination of methyl salicylate and menthol.^1,2 In 2006, the FDA had already ordered 5 firms to stop compounding topical pain relief formulations containing these ingredients, with concerns that it puts patients at increased risk because the compounded formulations had not received FDA approval.³ Despite package warnings, patients may not be aware of the concerning side effects and risks associated with use of OTC creams, especially in combination with occlusion or heating pad use. Our case highlights the importance of ongoing patient education and physician counseling when encountering patients with arthritis or musculoskeletal pain who may often try various OTC self-treatments for pain relief.⁷

In 2012, the FDA reports stated that the cases of mild to serious burns were associated with methyl salicylate and menthol usage, in some cases 24 hours after first usage. Typically, these effects occur when concentrations are more than either 3% menthol alone or a combination of more than 3% menthol and more than 10% methyl salicylate.^1,2 In our case, the patient had been using 2 different OTC products that may have contained as much as 11% menthol and/or 30% methyl salicylate. Electronic resources are available that disclose safety instructions including not to occlude the site, not to use on wounds, and not to be used in conjunction with a heating pad.^8,9 Skin breakdown and vasodilation are more likely to occur in a setting of heat and occlusion, which allows for more absorption and localized side effects.^4,10 Localized reactions may range from contact dermatitis⁴ to muscle necrosis.⁵

The most noteworthy case of localized destruction described a 62-year-old man who had applied topical methyl salicylate and menthol to the forearms, calves, and thighs, then intermittently used a heating pad for 15 to 20 minutes (total duration).⁵ He subsequently developed erythema and numerous 7.62- to 10.16-cm bullae, which was thought to be consistent with contact dermatitis. Three days later, he was found to have full-thickness cutaneous, fascial, and muscle necrosis in a linear pattern. He was hospitalized for approximately 1 year and treated with extensive debridement and a skin graft. His serum creatinine level increased from 0.7 mg per 100 mL to 2.7 mg per 100 mL (reference range, 0.6–1.2 mg/dL) with evidence of toxic nephrosis and persistent interstitial nephritis, demonstrating the severity of localized destruction that may result when combining these products with direct heat and potential subsequent systemic consequences of this combination.⁵

The systemic absorption of OTC formulations also has been studied. Morra et al¹⁰ studied 12 volunteers (6 women, 6 men) who applied either 5 g of methyl salicylate ointment 12.5% twice daily for 4 days to an area on the thigh (approximately equal to 567 mg salicylate) or trolamine cream 10% twice for 1 day. The participants underwent a break for 7 days and then switched to the alternate treatment. They found that 0.31 to 0.91 mg/L methyl salicylate was detected in the serum 1 hour after applying the ointment consisting of methyl salicylate, and 2 to 6 mg/L methyl salicylate was detected on day 4. Therapeutic serum salicylate levels are 150 to 300 mg/L. They found that approximately 22% of the methyl salicylate also was found in urine samples on day 4. Although these figures may appear small, this study was prompted when a 62-year-old man presented to the emergency department with symptoms of salicylate toxicity and a serum concentration of 518 mg/L from twice-daily use of an OTC formulation containing methyl salicylate over the course of multiple weeks.¹⁰ Additionally, those who have aspirin hypersensitivity should be cautious when using such products due to the risk for reported angioedema.⁴

Providers must exercise extreme caution while caring for geriatric patients, especially if patients are taking warfarin. The combined effects of warfarin and methyl salicylate have previously caused cutaneous purpura, gastrointestinal bleeding, and elevated international normalized ratio values.^4,10 Older individuals also have increased skin fragility, allowing microtraumatic insult to easily develop. This fragility, along with an overall decreased intactness of the skin barrier, may lead to increased skin absorption. Furthermore, the addition of applying any heat source places the geriatric patient at greater risk for adverse events.¹⁰

In considering the limits of age, the pediatric population also has been studied regarding salicylate toxicity. Most commonly, oral ingestion has caused fatalities, as oil of wintergreen has been cited as extremely dangerous for children if swallowed; doses as small as a teaspoon (5 mL: 7000 mg salicylate) have resulted in fatalities.^4,6 Although the consumption of a large amount of a cream- or ointment-based product is unlikely due to the consistency of the medication,⁶ the thought does merit consideration in the inquisitive toddler age group. For a 15-kg toddler, 150 mg/kg of aspirin or 2250 mg of aspirin, is considered the toxic level, which upon conversion to methyl salicylate levels using a 1.4 factor equates to 1607 mg of methyl salicylate to reach toxicity.⁶ If using a product with methyl salicylate 30% composition, 1 g of the product contains 300 mg of methyl salicylate; therefore if the toddler consumed approximately 5.3 g of the product (1607 mg methyl salicylate [toxic level] divided by 300 mg methyl salicylate per 1 g of product), he/she would reach toxic levels.^6,11 To put this into perspective, a 2-oz tube contains 57 g (approximately 10 times the toxic dose) of the product.⁸ Thus, although there is less concern overall for consumption of cream- or ointment-based methyl salicylate, there still is potential for harm if a small child were to ingest such a product containing higher percentages of methyl salicylate.⁶

There also have been reports of pediatric toxicity related to percutaneous absorption, even leading to pediatric fatality.^4,6 In particular, there was a case of a young boy hospitalized with ichthyosis who received escalating doses of percutaneous salicylate, which resulted in toxicity; when therapy was discontinued, he experienced full recovery.¹² In 2007, a 17-year-old adolescent girl died from methyl salicylate toxicity after numerous applications of salicylate-containing products in conjunction with medicated pads.⁷

Although the FDA has drawn attention and encouraged caution with use of OTC topical musculoskeletal pain relievers, the importance of ensuring patients are fully aware of potential burns, permanent skin or muscle damage, and even death if used inappropriately cannot be overstated. The FDA consumer health information website has 2 patient-directed handouts^2,3 that may be useful to post in patient waiting areas to increase overall understanding of the risks associated with OTC products containing methyl salicylate and menthol ingredients. Fortunately, our patient suffered only mild postinflammatory hyperpigmentation without substantial sustained consequences.

To the Editor:

The combination of menthol and methyl salicylate found in a variety of over-the-counter (OTC) creams in conjunction with a heat source such as a heating pad used for musculoskeletal symptoms can be a dire combination due to increased systemic absorption with associated toxicity and localized effects ranging from contact dermatitis or irritation to burn or necrosis.^1-6 We present a case of localized burn due a combination of topical methyl salicylate and heating pad use. We also discuss 2 commonly encountered side effects in the literature—localized burns and systemic toxicity associated with percutaneous absorption—and provide specific considerations related to the geriatric and pediatric populations.

A 62-year-old woman with a history of eczematous dermatitis and osteoarthritis with pain of the left shoulder presented to the dermatology clinic with painful skin-related changes on the left arm of 1 week’s duration. She was prescribed acetaminophen and ibuprofen. However, she self-medicated the left shoulder pain with 2 OTC products containing topical menthol and/or methyl salicylate in combination with a heating pad and likely fell asleep with this combination therapy applied. She noticed the burn the next morning. On examination, the left arm exhibited a geometric, irregularly shaped, erythematous, scaly plaque with a sharp transverse linear demarcation proximally and numerous erythematous linear scaly plaques oriented in an axial orientation with less-defined borders distally (Figure). The patient was diagnosed with burn secondary to combination of topical methyl salicylate and heating pad use. The patient was advised to discontinue the topical medication and to use caution with the heating pad in the future. She was prescribed pramoxine-hydrocortisone lotion to be applied to the affected area twice daily up to 5 days weekly until resolution. Subsequent evaluations revealed progressive improvement with only mild postinflammatory hyperpigmentation noted at 6 months after the burn.

The US Food and Drug Administration (FDA) released statements in 2012 regarding concern for burns related to use of OTC musculoskeletal pain relievers, with 43 cases of burns reported due to methyl salicylate and menthol from 2004 to 2010. Most of the second- and third-degree burns occurred following topical applications of products containing either menthol monotherapy or a combination of methyl salicylate and menthol.^1,2 In 2006, the FDA had already ordered 5 firms to stop compounding topical pain relief formulations containing these ingredients, with concerns that it puts patients at increased risk because the compounded formulations had not received FDA approval.³ Despite package warnings, patients may not be aware of the concerning side effects and risks associated with use of OTC creams, especially in combination with occlusion or heating pad use. Our case highlights the importance of ongoing patient education and physician counseling when encountering patients with arthritis or musculoskeletal pain who may often try various OTC self-treatments for pain relief.⁷

In 2012, the FDA reports stated that the cases of mild to serious burns were associated with methyl salicylate and menthol usage, in some cases 24 hours after first usage. Typically, these effects occur when concentrations are more than either 3% menthol alone or a combination of more than 3% menthol and more than 10% methyl salicylate.^1,2 In our case, the patient had been using 2 different OTC products that may have contained as much as 11% menthol and/or 30% methyl salicylate. Electronic resources are available that disclose safety instructions including not to occlude the site, not to use on wounds, and not to be used in conjunction with a heating pad.^8,9 Skin breakdown and vasodilation are more likely to occur in a setting of heat and occlusion, which allows for more absorption and localized side effects.^4,10 Localized reactions may range from contact dermatitis⁴ to muscle necrosis.⁵

The most noteworthy case of localized destruction described a 62-year-old man who had applied topical methyl salicylate and menthol to the forearms, calves, and thighs, then intermittently used a heating pad for 15 to 20 minutes (total duration).⁵ He subsequently developed erythema and numerous 7.62- to 10.16-cm bullae, which was thought to be consistent with contact dermatitis. Three days later, he was found to have full-thickness cutaneous, fascial, and muscle necrosis in a linear pattern. He was hospitalized for approximately 1 year and treated with extensive debridement and a skin graft. His serum creatinine level increased from 0.7 mg per 100 mL to 2.7 mg per 100 mL (reference range, 0.6–1.2 mg/dL) with evidence of toxic nephrosis and persistent interstitial nephritis, demonstrating the severity of localized destruction that may result when combining these products with direct heat and potential subsequent systemic consequences of this combination.⁵

The systemic absorption of OTC formulations also has been studied. Morra et al¹⁰ studied 12 volunteers (6 women, 6 men) who applied either 5 g of methyl salicylate ointment 12.5% twice daily for 4 days to an area on the thigh (approximately equal to 567 mg salicylate) or trolamine cream 10% twice for 1 day. The participants underwent a break for 7 days and then switched to the alternate treatment. They found that 0.31 to 0.91 mg/L methyl salicylate was detected in the serum 1 hour after applying the ointment consisting of methyl salicylate, and 2 to 6 mg/L methyl salicylate was detected on day 4. Therapeutic serum salicylate levels are 150 to 300 mg/L. They found that approximately 22% of the methyl salicylate also was found in urine samples on day 4. Although these figures may appear small, this study was prompted when a 62-year-old man presented to the emergency department with symptoms of salicylate toxicity and a serum concentration of 518 mg/L from twice-daily use of an OTC formulation containing methyl salicylate over the course of multiple weeks.¹⁰ Additionally, those who have aspirin hypersensitivity should be cautious when using such products due to the risk for reported angioedema.⁴

Providers must exercise extreme caution while caring for geriatric patients, especially if patients are taking warfarin. The combined effects of warfarin and methyl salicylate have previously caused cutaneous purpura, gastrointestinal bleeding, and elevated international normalized ratio values.^4,10 Older individuals also have increased skin fragility, allowing microtraumatic insult to easily develop. This fragility, along with an overall decreased intactness of the skin barrier, may lead to increased skin absorption. Furthermore, the addition of applying any heat source places the geriatric patient at greater risk for adverse events.¹⁰

In considering the limits of age, the pediatric population also has been studied regarding salicylate toxicity. Most commonly, oral ingestion has caused fatalities, as oil of wintergreen has been cited as extremely dangerous for children if swallowed; doses as small as a teaspoon (5 mL: 7000 mg salicylate) have resulted in fatalities.^4,6 Although the consumption of a large amount of a cream- or ointment-based product is unlikely due to the consistency of the medication,⁶ the thought does merit consideration in the inquisitive toddler age group. For a 15-kg toddler, 150 mg/kg of aspirin or 2250 mg of aspirin, is considered the toxic level, which upon conversion to methyl salicylate levels using a 1.4 factor equates to 1607 mg of methyl salicylate to reach toxicity.⁶ If using a product with methyl salicylate 30% composition, 1 g of the product contains 300 mg of methyl salicylate; therefore if the toddler consumed approximately 5.3 g of the product (1607 mg methyl salicylate [toxic level] divided by 300 mg methyl salicylate per 1 g of product), he/she would reach toxic levels.^6,11 To put this into perspective, a 2-oz tube contains 57 g (approximately 10 times the toxic dose) of the product.⁸ Thus, although there is less concern overall for consumption of cream- or ointment-based methyl salicylate, there still is potential for harm if a small child were to ingest such a product containing higher percentages of methyl salicylate.⁶

There also have been reports of pediatric toxicity related to percutaneous absorption, even leading to pediatric fatality.^4,6 In particular, there was a case of a young boy hospitalized with ichthyosis who received escalating doses of percutaneous salicylate, which resulted in toxicity; when therapy was discontinued, he experienced full recovery.¹² In 2007, a 17-year-old adolescent girl died from methyl salicylate toxicity after numerous applications of salicylate-containing products in conjunction with medicated pads.⁷

Although the FDA has drawn attention and encouraged caution with use of OTC topical musculoskeletal pain relievers, the importance of ensuring patients are fully aware of potential burns, permanent skin or muscle damage, and even death if used inappropriately cannot be overstated. The FDA consumer health information website has 2 patient-directed handouts^2,3 that may be useful to post in patient waiting areas to increase overall understanding of the risks associated with OTC products containing methyl salicylate and menthol ingredients. Fortunately, our patient suffered only mild postinflammatory hyperpigmentation without substantial sustained consequences.

For pediatricians to better help victims of human trafficking, it is critical that there be improvements in research, medical education, advocacy, and community collaborations, according to a policy statement issued by the American Academy of Pediatrics (AAP) Committee on Child Abuse and Neglect, Section on International Child Health.

The full effects of human trafficking are still very much hidden in shadows, leading the AAP to add human trafficking education to its list of top 10 priorities at the 2014 AAP Annual Leadership Forum.

The policy statement is the latest step in the AAP’s effort to involve medical professionals more heavily in combating child sex and labor trafficking, which the AAP asserts is a critical role for pediatricians. Even with the limited information available, the United Nations Office of Drugs and Crime 2016 report found 33% of the 40,000 trafficking victims reported were children, an indication of the vulnerability of younger populations.

“We wanted to give not just background information on trafficking, but we also wanted to give some guidance for academy members in regard to how we can increase awareness of human trafficking, how we can start to implement it into medical education for medical trainees and practicing pediatricians,” Nia Bodrick, MD, MPH, coauthor of the statement and a member of the AAP Section on International Child Health, said in an interview. “Due to the very narrow amount of evidence-based research that is available on this issue, there is a call to look more deeply into the topic.”

Currently, many health care professionals may be more exposed to child trafficking than they think because of a lack knowledge on how to recognize it. Victims can pass unnoticed.

“Most victims and survivors of human trafficking have had some sort of interaction with the health care setting at some point before they escape their situation,” said Dr. Bodrick. “So whether we as pediatricians realize it or not, we are more than likely interacting with young people who are in these situations.”

There are not enough data to list definitive characteristics of trafficking victims; however, there are certain signs associated with those who have been identified as victims so far. While history of neglect, homelessness, substance abuse, mental disorder, and identifying as a member of the LGBTQ community are more common among trafficking victims, many doctors are not equipped to handle confronting patients about the possibility of sex or labor trafficking, nor do they know what resources are available.

The AAP emphasized a need to expand the current scope of knowledge medical professionals have regarding such victims to create better, evidence-based care programs and protective policies.

An influx of information would help pediatricians understand the prevalence of trafficking, the extent of physical and emotional harm victims experience, and the effectiveness of psychological and mental health interventions, according to the statement (Pediatrics. 2017 November. doi: 10.1542/peds.2017-3138).

It also may help shed light on male trafficking victims, which Dr. Bodrick and coauthor Jordan Greenbaum, MD, of the Stephanie V. Blank Center for Safe and Healthy Children at Children’s Healthcare of Atlanta, assert are highly underrepresented.

Separating human trafficking from other types of violence and exploitation in the International Classification of Diseases codes may improve research initiatives, according to Dr. Bodrick.

There is also a need to delve deeper into the social determinants of health to better predict what makes victims more vulnerable.

While improving the number of studies on trafficking is essential, the results are more long term, which means in the mean time other actions can, and should, be made, according to the statement.

One of the best things pediatricians can do is gather as much knowledge on the topic as they can, according to Dr. Bodrick.

“For the average pediatrician, one of the first things one could do is educate oneself on the topic,” she explained. “Look for CME associated with your local AAP chapter or even on a national level online or even if you just have a couple hours for lunch, to become aware of what’s happening.”

The AAP also is encouraging physicians to advocate for legislative policies that will help improve victim care and to create partnerships within the community.

“In DC, in our local AAP chapter, we have opportunities to go to the Hill and advocate for bills, and while not everyone can do that, there are always local legislators that pediatricians can push to do more,” said Dr. Bodrick. “If you have a local paper, you could write an op-ed about the topic, you could educate your local schools about the topic by talking to the school board, or you could even engage in interviews on a local radio or television station.”

While many states have laws protecting victims of sex trafficking from being prosecuted for performing illegal acts, many have not passed such legislation.

Pediatricians can see what protections their states have through the National Conference of State Legislatures’ web page, as well as review current human trafficking laws.

Dr. Greenbaum and Dr. Bodrick reported no relevant financial disclosures.

[email protected]

On Twitter@eaztweets

For pediatricians to better help victims of human trafficking, it is critical that there be improvements in research, medical education, advocacy, and community collaborations, according to a policy statement issued by the American Academy of Pediatrics (AAP) Committee on Child Abuse and Neglect, Section on International Child Health.

The full effects of human trafficking are still very much hidden in shadows, leading the AAP to add human trafficking education to its list of top 10 priorities at the 2014 AAP Annual Leadership Forum.

The policy statement is the latest step in the AAP’s effort to involve medical professionals more heavily in combating child sex and labor trafficking, which the AAP asserts is a critical role for pediatricians. Even with the limited information available, the United Nations Office of Drugs and Crime 2016 report found 33% of the 40,000 trafficking victims reported were children, an indication of the vulnerability of younger populations.

“We wanted to give not just background information on trafficking, but we also wanted to give some guidance for academy members in regard to how we can increase awareness of human trafficking, how we can start to implement it into medical education for medical trainees and practicing pediatricians,” Nia Bodrick, MD, MPH, coauthor of the statement and a member of the AAP Section on International Child Health, said in an interview. “Due to the very narrow amount of evidence-based research that is available on this issue, there is a call to look more deeply into the topic.”

Currently, many health care professionals may be more exposed to child trafficking than they think because of a lack knowledge on how to recognize it. Victims can pass unnoticed.

“Most victims and survivors of human trafficking have had some sort of interaction with the health care setting at some point before they escape their situation,” said Dr. Bodrick. “So whether we as pediatricians realize it or not, we are more than likely interacting with young people who are in these situations.”

There are not enough data to list definitive characteristics of trafficking victims; however, there are certain signs associated with those who have been identified as victims so far. While history of neglect, homelessness, substance abuse, mental disorder, and identifying as a member of the LGBTQ community are more common among trafficking victims, many doctors are not equipped to handle confronting patients about the possibility of sex or labor trafficking, nor do they know what resources are available.

The AAP emphasized a need to expand the current scope of knowledge medical professionals have regarding such victims to create better, evidence-based care programs and protective policies.

An influx of information would help pediatricians understand the prevalence of trafficking, the extent of physical and emotional harm victims experience, and the effectiveness of psychological and mental health interventions, according to the statement (Pediatrics. 2017 November. doi: 10.1542/peds.2017-3138).

It also may help shed light on male trafficking victims, which Dr. Bodrick and coauthor Jordan Greenbaum, MD, of the Stephanie V. Blank Center for Safe and Healthy Children at Children’s Healthcare of Atlanta, assert are highly underrepresented.

Separating human trafficking from other types of violence and exploitation in the International Classification of Diseases codes may improve research initiatives, according to Dr. Bodrick.

There is also a need to delve deeper into the social determinants of health to better predict what makes victims more vulnerable.

While improving the number of studies on trafficking is essential, the results are more long term, which means in the mean time other actions can, and should, be made, according to the statement.

One of the best things pediatricians can do is gather as much knowledge on the topic as they can, according to Dr. Bodrick.

“For the average pediatrician, one of the first things one could do is educate oneself on the topic,” she explained. “Look for CME associated with your local AAP chapter or even on a national level online or even if you just have a couple hours for lunch, to become aware of what’s happening.”

The AAP also is encouraging physicians to advocate for legislative policies that will help improve victim care and to create partnerships within the community.

“In DC, in our local AAP chapter, we have opportunities to go to the Hill and advocate for bills, and while not everyone can do that, there are always local legislators that pediatricians can push to do more,” said Dr. Bodrick. “If you have a local paper, you could write an op-ed about the topic, you could educate your local schools about the topic by talking to the school board, or you could even engage in interviews on a local radio or television station.”

While many states have laws protecting victims of sex trafficking from being prosecuted for performing illegal acts, many have not passed such legislation.

Pediatricians can see what protections their states have through the National Conference of State Legislatures’ web page, as well as review current human trafficking laws.

Dr. Greenbaum and Dr. Bodrick reported no relevant financial disclosures.

[email protected]

On Twitter@eaztweets

For pediatricians to better help victims of human trafficking, it is critical that there be improvements in research, medical education, advocacy, and community collaborations, according to a policy statement issued by the American Academy of Pediatrics (AAP) Committee on Child Abuse and Neglect, Section on International Child Health.

The full effects of human trafficking are still very much hidden in shadows, leading the AAP to add human trafficking education to its list of top 10 priorities at the 2014 AAP Annual Leadership Forum.

The policy statement is the latest step in the AAP’s effort to involve medical professionals more heavily in combating child sex and labor trafficking, which the AAP asserts is a critical role for pediatricians. Even with the limited information available, the United Nations Office of Drugs and Crime 2016 report found 33% of the 40,000 trafficking victims reported were children, an indication of the vulnerability of younger populations.

“We wanted to give not just background information on trafficking, but we also wanted to give some guidance for academy members in regard to how we can increase awareness of human trafficking, how we can start to implement it into medical education for medical trainees and practicing pediatricians,” Nia Bodrick, MD, MPH, coauthor of the statement and a member of the AAP Section on International Child Health, said in an interview. “Due to the very narrow amount of evidence-based research that is available on this issue, there is a call to look more deeply into the topic.”

Currently, many health care professionals may be more exposed to child trafficking than they think because of a lack knowledge on how to recognize it. Victims can pass unnoticed.

“Most victims and survivors of human trafficking have had some sort of interaction with the health care setting at some point before they escape their situation,” said Dr. Bodrick. “So whether we as pediatricians realize it or not, we are more than likely interacting with young people who are in these situations.”

There are not enough data to list definitive characteristics of trafficking victims; however, there are certain signs associated with those who have been identified as victims so far. While history of neglect, homelessness, substance abuse, mental disorder, and identifying as a member of the LGBTQ community are more common among trafficking victims, many doctors are not equipped to handle confronting patients about the possibility of sex or labor trafficking, nor do they know what resources are available.

The AAP emphasized a need to expand the current scope of knowledge medical professionals have regarding such victims to create better, evidence-based care programs and protective policies.

An influx of information would help pediatricians understand the prevalence of trafficking, the extent of physical and emotional harm victims experience, and the effectiveness of psychological and mental health interventions, according to the statement (Pediatrics. 2017 November. doi: 10.1542/peds.2017-3138).

It also may help shed light on male trafficking victims, which Dr. Bodrick and coauthor Jordan Greenbaum, MD, of the Stephanie V. Blank Center for Safe and Healthy Children at Children’s Healthcare of Atlanta, assert are highly underrepresented.

Separating human trafficking from other types of violence and exploitation in the International Classification of Diseases codes may improve research initiatives, according to Dr. Bodrick.

There is also a need to delve deeper into the social determinants of health to better predict what makes victims more vulnerable.

While improving the number of studies on trafficking is essential, the results are more long term, which means in the mean time other actions can, and should, be made, according to the statement.

One of the best things pediatricians can do is gather as much knowledge on the topic as they can, according to Dr. Bodrick.

“For the average pediatrician, one of the first things one could do is educate oneself on the topic,” she explained. “Look for CME associated with your local AAP chapter or even on a national level online or even if you just have a couple hours for lunch, to become aware of what’s happening.”

The AAP also is encouraging physicians to advocate for legislative policies that will help improve victim care and to create partnerships within the community.

“In DC, in our local AAP chapter, we have opportunities to go to the Hill and advocate for bills, and while not everyone can do that, there are always local legislators that pediatricians can push to do more,” said Dr. Bodrick. “If you have a local paper, you could write an op-ed about the topic, you could educate your local schools about the topic by talking to the school board, or you could even engage in interviews on a local radio or television station.”

While many states have laws protecting victims of sex trafficking from being prosecuted for performing illegal acts, many have not passed such legislation.

Pediatricians can see what protections their states have through the National Conference of State Legislatures’ web page, as well as review current human trafficking laws.

Dr. Greenbaum and Dr. Bodrick reported no relevant financial disclosures.

[email protected]

On Twitter@eaztweets

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

Results

Study Protocol Amendments
Given the number of diabetic patients in the US veteran population, we anticipated that there would be enough participants meeting the inclusion and exclusion criteria; however, because of the difficulty with recruitment, the initial study criteria were modified. The study was initially designed to incorporate DFUs with a minimum size of 1.0 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C level of 10% of total hemoglobin or below.¹² Unfortunately, the majority of the potential participants had values substantially higher, and thus could not be enrolled in the trial, requiring another amendment to the study protocol in 2014, which was approved to include patients with an HbA_1C level less than 12% of total hemoglobin. This change contributed considerably to the noted increase in enrollment rates in 2015, which almost doubled relative to enrollment under the original exclusion criteria (Figure).

The study has screened more than 600 patients. Among them, 137 were assessed for eligibility; 71 were excluded for various reasons, including screen failure (eg, decrease in wound size by >40% during the 2-week screening phase), loss to follow-up, and adverse events. Sixty-six participants reached the primary outcome at week 12, while 55 participants completed the study (19 in the SOC group; 18 in the cellular matrix group; 18 in the acellular matrix group).

We have stopped enrolling patients from all sites and the community, as we have reached our target enrollment.

Comment

One of the challenges of clinical trials is the recruitment of an adequate number of participants within an appropriate time frame, which is explained by Lasagna’s Law,¹⁸ a well-described phenomenon whereby the investigator overestimates the number of potential participants available to meet the inclusion criteria. This so-called funnel-effect was partly encountered in our selection process. A review of the veteran population with DFUs seemed to be more than adequate to fulfill the sample size; however, some important participant-related factors also played a substantial role. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

In addition, the Veterans’ Affairs network centralizes health information, making it readily available to all providers participating in their care. As a result, patients with diabetes mellitus typically are seen by a primary care physician along with an endocrinologist, a diabetic nurse, and/or a dietician. Despite the collaboration with an interdisciplinary team, the glycemic control of the participants remains an issue along with other psychosocial factors that are deterrents in patient compliance. As a result, patients with poorly controlled diabetes and an HbA_1C level above 10% (and less than 12%) of total hemoglobin who were initially excluded from the study were reincluded after modifying the inclusion criteria. Some patients were interested in joining the study, but physical limitations (eg, impaired mobility) prompted their decision not to join the trial, even though they met all the inclusion criteria.

As far as research-related factors that could affect participation, it is notable that most of the patients were retired; thus, the interventions did not cause additional burden of taking time off from work or loss of productivity. Although randomization could be a deterrent in many clinical trials, the majority of patients were willing to participate without demanding to be assigned to a particular treatment group. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

There are many factors that are intertwined and can lead to enrollment and/or attrition rates. It was critical for our team to make some adjustment without compromising the controlled nature of a randomized trial.

Acknowledgment
The authors wish to acknowledge Huong Le, DPM, MPH, who was the coauthor of the study protocol.

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

Results

Study Protocol Amendments
Given the number of diabetic patients in the US veteran population, we anticipated that there would be enough participants meeting the inclusion and exclusion criteria; however, because of the difficulty with recruitment, the initial study criteria were modified. The study was initially designed to incorporate DFUs with a minimum size of 1.0 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C level of 10% of total hemoglobin or below.¹² Unfortunately, the majority of the potential participants had values substantially higher, and thus could not be enrolled in the trial, requiring another amendment to the study protocol in 2014, which was approved to include patients with an HbA_1C level less than 12% of total hemoglobin. This change contributed considerably to the noted increase in enrollment rates in 2015, which almost doubled relative to enrollment under the original exclusion criteria (Figure).

The study has screened more than 600 patients. Among them, 137 were assessed for eligibility; 71 were excluded for various reasons, including screen failure (eg, decrease in wound size by >40% during the 2-week screening phase), loss to follow-up, and adverse events. Sixty-six participants reached the primary outcome at week 12, while 55 participants completed the study (19 in the SOC group; 18 in the cellular matrix group; 18 in the acellular matrix group).

We have stopped enrolling patients from all sites and the community, as we have reached our target enrollment.

Comment

One of the challenges of clinical trials is the recruitment of an adequate number of participants within an appropriate time frame, which is explained by Lasagna’s Law,¹⁸ a well-described phenomenon whereby the investigator overestimates the number of potential participants available to meet the inclusion criteria. This so-called funnel-effect was partly encountered in our selection process. A review of the veteran population with DFUs seemed to be more than adequate to fulfill the sample size; however, some important participant-related factors also played a substantial role. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

In addition, the Veterans’ Affairs network centralizes health information, making it readily available to all providers participating in their care. As a result, patients with diabetes mellitus typically are seen by a primary care physician along with an endocrinologist, a diabetic nurse, and/or a dietician. Despite the collaboration with an interdisciplinary team, the glycemic control of the participants remains an issue along with other psychosocial factors that are deterrents in patient compliance. As a result, patients with poorly controlled diabetes and an HbA_1C level above 10% (and less than 12%) of total hemoglobin who were initially excluded from the study were reincluded after modifying the inclusion criteria. Some patients were interested in joining the study, but physical limitations (eg, impaired mobility) prompted their decision not to join the trial, even though they met all the inclusion criteria.

As far as research-related factors that could affect participation, it is notable that most of the patients were retired; thus, the interventions did not cause additional burden of taking time off from work or loss of productivity. Although randomization could be a deterrent in many clinical trials, the majority of patients were willing to participate without demanding to be assigned to a particular treatment group. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

There are many factors that are intertwined and can lead to enrollment and/or attrition rates. It was critical for our team to make some adjustment without compromising the controlled nature of a randomized trial.

Acknowledgment
The authors wish to acknowledge Huong Le, DPM, MPH, who was the coauthor of the study protocol.

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

Results

Study Protocol Amendments
Given the number of diabetic patients in the US veteran population, we anticipated that there would be enough participants meeting the inclusion and exclusion criteria; however, because of the difficulty with recruitment, the initial study criteria were modified. The study was initially designed to incorporate DFUs with a minimum size of 1.0 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C level of 10% of total hemoglobin or below.¹² Unfortunately, the majority of the potential participants had values substantially higher, and thus could not be enrolled in the trial, requiring another amendment to the study protocol in 2014, which was approved to include patients with an HbA_1C level less than 12% of total hemoglobin. This change contributed considerably to the noted increase in enrollment rates in 2015, which almost doubled relative to enrollment under the original exclusion criteria (Figure).

The study has screened more than 600 patients. Among them, 137 were assessed for eligibility; 71 were excluded for various reasons, including screen failure (eg, decrease in wound size by >40% during the 2-week screening phase), loss to follow-up, and adverse events. Sixty-six participants reached the primary outcome at week 12, while 55 participants completed the study (19 in the SOC group; 18 in the cellular matrix group; 18 in the acellular matrix group).

We have stopped enrolling patients from all sites and the community, as we have reached our target enrollment.

Comment

One of the challenges of clinical trials is the recruitment of an adequate number of participants within an appropriate time frame, which is explained by Lasagna’s Law,¹⁸ a well-described phenomenon whereby the investigator overestimates the number of potential participants available to meet the inclusion criteria. This so-called funnel-effect was partly encountered in our selection process. A review of the veteran population with DFUs seemed to be more than adequate to fulfill the sample size; however, some important participant-related factors also played a substantial role. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

In addition, the Veterans’ Affairs network centralizes health information, making it readily available to all providers participating in their care. As a result, patients with diabetes mellitus typically are seen by a primary care physician along with an endocrinologist, a diabetic nurse, and/or a dietician. Despite the collaboration with an interdisciplinary team, the glycemic control of the participants remains an issue along with other psychosocial factors that are deterrents in patient compliance. As a result, patients with poorly controlled diabetes and an HbA_1C level above 10% (and less than 12%) of total hemoglobin who were initially excluded from the study were reincluded after modifying the inclusion criteria. Some patients were interested in joining the study, but physical limitations (eg, impaired mobility) prompted their decision not to join the trial, even though they met all the inclusion criteria.

As far as research-related factors that could affect participation, it is notable that most of the patients were retired; thus, the interventions did not cause additional burden of taking time off from work or loss of productivity. Although randomization could be a deterrent in many clinical trials, the majority of patients were willing to participate without demanding to be assigned to a particular treatment group. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

There are many factors that are intertwined and can lead to enrollment and/or attrition rates. It was critical for our team to make some adjustment without compromising the controlled nature of a randomized trial.

Acknowledgment
The authors wish to acknowledge Huong Le, DPM, MPH, who was the coauthor of the study protocol.

For many, the holiday season is a time to celebrate, relax, and enjoy the company of family. Much of this celebrating centers on eating and food. For youth struggling with eating disorders, holidays can be a particularly challenging time. Historically, eating disorders were associated with young, straight, cisgender, white females. Data collected over the past 15 years suggest that eating disorders can affect youth of all ethnicities and genders.

Ingram Publishing/ThinkStock

Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus. She said she had no relevant financial disclosures. Email her at [email protected].

Resources

National Eating Disorders Association: www.nationaleatingdisorders.org

“Body image and eating disorders among lesbian, gay, bisexual, and transgender youth” (Pediatr Clin North Am. 2016 Dec;63[6]:1079-90.

References

1. Prev Chronic Dis. 2008 Oct;5(4):A114.

2. Arch Gen Psychiatry. 2011 Jul;68(7):714-23.

3. Pediatr Clin North Am. 2016 Dec;63(6):1079-90.

4. Curr Psychiatry Rep. 2012 Aug;14(4):391-7.

5. J Adolesc Health. 2015 Aug;57(2):144-9.

6. Am J Public Health. 2013 Feb;103(2):e16-22.

7. J Adolesc Health. 2009 Sep;45(3):238-45.
 

For many, the holiday season is a time to celebrate, relax, and enjoy the company of family. Much of this celebrating centers on eating and food. For youth struggling with eating disorders, holidays can be a particularly challenging time. Historically, eating disorders were associated with young, straight, cisgender, white females. Data collected over the past 15 years suggest that eating disorders can affect youth of all ethnicities and genders.

Ingram Publishing/ThinkStock

Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus. She said she had no relevant financial disclosures. Email her at [email protected].

Resources

National Eating Disorders Association: www.nationaleatingdisorders.org

“Body image and eating disorders among lesbian, gay, bisexual, and transgender youth” (Pediatr Clin North Am. 2016 Dec;63[6]:1079-90.

References

1. Prev Chronic Dis. 2008 Oct;5(4):A114.

2. Arch Gen Psychiatry. 2011 Jul;68(7):714-23.

3. Pediatr Clin North Am. 2016 Dec;63(6):1079-90.

4. Curr Psychiatry Rep. 2012 Aug;14(4):391-7.

5. J Adolesc Health. 2015 Aug;57(2):144-9.

6. Am J Public Health. 2013 Feb;103(2):e16-22.

7. J Adolesc Health. 2009 Sep;45(3):238-45.
 

For many, the holiday season is a time to celebrate, relax, and enjoy the company of family. Much of this celebrating centers on eating and food. For youth struggling with eating disorders, holidays can be a particularly challenging time. Historically, eating disorders were associated with young, straight, cisgender, white females. Data collected over the past 15 years suggest that eating disorders can affect youth of all ethnicities and genders.

Ingram Publishing/ThinkStock

Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus. She said she had no relevant financial disclosures. Email her at [email protected].

Resources

National Eating Disorders Association: www.nationaleatingdisorders.org

“Body image and eating disorders among lesbian, gay, bisexual, and transgender youth” (Pediatr Clin North Am. 2016 Dec;63[6]:1079-90.

References

1. Prev Chronic Dis. 2008 Oct;5(4):A114.

2. Arch Gen Psychiatry. 2011 Jul;68(7):714-23.

3. Pediatr Clin North Am. 2016 Dec;63(6):1079-90.

4. Curr Psychiatry Rep. 2012 Aug;14(4):391-7.

5. J Adolesc Health. 2015 Aug;57(2):144-9.

6. Am J Public Health. 2013 Feb;103(2):e16-22.

7. J Adolesc Health. 2009 Sep;45(3):238-45.
 

A 78-year-old man with a history of benign prostatic hyperplasia had double vision for 7 weeks. He also had pain in the right side of the face, altered taste, headaches that were worse when he was lying down, and lower abdominal lymphadenopathy.

His clinicians, at Brigham and Women’s Hospital in Boston, Massachusetts, say neurological examination revealed palsies of the right V, VI, VII, and XII cranial nerves. Magnetic resonance imaging revealed a clival mass and multiple lesions in the vertebrae. Radionuclide studies showed extensive tumor burden in the patient’s liver and peritoneum.

Because it is the most common cause of clival metastases, the clinicians initially suspected prostate cancer was the source of the symptoms. Moreover, the patient’s prostate-specific antigen was modestly elevated, a finding the clinicians called a red herring. The patient was instead diagnosed with a clival tumor, which is extremely rare—and made even more rare due to upper gastrointestinal (GI), the clinicians say. Only 5 cases have been reported of upper GI malignancy with clival metastasis.

Related: Cancer Prevention and Gastrointestinal Risk

The clivus is a bony structure located where the occipital and sphenoid bones meet, close to the long course of the abducens nerve. Double vision, caused by palsy at that nerve, is a prominent sign of a clival lesion, seen in > 40% of cases, the clinicians note. They suggest considering clival pathology as the cause of an abducens palsy or multiple cranial neuropathies.

The patient underwent several cycles of radiation therapy but ultimately decided on hospice care.

Source:

Lee C, Thon JM, Dhand A. BMJ Case Rep. 2017;2017: pii: bcr-2017-222725
doi: 10.1136/bcr-2017-222725.

A 78-year-old man with a history of benign prostatic hyperplasia had double vision for 7 weeks. He also had pain in the right side of the face, altered taste, headaches that were worse when he was lying down, and lower abdominal lymphadenopathy.

His clinicians, at Brigham and Women’s Hospital in Boston, Massachusetts, say neurological examination revealed palsies of the right V, VI, VII, and XII cranial nerves. Magnetic resonance imaging revealed a clival mass and multiple lesions in the vertebrae. Radionuclide studies showed extensive tumor burden in the patient’s liver and peritoneum.

Because it is the most common cause of clival metastases, the clinicians initially suspected prostate cancer was the source of the symptoms. Moreover, the patient’s prostate-specific antigen was modestly elevated, a finding the clinicians called a red herring. The patient was instead diagnosed with a clival tumor, which is extremely rare—and made even more rare due to upper gastrointestinal (GI), the clinicians say. Only 5 cases have been reported of upper GI malignancy with clival metastasis.

Related: Cancer Prevention and Gastrointestinal Risk

The clivus is a bony structure located where the occipital and sphenoid bones meet, close to the long course of the abducens nerve. Double vision, caused by palsy at that nerve, is a prominent sign of a clival lesion, seen in > 40% of cases, the clinicians note. They suggest considering clival pathology as the cause of an abducens palsy or multiple cranial neuropathies.

The patient underwent several cycles of radiation therapy but ultimately decided on hospice care.

Source:

Lee C, Thon JM, Dhand A. BMJ Case Rep. 2017;2017: pii: bcr-2017-222725
doi: 10.1136/bcr-2017-222725.

A 78-year-old man with a history of benign prostatic hyperplasia had double vision for 7 weeks. He also had pain in the right side of the face, altered taste, headaches that were worse when he was lying down, and lower abdominal lymphadenopathy.

His clinicians, at Brigham and Women’s Hospital in Boston, Massachusetts, say neurological examination revealed palsies of the right V, VI, VII, and XII cranial nerves. Magnetic resonance imaging revealed a clival mass and multiple lesions in the vertebrae. Radionuclide studies showed extensive tumor burden in the patient’s liver and peritoneum.

Because it is the most common cause of clival metastases, the clinicians initially suspected prostate cancer was the source of the symptoms. Moreover, the patient’s prostate-specific antigen was modestly elevated, a finding the clinicians called a red herring. The patient was instead diagnosed with a clival tumor, which is extremely rare—and made even more rare due to upper gastrointestinal (GI), the clinicians say. Only 5 cases have been reported of upper GI malignancy with clival metastasis.

Related: Cancer Prevention and Gastrointestinal Risk

The clivus is a bony structure located where the occipital and sphenoid bones meet, close to the long course of the abducens nerve. Double vision, caused by palsy at that nerve, is a prominent sign of a clival lesion, seen in > 40% of cases, the clinicians note. They suggest considering clival pathology as the cause of an abducens palsy or multiple cranial neuropathies.

The patient underwent several cycles of radiation therapy but ultimately decided on hospice care.

Source:

Lee C, Thon JM, Dhand A. BMJ Case Rep. 2017;2017: pii: bcr-2017-222725
doi: 10.1136/bcr-2017-222725.