LAS VEGAS – Combining the right products and anatomical knowledge translates patient concerns into better outcomes when using fillers, according to Burt Steffes, MD, a dermatologist in Fond du Lac, Wisc.

“If you understand differences in products, you’ll get better results and minimize complications” for different areas, Dr. Steffes said in a presentation at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

The physical properties of different fillers impact the results, he pointed out. For example, G prime, a measure of elasticity, varies among fillers; a filler with a higher G prime is more contour stable and is designed to lift tissue, while a product with a lower G prime is designed to spread through tissues and move more naturally with the face.

However, “lift capacity using G prime is only useful across products in the entire family and make up,” Dr. Steffes noted. A recent Allergan-sponsored study emphasized that “product performance is a complex interaction of various properties and tissue interactions not just G prime,” he said (Dermatol Surg, 2015;41:S373-81).

Determining the most effective filler to use depends on the location and area to be corrected.

• Tear troughs: Dr. Steffes recommends avoiding hydrophilic products; he prefers Belotero, Restylane, or Restylane Silk.

• Lips: More flexible products such as Juvederm, Restylane, or Belotero can provide patients with the desired result, he noted.

• Nasolabial fold: Juvederm, Restylane, or Radiesse are appropriate choices likely to produce favorable outcomes, Dr. Steffes said.

• Lateral and midface atrophy: For greater lift and cohesivity in these patients, Dr. Steffes considers Perlane, Voluma, Radiesse, or Sculptra as options.

“Fillers are a great way to help people look and feel better,” but complications occur, so be prepared, he said. “You have to know how to recognize and manage complications.”

Proper management starts with staff education. Provide instruction and training to staff (including reception) on how to recognize impending problems. “Have a written protocol available, and keep nitroglycerin paste, hyaluronidase, and aspirin on hand,” he advised.

Cases of swelling may require hyaluronidase to correct, as may lumps and bumps, Dr. Steffes said. Bruising may be managed with ice packs after the fact, but can often be avoided or minimized by using blunt tip cannulas, slow injections, small aliquots, and small-gauge needles, he added.

In cases of extreme complications such as vascular occlusion, start by massaging the area with nitroglycerin paste, and administer hyaluronidase if necessary, he said. However, be sure to proceed carefully if using hyaluronidase in patients with an allergy to bee stings; use it only in an emergency in these patients and treat anaphylaxis if necessary, he added.

Dr. Steffes had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Combining the right products and anatomical knowledge translates patient concerns into better outcomes when using fillers, according to Burt Steffes, MD, a dermatologist in Fond du Lac, Wisc.

“If you understand differences in products, you’ll get better results and minimize complications” for different areas, Dr. Steffes said in a presentation at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

The physical properties of different fillers impact the results, he pointed out. For example, G prime, a measure of elasticity, varies among fillers; a filler with a higher G prime is more contour stable and is designed to lift tissue, while a product with a lower G prime is designed to spread through tissues and move more naturally with the face.

However, “lift capacity using G prime is only useful across products in the entire family and make up,” Dr. Steffes noted. A recent Allergan-sponsored study emphasized that “product performance is a complex interaction of various properties and tissue interactions not just G prime,” he said (Dermatol Surg, 2015;41:S373-81).

Determining the most effective filler to use depends on the location and area to be corrected.

• Tear troughs: Dr. Steffes recommends avoiding hydrophilic products; he prefers Belotero, Restylane, or Restylane Silk.

• Lips: More flexible products such as Juvederm, Restylane, or Belotero can provide patients with the desired result, he noted.

• Nasolabial fold: Juvederm, Restylane, or Radiesse are appropriate choices likely to produce favorable outcomes, Dr. Steffes said.

• Lateral and midface atrophy: For greater lift and cohesivity in these patients, Dr. Steffes considers Perlane, Voluma, Radiesse, or Sculptra as options.

“Fillers are a great way to help people look and feel better,” but complications occur, so be prepared, he said. “You have to know how to recognize and manage complications.”

Proper management starts with staff education. Provide instruction and training to staff (including reception) on how to recognize impending problems. “Have a written protocol available, and keep nitroglycerin paste, hyaluronidase, and aspirin on hand,” he advised.

Cases of swelling may require hyaluronidase to correct, as may lumps and bumps, Dr. Steffes said. Bruising may be managed with ice packs after the fact, but can often be avoided or minimized by using blunt tip cannulas, slow injections, small aliquots, and small-gauge needles, he added.

In cases of extreme complications such as vascular occlusion, start by massaging the area with nitroglycerin paste, and administer hyaluronidase if necessary, he said. However, be sure to proceed carefully if using hyaluronidase in patients with an allergy to bee stings; use it only in an emergency in these patients and treat anaphylaxis if necessary, he added.

Dr. Steffes had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Combining the right products and anatomical knowledge translates patient concerns into better outcomes when using fillers, according to Burt Steffes, MD, a dermatologist in Fond du Lac, Wisc.

“If you understand differences in products, you’ll get better results and minimize complications” for different areas, Dr. Steffes said in a presentation at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

The physical properties of different fillers impact the results, he pointed out. For example, G prime, a measure of elasticity, varies among fillers; a filler with a higher G prime is more contour stable and is designed to lift tissue, while a product with a lower G prime is designed to spread through tissues and move more naturally with the face.

However, “lift capacity using G prime is only useful across products in the entire family and make up,” Dr. Steffes noted. A recent Allergan-sponsored study emphasized that “product performance is a complex interaction of various properties and tissue interactions not just G prime,” he said (Dermatol Surg, 2015;41:S373-81).

Determining the most effective filler to use depends on the location and area to be corrected.

• Tear troughs: Dr. Steffes recommends avoiding hydrophilic products; he prefers Belotero, Restylane, or Restylane Silk.

• Lips: More flexible products such as Juvederm, Restylane, or Belotero can provide patients with the desired result, he noted.

• Nasolabial fold: Juvederm, Restylane, or Radiesse are appropriate choices likely to produce favorable outcomes, Dr. Steffes said.

• Lateral and midface atrophy: For greater lift and cohesivity in these patients, Dr. Steffes considers Perlane, Voluma, Radiesse, or Sculptra as options.

“Fillers are a great way to help people look and feel better,” but complications occur, so be prepared, he said. “You have to know how to recognize and manage complications.”

Proper management starts with staff education. Provide instruction and training to staff (including reception) on how to recognize impending problems. “Have a written protocol available, and keep nitroglycerin paste, hyaluronidase, and aspirin on hand,” he advised.

Cases of swelling may require hyaluronidase to correct, as may lumps and bumps, Dr. Steffes said. Bruising may be managed with ice packs after the fact, but can often be avoided or minimized by using blunt tip cannulas, slow injections, small aliquots, and small-gauge needles, he added.

In cases of extreme complications such as vascular occlusion, start by massaging the area with nitroglycerin paste, and administer hyaluronidase if necessary, he said. However, be sure to proceed carefully if using hyaluronidase in patients with an allergy to bee stings; use it only in an emergency in these patients and treat anaphylaxis if necessary, he added.

Dr. Steffes had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Listening to patients is the “first and most important step” toward using neuromodulators successfully, according to Burt Steffes, MD.

Clinicians armed with a thorough knowledge of anatomy and the available products can use neuromodulators successfully for a range of aging concerns including the glabellar complex, crow’s feet, marionette lines, smoker’s lines, a dimpled chin, and platysmal bands, Dr. Steffes, a dermatologist in Fond du Lac, Wisc., said in a presentation at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

When diluting toxins, be consistent for best results, he advised. “Pick a concentration you like and stick with it,” he said. Establishing realistic expectations and taking preprocedure photos are essential for optimizing results, he added.

Dr. Steffes shared the following tips for successful toxin treatments:

• Horizontal forehead rhytids. Check the brow position and stay approximately 2 cm above the eyebrows. Be conservative with the amount of product used to avoid the frozen look. In cases of upper eyelid ptosis, “improvement can be achieved with apraclonidine 0.5% drops,” he said.

• Glabellar complex. Dr. Steffes said he usually uses 10-30 units. Avoid blood vessels to avoid bruising, he said, “and ask patients to scowl” to identify the exact location for injections.

• Crow’s feet. Treatment of crow’s feet means managing an area “of great variability,” Dr. Steffes said. He advised using superficial injections to minimize bruising, while staying 2 cm from the orbital rim and adjusting to match the patient’s rhytid pattern. He recommends 1-2 units placed 1 cm below the lower eyelid margin at the mid-pupillary line to decrease the bunching of the lower eyelid.

• Platysmal bands. Managing volume is the key to successful treatment of platysmal bands, said Dr. Steffes. “Injecting too much product into the neck can lead to asymmetry” he cautioned. Pinch the platysmal band between the fingers and inject intramuscularly, using 2 units per injection. “Use conservative amounts and adjust in two weeks if needed,” he said.

Be sure that all patients make follow-up appointments before they leave the office after a procedure, and schedule new patients for follow-up in 2 weeks, said Dr. Steffes. Instruct all patients to contact your office immediately for any concerns including bruising that may be managed within the first 24-48 hours with a low-fluence 595-nm, 532-nm, or 1,064-nm laser, he added.

Dr. Steffes had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Listening to patients is the “first and most important step” toward using neuromodulators successfully, according to Burt Steffes, MD.

Clinicians armed with a thorough knowledge of anatomy and the available products can use neuromodulators successfully for a range of aging concerns including the glabellar complex, crow’s feet, marionette lines, smoker’s lines, a dimpled chin, and platysmal bands, Dr. Steffes, a dermatologist in Fond du Lac, Wisc., said in a presentation at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

When diluting toxins, be consistent for best results, he advised. “Pick a concentration you like and stick with it,” he said. Establishing realistic expectations and taking preprocedure photos are essential for optimizing results, he added.

Dr. Steffes shared the following tips for successful toxin treatments:

• Horizontal forehead rhytids. Check the brow position and stay approximately 2 cm above the eyebrows. Be conservative with the amount of product used to avoid the frozen look. In cases of upper eyelid ptosis, “improvement can be achieved with apraclonidine 0.5% drops,” he said.

• Glabellar complex. Dr. Steffes said he usually uses 10-30 units. Avoid blood vessels to avoid bruising, he said, “and ask patients to scowl” to identify the exact location for injections.

• Crow’s feet. Treatment of crow’s feet means managing an area “of great variability,” Dr. Steffes said. He advised using superficial injections to minimize bruising, while staying 2 cm from the orbital rim and adjusting to match the patient’s rhytid pattern. He recommends 1-2 units placed 1 cm below the lower eyelid margin at the mid-pupillary line to decrease the bunching of the lower eyelid.

• Platysmal bands. Managing volume is the key to successful treatment of platysmal bands, said Dr. Steffes. “Injecting too much product into the neck can lead to asymmetry” he cautioned. Pinch the platysmal band between the fingers and inject intramuscularly, using 2 units per injection. “Use conservative amounts and adjust in two weeks if needed,” he said.

Be sure that all patients make follow-up appointments before they leave the office after a procedure, and schedule new patients for follow-up in 2 weeks, said Dr. Steffes. Instruct all patients to contact your office immediately for any concerns including bruising that may be managed within the first 24-48 hours with a low-fluence 595-nm, 532-nm, or 1,064-nm laser, he added.

Dr. Steffes had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Listening to patients is the “first and most important step” toward using neuromodulators successfully, according to Burt Steffes, MD.

Clinicians armed with a thorough knowledge of anatomy and the available products can use neuromodulators successfully for a range of aging concerns including the glabellar complex, crow’s feet, marionette lines, smoker’s lines, a dimpled chin, and platysmal bands, Dr. Steffes, a dermatologist in Fond du Lac, Wisc., said in a presentation at Skin Disease Education Foundation’s annual Las Vegas dermatology seminar.

When diluting toxins, be consistent for best results, he advised. “Pick a concentration you like and stick with it,” he said. Establishing realistic expectations and taking preprocedure photos are essential for optimizing results, he added.

Dr. Steffes shared the following tips for successful toxin treatments:

• Horizontal forehead rhytids. Check the brow position and stay approximately 2 cm above the eyebrows. Be conservative with the amount of product used to avoid the frozen look. In cases of upper eyelid ptosis, “improvement can be achieved with apraclonidine 0.5% drops,” he said.

• Glabellar complex. Dr. Steffes said he usually uses 10-30 units. Avoid blood vessels to avoid bruising, he said, “and ask patients to scowl” to identify the exact location for injections.

• Crow’s feet. Treatment of crow’s feet means managing an area “of great variability,” Dr. Steffes said. He advised using superficial injections to minimize bruising, while staying 2 cm from the orbital rim and adjusting to match the patient’s rhytid pattern. He recommends 1-2 units placed 1 cm below the lower eyelid margin at the mid-pupillary line to decrease the bunching of the lower eyelid.

• Platysmal bands. Managing volume is the key to successful treatment of platysmal bands, said Dr. Steffes. “Injecting too much product into the neck can lead to asymmetry” he cautioned. Pinch the platysmal band between the fingers and inject intramuscularly, using 2 units per injection. “Use conservative amounts and adjust in two weeks if needed,” he said.

Be sure that all patients make follow-up appointments before they leave the office after a procedure, and schedule new patients for follow-up in 2 weeks, said Dr. Steffes. Instruct all patients to contact your office immediately for any concerns including bruising that may be managed within the first 24-48 hours with a low-fluence 595-nm, 532-nm, or 1,064-nm laser, he added.

Dr. Steffes had no relevant financial conflicts to disclose.

SDEF and this news organization are owned by the same parent company.

The number of active airline pilots managing depressive symptoms might be severely underreported because of pilots’ fear of facing workplace stigma, a cross-sectional study of pilots from across the globe suggests.

“This study fills an important gap of knowledge by providing a current glimpse of mental health among commercial airline pilots, which to date had not been available,” wrote the authors, who added that such data are even more important in the wake of the March 2015 Germanwings flight 9525 crash.

In the study, Alexander C. Wu, MPH, and his coinvestigators conducted a descriptive, cross-sectional study by distributing an anonymous online survey through airline unions, companies, and airports. The survey, administered between April and December 2015, was received by 3,485 airline pilots. Among that number, 1,866 completed half the survey and 1,837 completed the entire survey. Symptoms of depression were evaluated based on the Patient Health Questionnaire (PHQ-9) depression module, with questions taken from the National Health and Nutrition Examination Survey – created by the Centers for Disease Control and Prevention’s National Center for Health Statistics – and the standardized Job Content Questionnaire (JCQ) (Environ Health. 2016 Dec 15. doi: 10.1186/s12940-016-0200-6).

The median age of those who responded was 42 years for females and 50 for males, and the average career length was 16 years across both genders, reported Mr. Wu, a doctoral candidate at the Harvard School of Public Health in Boston, and his coinvestigators. Nearly half of the respondents (45.5%) were from the United States, which was one of more than 50 countries represented, including Canada, Australia, Spain, the United Kingdom, Germany, the United Arab Emirates, Hong Kong, and Thailand.

More than 60% of the respondents had either a 4-year college/university degree or graduate education, and 80% of respondents had flown at least one “major trip” in the 30 days prior to completing the survey. Most of the respondents did not smoke, were married, and were white. Depression threshold was defined as a score of at least 10 on the PHQ-9, which was reported by 233 of the 1,848 responding airline pilots (12.6%), and 193 (13.5%) of the 1,430 pilots who reported flying in the 7 days prior to completing the survey. Furthermore, 75 (4.1%) of the 1,829 who answered the relevant question reported having suicidal thoughts at some point in the prior 2 weeks.

“We found a significant trend in proportions of depression at higher levels of use of sleep-aid medication (P less than .001) and among those experiencing sexual harassment (P = .001) or verbal harassment (P less than .001),” the investigators noted. In addition, 75 of the pilots “reported having thoughts of being better off dead or self-harm within the past 2 weeks,” the investigators wrote. “To our knowledge, this is the most current measure of the prevalence of suicidal thoughts among airline pilots.”

When asked about the study, Mark S. Gold, MD, said in an interview that workplace stigmas and the fear of facing criticism from their colleagues may be the prevailing factor in preventing pilots from openly discussing these issues among themselves. “Being a pilot, like a physician, is a drug-free occupation, [but] substance use disorders and depression are so commonly found together that the question is often ‘chicken or egg,’ ” said Dr. Gold, adjunct professor of psychiatry at Washington University in St. Louis, and former Donald R. Dizney Eminent Scholar and chairman of the psychiatry department at the University of Florida, Gainesville. “Add shame, guilt, and denial, and suicide ideation, [and] attempts and completions become all the more common.”

The solution, Dr. Gold said, is early detection, along with “multidisciplinary evaluation and diagnosis, prompt treatment and long-term follow-up by a physician’s health program or [an employee assistance program that] is associated with sustained remissions.” Mr. Wu and his coinvestigators said they would neither rate nor recommend a specific treatment. “However, [Internet-based cognitive-behavioral therapy] is one example of a possible intervention found in the literature,” they wrote.

The investigators cited several limitations. They conceded, for example, that there is “potential underestimation of frequencies of adverse mental health outcomes due to less participation among participants with more severe depression compared to those with less severe or without depression,” as well as the fact that the age of those who completed the survey were, on average, older, and they had flown more recently than had noncompleters. The age discrepancy might have skewed the results.

Harvard T.H. Chan School of Public Health funded the study. Mr. Wu and his coinvestigators reported no relevant financial disclosures.

[email protected]

The number of active airline pilots managing depressive symptoms might be severely underreported because of pilots’ fear of facing workplace stigma, a cross-sectional study of pilots from across the globe suggests.

“This study fills an important gap of knowledge by providing a current glimpse of mental health among commercial airline pilots, which to date had not been available,” wrote the authors, who added that such data are even more important in the wake of the March 2015 Germanwings flight 9525 crash.

In the study, Alexander C. Wu, MPH, and his coinvestigators conducted a descriptive, cross-sectional study by distributing an anonymous online survey through airline unions, companies, and airports. The survey, administered between April and December 2015, was received by 3,485 airline pilots. Among that number, 1,866 completed half the survey and 1,837 completed the entire survey. Symptoms of depression were evaluated based on the Patient Health Questionnaire (PHQ-9) depression module, with questions taken from the National Health and Nutrition Examination Survey – created by the Centers for Disease Control and Prevention’s National Center for Health Statistics – and the standardized Job Content Questionnaire (JCQ) (Environ Health. 2016 Dec 15. doi: 10.1186/s12940-016-0200-6).

The median age of those who responded was 42 years for females and 50 for males, and the average career length was 16 years across both genders, reported Mr. Wu, a doctoral candidate at the Harvard School of Public Health in Boston, and his coinvestigators. Nearly half of the respondents (45.5%) were from the United States, which was one of more than 50 countries represented, including Canada, Australia, Spain, the United Kingdom, Germany, the United Arab Emirates, Hong Kong, and Thailand.

More than 60% of the respondents had either a 4-year college/university degree or graduate education, and 80% of respondents had flown at least one “major trip” in the 30 days prior to completing the survey. Most of the respondents did not smoke, were married, and were white. Depression threshold was defined as a score of at least 10 on the PHQ-9, which was reported by 233 of the 1,848 responding airline pilots (12.6%), and 193 (13.5%) of the 1,430 pilots who reported flying in the 7 days prior to completing the survey. Furthermore, 75 (4.1%) of the 1,829 who answered the relevant question reported having suicidal thoughts at some point in the prior 2 weeks.

“We found a significant trend in proportions of depression at higher levels of use of sleep-aid medication (P less than .001) and among those experiencing sexual harassment (P = .001) or verbal harassment (P less than .001),” the investigators noted. In addition, 75 of the pilots “reported having thoughts of being better off dead or self-harm within the past 2 weeks,” the investigators wrote. “To our knowledge, this is the most current measure of the prevalence of suicidal thoughts among airline pilots.”

When asked about the study, Mark S. Gold, MD, said in an interview that workplace stigmas and the fear of facing criticism from their colleagues may be the prevailing factor in preventing pilots from openly discussing these issues among themselves. “Being a pilot, like a physician, is a drug-free occupation, [but] substance use disorders and depression are so commonly found together that the question is often ‘chicken or egg,’ ” said Dr. Gold, adjunct professor of psychiatry at Washington University in St. Louis, and former Donald R. Dizney Eminent Scholar and chairman of the psychiatry department at the University of Florida, Gainesville. “Add shame, guilt, and denial, and suicide ideation, [and] attempts and completions become all the more common.”

The solution, Dr. Gold said, is early detection, along with “multidisciplinary evaluation and diagnosis, prompt treatment and long-term follow-up by a physician’s health program or [an employee assistance program that] is associated with sustained remissions.” Mr. Wu and his coinvestigators said they would neither rate nor recommend a specific treatment. “However, [Internet-based cognitive-behavioral therapy] is one example of a possible intervention found in the literature,” they wrote.

The investigators cited several limitations. They conceded, for example, that there is “potential underestimation of frequencies of adverse mental health outcomes due to less participation among participants with more severe depression compared to those with less severe or without depression,” as well as the fact that the age of those who completed the survey were, on average, older, and they had flown more recently than had noncompleters. The age discrepancy might have skewed the results.

Harvard T.H. Chan School of Public Health funded the study. Mr. Wu and his coinvestigators reported no relevant financial disclosures.

[email protected]

The number of active airline pilots managing depressive symptoms might be severely underreported because of pilots’ fear of facing workplace stigma, a cross-sectional study of pilots from across the globe suggests.

“This study fills an important gap of knowledge by providing a current glimpse of mental health among commercial airline pilots, which to date had not been available,” wrote the authors, who added that such data are even more important in the wake of the March 2015 Germanwings flight 9525 crash.

In the study, Alexander C. Wu, MPH, and his coinvestigators conducted a descriptive, cross-sectional study by distributing an anonymous online survey through airline unions, companies, and airports. The survey, administered between April and December 2015, was received by 3,485 airline pilots. Among that number, 1,866 completed half the survey and 1,837 completed the entire survey. Symptoms of depression were evaluated based on the Patient Health Questionnaire (PHQ-9) depression module, with questions taken from the National Health and Nutrition Examination Survey – created by the Centers for Disease Control and Prevention’s National Center for Health Statistics – and the standardized Job Content Questionnaire (JCQ) (Environ Health. 2016 Dec 15. doi: 10.1186/s12940-016-0200-6).

The median age of those who responded was 42 years for females and 50 for males, and the average career length was 16 years across both genders, reported Mr. Wu, a doctoral candidate at the Harvard School of Public Health in Boston, and his coinvestigators. Nearly half of the respondents (45.5%) were from the United States, which was one of more than 50 countries represented, including Canada, Australia, Spain, the United Kingdom, Germany, the United Arab Emirates, Hong Kong, and Thailand.

More than 60% of the respondents had either a 4-year college/university degree or graduate education, and 80% of respondents had flown at least one “major trip” in the 30 days prior to completing the survey. Most of the respondents did not smoke, were married, and were white. Depression threshold was defined as a score of at least 10 on the PHQ-9, which was reported by 233 of the 1,848 responding airline pilots (12.6%), and 193 (13.5%) of the 1,430 pilots who reported flying in the 7 days prior to completing the survey. Furthermore, 75 (4.1%) of the 1,829 who answered the relevant question reported having suicidal thoughts at some point in the prior 2 weeks.

“We found a significant trend in proportions of depression at higher levels of use of sleep-aid medication (P less than .001) and among those experiencing sexual harassment (P = .001) or verbal harassment (P less than .001),” the investigators noted. In addition, 75 of the pilots “reported having thoughts of being better off dead or self-harm within the past 2 weeks,” the investigators wrote. “To our knowledge, this is the most current measure of the prevalence of suicidal thoughts among airline pilots.”

When asked about the study, Mark S. Gold, MD, said in an interview that workplace stigmas and the fear of facing criticism from their colleagues may be the prevailing factor in preventing pilots from openly discussing these issues among themselves. “Being a pilot, like a physician, is a drug-free occupation, [but] substance use disorders and depression are so commonly found together that the question is often ‘chicken or egg,’ ” said Dr. Gold, adjunct professor of psychiatry at Washington University in St. Louis, and former Donald R. Dizney Eminent Scholar and chairman of the psychiatry department at the University of Florida, Gainesville. “Add shame, guilt, and denial, and suicide ideation, [and] attempts and completions become all the more common.”

The solution, Dr. Gold said, is early detection, along with “multidisciplinary evaluation and diagnosis, prompt treatment and long-term follow-up by a physician’s health program or [an employee assistance program that] is associated with sustained remissions.” Mr. Wu and his coinvestigators said they would neither rate nor recommend a specific treatment. “However, [Internet-based cognitive-behavioral therapy] is one example of a possible intervention found in the literature,” they wrote.

The investigators cited several limitations. They conceded, for example, that there is “potential underestimation of frequencies of adverse mental health outcomes due to less participation among participants with more severe depression compared to those with less severe or without depression,” as well as the fact that the age of those who completed the survey were, on average, older, and they had flown more recently than had noncompleters. The age discrepancy might have skewed the results.

Harvard T.H. Chan School of Public Health funded the study. Mr. Wu and his coinvestigators reported no relevant financial disclosures.

[email protected]

Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.

A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.¹

©Ingram Publishing/Thinkstock

References

1. Int J Epidemiol. 2013 Dec;42(6):1702-13.

2. JAMA Pediatr. 2014 Apr;168(4):313-20.

3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.

4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.

5. Autism Res. 2016 Sep;9(9):951-8.

6. Epidemiology. 2016 Nov;27(6):912-8.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].

Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.

A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.¹

©Ingram Publishing/Thinkstock

References

1. Int J Epidemiol. 2013 Dec;42(6):1702-13.

2. JAMA Pediatr. 2014 Apr;168(4):313-20.

3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.

4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.

5. Autism Res. 2016 Sep;9(9):951-8.

6. Epidemiology. 2016 Nov;27(6):912-8.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].

Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.

A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.¹

©Ingram Publishing/Thinkstock

References

1. Int J Epidemiol. 2013 Dec;42(6):1702-13.

2. JAMA Pediatr. 2014 Apr;168(4):313-20.

3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.

4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.

5. Autism Res. 2016 Sep;9(9):951-8.

6. Epidemiology. 2016 Nov;27(6):912-8.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].

Jianjun Chen, PhD
Photo courtesy of
University of Cincinnati

Preclinical research indicates that a protein associated with obesity is also involved in the development of acute myeloid leukemia (AML) and may affect AML patients’ response to treatment.

Researchers found evidence to suggest that the fat mass- and obesity-associated protein (FTO) regulates the expression of a set of genes through a mechanism involving RNA modification, thereby increasing the reproduction of leukemia cells and prohibiting drug response. 

Jianjun Chen, PhD, of the University of Cincinnati in Ohio, and his colleagues conducted this research and reported the findings in Cancer Cell.

The team noted that N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in messenger RNAs (mRNAs) in genes. And they found that FTO, an m6A demethylase, plays a critical oncogenic role in AML.

The researchers made this discovery by analyzing 2 microarray datasets of samples from AML as well as samples from control subjects.

The team found that FTO was highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

The high level of FTO expression contributed to leukemia cells multiplying and surviving and also promoted the development of AML in animal models and the non-response of AML cells to therapeutic agents.

Additionally, the researchers found that genes like ASB2 and RARA, which were reported to inhibit leukemia cell growth and/or mediate the response of leukemia cells to therapeutic agents, were suppressed in the AML samples with higher FTO expression.

The suppression of these genes was attributed to FTO-controlled decreased stability of their mRNA and was connected to FTO’s m6A demethylase activity.

“Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia,” Dr Chen said. “In addition, given the functional importance of FTO in the formation of leukemia and drug response, targeting FTO signaling may present a new therapeutic strategy to treat leukemia.”

“As FTO may also play a cancer-promoting role in various types of solid tumors, besides leukemia, our discoveries may have a broad impact in cancer biology and cancer therapy. Further studies are needed to advance our understanding of the critical role of FTO in various types of cancers and to develop more effective novel therapeutic strategies based on such understanding to treat cancers.”

Jianjun Chen, PhD
Photo courtesy of
University of Cincinnati

Preclinical research indicates that a protein associated with obesity is also involved in the development of acute myeloid leukemia (AML) and may affect AML patients’ response to treatment.

Researchers found evidence to suggest that the fat mass- and obesity-associated protein (FTO) regulates the expression of a set of genes through a mechanism involving RNA modification, thereby increasing the reproduction of leukemia cells and prohibiting drug response. 

Jianjun Chen, PhD, of the University of Cincinnati in Ohio, and his colleagues conducted this research and reported the findings in Cancer Cell.

The team noted that N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in messenger RNAs (mRNAs) in genes. And they found that FTO, an m6A demethylase, plays a critical oncogenic role in AML.

The researchers made this discovery by analyzing 2 microarray datasets of samples from AML as well as samples from control subjects.

The team found that FTO was highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

The high level of FTO expression contributed to leukemia cells multiplying and surviving and also promoted the development of AML in animal models and the non-response of AML cells to therapeutic agents.

Additionally, the researchers found that genes like ASB2 and RARA, which were reported to inhibit leukemia cell growth and/or mediate the response of leukemia cells to therapeutic agents, were suppressed in the AML samples with higher FTO expression.

The suppression of these genes was attributed to FTO-controlled decreased stability of their mRNA and was connected to FTO’s m6A demethylase activity.

“Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia,” Dr Chen said. “In addition, given the functional importance of FTO in the formation of leukemia and drug response, targeting FTO signaling may present a new therapeutic strategy to treat leukemia.”

“As FTO may also play a cancer-promoting role in various types of solid tumors, besides leukemia, our discoveries may have a broad impact in cancer biology and cancer therapy. Further studies are needed to advance our understanding of the critical role of FTO in various types of cancers and to develop more effective novel therapeutic strategies based on such understanding to treat cancers.”

Jianjun Chen, PhD
Photo courtesy of
University of Cincinnati

Preclinical research indicates that a protein associated with obesity is also involved in the development of acute myeloid leukemia (AML) and may affect AML patients’ response to treatment.

Researchers found evidence to suggest that the fat mass- and obesity-associated protein (FTO) regulates the expression of a set of genes through a mechanism involving RNA modification, thereby increasing the reproduction of leukemia cells and prohibiting drug response. 

Jianjun Chen, PhD, of the University of Cincinnati in Ohio, and his colleagues conducted this research and reported the findings in Cancer Cell.

The team noted that N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in messenger RNAs (mRNAs) in genes. And they found that FTO, an m6A demethylase, plays a critical oncogenic role in AML.

The researchers made this discovery by analyzing 2 microarray datasets of samples from AML as well as samples from control subjects.

The team found that FTO was highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

The high level of FTO expression contributed to leukemia cells multiplying and surviving and also promoted the development of AML in animal models and the non-response of AML cells to therapeutic agents.

Additionally, the researchers found that genes like ASB2 and RARA, which were reported to inhibit leukemia cell growth and/or mediate the response of leukemia cells to therapeutic agents, were suppressed in the AML samples with higher FTO expression.

The suppression of these genes was attributed to FTO-controlled decreased stability of their mRNA and was connected to FTO’s m6A demethylase activity.

“Our study shows, for the first time, the functional importance of the m6A modification machinery in leukemia,” Dr Chen said. “In addition, given the functional importance of FTO in the formation of leukemia and drug response, targeting FTO signaling may present a new therapeutic strategy to treat leukemia.”

“As FTO may also play a cancer-promoting role in various types of solid tumors, besides leukemia, our discoveries may have a broad impact in cancer biology and cancer therapy. Further studies are needed to advance our understanding of the critical role of FTO in various types of cancers and to develop more effective novel therapeutic strategies based on such understanding to treat cancers.”

Burkholderia cepacia
Image courtesy of
CDC/Janice Carr

The US Food and Drug Administration (FDA) has announced a Class I, nationwide recall of Nurse Assist Inc.’s normal saline flush syringes due to incidents of Burkholderia cepacia contamination.

Nurse Assist reported that patients developed B cepacia bloodstream infections while receiving intravenous care using the company’s prepackaged saline flush syringes, so the company voluntarily recalled all unexpired lots of the product.

This recall was first announced last October, but, yesterday, the FDA classified it as a Class I recall and said use of these syringes may cause serious injuries or death.

Nurse Assist said it is investigating the link between the syringes and the infections with the FDA, the US Centers for Disease Control, and various state health departments.

Until the investigation can be completed, all healthcare facilities with affected product should discontinue use and return the product to the supplier.

The normal saline flush is a plastic syringe filled with 0.9% sodium chloride (a 12 mL IV flush syringe with a 3 mL, 5 mL, or 10 mL fill volume). It is used to clear out medical devices that deliver medicine directly into the veins of a patient through a needle or catheter.

All unexpired lots of this product are covered by the recall. Product Numbers 1203, 1205, and 1210 are packaged 30 syringes to an inner carton and 6 inner cartons in a case (180 syringes).

For product number 1210-BP, 100 syringes are packaged in an inner carton with 4 inner cartons in a case (400 syringes). Lot code information can be found on the outer case panel, the back panel of the inner carton, and on each syringe label.

The lots being recalled were distributed to customers and distributors between February 16, 2016, and September 30, 2016. Product can be identified by the labeling on the packaging and device.

Customers with questions can contact Nurse Assist Inc. at 1-800-649-6800 ext. 10, Monday through Friday, between the hours of 8 am and 5 pm, Central Time, or via email at [email protected].

Healthcare professionals and consumers can report adverse reactions or quality problems they experienced using these devices to MedWatch: The FDA Safety Information and Adverse Event Reporting Program.

Burkholderia cepacia
Image courtesy of
CDC/Janice Carr

The US Food and Drug Administration (FDA) has announced a Class I, nationwide recall of Nurse Assist Inc.’s normal saline flush syringes due to incidents of Burkholderia cepacia contamination.

Nurse Assist reported that patients developed B cepacia bloodstream infections while receiving intravenous care using the company’s prepackaged saline flush syringes, so the company voluntarily recalled all unexpired lots of the product.

This recall was first announced last October, but, yesterday, the FDA classified it as a Class I recall and said use of these syringes may cause serious injuries or death.

Nurse Assist said it is investigating the link between the syringes and the infections with the FDA, the US Centers for Disease Control, and various state health departments.

Until the investigation can be completed, all healthcare facilities with affected product should discontinue use and return the product to the supplier.

The normal saline flush is a plastic syringe filled with 0.9% sodium chloride (a 12 mL IV flush syringe with a 3 mL, 5 mL, or 10 mL fill volume). It is used to clear out medical devices that deliver medicine directly into the veins of a patient through a needle or catheter.

All unexpired lots of this product are covered by the recall. Product Numbers 1203, 1205, and 1210 are packaged 30 syringes to an inner carton and 6 inner cartons in a case (180 syringes).

For product number 1210-BP, 100 syringes are packaged in an inner carton with 4 inner cartons in a case (400 syringes). Lot code information can be found on the outer case panel, the back panel of the inner carton, and on each syringe label.

The lots being recalled were distributed to customers and distributors between February 16, 2016, and September 30, 2016. Product can be identified by the labeling on the packaging and device.

Customers with questions can contact Nurse Assist Inc. at 1-800-649-6800 ext. 10, Monday through Friday, between the hours of 8 am and 5 pm, Central Time, or via email at [email protected].

Healthcare professionals and consumers can report adverse reactions or quality problems they experienced using these devices to MedWatch: The FDA Safety Information and Adverse Event Reporting Program.

Burkholderia cepacia
Image courtesy of
CDC/Janice Carr

The US Food and Drug Administration (FDA) has announced a Class I, nationwide recall of Nurse Assist Inc.’s normal saline flush syringes due to incidents of Burkholderia cepacia contamination.

Nurse Assist reported that patients developed B cepacia bloodstream infections while receiving intravenous care using the company’s prepackaged saline flush syringes, so the company voluntarily recalled all unexpired lots of the product.

This recall was first announced last October, but, yesterday, the FDA classified it as a Class I recall and said use of these syringes may cause serious injuries or death.

Nurse Assist said it is investigating the link between the syringes and the infections with the FDA, the US Centers for Disease Control, and various state health departments.

Until the investigation can be completed, all healthcare facilities with affected product should discontinue use and return the product to the supplier.

The normal saline flush is a plastic syringe filled with 0.9% sodium chloride (a 12 mL IV flush syringe with a 3 mL, 5 mL, or 10 mL fill volume). It is used to clear out medical devices that deliver medicine directly into the veins of a patient through a needle or catheter.

All unexpired lots of this product are covered by the recall. Product Numbers 1203, 1205, and 1210 are packaged 30 syringes to an inner carton and 6 inner cartons in a case (180 syringes).

For product number 1210-BP, 100 syringes are packaged in an inner carton with 4 inner cartons in a case (400 syringes). Lot code information can be found on the outer case panel, the back panel of the inner carton, and on each syringe label.

The lots being recalled were distributed to customers and distributors between February 16, 2016, and September 30, 2016. Product can be identified by the labeling on the packaging and device.

Customers with questions can contact Nurse Assist Inc. at 1-800-649-6800 ext. 10, Monday through Friday, between the hours of 8 am and 5 pm, Central Time, or via email at [email protected].

Healthcare professionals and consumers can report adverse reactions or quality problems they experienced using these devices to MedWatch: The FDA Safety Information and Adverse Event Reporting Program.

Cynomolgus macaque
Photo by Sakurai Midori

Researchers say they have developed an antiplatelet agent that has demonstrated considerable

antithrombotic activity and low bleeding liability in monkeys.

The agent, known as BMS-986120, is a PAR4 antagonist.

Experiments in cynomolgus monkeys indicated that BMS-986120 can effectively fight thrombosis but poses a lower risk of bleeding than clopidogrel.

The researchers described these experiments in Science Translational Medicine.

The research was supported by Bristol-Myers Squibb but also benefited from funding from the “Fonds pour un Québec Innovant et en Santé” from the Ministry of Economy, Science and Innovation of Québec.

To investigate the effects of PAR4 inhibition, the researchers developed PAR4-targeted antibodies and tested them in guinea pigs. The antibodies exhibited antithrombotic activity in the animals, while posing a low risk of bleeding.

Because of these positive results, the researchers performed a high-throughput screen of more than 1 million molecules to find a PAR4 inhibitor. They identified BMS-986120 as a “highly potent, selective, and reversible” inhibitor of PAR4 in human platelets.

The researchers wanted to test BMS-986120 in cynomolgus monkey models of occlusive arterial thrombosis and provoked bleeding time (BT). But the team first had to validate the translatability of the models (for clinical prediction of efficacy and bleeding liability) by studying clopidogrel in the animals.

When compared to vehicle control, clopidogrel slowed vascular occlusion and reduced thrombus weight in the monkeys in a dose-dependent manner. But clopidogrel also had “strong effects” on hemostasis.

When the researchers tested BMS-986120 (vs vehicle control) in these models, they observed a wider therapeutic window with BMS-986120 than with clopidogrel.

The researchers said BMS-986120 was “highly effective” in preserving vascular patency during the induction of occlusive thrombosis. When given at 1 mg/kg, BMS-986120 prevented vascular occlusion in all monkeys.

BMS-986120 also decreased thrombus weight in a dose-dependent manner. When given at 1 mg/kg, BMS-986120 reduced thrombus formation by 82%.

BMS-986120 had a limited, though still statistically significant, impact on hemostasis. BMS-986120 at 1 mg/kg significantly increased kidney and mesenteric BT when compared to vehicle control (P<0.0001 for both).

The researchers plotted the relative antithrombotic (thrombus weight reduction) and BT effects of clopidogrel and BMS-986120 as a function of the dose of each drug.

They found that, at doses resulting in about 50% to 80% antithrombotic activity, clopidogrel produced about 8- to 9-fold increases in kidney and mesenteric BT. BMS-986120, on the other hand, produced increases of about 2-fold or less in kidney and mesenteric BT.

The researchers said these preclinical findings suggest that targeting PAR4 is an attractive antiplatelet strategy, and BMS-986120 has potential as an antiplatelet agent. The drug is currently being evaluated in clinical trials.

Cynomolgus macaque
Photo by Sakurai Midori

Researchers say they have developed an antiplatelet agent that has demonstrated considerable

antithrombotic activity and low bleeding liability in monkeys.

The agent, known as BMS-986120, is a PAR4 antagonist.

Experiments in cynomolgus monkeys indicated that BMS-986120 can effectively fight thrombosis but poses a lower risk of bleeding than clopidogrel.

The researchers described these experiments in Science Translational Medicine.

The research was supported by Bristol-Myers Squibb but also benefited from funding from the “Fonds pour un Québec Innovant et en Santé” from the Ministry of Economy, Science and Innovation of Québec.

To investigate the effects of PAR4 inhibition, the researchers developed PAR4-targeted antibodies and tested them in guinea pigs. The antibodies exhibited antithrombotic activity in the animals, while posing a low risk of bleeding.

Because of these positive results, the researchers performed a high-throughput screen of more than 1 million molecules to find a PAR4 inhibitor. They identified BMS-986120 as a “highly potent, selective, and reversible” inhibitor of PAR4 in human platelets.

The researchers wanted to test BMS-986120 in cynomolgus monkey models of occlusive arterial thrombosis and provoked bleeding time (BT). But the team first had to validate the translatability of the models (for clinical prediction of efficacy and bleeding liability) by studying clopidogrel in the animals.

When compared to vehicle control, clopidogrel slowed vascular occlusion and reduced thrombus weight in the monkeys in a dose-dependent manner. But clopidogrel also had “strong effects” on hemostasis.

When the researchers tested BMS-986120 (vs vehicle control) in these models, they observed a wider therapeutic window with BMS-986120 than with clopidogrel.

The researchers said BMS-986120 was “highly effective” in preserving vascular patency during the induction of occlusive thrombosis. When given at 1 mg/kg, BMS-986120 prevented vascular occlusion in all monkeys.

BMS-986120 also decreased thrombus weight in a dose-dependent manner. When given at 1 mg/kg, BMS-986120 reduced thrombus formation by 82%.

BMS-986120 had a limited, though still statistically significant, impact on hemostasis. BMS-986120 at 1 mg/kg significantly increased kidney and mesenteric BT when compared to vehicle control (P<0.0001 for both).

The researchers plotted the relative antithrombotic (thrombus weight reduction) and BT effects of clopidogrel and BMS-986120 as a function of the dose of each drug.

They found that, at doses resulting in about 50% to 80% antithrombotic activity, clopidogrel produced about 8- to 9-fold increases in kidney and mesenteric BT. BMS-986120, on the other hand, produced increases of about 2-fold or less in kidney and mesenteric BT.

The researchers said these preclinical findings suggest that targeting PAR4 is an attractive antiplatelet strategy, and BMS-986120 has potential as an antiplatelet agent. The drug is currently being evaluated in clinical trials.

Cynomolgus macaque
Photo by Sakurai Midori

Researchers say they have developed an antiplatelet agent that has demonstrated considerable

antithrombotic activity and low bleeding liability in monkeys.

The agent, known as BMS-986120, is a PAR4 antagonist.

Experiments in cynomolgus monkeys indicated that BMS-986120 can effectively fight thrombosis but poses a lower risk of bleeding than clopidogrel.

The researchers described these experiments in Science Translational Medicine.

The research was supported by Bristol-Myers Squibb but also benefited from funding from the “Fonds pour un Québec Innovant et en Santé” from the Ministry of Economy, Science and Innovation of Québec.

To investigate the effects of PAR4 inhibition, the researchers developed PAR4-targeted antibodies and tested them in guinea pigs. The antibodies exhibited antithrombotic activity in the animals, while posing a low risk of bleeding.

Because of these positive results, the researchers performed a high-throughput screen of more than 1 million molecules to find a PAR4 inhibitor. They identified BMS-986120 as a “highly potent, selective, and reversible” inhibitor of PAR4 in human platelets.

The researchers wanted to test BMS-986120 in cynomolgus monkey models of occlusive arterial thrombosis and provoked bleeding time (BT). But the team first had to validate the translatability of the models (for clinical prediction of efficacy and bleeding liability) by studying clopidogrel in the animals.

When compared to vehicle control, clopidogrel slowed vascular occlusion and reduced thrombus weight in the monkeys in a dose-dependent manner. But clopidogrel also had “strong effects” on hemostasis.

When the researchers tested BMS-986120 (vs vehicle control) in these models, they observed a wider therapeutic window with BMS-986120 than with clopidogrel.

The researchers said BMS-986120 was “highly effective” in preserving vascular patency during the induction of occlusive thrombosis. When given at 1 mg/kg, BMS-986120 prevented vascular occlusion in all monkeys.

BMS-986120 also decreased thrombus weight in a dose-dependent manner. When given at 1 mg/kg, BMS-986120 reduced thrombus formation by 82%.

BMS-986120 had a limited, though still statistically significant, impact on hemostasis. BMS-986120 at 1 mg/kg significantly increased kidney and mesenteric BT when compared to vehicle control (P<0.0001 for both).

The researchers plotted the relative antithrombotic (thrombus weight reduction) and BT effects of clopidogrel and BMS-986120 as a function of the dose of each drug.

They found that, at doses resulting in about 50% to 80% antithrombotic activity, clopidogrel produced about 8- to 9-fold increases in kidney and mesenteric BT. BMS-986120, on the other hand, produced increases of about 2-fold or less in kidney and mesenteric BT.

The researchers said these preclinical findings suggest that targeting PAR4 is an attractive antiplatelet strategy, and BMS-986120 has potential as an antiplatelet agent. The drug is currently being evaluated in clinical trials.

Plasmodium sporozoite
Image from Margaret Shear
and Ute Frevert

A next-generation malaria vaccine that uses genetically attenuated parasites (GAPs) has demonstrated promise in a phase 1 trial and in experiments with mice, according to researchers.

The team generated a genetically attenuated Plasmodium falciparum parasite by knocking out 3 genes that are required for the parasite to cause malaria in humans.

Healthy volunteers infected with this parasite, Pf GAP3KO, exhibited strong antibody responses, according to researchers, and experienced only mild or moderate adverse events (AEs).

When antibodies from these patients were transferred to humanized mice, they inhibited malaria infection in the liver.

The researchers described this work in Science Translational Medicine.

“This most recent publication builds on our previous work,” said study author Sebastian Mikolajczak, PhD, of the Center for Infectious Disease Research in Seattle, Washington.

“We had already good indicators in preclinical studies that this new ‘triple knock-out’ GAP (GAP3KO), which has 3 genes removed, is completely attenuated. The clinical study now shows that the GAP3KO vaccine is completely attenuated in humans and also shows that, even after only a single administration, it elicits a robust immune response against the malaria parasite. Together, these findings are critical milestones for malaria vaccine development.”

Dr Mikolajczak and his colleagues created GAP3KO by knocking out 3 genes in P falciparum that are required for the parasite to successfully infect and cause disease in humans—Pf p52⁻/p36⁻/sap1⁻. 

The researchers then tested Pf GAP3KO sporozoites in 10 healthy human volunteers. The sporozoites were delivered via bites from infected mosquitoes.

All subjects experienced grade 1 AEs, and 70% had grade 2 AEs. There were no grade 3 or higher AEs.

Grade 2 AEs included 1 case of fatigue and several cases of administration-site reactions, including erythema (n=6), pruritus (n=2), and swelling (n=3).

All 10 volunteers completed the 28-day study period without exhibiting any symptoms of malaria. They also remained negative for blood-stage parasitemia throughout the study period.

All subjects experienced antibody responses as well. The researchers collected sera from the volunteers on day 0, 7, 13, and 28 after immunization and analyzed it for anti-circumsporozoite protein (CSP) antibody responses.

The team measured anti-CSP immunoglobulin G (IgG) by enzyme-linked immunosorbent assay (ELISA) using full-length recombinant PfCSP protein.

At day 0, volunteers’ sera showed an average of 1436 ± 257.3 arbitrary units (AU) of anti-CSP titers by ELISA. However, 3 volunteers were slightly above the 2000 AU cutoff for positivity.

At day 7, 8 of the 10 volunteers were positive for anti-CSP IgG, with an average titer of 3821 ± 808.1 AU. At day 13, all volunteers were positive, with an average of 11,547 ± 2084 AU. Positivity was maintained through day 28, with an average of 5774± 840 AU.

To determine whether these antibodies could inhibit Pf sporozoite invasion in vivo, the researchers transferred them to FRG huHep liver chimeric humanized mice, which allow for complete development of liver-stage parasites.

The researchers chose 5 volunteers whose immune serum showed high levels of invasion inhibition in vitro and varying CSP IgG titers. The mice received purified IgG from these volunteers from day 0 and day 13 immune samples (5 mice per volunteer per time point).

The mice were then challenged with bites from mosquitoes infected with sporozoites of a green fluorescent protein–luciferase–expressing P falciparum strain.

The researchers calculated inhibition of infection by comparing the liver-stage burden of mice receiving day 13 IgG samples to the mean value of liver-stage burden in mice receiving day 0 IgG samples.

The day 13 IgG samples inhibited liver infection by an average of 23.18 ± 57%, 32.23 ± 29.16%, 69.38 ± 18.64%, 76.63 ± 19.98%, and 87.99 ± 15.56% (per volunteer).

The 3 volunteers whose serum exhibited the highest inhibition had the lowest Pf CSP titers of the 5 samples.

The researchers said these promising results in mice and humans pave the way to a phase 1b trial of the GAP3KO vaccine candidate using controlled human malaria infection.

Plasmodium sporozoite
Image from Margaret Shear
and Ute Frevert

A next-generation malaria vaccine that uses genetically attenuated parasites (GAPs) has demonstrated promise in a phase 1 trial and in experiments with mice, according to researchers.

The team generated a genetically attenuated Plasmodium falciparum parasite by knocking out 3 genes that are required for the parasite to cause malaria in humans.

Healthy volunteers infected with this parasite, Pf GAP3KO, exhibited strong antibody responses, according to researchers, and experienced only mild or moderate adverse events (AEs).

When antibodies from these patients were transferred to humanized mice, they inhibited malaria infection in the liver.

The researchers described this work in Science Translational Medicine.

“This most recent publication builds on our previous work,” said study author Sebastian Mikolajczak, PhD, of the Center for Infectious Disease Research in Seattle, Washington.

“We had already good indicators in preclinical studies that this new ‘triple knock-out’ GAP (GAP3KO), which has 3 genes removed, is completely attenuated. The clinical study now shows that the GAP3KO vaccine is completely attenuated in humans and also shows that, even after only a single administration, it elicits a robust immune response against the malaria parasite. Together, these findings are critical milestones for malaria vaccine development.”

Dr Mikolajczak and his colleagues created GAP3KO by knocking out 3 genes in P falciparum that are required for the parasite to successfully infect and cause disease in humans—Pf p52⁻/p36⁻/sap1⁻. 

The researchers then tested Pf GAP3KO sporozoites in 10 healthy human volunteers. The sporozoites were delivered via bites from infected mosquitoes.

All subjects experienced grade 1 AEs, and 70% had grade 2 AEs. There were no grade 3 or higher AEs.

Grade 2 AEs included 1 case of fatigue and several cases of administration-site reactions, including erythema (n=6), pruritus (n=2), and swelling (n=3).

All 10 volunteers completed the 28-day study period without exhibiting any symptoms of malaria. They also remained negative for blood-stage parasitemia throughout the study period.

All subjects experienced antibody responses as well. The researchers collected sera from the volunteers on day 0, 7, 13, and 28 after immunization and analyzed it for anti-circumsporozoite protein (CSP) antibody responses.

The team measured anti-CSP immunoglobulin G (IgG) by enzyme-linked immunosorbent assay (ELISA) using full-length recombinant PfCSP protein.

At day 0, volunteers’ sera showed an average of 1436 ± 257.3 arbitrary units (AU) of anti-CSP titers by ELISA. However, 3 volunteers were slightly above the 2000 AU cutoff for positivity.

At day 7, 8 of the 10 volunteers were positive for anti-CSP IgG, with an average titer of 3821 ± 808.1 AU. At day 13, all volunteers were positive, with an average of 11,547 ± 2084 AU. Positivity was maintained through day 28, with an average of 5774± 840 AU.

To determine whether these antibodies could inhibit Pf sporozoite invasion in vivo, the researchers transferred them to FRG huHep liver chimeric humanized mice, which allow for complete development of liver-stage parasites.

The researchers chose 5 volunteers whose immune serum showed high levels of invasion inhibition in vitro and varying CSP IgG titers. The mice received purified IgG from these volunteers from day 0 and day 13 immune samples (5 mice per volunteer per time point).

The mice were then challenged with bites from mosquitoes infected with sporozoites of a green fluorescent protein–luciferase–expressing P falciparum strain.

The researchers calculated inhibition of infection by comparing the liver-stage burden of mice receiving day 13 IgG samples to the mean value of liver-stage burden in mice receiving day 0 IgG samples.

The day 13 IgG samples inhibited liver infection by an average of 23.18 ± 57%, 32.23 ± 29.16%, 69.38 ± 18.64%, 76.63 ± 19.98%, and 87.99 ± 15.56% (per volunteer).

The 3 volunteers whose serum exhibited the highest inhibition had the lowest Pf CSP titers of the 5 samples.

The researchers said these promising results in mice and humans pave the way to a phase 1b trial of the GAP3KO vaccine candidate using controlled human malaria infection.

Plasmodium sporozoite
Image from Margaret Shear
and Ute Frevert

A next-generation malaria vaccine that uses genetically attenuated parasites (GAPs) has demonstrated promise in a phase 1 trial and in experiments with mice, according to researchers.

The team generated a genetically attenuated Plasmodium falciparum parasite by knocking out 3 genes that are required for the parasite to cause malaria in humans.

Healthy volunteers infected with this parasite, Pf GAP3KO, exhibited strong antibody responses, according to researchers, and experienced only mild or moderate adverse events (AEs).

When antibodies from these patients were transferred to humanized mice, they inhibited malaria infection in the liver.

The researchers described this work in Science Translational Medicine.

“This most recent publication builds on our previous work,” said study author Sebastian Mikolajczak, PhD, of the Center for Infectious Disease Research in Seattle, Washington.

“We had already good indicators in preclinical studies that this new ‘triple knock-out’ GAP (GAP3KO), which has 3 genes removed, is completely attenuated. The clinical study now shows that the GAP3KO vaccine is completely attenuated in humans and also shows that, even after only a single administration, it elicits a robust immune response against the malaria parasite. Together, these findings are critical milestones for malaria vaccine development.”

Dr Mikolajczak and his colleagues created GAP3KO by knocking out 3 genes in P falciparum that are required for the parasite to successfully infect and cause disease in humans—Pf p52⁻/p36⁻/sap1⁻. 

The researchers then tested Pf GAP3KO sporozoites in 10 healthy human volunteers. The sporozoites were delivered via bites from infected mosquitoes.

All subjects experienced grade 1 AEs, and 70% had grade 2 AEs. There were no grade 3 or higher AEs.

Grade 2 AEs included 1 case of fatigue and several cases of administration-site reactions, including erythema (n=6), pruritus (n=2), and swelling (n=3).

All 10 volunteers completed the 28-day study period without exhibiting any symptoms of malaria. They also remained negative for blood-stage parasitemia throughout the study period.

All subjects experienced antibody responses as well. The researchers collected sera from the volunteers on day 0, 7, 13, and 28 after immunization and analyzed it for anti-circumsporozoite protein (CSP) antibody responses.

The team measured anti-CSP immunoglobulin G (IgG) by enzyme-linked immunosorbent assay (ELISA) using full-length recombinant PfCSP protein.

At day 0, volunteers’ sera showed an average of 1436 ± 257.3 arbitrary units (AU) of anti-CSP titers by ELISA. However, 3 volunteers were slightly above the 2000 AU cutoff for positivity.

At day 7, 8 of the 10 volunteers were positive for anti-CSP IgG, with an average titer of 3821 ± 808.1 AU. At day 13, all volunteers were positive, with an average of 11,547 ± 2084 AU. Positivity was maintained through day 28, with an average of 5774± 840 AU.

To determine whether these antibodies could inhibit Pf sporozoite invasion in vivo, the researchers transferred them to FRG huHep liver chimeric humanized mice, which allow for complete development of liver-stage parasites.

The researchers chose 5 volunteers whose immune serum showed high levels of invasion inhibition in vitro and varying CSP IgG titers. The mice received purified IgG from these volunteers from day 0 and day 13 immune samples (5 mice per volunteer per time point).

The mice were then challenged with bites from mosquitoes infected with sporozoites of a green fluorescent protein–luciferase–expressing P falciparum strain.

The researchers calculated inhibition of infection by comparing the liver-stage burden of mice receiving day 13 IgG samples to the mean value of liver-stage burden in mice receiving day 0 IgG samples.

The day 13 IgG samples inhibited liver infection by an average of 23.18 ± 57%, 32.23 ± 29.16%, 69.38 ± 18.64%, 76.63 ± 19.98%, and 87.99 ± 15.56% (per volunteer).

The 3 volunteers whose serum exhibited the highest inhibition had the lowest Pf CSP titers of the 5 samples.

The researchers said these promising results in mice and humans pave the way to a phase 1b trial of the GAP3KO vaccine candidate using controlled human malaria infection.

An “innovative collaboration” will bring best practices of the American College of Emergency Physicians (ACEP) to 26 emergency departments (EDs) in rural and remote Native communities. The IHS and ACEP are building on “the aggressive strategy at IHS to improve quality health care,” said IHS Principal Deputy Director Mary Smith.

Related: Dangerous Staff Shortages in the IHS

Top-level physicians and emergency medical professionals will share training resources and knowledge of telehealth and emergency care. At a work session in Winnebago, Nevada, participants covered topics, including ED leadership; responsibility, accountability, workflow, and workforce issues in rural facilities; how emergency telemedicine can help meet rural health care needs; and identifying areas for leveraging resources.

The new partnership’s plans dovetail with the Quality Framework, announced in November, which “provides a road map for quality at every level of IHS,” Smith said. The Quality Framework is the brainchild of experts from IHS, tribal partners, and HHS. Specific objectives include promoting a culture of patient safety in which all staff feel comfortable reporting medical errors, instituting processes to support learning from experiences, and reducing patient wait times for appointments.

Related: Pharmacists in the Emergency Department: Feasibility and Cost

The Quality Framework is but one product of a year in which IHS has been collaborating with tribal leaders and local health partners on a series of actions “to aggressively confront some long-standing health care service challenges.” Other actions include awarding a contract to the Joint Commission for accreditation services, technical assistance and training, and a contract with Avera Health to expand telehealth and emergency services in the Great Plains.

An “innovative collaboration” will bring best practices of the American College of Emergency Physicians (ACEP) to 26 emergency departments (EDs) in rural and remote Native communities. The IHS and ACEP are building on “the aggressive strategy at IHS to improve quality health care,” said IHS Principal Deputy Director Mary Smith.

Related: Dangerous Staff Shortages in the IHS

Top-level physicians and emergency medical professionals will share training resources and knowledge of telehealth and emergency care. At a work session in Winnebago, Nevada, participants covered topics, including ED leadership; responsibility, accountability, workflow, and workforce issues in rural facilities; how emergency telemedicine can help meet rural health care needs; and identifying areas for leveraging resources.

The new partnership’s plans dovetail with the Quality Framework, announced in November, which “provides a road map for quality at every level of IHS,” Smith said. The Quality Framework is the brainchild of experts from IHS, tribal partners, and HHS. Specific objectives include promoting a culture of patient safety in which all staff feel comfortable reporting medical errors, instituting processes to support learning from experiences, and reducing patient wait times for appointments.

Related: Pharmacists in the Emergency Department: Feasibility and Cost

The Quality Framework is but one product of a year in which IHS has been collaborating with tribal leaders and local health partners on a series of actions “to aggressively confront some long-standing health care service challenges.” Other actions include awarding a contract to the Joint Commission for accreditation services, technical assistance and training, and a contract with Avera Health to expand telehealth and emergency services in the Great Plains.

An “innovative collaboration” will bring best practices of the American College of Emergency Physicians (ACEP) to 26 emergency departments (EDs) in rural and remote Native communities. The IHS and ACEP are building on “the aggressive strategy at IHS to improve quality health care,” said IHS Principal Deputy Director Mary Smith.

Related: Dangerous Staff Shortages in the IHS

Top-level physicians and emergency medical professionals will share training resources and knowledge of telehealth and emergency care. At a work session in Winnebago, Nevada, participants covered topics, including ED leadership; responsibility, accountability, workflow, and workforce issues in rural facilities; how emergency telemedicine can help meet rural health care needs; and identifying areas for leveraging resources.

The new partnership’s plans dovetail with the Quality Framework, announced in November, which “provides a road map for quality at every level of IHS,” Smith said. The Quality Framework is the brainchild of experts from IHS, tribal partners, and HHS. Specific objectives include promoting a culture of patient safety in which all staff feel comfortable reporting medical errors, instituting processes to support learning from experiences, and reducing patient wait times for appointments.

Related: Pharmacists in the Emergency Department: Feasibility and Cost

The Quality Framework is but one product of a year in which IHS has been collaborating with tribal leaders and local health partners on a series of actions “to aggressively confront some long-standing health care service challenges.” Other actions include awarding a contract to the Joint Commission for accreditation services, technical assistance and training, and a contract with Avera Health to expand telehealth and emergency services in the Great Plains.

The FP considered the diagnoses of vitiligo and tinea versicolor. He performed a potassium hydroxide (KOH) preparation and saw the “spaghetti and meatballs” pattern of Malassezia furfur. (See a video on how to perform a KOH preparation.) The “spaghetti” or “ziti” is the short mycelial form of M furfur and the “meatballs” are the round yeast form (Pityrosporum).

This was definitive proof that the patient had tinea versicolor caused by M furfur, a lipophilic yeast that can be found on healthy skin. Tinea versicolor starts when the yeast that normally colonizes the skin changes from the round form to the pathologic mycelial form and then invades the stratum corneum. M furfur thrives on sebum and moisture and tends to grow on the skin in areas where there are sebaceous follicles secreting sebum. Patients with tinea versicolor present with skin discolorations that are white, pink, or brown.

The patient in this case chose a single oral dose of 400 mg fluconazole to be repeated one week later. The condition cleared and the patient's skin color returned to normal in the following months.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Tinea versicolor. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:566-569.

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 considered the diagnoses of vitiligo and tinea versicolor. He performed a potassium hydroxide (KOH) preparation and saw the “spaghetti and meatballs” pattern of Malassezia furfur. (See a video on how to perform a KOH preparation.) The “spaghetti” or “ziti” is the short mycelial form of M furfur and the “meatballs” are the round yeast form (Pityrosporum).

This was definitive proof that the patient had tinea versicolor caused by M furfur, a lipophilic yeast that can be found on healthy skin. Tinea versicolor starts when the yeast that normally colonizes the skin changes from the round form to the pathologic mycelial form and then invades the stratum corneum. M furfur thrives on sebum and moisture and tends to grow on the skin in areas where there are sebaceous follicles secreting sebum. Patients with tinea versicolor present with skin discolorations that are white, pink, or brown.

The patient in this case chose a single oral dose of 400 mg fluconazole to be repeated one week later. The condition cleared and the patient's skin color returned to normal in the following months.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Tinea versicolor. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:566-569.

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 considered the diagnoses of vitiligo and tinea versicolor. He performed a potassium hydroxide (KOH) preparation and saw the “spaghetti and meatballs” pattern of Malassezia furfur. (See a video on how to perform a KOH preparation.) The “spaghetti” or “ziti” is the short mycelial form of M furfur and the “meatballs” are the round yeast form (Pityrosporum).

This was definitive proof that the patient had tinea versicolor caused by M furfur, a lipophilic yeast that can be found on healthy skin. Tinea versicolor starts when the yeast that normally colonizes the skin changes from the round form to the pathologic mycelial form and then invades the stratum corneum. M furfur thrives on sebum and moisture and tends to grow on the skin in areas where there are sebaceous follicles secreting sebum. Patients with tinea versicolor present with skin discolorations that are white, pink, or brown.

The patient in this case chose a single oral dose of 400 mg fluconazole to be repeated one week later. The condition cleared and the patient's skin color returned to normal in the following months.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Tinea versicolor. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:566-569.

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