The FP diagnosed this patient with palmar warts, which are similar in morphology to plantar warts. Plantar (or palmar) warts are lesions caused by human papillomavirus (HPV) that occur on the soles of the feet and palms of the hands. Plantar warts occur mostly in adolescents and young adults and affect up to 10% of people in these age groups.

Plantar warts usually occur at points of maximum pressure, such as on the heels or over the heads of the metatarsal bones, but may appear anywhere on the plantar surface, including the tips of the toes. A cluster of multiple warts that appear to fuse together is referred to as a mosaic wart. HIV is a risk factor for any type of HPV infection.

Distinguish warts from calluses by noting the skin lines; warts lack skin lines crossing their surface, whereas normal skin lines cross through a callus without any disturbance. Additionally, plantar/palmar warts may have a highly organized mosaic pattern on the surface when examined with a hand lens and have prominent black dots (thrombosed capillaries).

The most common treatments for warts include topical salicylic acid and cryotherapy. Topical salicylic acid preparations are nonscarring, minimally painful, and relatively effective, but require persistent application of medication once a day for weeks to months. Cryotherapy with liquid nitrogen therapy is commonly used, but plantar warts are more resistant than other HPV lesions. The liquid nitrogen is applied to form a freeze ball that covers the lesion and 2 mm of surrounding normal tissue for usually 10 to 20 seconds per treatment. This can be performed as a single long freeze or divided into 2 freezing episodes with thawing in between. This allows for more freeze time in a way that is less painful to the patient.

In this case, the patient chose cryotherapy and arranged for a follow-up appointment in 3 to 4 weeks for a second round.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Mayeaux EJ. Plantar warts. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:766-770.

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 this patient with palmar warts, which are similar in morphology to plantar warts. Plantar (or palmar) warts are lesions caused by human papillomavirus (HPV) that occur on the soles of the feet and palms of the hands. Plantar warts occur mostly in adolescents and young adults and affect up to 10% of people in these age groups.

Plantar warts usually occur at points of maximum pressure, such as on the heels or over the heads of the metatarsal bones, but may appear anywhere on the plantar surface, including the tips of the toes. A cluster of multiple warts that appear to fuse together is referred to as a mosaic wart. HIV is a risk factor for any type of HPV infection.

Distinguish warts from calluses by noting the skin lines; warts lack skin lines crossing their surface, whereas normal skin lines cross through a callus without any disturbance. Additionally, plantar/palmar warts may have a highly organized mosaic pattern on the surface when examined with a hand lens and have prominent black dots (thrombosed capillaries).

The most common treatments for warts include topical salicylic acid and cryotherapy. Topical salicylic acid preparations are nonscarring, minimally painful, and relatively effective, but require persistent application of medication once a day for weeks to months. Cryotherapy with liquid nitrogen therapy is commonly used, but plantar warts are more resistant than other HPV lesions. The liquid nitrogen is applied to form a freeze ball that covers the lesion and 2 mm of surrounding normal tissue for usually 10 to 20 seconds per treatment. This can be performed as a single long freeze or divided into 2 freezing episodes with thawing in between. This allows for more freeze time in a way that is less painful to the patient.

In this case, the patient chose cryotherapy and arranged for a follow-up appointment in 3 to 4 weeks for a second round.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Mayeaux EJ. Plantar warts. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:766-770.

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 this patient with palmar warts, which are similar in morphology to plantar warts. Plantar (or palmar) warts are lesions caused by human papillomavirus (HPV) that occur on the soles of the feet and palms of the hands. Plantar warts occur mostly in adolescents and young adults and affect up to 10% of people in these age groups.

Plantar warts usually occur at points of maximum pressure, such as on the heels or over the heads of the metatarsal bones, but may appear anywhere on the plantar surface, including the tips of the toes. A cluster of multiple warts that appear to fuse together is referred to as a mosaic wart. HIV is a risk factor for any type of HPV infection.

Distinguish warts from calluses by noting the skin lines; warts lack skin lines crossing their surface, whereas normal skin lines cross through a callus without any disturbance. Additionally, plantar/palmar warts may have a highly organized mosaic pattern on the surface when examined with a hand lens and have prominent black dots (thrombosed capillaries).

The most common treatments for warts include topical salicylic acid and cryotherapy. Topical salicylic acid preparations are nonscarring, minimally painful, and relatively effective, but require persistent application of medication once a day for weeks to months. Cryotherapy with liquid nitrogen therapy is commonly used, but plantar warts are more resistant than other HPV lesions. The liquid nitrogen is applied to form a freeze ball that covers the lesion and 2 mm of surrounding normal tissue for usually 10 to 20 seconds per treatment. This can be performed as a single long freeze or divided into 2 freezing episodes with thawing in between. This allows for more freeze time in a way that is less painful to the patient.

In this case, the patient chose cryotherapy and arranged for a follow-up appointment in 3 to 4 weeks for a second round.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Mayeaux EJ. Plantar warts. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:766-770.

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

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

[email protected]

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

[email protected]

Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.

The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.

©Kativ/iStockphoto

Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.

Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.

They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.

The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.

The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).

These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.

This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.

[email protected]

Seven-Module Anticoagulation Series

This comprehensive series of recorded webinars reviews best practices for inpatient anticoagulation, including the evidence-based management of atrial fibrillation, venous thromboembolism, perioperative anticoagulation, and anticoagulant-related bleeding. Features include:

• Seven 60-minute webinar-based sessions accessible on-demand
• Brief introductory materials accompanying each webinar as well as a post-test
• Links to additional resources with each webinar
• 6.5 CME credits for all seven sessions

This module is free for SHM members and non-members.

Acute Coronary Syndrome Performance Improvement CME Activity

Improve quality improvement strategies around acute coronary syndrome (ACS) while earning CME. This tool is a free, self-directed, web-based, yearlong activity designed to help you evaluate your practice. Upon completion of the activity you will receive 20 CME credits. The activity features three stages, including completing a performance assessment measurement through a self-evaluation, building an action plan for personal improvement, and using a performance analysis tool to compare performance from the previous stages.

The deadline to participate is fall 2016. This module is free for SHM members and non-members.

Adolescent and Young Adult Inpatient Care: Not a Kid Anymore

This online case-based module allows participants to:

• Identify appropriate interview techniques with the adolescent inpatient
• Recognize the components in a complete psychosocial interview with an adolescent inpatient
• Define the necessary elements of a pelvic examination in an adolescent female inpatient
• Select the appropriate diagnosis, treatment, and partner notification for STI in the inpatient setting
• Earn 10 self-evaluation points when enrolled in the American Board of Pediatrics’ MOC program and 3.0 AMA PRA Category 1 Credits upon completion of the activity

This module is free for SHM members and $50 for non-members.

Updated Hospital Quality and Patient Safety MOC Self-Assessment (Adult and Pediatrics)

• Quality improvement and patient safety principles such as QI theory, system processes, measurement tools for implementation and error types, disclosure, and prevention strategies
• 26 multiple-choice questions with accompanying answers, rationales, and references
• 8 self-evaluation points for diplomates enrolled in ABIM’s MOC program as well as 2.0 AMA PRA Category 1 Credits

SHM members receive a special price of $65; the non-member price is $100.

Seven-Module Anticoagulation Series

This comprehensive series of recorded webinars reviews best practices for inpatient anticoagulation, including the evidence-based management of atrial fibrillation, venous thromboembolism, perioperative anticoagulation, and anticoagulant-related bleeding. Features include:

• Seven 60-minute webinar-based sessions accessible on-demand
• Brief introductory materials accompanying each webinar as well as a post-test
• Links to additional resources with each webinar
• 6.5 CME credits for all seven sessions

This module is free for SHM members and non-members.

Acute Coronary Syndrome Performance Improvement CME Activity

Improve quality improvement strategies around acute coronary syndrome (ACS) while earning CME. This tool is a free, self-directed, web-based, yearlong activity designed to help you evaluate your practice. Upon completion of the activity you will receive 20 CME credits. The activity features three stages, including completing a performance assessment measurement through a self-evaluation, building an action plan for personal improvement, and using a performance analysis tool to compare performance from the previous stages.

The deadline to participate is fall 2016. This module is free for SHM members and non-members.

Adolescent and Young Adult Inpatient Care: Not a Kid Anymore

This online case-based module allows participants to:

• Identify appropriate interview techniques with the adolescent inpatient
• Recognize the components in a complete psychosocial interview with an adolescent inpatient
• Define the necessary elements of a pelvic examination in an adolescent female inpatient
• Select the appropriate diagnosis, treatment, and partner notification for STI in the inpatient setting
• Earn 10 self-evaluation points when enrolled in the American Board of Pediatrics’ MOC program and 3.0 AMA PRA Category 1 Credits upon completion of the activity

This module is free for SHM members and $50 for non-members.

Updated Hospital Quality and Patient Safety MOC Self-Assessment (Adult and Pediatrics)

• Quality improvement and patient safety principles such as QI theory, system processes, measurement tools for implementation and error types, disclosure, and prevention strategies
• 26 multiple-choice questions with accompanying answers, rationales, and references
• 8 self-evaluation points for diplomates enrolled in ABIM’s MOC program as well as 2.0 AMA PRA Category 1 Credits

SHM members receive a special price of $65; the non-member price is $100.

Seven-Module Anticoagulation Series

This comprehensive series of recorded webinars reviews best practices for inpatient anticoagulation, including the evidence-based management of atrial fibrillation, venous thromboembolism, perioperative anticoagulation, and anticoagulant-related bleeding. Features include:

• Seven 60-minute webinar-based sessions accessible on-demand
• Brief introductory materials accompanying each webinar as well as a post-test
• Links to additional resources with each webinar
• 6.5 CME credits for all seven sessions

This module is free for SHM members and non-members.

Acute Coronary Syndrome Performance Improvement CME Activity

Improve quality improvement strategies around acute coronary syndrome (ACS) while earning CME. This tool is a free, self-directed, web-based, yearlong activity designed to help you evaluate your practice. Upon completion of the activity you will receive 20 CME credits. The activity features three stages, including completing a performance assessment measurement through a self-evaluation, building an action plan for personal improvement, and using a performance analysis tool to compare performance from the previous stages.

The deadline to participate is fall 2016. This module is free for SHM members and non-members.

Adolescent and Young Adult Inpatient Care: Not a Kid Anymore

This online case-based module allows participants to:

• Identify appropriate interview techniques with the adolescent inpatient
• Recognize the components in a complete psychosocial interview with an adolescent inpatient
• Define the necessary elements of a pelvic examination in an adolescent female inpatient
• Select the appropriate diagnosis, treatment, and partner notification for STI in the inpatient setting
• Earn 10 self-evaluation points when enrolled in the American Board of Pediatrics’ MOC program and 3.0 AMA PRA Category 1 Credits upon completion of the activity

This module is free for SHM members and $50 for non-members.

Updated Hospital Quality and Patient Safety MOC Self-Assessment (Adult and Pediatrics)

• Quality improvement and patient safety principles such as QI theory, system processes, measurement tools for implementation and error types, disclosure, and prevention strategies
• 26 multiple-choice questions with accompanying answers, rationales, and references
• 8 self-evaluation points for diplomates enrolled in ABIM’s MOC program as well as 2.0 AMA PRA Category 1 Credits

SHM members receive a special price of $65; the non-member price is $100.

Structure of RNA

ORLANDO—Results from an ongoing phase 1 study suggest fitusiran, a small interfering RNA therapeutic targeting antithrombin (AT), can restore hemostasis and prevent bleeding in patients with hemophilia A or B, with or without inhibitors.

In patients with inhibitors, fitusiran exhibited preliminary evidence of reduced bleeding. In patients without inhibitors, fitusiran reduced the median estimated annualized bleeding rate (ABR) to 0.

In addition, researchers said fitusiran was generally well tolerated, and none of the patients developed anti-drug antibodies.

These results were presented at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Alnylam Pharmaceuticals, Inc.

Study design

This phase 1 trial consists of 4 parts. Part A enrolled healthy volunteers who were randomized 3:1 to fitusiran or placebo. This part of the study was completed after the first dose cohort received a single subcutaneous dose of fitusiran at 30 mcg/kg.

Part B, which is also complete, enrolled 12 patients with severe hemophilia A or B. Patients received 3 weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg.

Part C, in which dosing is complete, enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients received 3 monthly subcutaneous doses of fitusiran at 225, 450, 900, or 1800 mcg/kg. Six patients received 3 fixed monthly subcutaneous doses of fitusiran at 80 mg.

Part D is designed to enroll up to 18 patients with inhibitors. The first cohort of 6 patients received a 50 mg, fixed, once-monthly, subcutaneous dose. The second cohort has completed enrollment, with 6 patients receiving an 80 mg, fixed, once-monthly, subcutaneous dose.

Results from Parts C and D were presented at the meeting.

Part C results

Treatment with fitusiran resulted in a dose-dependent, statistically significant decrease in AT and increase in thrombin generation. At the 80 mg monthly dose, fitusiran achieved 87±1% mean maximal AT lowering with low inter-patient variability.

Researchers assessed the association between AT lowering and increased thrombin generation in a post-hoc exploratory analysis in which AT lowering was grouped by 25% increments for completed patients in Parts B (n=12) and C (n=17) of the study.

In the highest quartile of ≥75% AT lowering (n=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290% relative to baseline (P<0.001, as compared to the lowest AT-lowering quartile).

There was a significant, AT-lowering-dependent reduction in bleeding frequency as well.

To obtain a comprehensive assessment of fitusiran’s potential effects on bleeding, researchers performed a post-hoc analysis in evaluable patients from Part C (n=17).

The team compared bleeding events that occurred over the 6-month period prior to study entry, bleeding events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the onset period), and bleeding events that occurred beyond day 29 up to day 112 (the observation period).

Prior to study entry, the estimated median ABR was 28 for patients receiving on-demand factor therapy (n=4) and 2 for patients receiving prophylactic factor therapy (n=13).

The estimated median ABR was 13 among all evaluable patients during the onset period and 0 during the observation period.

In all Part C dose cohorts during the observation period, 53% of patients (9/17) were bleed-free, and 82% of patients reported no spontaneous bleeds.

Part D results

Prior to study entry, all patients in Part D utilized bypass agents, including recombinant factor VIIa and activated prothrombin complex concentrate, to manage their bleeds. They had a pre-study ABR of up to 80.

The first cohort (n=6) of patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81±2% and a mean maximal thrombin generation increase of approximately 368%.

In addition, there was preliminary evidence of reduced bleeding, with a 49% to 100% reduction in estimated ABR during the observation period compared with pre-study values.

Safety results

As of July 11, 2016, fitusiran appears to be generally well tolerated in hemophilia patients, with or without inhibitors (n=31, with 5 patients participating in both Parts B and C).

There have been no serious adverse events related to the drug and no thromboembolic events or laboratory evidence of pathologic clot formation.

One non-inhibitor patient in Part C treated with the 80 mg fixed dose discontinued treatment due to an adverse event that was considered severe and possibly related to the study drug.

This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal), AST (8x upper limit of normal), C-reactive protein, and D-dimer, without an increase in total bilirubin. The event resolved with symptomatic management, including antacids and analgesics.

Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site.

Additional adverse events reported in at least 10% of patients included upper respiratory tract infection (10%) and arthralgia (10%). The majority of these events were mild or moderate in severity.

*Pasi K J et al, A Subcutaneously Administered Investigational RNAi Therapeutic, Fitusiran (ALN- AT3), Targeting Antithrombin for Treatment of Hemophilia: Interim Results in Patients with Hemophilia A or B, WFH 2016 World Congress, July 2016.

Structure of RNA

ORLANDO—Results from an ongoing phase 1 study suggest fitusiran, a small interfering RNA therapeutic targeting antithrombin (AT), can restore hemostasis and prevent bleeding in patients with hemophilia A or B, with or without inhibitors.

In patients with inhibitors, fitusiran exhibited preliminary evidence of reduced bleeding. In patients without inhibitors, fitusiran reduced the median estimated annualized bleeding rate (ABR) to 0.

In addition, researchers said fitusiran was generally well tolerated, and none of the patients developed anti-drug antibodies.

These results were presented at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Alnylam Pharmaceuticals, Inc.

Study design

This phase 1 trial consists of 4 parts. Part A enrolled healthy volunteers who were randomized 3:1 to fitusiran or placebo. This part of the study was completed after the first dose cohort received a single subcutaneous dose of fitusiran at 30 mcg/kg.

Part B, which is also complete, enrolled 12 patients with severe hemophilia A or B. Patients received 3 weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg.

Part C, in which dosing is complete, enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients received 3 monthly subcutaneous doses of fitusiran at 225, 450, 900, or 1800 mcg/kg. Six patients received 3 fixed monthly subcutaneous doses of fitusiran at 80 mg.

Part D is designed to enroll up to 18 patients with inhibitors. The first cohort of 6 patients received a 50 mg, fixed, once-monthly, subcutaneous dose. The second cohort has completed enrollment, with 6 patients receiving an 80 mg, fixed, once-monthly, subcutaneous dose.

Results from Parts C and D were presented at the meeting.

Part C results

Treatment with fitusiran resulted in a dose-dependent, statistically significant decrease in AT and increase in thrombin generation. At the 80 mg monthly dose, fitusiran achieved 87±1% mean maximal AT lowering with low inter-patient variability.

Researchers assessed the association between AT lowering and increased thrombin generation in a post-hoc exploratory analysis in which AT lowering was grouped by 25% increments for completed patients in Parts B (n=12) and C (n=17) of the study.

In the highest quartile of ≥75% AT lowering (n=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290% relative to baseline (P<0.001, as compared to the lowest AT-lowering quartile).

There was a significant, AT-lowering-dependent reduction in bleeding frequency as well.

To obtain a comprehensive assessment of fitusiran’s potential effects on bleeding, researchers performed a post-hoc analysis in evaluable patients from Part C (n=17).

The team compared bleeding events that occurred over the 6-month period prior to study entry, bleeding events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the onset period), and bleeding events that occurred beyond day 29 up to day 112 (the observation period).

Prior to study entry, the estimated median ABR was 28 for patients receiving on-demand factor therapy (n=4) and 2 for patients receiving prophylactic factor therapy (n=13).

The estimated median ABR was 13 among all evaluable patients during the onset period and 0 during the observation period.

In all Part C dose cohorts during the observation period, 53% of patients (9/17) were bleed-free, and 82% of patients reported no spontaneous bleeds.

Part D results

Prior to study entry, all patients in Part D utilized bypass agents, including recombinant factor VIIa and activated prothrombin complex concentrate, to manage their bleeds. They had a pre-study ABR of up to 80.

The first cohort (n=6) of patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81±2% and a mean maximal thrombin generation increase of approximately 368%.

In addition, there was preliminary evidence of reduced bleeding, with a 49% to 100% reduction in estimated ABR during the observation period compared with pre-study values.

Safety results

As of July 11, 2016, fitusiran appears to be generally well tolerated in hemophilia patients, with or without inhibitors (n=31, with 5 patients participating in both Parts B and C).

There have been no serious adverse events related to the drug and no thromboembolic events or laboratory evidence of pathologic clot formation.

One non-inhibitor patient in Part C treated with the 80 mg fixed dose discontinued treatment due to an adverse event that was considered severe and possibly related to the study drug.

This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal), AST (8x upper limit of normal), C-reactive protein, and D-dimer, without an increase in total bilirubin. The event resolved with symptomatic management, including antacids and analgesics.

Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site.

Additional adverse events reported in at least 10% of patients included upper respiratory tract infection (10%) and arthralgia (10%). The majority of these events were mild or moderate in severity.

*Pasi K J et al, A Subcutaneously Administered Investigational RNAi Therapeutic, Fitusiran (ALN- AT3), Targeting Antithrombin for Treatment of Hemophilia: Interim Results in Patients with Hemophilia A or B, WFH 2016 World Congress, July 2016.

Structure of RNA

ORLANDO—Results from an ongoing phase 1 study suggest fitusiran, a small interfering RNA therapeutic targeting antithrombin (AT), can restore hemostasis and prevent bleeding in patients with hemophilia A or B, with or without inhibitors.

In patients with inhibitors, fitusiran exhibited preliminary evidence of reduced bleeding. In patients without inhibitors, fitusiran reduced the median estimated annualized bleeding rate (ABR) to 0.

In addition, researchers said fitusiran was generally well tolerated, and none of the patients developed anti-drug antibodies.

These results were presented at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Alnylam Pharmaceuticals, Inc.

Study design

This phase 1 trial consists of 4 parts. Part A enrolled healthy volunteers who were randomized 3:1 to fitusiran or placebo. This part of the study was completed after the first dose cohort received a single subcutaneous dose of fitusiran at 30 mcg/kg.

Part B, which is also complete, enrolled 12 patients with severe hemophilia A or B. Patients received 3 weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg.

Part C, in which dosing is complete, enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients received 3 monthly subcutaneous doses of fitusiran at 225, 450, 900, or 1800 mcg/kg. Six patients received 3 fixed monthly subcutaneous doses of fitusiran at 80 mg.

Part D is designed to enroll up to 18 patients with inhibitors. The first cohort of 6 patients received a 50 mg, fixed, once-monthly, subcutaneous dose. The second cohort has completed enrollment, with 6 patients receiving an 80 mg, fixed, once-monthly, subcutaneous dose.

Results from Parts C and D were presented at the meeting.

Part C results

Treatment with fitusiran resulted in a dose-dependent, statistically significant decrease in AT and increase in thrombin generation. At the 80 mg monthly dose, fitusiran achieved 87±1% mean maximal AT lowering with low inter-patient variability.

Researchers assessed the association between AT lowering and increased thrombin generation in a post-hoc exploratory analysis in which AT lowering was grouped by 25% increments for completed patients in Parts B (n=12) and C (n=17) of the study.

In the highest quartile of ≥75% AT lowering (n=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290% relative to baseline (P<0.001, as compared to the lowest AT-lowering quartile).

There was a significant, AT-lowering-dependent reduction in bleeding frequency as well.

To obtain a comprehensive assessment of fitusiran’s potential effects on bleeding, researchers performed a post-hoc analysis in evaluable patients from Part C (n=17).

The team compared bleeding events that occurred over the 6-month period prior to study entry, bleeding events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the onset period), and bleeding events that occurred beyond day 29 up to day 112 (the observation period).

Prior to study entry, the estimated median ABR was 28 for patients receiving on-demand factor therapy (n=4) and 2 for patients receiving prophylactic factor therapy (n=13).

The estimated median ABR was 13 among all evaluable patients during the onset period and 0 during the observation period.

In all Part C dose cohorts during the observation period, 53% of patients (9/17) were bleed-free, and 82% of patients reported no spontaneous bleeds.

Part D results

Prior to study entry, all patients in Part D utilized bypass agents, including recombinant factor VIIa and activated prothrombin complex concentrate, to manage their bleeds. They had a pre-study ABR of up to 80.

The first cohort (n=6) of patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81±2% and a mean maximal thrombin generation increase of approximately 368%.

In addition, there was preliminary evidence of reduced bleeding, with a 49% to 100% reduction in estimated ABR during the observation period compared with pre-study values.

Safety results

As of July 11, 2016, fitusiran appears to be generally well tolerated in hemophilia patients, with or without inhibitors (n=31, with 5 patients participating in both Parts B and C).

There have been no serious adverse events related to the drug and no thromboembolic events or laboratory evidence of pathologic clot formation.

One non-inhibitor patient in Part C treated with the 80 mg fixed dose discontinued treatment due to an adverse event that was considered severe and possibly related to the study drug.

This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal), AST (8x upper limit of normal), C-reactive protein, and D-dimer, without an increase in total bilirubin. The event resolved with symptomatic management, including antacids and analgesics.

Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site.

Additional adverse events reported in at least 10% of patients included upper respiratory tract infection (10%) and arthralgia (10%). The majority of these events were mild or moderate in severity.

*Pasi K J et al, A Subcutaneously Administered Investigational RNAi Therapeutic, Fitusiran (ALN- AT3), Targeting Antithrombin for Treatment of Hemophilia: Interim Results in Patients with Hemophilia A or B, WFH 2016 World Congress, July 2016.

US soldiers

Results of a large study contradict the view that having sickle cell trait increases a person’s risk of death.

Health records of nearly 50,000 active-duty US Army soldiers showed no significant difference in the risk of death between soldiers who had sickle cell trait and those who did not.

The risk of exertional rhabdomyolysis (ER) was 54% higher among soldiers with sickle cell trait than those without it.

But the study suggested that tobacco use, obesity, and taking certain drugs also incur a heightened risk of ER.

Lianne Kurina, PhD, of Stanford University School of Medicine in California, and her colleagues reported these findings in NEJM.

Previous studies have suggested the health consequences of sickle cell trait might be dire, including higher mortality from ER. ER is characterized by the severe breakdown of skeletal-muscle tissue due to extreme physical exertion. The condition has been known to affect athletes and soldiers.

To assess the risk of ER and death among people with sickle cell trait, Dr Kurina and her colleagues reviewed the health records of 47,944 African-American soldiers who served on active duty between 2011 and 2014 and for whom sickle cell status was known.

The team found no significant difference in the risk of death among soldiers with sickle cell trait and those without. The hazard ratio (HR) was 0.99 (95% confidence interval [CI], 0.46 to 2.13; P=0.97).

Sickle cell trait was associated with a significantly higher adjusted risk of ER, with an HR of 1.54 (95% CI, 1.12 to 2.12; P=0.008).

However, the risk of ER was also higher for the following groups:

• Soldiers who used tobacco (HR=1.54, 95% CI, 1.23 to 1.94; P<0.001)
• Those with a body mass index of 30 or higher, as compared to 25 or lower (HR=1.39, 95% CI, 1.04 to 1.86; P=0.03)
• Those who recently used a statin (HR=2.89, 95% CI, 1.51 to 5.55; P=0.001)
• Those who recently used an antipsychotic agent (HR=3.02, 95% CI, 1.34 to 6.82; P=0.008).

Dr Kurina said the reason the results of this study differ from those of previous studies may be better safety for active-duty soldiers.

As of 2003, soldiers who are engaged in strenuous exercise are required to drink plenty of fluids, build up to strenuous exercise gradually, and take regular rests when it’s hot. All of these measures are known to reduce exercise-related fatality rates, regardless of whether individuals have sickle cell trait, the researchers said.

“Another critical difference between our study and the earlier, population-based studies is that, in our study, we knew the sickle cell status of everyone in the population,” Dr Kurina said.

She and her team looked only at soldiers whose sickle cell status was confirmed by blood tests taken during their years of service, instead of from self-reported sickle cell status or past medical history, as had been done in the other studies.

“The most important thing to come out of this study is the really reassuring news that, under conditions of universal precautions against dehydration and overheating, we don’t see an elevation in the risk of mortality in people with sickle cell trait,” Dr Kurina said.

She added that the study’s results call into question the need to screen service members with sickle cell trait, especially with better safety precautions during intense exertion.

US soldiers

Results of a large study contradict the view that having sickle cell trait increases a person’s risk of death.

Health records of nearly 50,000 active-duty US Army soldiers showed no significant difference in the risk of death between soldiers who had sickle cell trait and those who did not.

The risk of exertional rhabdomyolysis (ER) was 54% higher among soldiers with sickle cell trait than those without it.

But the study suggested that tobacco use, obesity, and taking certain drugs also incur a heightened risk of ER.

Lianne Kurina, PhD, of Stanford University School of Medicine in California, and her colleagues reported these findings in NEJM.

Previous studies have suggested the health consequences of sickle cell trait might be dire, including higher mortality from ER. ER is characterized by the severe breakdown of skeletal-muscle tissue due to extreme physical exertion. The condition has been known to affect athletes and soldiers.

To assess the risk of ER and death among people with sickle cell trait, Dr Kurina and her colleagues reviewed the health records of 47,944 African-American soldiers who served on active duty between 2011 and 2014 and for whom sickle cell status was known.

The team found no significant difference in the risk of death among soldiers with sickle cell trait and those without. The hazard ratio (HR) was 0.99 (95% confidence interval [CI], 0.46 to 2.13; P=0.97).

Sickle cell trait was associated with a significantly higher adjusted risk of ER, with an HR of 1.54 (95% CI, 1.12 to 2.12; P=0.008).

However, the risk of ER was also higher for the following groups:

• Soldiers who used tobacco (HR=1.54, 95% CI, 1.23 to 1.94; P<0.001)
• Those with a body mass index of 30 or higher, as compared to 25 or lower (HR=1.39, 95% CI, 1.04 to 1.86; P=0.03)
• Those who recently used a statin (HR=2.89, 95% CI, 1.51 to 5.55; P=0.001)
• Those who recently used an antipsychotic agent (HR=3.02, 95% CI, 1.34 to 6.82; P=0.008).

Dr Kurina said the reason the results of this study differ from those of previous studies may be better safety for active-duty soldiers.

As of 2003, soldiers who are engaged in strenuous exercise are required to drink plenty of fluids, build up to strenuous exercise gradually, and take regular rests when it’s hot. All of these measures are known to reduce exercise-related fatality rates, regardless of whether individuals have sickle cell trait, the researchers said.

“Another critical difference between our study and the earlier, population-based studies is that, in our study, we knew the sickle cell status of everyone in the population,” Dr Kurina said.

She and her team looked only at soldiers whose sickle cell status was confirmed by blood tests taken during their years of service, instead of from self-reported sickle cell status or past medical history, as had been done in the other studies.

“The most important thing to come out of this study is the really reassuring news that, under conditions of universal precautions against dehydration and overheating, we don’t see an elevation in the risk of mortality in people with sickle cell trait,” Dr Kurina said.

She added that the study’s results call into question the need to screen service members with sickle cell trait, especially with better safety precautions during intense exertion.

US soldiers

Results of a large study contradict the view that having sickle cell trait increases a person’s risk of death.

Health records of nearly 50,000 active-duty US Army soldiers showed no significant difference in the risk of death between soldiers who had sickle cell trait and those who did not.

The risk of exertional rhabdomyolysis (ER) was 54% higher among soldiers with sickle cell trait than those without it.

But the study suggested that tobacco use, obesity, and taking certain drugs also incur a heightened risk of ER.

Lianne Kurina, PhD, of Stanford University School of Medicine in California, and her colleagues reported these findings in NEJM.

Previous studies have suggested the health consequences of sickle cell trait might be dire, including higher mortality from ER. ER is characterized by the severe breakdown of skeletal-muscle tissue due to extreme physical exertion. The condition has been known to affect athletes and soldiers.

To assess the risk of ER and death among people with sickle cell trait, Dr Kurina and her colleagues reviewed the health records of 47,944 African-American soldiers who served on active duty between 2011 and 2014 and for whom sickle cell status was known.

The team found no significant difference in the risk of death among soldiers with sickle cell trait and those without. The hazard ratio (HR) was 0.99 (95% confidence interval [CI], 0.46 to 2.13; P=0.97).

Sickle cell trait was associated with a significantly higher adjusted risk of ER, with an HR of 1.54 (95% CI, 1.12 to 2.12; P=0.008).

However, the risk of ER was also higher for the following groups:

• Soldiers who used tobacco (HR=1.54, 95% CI, 1.23 to 1.94; P<0.001)
• Those with a body mass index of 30 or higher, as compared to 25 or lower (HR=1.39, 95% CI, 1.04 to 1.86; P=0.03)
• Those who recently used a statin (HR=2.89, 95% CI, 1.51 to 5.55; P=0.001)
• Those who recently used an antipsychotic agent (HR=3.02, 95% CI, 1.34 to 6.82; P=0.008).

Dr Kurina said the reason the results of this study differ from those of previous studies may be better safety for active-duty soldiers.

As of 2003, soldiers who are engaged in strenuous exercise are required to drink plenty of fluids, build up to strenuous exercise gradually, and take regular rests when it’s hot. All of these measures are known to reduce exercise-related fatality rates, regardless of whether individuals have sickle cell trait, the researchers said.

“Another critical difference between our study and the earlier, population-based studies is that, in our study, we knew the sickle cell status of everyone in the population,” Dr Kurina said.

She and her team looked only at soldiers whose sickle cell status was confirmed by blood tests taken during their years of service, instead of from self-reported sickle cell status or past medical history, as had been done in the other studies.

“The most important thing to come out of this study is the really reassuring news that, under conditions of universal precautions against dehydration and overheating, we don’t see an elevation in the risk of mortality in people with sickle cell trait,” Dr Kurina said.

She added that the study’s results call into question the need to screen service members with sickle cell trait, especially with better safety precautions during intense exertion.

E. John Wherry, PhD

Photo by Rob Press

Manipulating metabolic events might reinvigorate exhausted T cells and complement the effects of checkpoint inhibitors in the treatment of cancers, according to research published in Immunity.

When T cells are activated because of a tumor or microbe, they transition from a catabolic existence of slow metabolic burn to an anabolic one in which the body revs up to generate chemical intermediates to build new cells.

However, T cells are hard-wired to stop the anabolic mode at a certain point because functioning at that level is unsustainable.

PD-1, a cell surface receptor and target of checkpoint inhibitors, tells T cells to turn off the anabolic pathway, but other molecular signals attempt to keep this pathway turned on because growing tumors or chronic infection are still present.

This results in “metabolically confused” T cells, said study author E. John Wherry, PhD, of the University of Pennsylvania School of Medicine in Philadelphia.

To study this, Dr Wherry and his colleagues induced infection in mice using 2 different strains of the lymphocytic choriomeningitis virus, a model system for exploring T-cell biology.

“We found that, as early as the first week of a chronic viral infection, even before severe T-cell dysfunction becomes established, virus-specific T cells are already unable to match the bioenergetic demands of T cells generated during the height of fighting a well-contained viral infection in a mouse model,” Dr Wherry said.

In other words, these experiments revealed when PD-1 turns off the anabolic metabolism signal, and it’s earlier than previously thought.

The researchers said this finding is important because it identifies the altered metabolism as a distinct point in the development of exhausted T cells, rather than as a later consequence of exhausted T cells.

This research also revealed PD-1’s role as the metabolic switch in shutting down anabolic pathways and characterized downstream metabolic regulator targets of PD-1.

For example, restriction of glucose uptake and utilization, despite the upregulation of multiple backup metabolic pathways, was one metabolic defect in the exhausted T cells. PD-1 partially controls the development of this early defect in using glucose as a fuel, as well as the size and quality of mitochondria.

A second pathway repressed by PD-1 involved PGC-1α, a protein that regulates genes involved in metabolism. Correcting this PD-1-induced defect by overexpressing PGC-1α improved exhausted T-cell bioenergetics.

The researchers said these results have implications for therapeutic strategies aimed at the reinvigoration of exhausted T cells in chronic infections and cancer. And targeting exhausted T-cell metabolism could complement the effects of blocking PD-1 and other checkpoints.

E. John Wherry, PhD

Photo by Rob Press

Manipulating metabolic events might reinvigorate exhausted T cells and complement the effects of checkpoint inhibitors in the treatment of cancers, according to research published in Immunity.

When T cells are activated because of a tumor or microbe, they transition from a catabolic existence of slow metabolic burn to an anabolic one in which the body revs up to generate chemical intermediates to build new cells.

However, T cells are hard-wired to stop the anabolic mode at a certain point because functioning at that level is unsustainable.

PD-1, a cell surface receptor and target of checkpoint inhibitors, tells T cells to turn off the anabolic pathway, but other molecular signals attempt to keep this pathway turned on because growing tumors or chronic infection are still present.

This results in “metabolically confused” T cells, said study author E. John Wherry, PhD, of the University of Pennsylvania School of Medicine in Philadelphia.

To study this, Dr Wherry and his colleagues induced infection in mice using 2 different strains of the lymphocytic choriomeningitis virus, a model system for exploring T-cell biology.

“We found that, as early as the first week of a chronic viral infection, even before severe T-cell dysfunction becomes established, virus-specific T cells are already unable to match the bioenergetic demands of T cells generated during the height of fighting a well-contained viral infection in a mouse model,” Dr Wherry said.

In other words, these experiments revealed when PD-1 turns off the anabolic metabolism signal, and it’s earlier than previously thought.

The researchers said this finding is important because it identifies the altered metabolism as a distinct point in the development of exhausted T cells, rather than as a later consequence of exhausted T cells.

This research also revealed PD-1’s role as the metabolic switch in shutting down anabolic pathways and characterized downstream metabolic regulator targets of PD-1.

For example, restriction of glucose uptake and utilization, despite the upregulation of multiple backup metabolic pathways, was one metabolic defect in the exhausted T cells. PD-1 partially controls the development of this early defect in using glucose as a fuel, as well as the size and quality of mitochondria.

A second pathway repressed by PD-1 involved PGC-1α, a protein that regulates genes involved in metabolism. Correcting this PD-1-induced defect by overexpressing PGC-1α improved exhausted T-cell bioenergetics.

The researchers said these results have implications for therapeutic strategies aimed at the reinvigoration of exhausted T cells in chronic infections and cancer. And targeting exhausted T-cell metabolism could complement the effects of blocking PD-1 and other checkpoints.

E. John Wherry, PhD

Photo by Rob Press

Manipulating metabolic events might reinvigorate exhausted T cells and complement the effects of checkpoint inhibitors in the treatment of cancers, according to research published in Immunity.

When T cells are activated because of a tumor or microbe, they transition from a catabolic existence of slow metabolic burn to an anabolic one in which the body revs up to generate chemical intermediates to build new cells.

However, T cells are hard-wired to stop the anabolic mode at a certain point because functioning at that level is unsustainable.

PD-1, a cell surface receptor and target of checkpoint inhibitors, tells T cells to turn off the anabolic pathway, but other molecular signals attempt to keep this pathway turned on because growing tumors or chronic infection are still present.

This results in “metabolically confused” T cells, said study author E. John Wherry, PhD, of the University of Pennsylvania School of Medicine in Philadelphia.

To study this, Dr Wherry and his colleagues induced infection in mice using 2 different strains of the lymphocytic choriomeningitis virus, a model system for exploring T-cell biology.

“We found that, as early as the first week of a chronic viral infection, even before severe T-cell dysfunction becomes established, virus-specific T cells are already unable to match the bioenergetic demands of T cells generated during the height of fighting a well-contained viral infection in a mouse model,” Dr Wherry said.

In other words, these experiments revealed when PD-1 turns off the anabolic metabolism signal, and it’s earlier than previously thought.

The researchers said this finding is important because it identifies the altered metabolism as a distinct point in the development of exhausted T cells, rather than as a later consequence of exhausted T cells.

This research also revealed PD-1’s role as the metabolic switch in shutting down anabolic pathways and characterized downstream metabolic regulator targets of PD-1.

For example, restriction of glucose uptake and utilization, despite the upregulation of multiple backup metabolic pathways, was one metabolic defect in the exhausted T cells. PD-1 partially controls the development of this early defect in using glucose as a fuel, as well as the size and quality of mitochondria.

A second pathway repressed by PD-1 involved PGC-1α, a protein that regulates genes involved in metabolism. Correcting this PD-1-induced defect by overexpressing PGC-1α improved exhausted T-cell bioenergetics.

The researchers said these results have implications for therapeutic strategies aimed at the reinvigoration of exhausted T cells in chronic infections and cancer. And targeting exhausted T-cell metabolism could complement the effects of blocking PD-1 and other checkpoints.

Doctor examines child
Photo by Logan Tuttle

Clinical trials in children too often go uncompleted or unpublished, according to a pair of researchers.

The duo evaluated nearly 560 pediatric trials and found that 19% were discontinued early. Of the trials that were completed, 30% remained unpublished several years later.

Industry-sponsored trials were more likely to be completed than trials sponsored by academic institutions. However, completed trials sponsored by industry were less likely to be published than trials sponsored by academia.

“Our findings are in line with previously published studies focusing on adult trials, which may speak to how commonplace discontinuation and non-publication are in medical research in general,” said study author Natalie Pica, MD, PhD, of Boston Children’s Hospital in Massachusetts.

She and Florence Bourgeois, MD, also of Boston Children’s Hospital, reported these findings in Pediatrics.

The researchers tracked 559 randomized, controlled pediatric trials registered on ClinicalTrials.gov from 2008 to 2010 and whose final status (completed or discontinued) was confirmed by the end of 2012.

The pair then searched for related peer-reviewed articles published through September 1, 2015. When no publication could be found, the researchers inquired with study investigators and sponsors via email.

Of the 559 trials, 104 (19%) were discontinued early. Two-thirds of these had enrolled participants.

Of the 455 completed trials, 136 (30%) remained unpublished after an average of 58 months post-completion. However, 42 of these (31%) did have results posted on ClinicalTrials.gov.

Of the 104 discontinued trials, 39% were sponsored by industry, and 55% were sponsored by academic institutions. (The rest were funded by other sources.)

Two years after trial completion, academia-sponsored trials accounted for 30% of unpublished trials, and industry-sponsored trials accounted for 63%.

Three years after trial completion, academia-sponsored trials accounted for 23% of unpublished trials, and industry-sponsored trials accounted for 70%.

In a multivariate analysis, the likelihood of non-publication was more than doubled for industry-sponsored trials 2 years after completion (odds ratio=2.21) and more than tripled 3 years after completion (odds ratio=3.12).

Overall, more than 8000 children were enrolled in trials that were never completed, and more than 69,000 children were enrolled in completed trials that were never published.

“This is the first study to look systematically at discontinuation and nonpublication of interventional pediatric clinical trials,” Dr Bourgeois said.

“A number of legislative initiatives have been implemented to increase the study of interventions in children. Now, we need to make sure that the proper resources are in place to ensure that information gleaned from these studies reaches the scientific community.”

One proposed initiative cited by Drs Bourgeois and Pica is RIAT (Restoring Invisible and Abandoned Trials), which is supported by some high-profile journals. RIAT invites researchers with unpublished trials to either commit to publish within a year or provide public access to their data.

“It’s hard to reanalyze others’ data,” Dr Pica noted, “but this may be a useful mechanism to make sure that findings from completed trials are disseminated in the medical literature.”

Doctor examines child
Photo by Logan Tuttle

Clinical trials in children too often go uncompleted or unpublished, according to a pair of researchers.

The duo evaluated nearly 560 pediatric trials and found that 19% were discontinued early. Of the trials that were completed, 30% remained unpublished several years later.

Industry-sponsored trials were more likely to be completed than trials sponsored by academic institutions. However, completed trials sponsored by industry were less likely to be published than trials sponsored by academia.

“Our findings are in line with previously published studies focusing on adult trials, which may speak to how commonplace discontinuation and non-publication are in medical research in general,” said study author Natalie Pica, MD, PhD, of Boston Children’s Hospital in Massachusetts.

She and Florence Bourgeois, MD, also of Boston Children’s Hospital, reported these findings in Pediatrics.

The researchers tracked 559 randomized, controlled pediatric trials registered on ClinicalTrials.gov from 2008 to 2010 and whose final status (completed or discontinued) was confirmed by the end of 2012.

The pair then searched for related peer-reviewed articles published through September 1, 2015. When no publication could be found, the researchers inquired with study investigators and sponsors via email.

Of the 559 trials, 104 (19%) were discontinued early. Two-thirds of these had enrolled participants.

Of the 455 completed trials, 136 (30%) remained unpublished after an average of 58 months post-completion. However, 42 of these (31%) did have results posted on ClinicalTrials.gov.

Of the 104 discontinued trials, 39% were sponsored by industry, and 55% were sponsored by academic institutions. (The rest were funded by other sources.)

Two years after trial completion, academia-sponsored trials accounted for 30% of unpublished trials, and industry-sponsored trials accounted for 63%.

Three years after trial completion, academia-sponsored trials accounted for 23% of unpublished trials, and industry-sponsored trials accounted for 70%.

In a multivariate analysis, the likelihood of non-publication was more than doubled for industry-sponsored trials 2 years after completion (odds ratio=2.21) and more than tripled 3 years after completion (odds ratio=3.12).

Overall, more than 8000 children were enrolled in trials that were never completed, and more than 69,000 children were enrolled in completed trials that were never published.

“This is the first study to look systematically at discontinuation and nonpublication of interventional pediatric clinical trials,” Dr Bourgeois said.

“A number of legislative initiatives have been implemented to increase the study of interventions in children. Now, we need to make sure that the proper resources are in place to ensure that information gleaned from these studies reaches the scientific community.”

One proposed initiative cited by Drs Bourgeois and Pica is RIAT (Restoring Invisible and Abandoned Trials), which is supported by some high-profile journals. RIAT invites researchers with unpublished trials to either commit to publish within a year or provide public access to their data.

“It’s hard to reanalyze others’ data,” Dr Pica noted, “but this may be a useful mechanism to make sure that findings from completed trials are disseminated in the medical literature.”

Doctor examines child
Photo by Logan Tuttle

Clinical trials in children too often go uncompleted or unpublished, according to a pair of researchers.

The duo evaluated nearly 560 pediatric trials and found that 19% were discontinued early. Of the trials that were completed, 30% remained unpublished several years later.

Industry-sponsored trials were more likely to be completed than trials sponsored by academic institutions. However, completed trials sponsored by industry were less likely to be published than trials sponsored by academia.

“Our findings are in line with previously published studies focusing on adult trials, which may speak to how commonplace discontinuation and non-publication are in medical research in general,” said study author Natalie Pica, MD, PhD, of Boston Children’s Hospital in Massachusetts.

She and Florence Bourgeois, MD, also of Boston Children’s Hospital, reported these findings in Pediatrics.

The researchers tracked 559 randomized, controlled pediatric trials registered on ClinicalTrials.gov from 2008 to 2010 and whose final status (completed or discontinued) was confirmed by the end of 2012.

The pair then searched for related peer-reviewed articles published through September 1, 2015. When no publication could be found, the researchers inquired with study investigators and sponsors via email.

Of the 559 trials, 104 (19%) were discontinued early. Two-thirds of these had enrolled participants.

Of the 455 completed trials, 136 (30%) remained unpublished after an average of 58 months post-completion. However, 42 of these (31%) did have results posted on ClinicalTrials.gov.

Of the 104 discontinued trials, 39% were sponsored by industry, and 55% were sponsored by academic institutions. (The rest were funded by other sources.)

Two years after trial completion, academia-sponsored trials accounted for 30% of unpublished trials, and industry-sponsored trials accounted for 63%.

Three years after trial completion, academia-sponsored trials accounted for 23% of unpublished trials, and industry-sponsored trials accounted for 70%.

In a multivariate analysis, the likelihood of non-publication was more than doubled for industry-sponsored trials 2 years after completion (odds ratio=2.21) and more than tripled 3 years after completion (odds ratio=3.12).

Overall, more than 8000 children were enrolled in trials that were never completed, and more than 69,000 children were enrolled in completed trials that were never published.

“This is the first study to look systematically at discontinuation and nonpublication of interventional pediatric clinical trials,” Dr Bourgeois said.

“A number of legislative initiatives have been implemented to increase the study of interventions in children. Now, we need to make sure that the proper resources are in place to ensure that information gleaned from these studies reaches the scientific community.”

One proposed initiative cited by Drs Bourgeois and Pica is RIAT (Restoring Invisible and Abandoned Trials), which is supported by some high-profile journals. RIAT invites researchers with unpublished trials to either commit to publish within a year or provide public access to their data.

“It’s hard to reanalyze others’ data,” Dr Pica noted, “but this may be a useful mechanism to make sure that findings from completed trials are disseminated in the medical literature.”

Many patients with advanced renal cell carcinoma have tumors that do not respond to immune checkpoint inhibitors targeted against the programmed death-1 (PD-1) pathway, despite expression of the target PD ligand 1 (PD-L1) on their tumors. Now investigators think they know why, and hope to use the information to predict which patients are likely to benefit and identify potential new therapies or combinations.

A study of renal cell carcinoma (RCC) samples from tumors with both good and poor clinical responses to treatment with the anti–PD-1 agent nivolumab (Opdivo) showed that a tumor gene–expression profile tipped more toward genes for controlling metabolic functions rather than immune functions was associated with a lack of response to anti-PD-1 therapy, reported Suzanne L. Topalian, MD, and her colleagues from Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center, both in Baltimore.

“These findings suggest that tumor cell–intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti–PD-1,” they wrote in a study published online in Cancer Immunology Research.

The investigators obtained tumor samples from 13 patients with unresectable metastatic RCC treated in one of four clinical trials. They used radiographic staging to classify each patient as either a responder or nonresponder to anti–PD-1 therapy according to RECIST (Response Evaluation Criteria in Solid Tumors). The samples were evaluated with whole genome microarray and multiplex quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling and analysis, and the results were compared with those from eight renal cell carcinoma cell lines.

They looked for expression of nearly 30,000 gene targets in samples from responders and nonresponders and found a pattern of differential expression of genes encoding for metabolic pathways and immune functions.

Specifically, they found that the expression of genes involved in metabolic and solute transport functions (for example, UGT1A) were associated with poor response to nivolumab, whereas overexpression of genes for immune markers involved in T-cell differentiation (BACH2) and leukocyte migration (CCL3) were associated with a good response.

The investigators acknowledge that the study was retrospective and limited by the analysis of only a small number of tumor samples but suggest that their findings point the way to further investigations in larger groups of patients with RCC tumors, including those both positive and negative for PD-L1 expression.

“The general approach to identifying biomarkers of clinical response to PD-1–targeted therapies has so far focused on immunologic factors in the [tumor microenvironment]. However, a deeper level of investigation may be warranted for individual tumor types, and intersections of tumor cell–intrinsic factors with immunologic factors may be particularly revealing,” they wrote.

The study was supported by research grants from the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Bristol-Myers Squibb, the National Cancer Institute, and Stand Up To Cancer. Dr. Topalian has served as a consultant/advisory board member for Five Prime Therapeutics, MedImmune, Merck, and Pfizer, and has an ownership interest in Bristol-Myers Squibb, Five Prime Therapeutics,and Potenza Therapeutics. Other coauthors reported similar potential conflicts of interest.

Many patients with advanced renal cell carcinoma have tumors that do not respond to immune checkpoint inhibitors targeted against the programmed death-1 (PD-1) pathway, despite expression of the target PD ligand 1 (PD-L1) on their tumors. Now investigators think they know why, and hope to use the information to predict which patients are likely to benefit and identify potential new therapies or combinations.

A study of renal cell carcinoma (RCC) samples from tumors with both good and poor clinical responses to treatment with the anti–PD-1 agent nivolumab (Opdivo) showed that a tumor gene–expression profile tipped more toward genes for controlling metabolic functions rather than immune functions was associated with a lack of response to anti-PD-1 therapy, reported Suzanne L. Topalian, MD, and her colleagues from Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center, both in Baltimore.

“These findings suggest that tumor cell–intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti–PD-1,” they wrote in a study published online in Cancer Immunology Research.

The investigators obtained tumor samples from 13 patients with unresectable metastatic RCC treated in one of four clinical trials. They used radiographic staging to classify each patient as either a responder or nonresponder to anti–PD-1 therapy according to RECIST (Response Evaluation Criteria in Solid Tumors). The samples were evaluated with whole genome microarray and multiplex quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling and analysis, and the results were compared with those from eight renal cell carcinoma cell lines.

They looked for expression of nearly 30,000 gene targets in samples from responders and nonresponders and found a pattern of differential expression of genes encoding for metabolic pathways and immune functions.

Specifically, they found that the expression of genes involved in metabolic and solute transport functions (for example, UGT1A) were associated with poor response to nivolumab, whereas overexpression of genes for immune markers involved in T-cell differentiation (BACH2) and leukocyte migration (CCL3) were associated with a good response.

The investigators acknowledge that the study was retrospective and limited by the analysis of only a small number of tumor samples but suggest that their findings point the way to further investigations in larger groups of patients with RCC tumors, including those both positive and negative for PD-L1 expression.

“The general approach to identifying biomarkers of clinical response to PD-1–targeted therapies has so far focused on immunologic factors in the [tumor microenvironment]. However, a deeper level of investigation may be warranted for individual tumor types, and intersections of tumor cell–intrinsic factors with immunologic factors may be particularly revealing,” they wrote.

The study was supported by research grants from the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Bristol-Myers Squibb, the National Cancer Institute, and Stand Up To Cancer. Dr. Topalian has served as a consultant/advisory board member for Five Prime Therapeutics, MedImmune, Merck, and Pfizer, and has an ownership interest in Bristol-Myers Squibb, Five Prime Therapeutics,and Potenza Therapeutics. Other coauthors reported similar potential conflicts of interest.

Many patients with advanced renal cell carcinoma have tumors that do not respond to immune checkpoint inhibitors targeted against the programmed death-1 (PD-1) pathway, despite expression of the target PD ligand 1 (PD-L1) on their tumors. Now investigators think they know why, and hope to use the information to predict which patients are likely to benefit and identify potential new therapies or combinations.

A study of renal cell carcinoma (RCC) samples from tumors with both good and poor clinical responses to treatment with the anti–PD-1 agent nivolumab (Opdivo) showed that a tumor gene–expression profile tipped more toward genes for controlling metabolic functions rather than immune functions was associated with a lack of response to anti-PD-1 therapy, reported Suzanne L. Topalian, MD, and her colleagues from Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center, both in Baltimore.

“These findings suggest that tumor cell–intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti–PD-1,” they wrote in a study published online in Cancer Immunology Research.

The investigators obtained tumor samples from 13 patients with unresectable metastatic RCC treated in one of four clinical trials. They used radiographic staging to classify each patient as either a responder or nonresponder to anti–PD-1 therapy according to RECIST (Response Evaluation Criteria in Solid Tumors). The samples were evaluated with whole genome microarray and multiplex quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling and analysis, and the results were compared with those from eight renal cell carcinoma cell lines.

They looked for expression of nearly 30,000 gene targets in samples from responders and nonresponders and found a pattern of differential expression of genes encoding for metabolic pathways and immune functions.

Specifically, they found that the expression of genes involved in metabolic and solute transport functions (for example, UGT1A) were associated with poor response to nivolumab, whereas overexpression of genes for immune markers involved in T-cell differentiation (BACH2) and leukocyte migration (CCL3) were associated with a good response.

The investigators acknowledge that the study was retrospective and limited by the analysis of only a small number of tumor samples but suggest that their findings point the way to further investigations in larger groups of patients with RCC tumors, including those both positive and negative for PD-L1 expression.

“The general approach to identifying biomarkers of clinical response to PD-1–targeted therapies has so far focused on immunologic factors in the [tumor microenvironment]. However, a deeper level of investigation may be warranted for individual tumor types, and intersections of tumor cell–intrinsic factors with immunologic factors may be particularly revealing,” they wrote.

The study was supported by research grants from the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Bristol-Myers Squibb, the National Cancer Institute, and Stand Up To Cancer. Dr. Topalian has served as a consultant/advisory board member for Five Prime Therapeutics, MedImmune, Merck, and Pfizer, and has an ownership interest in Bristol-Myers Squibb, Five Prime Therapeutics,and Potenza Therapeutics. Other coauthors reported similar potential conflicts of interest.

The use of psychotropic medications was similar between patients seeking cosmetic dermatology treatment and those presenting with medical dermatologic conditions in a study published in the Journal of Drugs in Dermatology.

A retrospective chart review of 154 adult female patients presenting for cosmetic dermatology and 156 presenting for medical reasons to a suburban dermatology private practice found that 26.8% of the cosmetic group and 22.2% of the medical group reported taking psychotropic medications (P = .09).

©moodboard/Thinkstock

The most common medication type was a selective serotonin reuptake inhibitor antidepressant, reported Dr. Heather K. Hamilton, a dermatologist in Chestnut Hill, Mass., at the time of the study, and her associates. An SSRI was used by 23 patients (56.1%) in the cosmetic group and 25 (71.4%) of the general dermatology patients, followed by benzodiazepines, tricyclic antidepressants, and attention-deficit/hyperactivity disorder medications (J Drugs Dermatol. 2016; 15 9[7]:858-61).

The study also found no significant difference between the two groups in self-reported record of a psychiatric disorder, with four such cases in the medical group and six in the cosmetic group (P = .139).

Cosmetic patients presenting for appearance-related dermatologic therapy are often perceived as being more difficult to satisfy than those with dermatologic problems, the authors noted. “While the reasons for this perception are many, some have hypothesized that this may be related to a higher rate of anxiety, mild depression, or body image issues among this patient population,” they wrote.

The authors referred to the high proportion of patients in both groups taking psychotropic medications in the study, a finding that was “even more striking” since the study excluded patients with conditions known to be associated with psychopathology, such as vitiligo, psoriasis, and neurotic excoriations.

“This finding serves as a reminder that we should take full medical histories as mental health may play a role in compliance and satisfaction with treatment,” the authors stated.

They acknowledged that there were limitations of the study, including using psychotropic medication as a marker for mental health problems and the use of self-reported data.

No conflicts of interest were declared. Dr. Hamilton now practices outside of New York.

The use of psychotropic medications was similar between patients seeking cosmetic dermatology treatment and those presenting with medical dermatologic conditions in a study published in the Journal of Drugs in Dermatology.

A retrospective chart review of 154 adult female patients presenting for cosmetic dermatology and 156 presenting for medical reasons to a suburban dermatology private practice found that 26.8% of the cosmetic group and 22.2% of the medical group reported taking psychotropic medications (P = .09).

©moodboard/Thinkstock

The most common medication type was a selective serotonin reuptake inhibitor antidepressant, reported Dr. Heather K. Hamilton, a dermatologist in Chestnut Hill, Mass., at the time of the study, and her associates. An SSRI was used by 23 patients (56.1%) in the cosmetic group and 25 (71.4%) of the general dermatology patients, followed by benzodiazepines, tricyclic antidepressants, and attention-deficit/hyperactivity disorder medications (J Drugs Dermatol. 2016; 15 9[7]:858-61).

The study also found no significant difference between the two groups in self-reported record of a psychiatric disorder, with four such cases in the medical group and six in the cosmetic group (P = .139).

Cosmetic patients presenting for appearance-related dermatologic therapy are often perceived as being more difficult to satisfy than those with dermatologic problems, the authors noted. “While the reasons for this perception are many, some have hypothesized that this may be related to a higher rate of anxiety, mild depression, or body image issues among this patient population,” they wrote.

The authors referred to the high proportion of patients in both groups taking psychotropic medications in the study, a finding that was “even more striking” since the study excluded patients with conditions known to be associated with psychopathology, such as vitiligo, psoriasis, and neurotic excoriations.

“This finding serves as a reminder that we should take full medical histories as mental health may play a role in compliance and satisfaction with treatment,” the authors stated.

They acknowledged that there were limitations of the study, including using psychotropic medication as a marker for mental health problems and the use of self-reported data.

No conflicts of interest were declared. Dr. Hamilton now practices outside of New York.

The use of psychotropic medications was similar between patients seeking cosmetic dermatology treatment and those presenting with medical dermatologic conditions in a study published in the Journal of Drugs in Dermatology.

A retrospective chart review of 154 adult female patients presenting for cosmetic dermatology and 156 presenting for medical reasons to a suburban dermatology private practice found that 26.8% of the cosmetic group and 22.2% of the medical group reported taking psychotropic medications (P = .09).

©moodboard/Thinkstock

The most common medication type was a selective serotonin reuptake inhibitor antidepressant, reported Dr. Heather K. Hamilton, a dermatologist in Chestnut Hill, Mass., at the time of the study, and her associates. An SSRI was used by 23 patients (56.1%) in the cosmetic group and 25 (71.4%) of the general dermatology patients, followed by benzodiazepines, tricyclic antidepressants, and attention-deficit/hyperactivity disorder medications (J Drugs Dermatol. 2016; 15 9[7]:858-61).

The study also found no significant difference between the two groups in self-reported record of a psychiatric disorder, with four such cases in the medical group and six in the cosmetic group (P = .139).

Cosmetic patients presenting for appearance-related dermatologic therapy are often perceived as being more difficult to satisfy than those with dermatologic problems, the authors noted. “While the reasons for this perception are many, some have hypothesized that this may be related to a higher rate of anxiety, mild depression, or body image issues among this patient population,” they wrote.

The authors referred to the high proportion of patients in both groups taking psychotropic medications in the study, a finding that was “even more striking” since the study excluded patients with conditions known to be associated with psychopathology, such as vitiligo, psoriasis, and neurotic excoriations.

“This finding serves as a reminder that we should take full medical histories as mental health may play a role in compliance and satisfaction with treatment,” the authors stated.

They acknowledged that there were limitations of the study, including using psychotropic medication as a marker for mental health problems and the use of self-reported data.

No conflicts of interest were declared. Dr. Hamilton now practices outside of New York.