With the rise of obesity and diabetes, especially type 2 diabetes, in the general population, the likelihood of encountering a patient with diabetes in pregnancy also continues to increase. Women with diabetes who are pregnant require specialized medical guidance, additional monitoring, and a health care team well versed in the possible complications that can arise during pregnancy, delivery, and after birth.

Even with strict glycemic control, women with diabetes in pregnancy are much more likely to experience complications, such as preeclampsia, babies with major congenital defects, large-for-gestational-age fetuses, and children with a higher propensity for chronic diseases later in life, compared with women without diabetes.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at obnews@frontlinemedcom.com.

With the rise of obesity and diabetes, especially type 2 diabetes, in the general population, the likelihood of encountering a patient with diabetes in pregnancy also continues to increase. Women with diabetes who are pregnant require specialized medical guidance, additional monitoring, and a health care team well versed in the possible complications that can arise during pregnancy, delivery, and after birth.

Even with strict glycemic control, women with diabetes in pregnancy are much more likely to experience complications, such as preeclampsia, babies with major congenital defects, large-for-gestational-age fetuses, and children with a higher propensity for chronic diseases later in life, compared with women without diabetes.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at obnews@frontlinemedcom.com.

With the rise of obesity and diabetes, especially type 2 diabetes, in the general population, the likelihood of encountering a patient with diabetes in pregnancy also continues to increase. Women with diabetes who are pregnant require specialized medical guidance, additional monitoring, and a health care team well versed in the possible complications that can arise during pregnancy, delivery, and after birth.

Even with strict glycemic control, women with diabetes in pregnancy are much more likely to experience complications, such as preeclampsia, babies with major congenital defects, large-for-gestational-age fetuses, and children with a higher propensity for chronic diseases later in life, compared with women without diabetes.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at obnews@frontlinemedcom.com.

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

Human papillomavirus (HPV) is the most common sexually transmitted infection. Exposure is widespread and most individuals clear the infection without symptoms or development of disease. However, a subset of individuals experience persistent infection, a state which can lead to carcinogenesis of lower genital tract malignancies, particularly cervical cancer.¹

jarun011/Thinkstock

Vaccine coverage

Persistent infection with high-risk (oncogenic) HPV is well known to be the cause of cervical cancer. There are two HPV vaccines manufactured for the purposes of cervical cancer, anal cancer, and genital wart prevention (Cervarix and Gardasil). The Cervarix vaccine covers high-risk HPV subtypes 16 and 18 and the Gardasil vaccine prevents both low-risk HPV subtypes 6 and 11, which can cause genital warts, and high-risk HPV subtypes 16, 18, 31, 33, 45, 52 and 58, which cause cervical dysplasia and cancer.

High-risk HPV is also associated with head and neck, vulvar, vaginal, and penile cancers, though the vaccines are not approved by the Food and Drug Administration for prevention of these diseases.²

Vaccination indications

Alex Raths/thinkstockphotos

Since vaccination prevents multiple subtypes of HPV, an individual who has already been exposed will still benefit from protection from other subtypes of HPV through vaccination. HPV vaccination is not approved during pregnancy but can be initiated in the postpartum period when women are engaged in their health care and receiving other vaccinations, such as varicella or the MMR vaccine.

Recommended schedule

Until October 2016, the vaccination schedule was based on a three-dose series (0, 2, and 6 months). Currently, the CDC recommends that children aged under 15 years at the time of first dose may opt for a two-dose series (0 and 6-12 months). For those aged 15-26 years, the three-dose schedule remains the recommended course.

The benefits of two-dose schedule are convenience, cost, and increased likelihood of completion. Data presented at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that rates of cervical dysplasia were equivalent for women who completed a two-dose schedule versus a three-dose schedule.⁴

Efficacy

A recent meta-analysis of clinical trials of the HPV vaccines describe efficacy of 95%-97% in prevention of CIN 1-3.⁵ While its greatest efficacy is in its ability to prevent primary HPV infection, there still is some benefit for individuals who already were exposed to HPV prior to vaccination. As stated previously, women with a history of prior HPV vaccination have lower rates of recurrence of cervical dysplasia after treatment. Additionally, recent research has shown that women who received HPV vaccinations after a LEEP procedure for CIN 2 or 3 experience significantly lower recurrence rates, compared with women who did not receive vaccinations after LEEP (2.5% vs. 8.5%).⁶ This raises the possibility of a therapeutic role for HPV vaccination in women infected with HPV. Prospective studies are currently evaluating this question.

Myths

The most common side effects of the HPV vaccine are pain, redness, or swelling at the injection site. Other known side effects include fever, headache or malaise, nausea, syncope, or muscle/joint pain – similar to other vaccinations. Anaphylaxis is a rare complication.

Some parents and pediatricians report concerns that vaccination could lead to earlier sexual activity. Multiple studies have shown that girls who receive HPV vaccination are no more likely to become pregnant or get a sexually transmitted infection (proxies for intercourse) than are girls who were not vaccinated.^7,8

Maximizing vaccination rates

HPV vaccination rates in the United States lag significantly behind rates in countries with national vaccine programs, such as Australia and Denmark.⁹ Early data from Australia already have shown a decrease in genital warts and CIN 2+ incidence within the 10 years of starting its school-based vaccine program, with approximately 73% of 12- to 15-year-olds having completed the vaccine series.² In contrast, just 40% and 22% of 13- to 17-year-old girls and boys in the United States, respectively, had completed the vaccine series in 2014, according to the CDC.¹⁰

Vaccination gaps between girls and boys are narrowing, and more teens will be able to complete the series with the new two-dose recommendation for those younger than 15 years. However, our current rates of vaccination are significantly lower for HPV than for other routinely recommended adolescent vaccines (such as Tdap and meningococcal) and more must be done to encourage vaccination.

Studies have shown that parents are more likely to vaccinate their children if providers recommend the vaccine.¹¹ As women’s health care providers, we do not always see children during the time period that is ideal for vaccination. However, we take care of many women who are presenting for routine gynecologic care, pregnancy, or with abnormal Pap smear screenings. These are ideal opportunities to educate and offer HPV vaccination to women in the approved age groups, as well as to encourage parents to vaccinate their children.

As with other vaccines, the recommendation should be clear and focused on the cancer prevention benefit. Using methods in which the recommendation is “announced” in a brief statement assuming parents/patients are ready to vaccinate versus open-ended conversations, has been studied as a potentially successful method to increase uptake of HPV vaccination.¹² Additionally, documentation of HPV vaccination status should be built into electronic medical record templates to prompt clinicians to ask and offer HPV vaccination at visits, including postpartum visits.

Dr. Rahangdale is an associate professor of ob.gyn. at the University of North Carolina, Chapel Hill, and is director of the North Carolina Women’s Hospital Cervical Dysplasia Clinic. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Epidemiol. 2008 Jul 15;168(2):123-37.

2. Int J Cancer. 2012 Nov 1;131(9):1969-82.

3. BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.

4. Gynecol Oncol. 2017 Jun. doi. org/10.1016/j.ygyno.2017.03.031.

5. Int J Prev Med. 2017 Jun 1;8:44. doi: 10.4103/ijpvm.IJPVM_413_16.

6. Gynecol Oncol. 2013 Aug;130(2):264-8.

7. Pediatrics. 2012 Nov;130(5):798-805.

8. JAMA Intern Med. 2015 Apr;175(4):617-23.

9. Clin Pediatr (Phila). 2016 Sep;55(10):904-14.

10. MMWR Morb Mortal Wkly Rep. 2015 Jul 31;64(29):784-92.

11. Vaccine. 2016 Feb 24;34(9):1187-92.

12. Pediatrics. 2017 Jan;139(1). pii:e20161764. doi: 10.1542/peds.2016-1764.


 

Human papillomavirus (HPV) is the most common sexually transmitted infection. Exposure is widespread and most individuals clear the infection without symptoms or development of disease. However, a subset of individuals experience persistent infection, a state which can lead to carcinogenesis of lower genital tract malignancies, particularly cervical cancer.¹

jarun011/Thinkstock

Vaccine coverage

Persistent infection with high-risk (oncogenic) HPV is well known to be the cause of cervical cancer. There are two HPV vaccines manufactured for the purposes of cervical cancer, anal cancer, and genital wart prevention (Cervarix and Gardasil). The Cervarix vaccine covers high-risk HPV subtypes 16 and 18 and the Gardasil vaccine prevents both low-risk HPV subtypes 6 and 11, which can cause genital warts, and high-risk HPV subtypes 16, 18, 31, 33, 45, 52 and 58, which cause cervical dysplasia and cancer.

High-risk HPV is also associated with head and neck, vulvar, vaginal, and penile cancers, though the vaccines are not approved by the Food and Drug Administration for prevention of these diseases.²

Vaccination indications

Alex Raths/thinkstockphotos

Since vaccination prevents multiple subtypes of HPV, an individual who has already been exposed will still benefit from protection from other subtypes of HPV through vaccination. HPV vaccination is not approved during pregnancy but can be initiated in the postpartum period when women are engaged in their health care and receiving other vaccinations, such as varicella or the MMR vaccine.

Recommended schedule

Until October 2016, the vaccination schedule was based on a three-dose series (0, 2, and 6 months). Currently, the CDC recommends that children aged under 15 years at the time of first dose may opt for a two-dose series (0 and 6-12 months). For those aged 15-26 years, the three-dose schedule remains the recommended course.

The benefits of two-dose schedule are convenience, cost, and increased likelihood of completion. Data presented at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that rates of cervical dysplasia were equivalent for women who completed a two-dose schedule versus a three-dose schedule.⁴

Efficacy

A recent meta-analysis of clinical trials of the HPV vaccines describe efficacy of 95%-97% in prevention of CIN 1-3.⁵ While its greatest efficacy is in its ability to prevent primary HPV infection, there still is some benefit for individuals who already were exposed to HPV prior to vaccination. As stated previously, women with a history of prior HPV vaccination have lower rates of recurrence of cervical dysplasia after treatment. Additionally, recent research has shown that women who received HPV vaccinations after a LEEP procedure for CIN 2 or 3 experience significantly lower recurrence rates, compared with women who did not receive vaccinations after LEEP (2.5% vs. 8.5%).⁶ This raises the possibility of a therapeutic role for HPV vaccination in women infected with HPV. Prospective studies are currently evaluating this question.

Myths

The most common side effects of the HPV vaccine are pain, redness, or swelling at the injection site. Other known side effects include fever, headache or malaise, nausea, syncope, or muscle/joint pain – similar to other vaccinations. Anaphylaxis is a rare complication.

Some parents and pediatricians report concerns that vaccination could lead to earlier sexual activity. Multiple studies have shown that girls who receive HPV vaccination are no more likely to become pregnant or get a sexually transmitted infection (proxies for intercourse) than are girls who were not vaccinated.^7,8

Maximizing vaccination rates

HPV vaccination rates in the United States lag significantly behind rates in countries with national vaccine programs, such as Australia and Denmark.⁹ Early data from Australia already have shown a decrease in genital warts and CIN 2+ incidence within the 10 years of starting its school-based vaccine program, with approximately 73% of 12- to 15-year-olds having completed the vaccine series.² In contrast, just 40% and 22% of 13- to 17-year-old girls and boys in the United States, respectively, had completed the vaccine series in 2014, according to the CDC.¹⁰

Vaccination gaps between girls and boys are narrowing, and more teens will be able to complete the series with the new two-dose recommendation for those younger than 15 years. However, our current rates of vaccination are significantly lower for HPV than for other routinely recommended adolescent vaccines (such as Tdap and meningococcal) and more must be done to encourage vaccination.

Studies have shown that parents are more likely to vaccinate their children if providers recommend the vaccine.¹¹ As women’s health care providers, we do not always see children during the time period that is ideal for vaccination. However, we take care of many women who are presenting for routine gynecologic care, pregnancy, or with abnormal Pap smear screenings. These are ideal opportunities to educate and offer HPV vaccination to women in the approved age groups, as well as to encourage parents to vaccinate their children.

As with other vaccines, the recommendation should be clear and focused on the cancer prevention benefit. Using methods in which the recommendation is “announced” in a brief statement assuming parents/patients are ready to vaccinate versus open-ended conversations, has been studied as a potentially successful method to increase uptake of HPV vaccination.¹² Additionally, documentation of HPV vaccination status should be built into electronic medical record templates to prompt clinicians to ask and offer HPV vaccination at visits, including postpartum visits.

Dr. Rahangdale is an associate professor of ob.gyn. at the University of North Carolina, Chapel Hill, and is director of the North Carolina Women’s Hospital Cervical Dysplasia Clinic. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Epidemiol. 2008 Jul 15;168(2):123-37.

2. Int J Cancer. 2012 Nov 1;131(9):1969-82.

3. BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.

4. Gynecol Oncol. 2017 Jun. doi. org/10.1016/j.ygyno.2017.03.031.

5. Int J Prev Med. 2017 Jun 1;8:44. doi: 10.4103/ijpvm.IJPVM_413_16.

6. Gynecol Oncol. 2013 Aug;130(2):264-8.

7. Pediatrics. 2012 Nov;130(5):798-805.

8. JAMA Intern Med. 2015 Apr;175(4):617-23.

9. Clin Pediatr (Phila). 2016 Sep;55(10):904-14.

10. MMWR Morb Mortal Wkly Rep. 2015 Jul 31;64(29):784-92.

11. Vaccine. 2016 Feb 24;34(9):1187-92.

12. Pediatrics. 2017 Jan;139(1). pii:e20161764. doi: 10.1542/peds.2016-1764.


 

Human papillomavirus (HPV) is the most common sexually transmitted infection. Exposure is widespread and most individuals clear the infection without symptoms or development of disease. However, a subset of individuals experience persistent infection, a state which can lead to carcinogenesis of lower genital tract malignancies, particularly cervical cancer.¹

jarun011/Thinkstock

Vaccine coverage

Persistent infection with high-risk (oncogenic) HPV is well known to be the cause of cervical cancer. There are two HPV vaccines manufactured for the purposes of cervical cancer, anal cancer, and genital wart prevention (Cervarix and Gardasil). The Cervarix vaccine covers high-risk HPV subtypes 16 and 18 and the Gardasil vaccine prevents both low-risk HPV subtypes 6 and 11, which can cause genital warts, and high-risk HPV subtypes 16, 18, 31, 33, 45, 52 and 58, which cause cervical dysplasia and cancer.

High-risk HPV is also associated with head and neck, vulvar, vaginal, and penile cancers, though the vaccines are not approved by the Food and Drug Administration for prevention of these diseases.²

Vaccination indications

Alex Raths/thinkstockphotos

Since vaccination prevents multiple subtypes of HPV, an individual who has already been exposed will still benefit from protection from other subtypes of HPV through vaccination. HPV vaccination is not approved during pregnancy but can be initiated in the postpartum period when women are engaged in their health care and receiving other vaccinations, such as varicella or the MMR vaccine.

Recommended schedule

Until October 2016, the vaccination schedule was based on a three-dose series (0, 2, and 6 months). Currently, the CDC recommends that children aged under 15 years at the time of first dose may opt for a two-dose series (0 and 6-12 months). For those aged 15-26 years, the three-dose schedule remains the recommended course.

The benefits of two-dose schedule are convenience, cost, and increased likelihood of completion. Data presented at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that rates of cervical dysplasia were equivalent for women who completed a two-dose schedule versus a three-dose schedule.⁴

Efficacy

A recent meta-analysis of clinical trials of the HPV vaccines describe efficacy of 95%-97% in prevention of CIN 1-3.⁵ While its greatest efficacy is in its ability to prevent primary HPV infection, there still is some benefit for individuals who already were exposed to HPV prior to vaccination. As stated previously, women with a history of prior HPV vaccination have lower rates of recurrence of cervical dysplasia after treatment. Additionally, recent research has shown that women who received HPV vaccinations after a LEEP procedure for CIN 2 or 3 experience significantly lower recurrence rates, compared with women who did not receive vaccinations after LEEP (2.5% vs. 8.5%).⁶ This raises the possibility of a therapeutic role for HPV vaccination in women infected with HPV. Prospective studies are currently evaluating this question.

Myths

The most common side effects of the HPV vaccine are pain, redness, or swelling at the injection site. Other known side effects include fever, headache or malaise, nausea, syncope, or muscle/joint pain – similar to other vaccinations. Anaphylaxis is a rare complication.

Some parents and pediatricians report concerns that vaccination could lead to earlier sexual activity. Multiple studies have shown that girls who receive HPV vaccination are no more likely to become pregnant or get a sexually transmitted infection (proxies for intercourse) than are girls who were not vaccinated.^7,8

Maximizing vaccination rates

HPV vaccination rates in the United States lag significantly behind rates in countries with national vaccine programs, such as Australia and Denmark.⁹ Early data from Australia already have shown a decrease in genital warts and CIN 2+ incidence within the 10 years of starting its school-based vaccine program, with approximately 73% of 12- to 15-year-olds having completed the vaccine series.² In contrast, just 40% and 22% of 13- to 17-year-old girls and boys in the United States, respectively, had completed the vaccine series in 2014, according to the CDC.¹⁰

Vaccination gaps between girls and boys are narrowing, and more teens will be able to complete the series with the new two-dose recommendation for those younger than 15 years. However, our current rates of vaccination are significantly lower for HPV than for other routinely recommended adolescent vaccines (such as Tdap and meningococcal) and more must be done to encourage vaccination.

Studies have shown that parents are more likely to vaccinate their children if providers recommend the vaccine.¹¹ As women’s health care providers, we do not always see children during the time period that is ideal for vaccination. However, we take care of many women who are presenting for routine gynecologic care, pregnancy, or with abnormal Pap smear screenings. These are ideal opportunities to educate and offer HPV vaccination to women in the approved age groups, as well as to encourage parents to vaccinate their children.

As with other vaccines, the recommendation should be clear and focused on the cancer prevention benefit. Using methods in which the recommendation is “announced” in a brief statement assuming parents/patients are ready to vaccinate versus open-ended conversations, has been studied as a potentially successful method to increase uptake of HPV vaccination.¹² Additionally, documentation of HPV vaccination status should be built into electronic medical record templates to prompt clinicians to ask and offer HPV vaccination at visits, including postpartum visits.

Dr. Rahangdale is an associate professor of ob.gyn. at the University of North Carolina, Chapel Hill, and is director of the North Carolina Women’s Hospital Cervical Dysplasia Clinic. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Epidemiol. 2008 Jul 15;168(2):123-37.

2. Int J Cancer. 2012 Nov 1;131(9):1969-82.

3. BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.

4. Gynecol Oncol. 2017 Jun. doi. org/10.1016/j.ygyno.2017.03.031.

5. Int J Prev Med. 2017 Jun 1;8:44. doi: 10.4103/ijpvm.IJPVM_413_16.

6. Gynecol Oncol. 2013 Aug;130(2):264-8.

7. Pediatrics. 2012 Nov;130(5):798-805.

8. JAMA Intern Med. 2015 Apr;175(4):617-23.

9. Clin Pediatr (Phila). 2016 Sep;55(10):904-14.

10. MMWR Morb Mortal Wkly Rep. 2015 Jul 31;64(29):784-92.

11. Vaccine. 2016 Feb 24;34(9):1187-92.

12. Pediatrics. 2017 Jan;139(1). pii:e20161764. doi: 10.1542/peds.2016-1764.


 

The Ebola epidemic of 2014-2016 challenged many federal agencies to find creative ways to help address the vexing problems created by the spread of the disease. There were many factors complicating the response, including the recovery from civil wars in Liberia and Sierra Leone that decimated the physical infrastructure as well as education and other vital services.

The response from the U.S. and the global community took many forms: Not only was there a need for the typical medical care support, but also for basic public health systems to track the spread of disease, provide clean water, and dispose of infectious waste. Because no known preventive vaccines or therapeutics existed for those infected, the recognition of a research component to the response became abundantly clear as the epidemic continued. As a result, the National Institutes of Health (NIH) and the USPHS Commissioned Corps (Corps) serendipitously found themselves allied in a mutually beneficial relationship in the establishment of an Ebola clinical research program in West Africa.

This article describes the events that led to the NIH and Corps participation in the Ebola response, the roles filled by the Corps in supporting the NIH, and the lessons observed from that collaboration. Also presented are considerations regarding preparation of a clinical research response to future outbreaks.

NIH Clinical Research first Response

The 2014-2016 Ebola epidemic in West Africa demonstrated the need for federal agencies to reassess their capacity to respond to global threats to protect the health security of the U.S.¹ The outbreak also challenged the U.S. government to mobilize unique resources that matched the need of this international (and domestic) response.

In 2014, President Barack Obama announced that the U.S. would launch a government response to the Ebola effort. Although a comprehensive research and development program already was in place to establish Ebola virus disease (EVD) countermeasures, no FDA-approved diagnostics, therapeutics, or preventive vaccines were readily available. Fortunately, FDA regulations regarding emergency use authorizations allowed for the use of several EVD diagnostics during this outbreak.² However, the development of drugs and vaccines specific to Ebola had yet to make their way to phase 1 safety studies.

Two vaccine products went into phase 1 studies in the U.S. within months of the declaration of the emergency.^3,4 Additionally, the NIH had organized a collaborative effort between the U.S. government and academic community to identify a research strategy for the evaluation of therapeutics.⁵ Regardless of the state of countermeasures and research proposals, the initial need was for disease control measures and care for Ebola patients. The CDC took the lead in working within the international community to establish an incident management system that could help the impacted countries enact mechanisms to bring the epidemic under control.⁶

As the epidemic progressed, leaders in the Corps and the NIH responded on pathways that eventually would intersect. One of the unfortunate outcomes of the early efforts of improperly protected health care providers was the unintentional transmission of Ebola.⁷ The Corps identified the need to provide high-level care to the health care worker community as one incentive to motivate health care workers to volunteer for hazardous duty inside Ebola treatment units (ETUs).^8,9 Engulfed in the epidemic response, the U.S. government through the National Security Council and secretary of the Department of Health and Human Services (DHHS) evoked its statutory authority to deploy the Corps (42 U.S. Code 204a).

In the first week of October 2014, the Corps sent an advanced echelon team to assess the situation, partner with key host country and international stakeholders, and begin establishment of the U.S. government’s first ever ETU. With logistics, security, and resource support from the DoD and response coordination from the U.S. Agency for International Development, the Corps then deployed the first of four 70-person team rotations to staff the Monrovia Medical Unit (MMU), an ETU specifically dedicated to the treatment of Ebola-infected health care workers. At the time, it was the only ETU specifically dedicated to health care workers in all of Africa. The MMU operated until May 2015 and provided direct patient care for health care workers with Ebola, malaria, and other illnesses.^8,10

In August 2014, representatives from the CDC met with Liberia’s Minister of Health and Social Welfare Walter T. Gwenigale, MD, to discuss the range of available options that could facilitate a better understanding of the prevention and treatment of the disease. This meeting resulted in a letter dated August 22, 2014, from Dr. Gwenigale to then DHHS Sylvia Burwell, requesting a research response. Secretary Burwell responded on October 2, 2014, describing the immediate dispatch of the deputy director for clinical research of the National Institute of Allergy and Infectious Diseases (NIAID) to Liberia to engage in initial discussions with the Liberian minister and other key Liberians involved in the response.

Representatives from the CDC and the commander of the Corps’ Ebola response (and acting deputy surgeon general) were included in those initial meetings, which led to a recognized need for a robust clinical research program of the highest ethical and scientific standards consistent with the expressed requirements of Liberia.¹¹ A second and third trip to Liberia with larger U.S. teams resulted in an agreement signed on November 19, 2014 for the scientific investigation of strategies that tested interventions for treatment, control, and prevention of Ebola.¹²

The agreement led to the establishment of the Partnership for Research on Ebola Virus in Liberia (PREVAIL) to identify research priorities in a collaborative manner between Liberian and American scientists. The first protocol, a vaccine study, was launched in early February 2015.¹² This monumental task involved the support of hundreds of Liberians and dozens of NIH staff who volunteered for rotations to Liberia. Of the 108 volunteers from within the NIH, 18 were PHS officers. 
Shortly after launching the vaccine study, the next priority was initiating the treatment study. This study was delayed primarily due to ZMapp (Mapp Biopharmaceatical, San Diego,CA) production limitations. ZMapp, a monoclonal antibody cocktail, was the first Ebola therapeutic product to be evaluated in a randomized trial.^5,13

During the planning for the study, NIAID staff in Liberia met with Corps staff of the MMU to discuss the logistics associated with implementation of the ZMapp protocol at the MMU. During that meeting, the NIAID deputy director for clinical research expressed interest in obtaining Corps support from outside the NIH to sustain the research effort in West Africa. More specifically, additional pharmacy and laboratory staff were needed to augment NIH research operations. At the time, the MMU commander had recently transitioned from service as the acting surgeon general and was in a unique position to recommend additional Corps resources that could help in the research response.

The February 2015 discussion resulted in the establishment of an NIH/PHS research partnership that continues to exist. This new opportunity was not a significant stretch for the PHS as there was great interest from the Corps for responding to the Ebola crisis. The enthusiasm was consistent with the overall ethos of the Corps, which as a service was composed of highly qualified active-duty, deployable, uniformed, public health professionals who respond to public health crises at home and abroad. To date, 19 Corps officers from outside the NIH have deployed in support of the NIH Ebola clinical research program. An additional 18 Corps officers assigned within the NIH also volunteered for duty in West Africa. Of the 37 Corps officers supporting the NIH clinical research program, 7 served on more than 1 rotation.

Program Expansion

The Ebola clinical research program expanded over time from the initial PREVAIL vaccine study to include studies of therapeutic agents, natural history in Ebola survivors, and an additional vaccine study. The PHS officers have been integral in conducting these studies. The initial study implemented in Liberia, known as PREVAIL I, involved the evaluation of 2 vaccine strategies vs placebo.^12,14 In addition to the NIH-based Corps officers supporting the study, the Readiness and Deployment Operations Group (RedDOG) initiated deployments for an additional 2 pharmacy and 7 laboratory officers to support this study. During the deployment, the pharmacists were asked to extend their reach to Sierra Leone and later to Guinea to help establish PREVAIL II, an evaluation of ZMapp in the treatment of Ebola.¹³ A total of 9 Corps pharmacists, 2 nurses, and 3 physicians deployed to Sierra Leone or Guinea to assist in the PREVAIL II study.

As the epidemic came to an end in Liberia in May 2015, the need for a long-term assessment of Ebola survivors was recognized, resulting in PREVAIL III.¹⁵ Noteworthy in the survivor study was an ophthalmic substudy led by a Corps officer assigned to the National Eye Institute.^16,17 The survivor study also identified that the persistence of the Ebola virus was longer than previously known and that sexual transmission via semen from infected males remained a potential mode of transmission.¹⁸ To address the lingering viral load, a study of an antiviral drug was initiated in Liberia in the summer of 2016, PREVAIL IV.¹⁹

Four Corps pharmacists helped train Liberian pharmacists to establish and sustain this randomized, double-blind, placebo-controlled study. Most recently, Corps pharmacists were deployed to support the initiation of the Partnership for Research on Ebola Vaccines (PREVAC), a collaborative partnership with researchers from Liberia, Guinea, and Sierra Leone with cosponsors from the NIH, Institut national de la santé et de la recherche médicale (Inserm) in France, and the London School of Hygiene and Tropical Medicine in the United Kingdom.²⁰

Deployment Procedures

As previously mentioned, 108 staff (civil service, assigned PHS, and contractors) from within the NIH volunteered for deployment to assist in the clinical research Ebola response. The typical rotation for those volunteers was limited to 3 weeks to minimize the disruption of their normal work assignments. Volunteers were organized into small teams within the Division of Clinical Research were composed of the right mix of physicians, nurses, medical technologists, and pharmacists. The team ensured that staff obtained official government passports, scheduled airline reservations, and received an orientation to the deployment setting as well as to the research studies (Table). Additionally, the team coordinated the voucher submission process for reimbursement of expenses on return from the country. An additional team member was stationed in Liberia to coordinate the housing and transportation arrangements with a local hotel near the U.S. Embassy.

Within a week of the February 2015 initial meeting in Liberia to establish the NIH/PHS collaboration, the NIH deployment team met by phone with the Corps’ RedDOG to discuss initial requirements (eg, number of officers needed, disciplines, time lines, and documentation needed for deployment). These initial discussions resulted in the establishment of more formal processes that evolved over time as the 2 organizations gained experience. Based on the identification of the numbers and types of officers needed, RedDOG used procedures similar to the process for staffing the MMU. A communication went out to the Corps seeking interested officers.

Deployment slots were filled based on the personal availability of the officer and coordination with their immediate supervisor and agency. Officers needed to meet medical clearance requirements and provide current health care provider licensure information. Additional training requirements needed to be completed (eg, U.S. State Department training and good clinical practice [GCP] if not already current). Corps officers also took part in the NIH orientation program for deploying personnel to familiarize them to the situation on the ground in West Africa and the specific clinical research protocols that they would encounter. Given that most of the Corps officers were coming from outside the NIH, the onboarding activities required significant attention to detail as procedures for arranging travel (eg, passport, visa, and airline reservations) and processes for reimbursement of travel/per diem pay differed from more traditional deployments directed through the Corps headquarters.

Commissioned Corps Roles in the Research Response

Whereas the establishment of the research program in Liberia was based primarily on relationships forged over a 2-month period by the NIAID deputy director for clinical research and staff, the extension of the research program into Sierra Leone (March 2015) and Guinea (June 2015) was on a substantially shorter time line. As a result, Corps officers were thrust into roles that immediately employed their leadership and diplomacy skills.

In Sierra Leone and Guinea, the NIAID deputy director for clinical research established initial relationships within the countries. However, Corps officers found themselves in regular interactions with regulators in the Ministry of Health to ensure that applications were complete and import permits for incoming shipments were cleared. Additionally, the research collaboration in Sierra Leone was coordinated through an investigator assigned to a military hospital converted into an ETU. The Corps officers were well suited to maintain and build on that relationship in expanding the protocol to other ETUs throughout Sierra Leone. A site established by the CDC within the Sierra Leone Ministry of Health coordinated ZMapp storage. The Corps officers formed working relationships with the CDC team to establish and improve cold-chain logistics and transportation of the ZMapp to the various ETUs around the country. Corps officers were integral in working with the in-country contract hiring agency. Activities included establishing criteria for clinical research positions, providing input on the interview of respective candidates, and training staff as the team formed. In Sierra Leone, local staff members were hired to work at specific facilities as research coordinators working with the health care delivery teams.

The U.S. team consisted of a physician, nurse research coordinator, and a pharmacist travelling to the sites with a logistics/operations staff member remaining in Freetown.

Fortunately, a Corps nurse on the team had been part of the initial MMU deployment and was trained to work in a special care unit at the NIH for patients with highly contagious infections. This practical experience was essential in the establishment of procedures in a hazardous environment for the administration of the IV ZMapp, monitoring of adverse effects (AEs), provision of medications to mitigate infusion-related reactions, and documentation of those AEs.

The U.S. research team regularly departed Freetown early in the morning 7 days a week with the various supplies needed as they visited up to 4 ETU sites to prepare the ZMapp at the site, await information on any AEs, and collect case report forms (Figures 1 and 2). The ETUs were spread out over a 90-mile radius and could be described as austere platforms for health care delivery.

An additional challenge was dealing with the multinational organizations that staffed the various ETUs. Relief organizations from Italy, the United Kingdom, China, as well as the Sierra Leone military provided the staffing for the 4 ETUs. Regardless of who operated the ETU, the concept of randomization to ZMapp or standard of care required significant tact and diplomacy in communicating the scientific necessity in order to appropriately answer the research question. As Davey and colleagues pointed out, the randomized, controlled trial established the appropriate ethical framework to determine whether the research intervention was associated with harmful effects as there had not been a phase 1 safety study with the drug.¹³

As the summer approached in Sierra Leone, the team worked through challenges in the IV administration of ZMapp as the protein structure of the monoclonal antibody had not previously been subjected to West African environmental extremes. A balance between speed of administration to prevent protein aggregation in the heat as opposed to the risk of infusion reactions from a foreign protein required the team to communicate frequently with, the manufacturer of ZMapp, to establish realistic infusion rate tables. Additionally, as the various deployment teams rotated in and out, procedures for establishing continuity of research operations were enacted and improved on with each rotation. Good documentation practices to adequately collect all required study information (eg, recording AEs, deviations, and signatures on various forms) proved critical to continuity of research operations.

In Guinea, not only was there the new wrinkle of working within a country where the primary language was French, but also a French cosponsor, Inserm. The NIAID clinical director capitalized on the research infrastructure established for a recently completed Inserm study of favipiravir in the treatment of Ebola to extend the ZMapp study to Guinea. Fortunately, many of the Inserm staff were bilingual and readily responded to the NIH training on the requirements of the ZMapp protocol. However, procedures for cold-chain storage and transportation needed to be established. In Guinea, the PHS officers were key in establishing access and temperature monitoring procedures for a secure room inside the U.S. embassy. The issues associated with cold-chain procedures in the infrastructure-limited environments of West Africa are substantial and warrant consideration of a stand-alone paper. Corps officers also took part in weekly country-focused team meetings with embassy staff to describe progress with the ZMapp study.

As the epidemic waned and NIH transitioned to the survivor and viral persistence studies, the operational tempo changed to allow Corps officers to take part in more definitive capacity building efforts. An initial PHS volunteer from the FDA accepted a position within NIAID as a clinical research oversight manager for pharmacy operations. This individual deployed on numerous occasions to the 3 affected West African countries to further establish cold-chain processes for pharmaceuticals and biologics. He also worked with a multidisciplinary team to renovate a clinical research facility in a rural setting in Guinea. In Liberia, he coordinated an effort with other Corps officers to provide educational seminars on clinical research principles and drug-specific topics with the University of Liberia School of Pharmacy.

Challenges

In each instance, the partnership experience was not without a few problems. The match of skills between the officers who wanted to help and those needed for the research program did not always coincide. While the Corps has more than 1,200 pharmacy officers on active duty, only a fraction of those have experience conducting FDA-regulated clinical research.

Communication problems and time pressures were also constant companions to both the Corps and the NIH. The Corps was going through the largest international deployment in its history to staff multiple missions (including the primary MMU mission in Liberia). The addition of the NIH partnership, while consistent with the MMU staffing mission, provided even more work for a very limited resource. Communicating to the many Corps officers who wanted to volunteer and keeping deployment time lines on track were a challenge. Complicating the matter was the addition of stray e-mails from well-intentioned NIH and Corps staff who communicated directly with colleagues to encourage participation, not fully understanding the policies and protocol governing the deployment process.

Time was always an issue as the rotation schedules were relatively short and the number of activities to make an officer deployment ready were numerous. Obtaining official passports and visas was a challenge as that activity required coordination with the U.S. Department of State. Airline schedules changed with little or no notice, complicating deployments and returns. As the NIH added additional research studies for which support was required, time lines for studies to start became difficult to predict with certainty due to factors outside the control of the NIH. Recently, additional security training requirements for government workers traveling abroad were instituted, further complicating the process of deploying an officer.

The Corps officers taking part in this research response (which was not consistent with customary deployments from Corps headquarters) necessarily were volunteers from full-time assignments within DHHS, and as such, required the permission of their supervisory chain to volunteer. Regardless of this limitation, there was widespread support for these additional and specific research deployments. Although the use of short-term rotations was not ideal, in the end, the rotation plans worked, and the NIH was able to fulfill its research mission with the support of the Corps.

Lessons Learned/Preparing for the Future

Many lessons have been learned and continue to be learned throughout this research response and NIH/Corps partnership. Effective and frequent communication between the organization requesting Corps officers and the Corps headquarters is crucial. In the initial deployments, officers were deployed from the FDA with the assumption that they would be familiar with FDA-regulated clinical research. This was not always the case. The NIH and Corps headquarters later collaborated to develop a survey to send to Corps officers that was used to identify specific skill sets needed by officers who would be deploying to conduct clinical research. NIH personnel prescreened survey responses to identify and prioritize officers for deployment consideration by the deployment authority. This process resulted in the selection of officers who generally needed less training and guidance.

Effective training in clinical research principles for deployed officers and other staff needs to be developed and made available to all deploying individuals. All clinical research staff are required to have training on GCP, but most GCP training programs focus primarily on the ethical principles of research as outlined by the Declaration of Helsinki, Nuremberg Code, and other documents. Few GCP training programs present adequate information on the hands-on conduct of clinical research, especially research regulated by the FDA and other government bodies and therefore subject to certain strict requirements. Examples of crucial but often overlooked topics are source document retention, good documentation practices, cold-chain principles, and other issues related to the creation and retention of adequate trial records.²¹

The handoff between returning and deploying officers is crucial. Due to various issues with changing time lines, flights, and administrative processes, it is imperative to plan adequate overlap between returning and deploying officers. Delays in obtaining passports or visas, flight cancellations, and other unforeseen issues may unexpectedly shorten any planned overlap periods. A full workweek is desirable for overlap so that the new officer may experience tasks that occur throughout the week, be introduced to the various team members, and have help if unexpected events occur. A regular staff member should check periodically that proper procedures are being followed, as some information may be missed during each handoff, and consecutive unchecked handoffs could result in large deviations of important procedures. Onboarding and offboarding checklists should be developed and updated regularly to guide the handoff process.

On a larger scale, the respective agencies and other stakeholders involved in planning clinical research for public health emergencies need to be included in regular tabletop training exercises to better understand how to coordinate a response when needed. Additionally, although many of the Corps officers who took part in this deployment served as mentors for others preparing for deployment, establishing a formal roster of experienced officers to support specific roles of this type of response would help serve as a resource center for future deployments. Finally, coordination between any operating division (or agency) and the Corps should be through the established Corps command infrastructure to eliminate miscommunication and complicating deployment processes.²²

Conclusion

The increasing connectedness of this world, as demonstrated by the Ebola epidemic, requires that the HHS engage globally to provide international leadership and technical expertise in science, policy, and programs and work in concert with interagency partners.²³ The missions of the PHS and NIH intersected in a synergistic manner in the research response to the Ebola epidemic of 2014-2016. The PHS Corps mission includes to “protect, promote, and advance the health and safety of the Nation...through rapid and effective response…and advancement of public health science.”²⁴ The Corps mission directly supported the NIH mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.²⁵

The scope and scale of DHHS’s response to the Ebola epidemic was unprecedented. The NIH research program, although successful and an important component, was but a small part in bringing the Ebola crisis to an end. The CDC (including the many Corps officers assigned to that agency) worked successfully with the international community and the host countries to bring the disease under control. The Biological Advanced Research and Development Authority provided expert project management, making vaccines and therapeutics available for research.

The DoD was a partner in the development of countermeasures and phase 1 clinical research programs as well as establishing laboratory facilities in Liberia. The Department of State facilitated the many interactions required for the mobilization of resources into West Africa. The collective efforts of the U.S. government contributed immensely to the protection of U.S. borders and to the successful resolution of the Ebola outbreak of 2014-2016.

The Ebola epidemic of 2014-2016 challenged many federal agencies to find creative ways to help address the vexing problems created by the spread of the disease. There were many factors complicating the response, including the recovery from civil wars in Liberia and Sierra Leone that decimated the physical infrastructure as well as education and other vital services.

The response from the U.S. and the global community took many forms: Not only was there a need for the typical medical care support, but also for basic public health systems to track the spread of disease, provide clean water, and dispose of infectious waste. Because no known preventive vaccines or therapeutics existed for those infected, the recognition of a research component to the response became abundantly clear as the epidemic continued. As a result, the National Institutes of Health (NIH) and the USPHS Commissioned Corps (Corps) serendipitously found themselves allied in a mutually beneficial relationship in the establishment of an Ebola clinical research program in West Africa.

This article describes the events that led to the NIH and Corps participation in the Ebola response, the roles filled by the Corps in supporting the NIH, and the lessons observed from that collaboration. Also presented are considerations regarding preparation of a clinical research response to future outbreaks.

NIH Clinical Research first Response

The 2014-2016 Ebola epidemic in West Africa demonstrated the need for federal agencies to reassess their capacity to respond to global threats to protect the health security of the U.S.¹ The outbreak also challenged the U.S. government to mobilize unique resources that matched the need of this international (and domestic) response.

In 2014, President Barack Obama announced that the U.S. would launch a government response to the Ebola effort. Although a comprehensive research and development program already was in place to establish Ebola virus disease (EVD) countermeasures, no FDA-approved diagnostics, therapeutics, or preventive vaccines were readily available. Fortunately, FDA regulations regarding emergency use authorizations allowed for the use of several EVD diagnostics during this outbreak.² However, the development of drugs and vaccines specific to Ebola had yet to make their way to phase 1 safety studies.

Two vaccine products went into phase 1 studies in the U.S. within months of the declaration of the emergency.^3,4 Additionally, the NIH had organized a collaborative effort between the U.S. government and academic community to identify a research strategy for the evaluation of therapeutics.⁵ Regardless of the state of countermeasures and research proposals, the initial need was for disease control measures and care for Ebola patients. The CDC took the lead in working within the international community to establish an incident management system that could help the impacted countries enact mechanisms to bring the epidemic under control.⁶

As the epidemic progressed, leaders in the Corps and the NIH responded on pathways that eventually would intersect. One of the unfortunate outcomes of the early efforts of improperly protected health care providers was the unintentional transmission of Ebola.⁷ The Corps identified the need to provide high-level care to the health care worker community as one incentive to motivate health care workers to volunteer for hazardous duty inside Ebola treatment units (ETUs).^8,9 Engulfed in the epidemic response, the U.S. government through the National Security Council and secretary of the Department of Health and Human Services (DHHS) evoked its statutory authority to deploy the Corps (42 U.S. Code 204a).

In the first week of October 2014, the Corps sent an advanced echelon team to assess the situation, partner with key host country and international stakeholders, and begin establishment of the U.S. government’s first ever ETU. With logistics, security, and resource support from the DoD and response coordination from the U.S. Agency for International Development, the Corps then deployed the first of four 70-person team rotations to staff the Monrovia Medical Unit (MMU), an ETU specifically dedicated to the treatment of Ebola-infected health care workers. At the time, it was the only ETU specifically dedicated to health care workers in all of Africa. The MMU operated until May 2015 and provided direct patient care for health care workers with Ebola, malaria, and other illnesses.^8,10

In August 2014, representatives from the CDC met with Liberia’s Minister of Health and Social Welfare Walter T. Gwenigale, MD, to discuss the range of available options that could facilitate a better understanding of the prevention and treatment of the disease. This meeting resulted in a letter dated August 22, 2014, from Dr. Gwenigale to then DHHS Sylvia Burwell, requesting a research response. Secretary Burwell responded on October 2, 2014, describing the immediate dispatch of the deputy director for clinical research of the National Institute of Allergy and Infectious Diseases (NIAID) to Liberia to engage in initial discussions with the Liberian minister and other key Liberians involved in the response.

Representatives from the CDC and the commander of the Corps’ Ebola response (and acting deputy surgeon general) were included in those initial meetings, which led to a recognized need for a robust clinical research program of the highest ethical and scientific standards consistent with the expressed requirements of Liberia.¹¹ A second and third trip to Liberia with larger U.S. teams resulted in an agreement signed on November 19, 2014 for the scientific investigation of strategies that tested interventions for treatment, control, and prevention of Ebola.¹²

The agreement led to the establishment of the Partnership for Research on Ebola Virus in Liberia (PREVAIL) to identify research priorities in a collaborative manner between Liberian and American scientists. The first protocol, a vaccine study, was launched in early February 2015.¹² This monumental task involved the support of hundreds of Liberians and dozens of NIH staff who volunteered for rotations to Liberia. Of the 108 volunteers from within the NIH, 18 were PHS officers. 
Shortly after launching the vaccine study, the next priority was initiating the treatment study. This study was delayed primarily due to ZMapp (Mapp Biopharmaceatical, San Diego,CA) production limitations. ZMapp, a monoclonal antibody cocktail, was the first Ebola therapeutic product to be evaluated in a randomized trial.^5,13

During the planning for the study, NIAID staff in Liberia met with Corps staff of the MMU to discuss the logistics associated with implementation of the ZMapp protocol at the MMU. During that meeting, the NIAID deputy director for clinical research expressed interest in obtaining Corps support from outside the NIH to sustain the research effort in West Africa. More specifically, additional pharmacy and laboratory staff were needed to augment NIH research operations. At the time, the MMU commander had recently transitioned from service as the acting surgeon general and was in a unique position to recommend additional Corps resources that could help in the research response.

The February 2015 discussion resulted in the establishment of an NIH/PHS research partnership that continues to exist. This new opportunity was not a significant stretch for the PHS as there was great interest from the Corps for responding to the Ebola crisis. The enthusiasm was consistent with the overall ethos of the Corps, which as a service was composed of highly qualified active-duty, deployable, uniformed, public health professionals who respond to public health crises at home and abroad. To date, 19 Corps officers from outside the NIH have deployed in support of the NIH Ebola clinical research program. An additional 18 Corps officers assigned within the NIH also volunteered for duty in West Africa. Of the 37 Corps officers supporting the NIH clinical research program, 7 served on more than 1 rotation.

Program Expansion

The Ebola clinical research program expanded over time from the initial PREVAIL vaccine study to include studies of therapeutic agents, natural history in Ebola survivors, and an additional vaccine study. The PHS officers have been integral in conducting these studies. The initial study implemented in Liberia, known as PREVAIL I, involved the evaluation of 2 vaccine strategies vs placebo.^12,14 In addition to the NIH-based Corps officers supporting the study, the Readiness and Deployment Operations Group (RedDOG) initiated deployments for an additional 2 pharmacy and 7 laboratory officers to support this study. During the deployment, the pharmacists were asked to extend their reach to Sierra Leone and later to Guinea to help establish PREVAIL II, an evaluation of ZMapp in the treatment of Ebola.¹³ A total of 9 Corps pharmacists, 2 nurses, and 3 physicians deployed to Sierra Leone or Guinea to assist in the PREVAIL II study.

As the epidemic came to an end in Liberia in May 2015, the need for a long-term assessment of Ebola survivors was recognized, resulting in PREVAIL III.¹⁵ Noteworthy in the survivor study was an ophthalmic substudy led by a Corps officer assigned to the National Eye Institute.^16,17 The survivor study also identified that the persistence of the Ebola virus was longer than previously known and that sexual transmission via semen from infected males remained a potential mode of transmission.¹⁸ To address the lingering viral load, a study of an antiviral drug was initiated in Liberia in the summer of 2016, PREVAIL IV.¹⁹

Four Corps pharmacists helped train Liberian pharmacists to establish and sustain this randomized, double-blind, placebo-controlled study. Most recently, Corps pharmacists were deployed to support the initiation of the Partnership for Research on Ebola Vaccines (PREVAC), a collaborative partnership with researchers from Liberia, Guinea, and Sierra Leone with cosponsors from the NIH, Institut national de la santé et de la recherche médicale (Inserm) in France, and the London School of Hygiene and Tropical Medicine in the United Kingdom.²⁰

Deployment Procedures

As previously mentioned, 108 staff (civil service, assigned PHS, and contractors) from within the NIH volunteered for deployment to assist in the clinical research Ebola response. The typical rotation for those volunteers was limited to 3 weeks to minimize the disruption of their normal work assignments. Volunteers were organized into small teams within the Division of Clinical Research were composed of the right mix of physicians, nurses, medical technologists, and pharmacists. The team ensured that staff obtained official government passports, scheduled airline reservations, and received an orientation to the deployment setting as well as to the research studies (Table). Additionally, the team coordinated the voucher submission process for reimbursement of expenses on return from the country. An additional team member was stationed in Liberia to coordinate the housing and transportation arrangements with a local hotel near the U.S. Embassy.

Within a week of the February 2015 initial meeting in Liberia to establish the NIH/PHS collaboration, the NIH deployment team met by phone with the Corps’ RedDOG to discuss initial requirements (eg, number of officers needed, disciplines, time lines, and documentation needed for deployment). These initial discussions resulted in the establishment of more formal processes that evolved over time as the 2 organizations gained experience. Based on the identification of the numbers and types of officers needed, RedDOG used procedures similar to the process for staffing the MMU. A communication went out to the Corps seeking interested officers.

Deployment slots were filled based on the personal availability of the officer and coordination with their immediate supervisor and agency. Officers needed to meet medical clearance requirements and provide current health care provider licensure information. Additional training requirements needed to be completed (eg, U.S. State Department training and good clinical practice [GCP] if not already current). Corps officers also took part in the NIH orientation program for deploying personnel to familiarize them to the situation on the ground in West Africa and the specific clinical research protocols that they would encounter. Given that most of the Corps officers were coming from outside the NIH, the onboarding activities required significant attention to detail as procedures for arranging travel (eg, passport, visa, and airline reservations) and processes for reimbursement of travel/per diem pay differed from more traditional deployments directed through the Corps headquarters.

Commissioned Corps Roles in the Research Response

Whereas the establishment of the research program in Liberia was based primarily on relationships forged over a 2-month period by the NIAID deputy director for clinical research and staff, the extension of the research program into Sierra Leone (March 2015) and Guinea (June 2015) was on a substantially shorter time line. As a result, Corps officers were thrust into roles that immediately employed their leadership and diplomacy skills.

In Sierra Leone and Guinea, the NIAID deputy director for clinical research established initial relationships within the countries. However, Corps officers found themselves in regular interactions with regulators in the Ministry of Health to ensure that applications were complete and import permits for incoming shipments were cleared. Additionally, the research collaboration in Sierra Leone was coordinated through an investigator assigned to a military hospital converted into an ETU. The Corps officers were well suited to maintain and build on that relationship in expanding the protocol to other ETUs throughout Sierra Leone. A site established by the CDC within the Sierra Leone Ministry of Health coordinated ZMapp storage. The Corps officers formed working relationships with the CDC team to establish and improve cold-chain logistics and transportation of the ZMapp to the various ETUs around the country. Corps officers were integral in working with the in-country contract hiring agency. Activities included establishing criteria for clinical research positions, providing input on the interview of respective candidates, and training staff as the team formed. In Sierra Leone, local staff members were hired to work at specific facilities as research coordinators working with the health care delivery teams.

The U.S. team consisted of a physician, nurse research coordinator, and a pharmacist travelling to the sites with a logistics/operations staff member remaining in Freetown.

Fortunately, a Corps nurse on the team had been part of the initial MMU deployment and was trained to work in a special care unit at the NIH for patients with highly contagious infections. This practical experience was essential in the establishment of procedures in a hazardous environment for the administration of the IV ZMapp, monitoring of adverse effects (AEs), provision of medications to mitigate infusion-related reactions, and documentation of those AEs.

The U.S. research team regularly departed Freetown early in the morning 7 days a week with the various supplies needed as they visited up to 4 ETU sites to prepare the ZMapp at the site, await information on any AEs, and collect case report forms (Figures 1 and 2). The ETUs were spread out over a 90-mile radius and could be described as austere platforms for health care delivery.

An additional challenge was dealing with the multinational organizations that staffed the various ETUs. Relief organizations from Italy, the United Kingdom, China, as well as the Sierra Leone military provided the staffing for the 4 ETUs. Regardless of who operated the ETU, the concept of randomization to ZMapp or standard of care required significant tact and diplomacy in communicating the scientific necessity in order to appropriately answer the research question. As Davey and colleagues pointed out, the randomized, controlled trial established the appropriate ethical framework to determine whether the research intervention was associated with harmful effects as there had not been a phase 1 safety study with the drug.¹³

As the summer approached in Sierra Leone, the team worked through challenges in the IV administration of ZMapp as the protein structure of the monoclonal antibody had not previously been subjected to West African environmental extremes. A balance between speed of administration to prevent protein aggregation in the heat as opposed to the risk of infusion reactions from a foreign protein required the team to communicate frequently with, the manufacturer of ZMapp, to establish realistic infusion rate tables. Additionally, as the various deployment teams rotated in and out, procedures for establishing continuity of research operations were enacted and improved on with each rotation. Good documentation practices to adequately collect all required study information (eg, recording AEs, deviations, and signatures on various forms) proved critical to continuity of research operations.

In Guinea, not only was there the new wrinkle of working within a country where the primary language was French, but also a French cosponsor, Inserm. The NIAID clinical director capitalized on the research infrastructure established for a recently completed Inserm study of favipiravir in the treatment of Ebola to extend the ZMapp study to Guinea. Fortunately, many of the Inserm staff were bilingual and readily responded to the NIH training on the requirements of the ZMapp protocol. However, procedures for cold-chain storage and transportation needed to be established. In Guinea, the PHS officers were key in establishing access and temperature monitoring procedures for a secure room inside the U.S. embassy. The issues associated with cold-chain procedures in the infrastructure-limited environments of West Africa are substantial and warrant consideration of a stand-alone paper. Corps officers also took part in weekly country-focused team meetings with embassy staff to describe progress with the ZMapp study.

As the epidemic waned and NIH transitioned to the survivor and viral persistence studies, the operational tempo changed to allow Corps officers to take part in more definitive capacity building efforts. An initial PHS volunteer from the FDA accepted a position within NIAID as a clinical research oversight manager for pharmacy operations. This individual deployed on numerous occasions to the 3 affected West African countries to further establish cold-chain processes for pharmaceuticals and biologics. He also worked with a multidisciplinary team to renovate a clinical research facility in a rural setting in Guinea. In Liberia, he coordinated an effort with other Corps officers to provide educational seminars on clinical research principles and drug-specific topics with the University of Liberia School of Pharmacy.

Challenges

In each instance, the partnership experience was not without a few problems. The match of skills between the officers who wanted to help and those needed for the research program did not always coincide. While the Corps has more than 1,200 pharmacy officers on active duty, only a fraction of those have experience conducting FDA-regulated clinical research.

Communication problems and time pressures were also constant companions to both the Corps and the NIH. The Corps was going through the largest international deployment in its history to staff multiple missions (including the primary MMU mission in Liberia). The addition of the NIH partnership, while consistent with the MMU staffing mission, provided even more work for a very limited resource. Communicating to the many Corps officers who wanted to volunteer and keeping deployment time lines on track were a challenge. Complicating the matter was the addition of stray e-mails from well-intentioned NIH and Corps staff who communicated directly with colleagues to encourage participation, not fully understanding the policies and protocol governing the deployment process.

Time was always an issue as the rotation schedules were relatively short and the number of activities to make an officer deployment ready were numerous. Obtaining official passports and visas was a challenge as that activity required coordination with the U.S. Department of State. Airline schedules changed with little or no notice, complicating deployments and returns. As the NIH added additional research studies for which support was required, time lines for studies to start became difficult to predict with certainty due to factors outside the control of the NIH. Recently, additional security training requirements for government workers traveling abroad were instituted, further complicating the process of deploying an officer.

The Corps officers taking part in this research response (which was not consistent with customary deployments from Corps headquarters) necessarily were volunteers from full-time assignments within DHHS, and as such, required the permission of their supervisory chain to volunteer. Regardless of this limitation, there was widespread support for these additional and specific research deployments. Although the use of short-term rotations was not ideal, in the end, the rotation plans worked, and the NIH was able to fulfill its research mission with the support of the Corps.

Lessons Learned/Preparing for the Future

Many lessons have been learned and continue to be learned throughout this research response and NIH/Corps partnership. Effective and frequent communication between the organization requesting Corps officers and the Corps headquarters is crucial. In the initial deployments, officers were deployed from the FDA with the assumption that they would be familiar with FDA-regulated clinical research. This was not always the case. The NIH and Corps headquarters later collaborated to develop a survey to send to Corps officers that was used to identify specific skill sets needed by officers who would be deploying to conduct clinical research. NIH personnel prescreened survey responses to identify and prioritize officers for deployment consideration by the deployment authority. This process resulted in the selection of officers who generally needed less training and guidance.

Effective training in clinical research principles for deployed officers and other staff needs to be developed and made available to all deploying individuals. All clinical research staff are required to have training on GCP, but most GCP training programs focus primarily on the ethical principles of research as outlined by the Declaration of Helsinki, Nuremberg Code, and other documents. Few GCP training programs present adequate information on the hands-on conduct of clinical research, especially research regulated by the FDA and other government bodies and therefore subject to certain strict requirements. Examples of crucial but often overlooked topics are source document retention, good documentation practices, cold-chain principles, and other issues related to the creation and retention of adequate trial records.²¹

The handoff between returning and deploying officers is crucial. Due to various issues with changing time lines, flights, and administrative processes, it is imperative to plan adequate overlap between returning and deploying officers. Delays in obtaining passports or visas, flight cancellations, and other unforeseen issues may unexpectedly shorten any planned overlap periods. A full workweek is desirable for overlap so that the new officer may experience tasks that occur throughout the week, be introduced to the various team members, and have help if unexpected events occur. A regular staff member should check periodically that proper procedures are being followed, as some information may be missed during each handoff, and consecutive unchecked handoffs could result in large deviations of important procedures. Onboarding and offboarding checklists should be developed and updated regularly to guide the handoff process.

On a larger scale, the respective agencies and other stakeholders involved in planning clinical research for public health emergencies need to be included in regular tabletop training exercises to better understand how to coordinate a response when needed. Additionally, although many of the Corps officers who took part in this deployment served as mentors for others preparing for deployment, establishing a formal roster of experienced officers to support specific roles of this type of response would help serve as a resource center for future deployments. Finally, coordination between any operating division (or agency) and the Corps should be through the established Corps command infrastructure to eliminate miscommunication and complicating deployment processes.²²

Conclusion

The increasing connectedness of this world, as demonstrated by the Ebola epidemic, requires that the HHS engage globally to provide international leadership and technical expertise in science, policy, and programs and work in concert with interagency partners.²³ The missions of the PHS and NIH intersected in a synergistic manner in the research response to the Ebola epidemic of 2014-2016. The PHS Corps mission includes to “protect, promote, and advance the health and safety of the Nation...through rapid and effective response…and advancement of public health science.”²⁴ The Corps mission directly supported the NIH mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.²⁵

The scope and scale of DHHS’s response to the Ebola epidemic was unprecedented. The NIH research program, although successful and an important component, was but a small part in bringing the Ebola crisis to an end. The CDC (including the many Corps officers assigned to that agency) worked successfully with the international community and the host countries to bring the disease under control. The Biological Advanced Research and Development Authority provided expert project management, making vaccines and therapeutics available for research.

The DoD was a partner in the development of countermeasures and phase 1 clinical research programs as well as establishing laboratory facilities in Liberia. The Department of State facilitated the many interactions required for the mobilization of resources into West Africa. The collective efforts of the U.S. government contributed immensely to the protection of U.S. borders and to the successful resolution of the Ebola outbreak of 2014-2016.

The Ebola epidemic of 2014-2016 challenged many federal agencies to find creative ways to help address the vexing problems created by the spread of the disease. There were many factors complicating the response, including the recovery from civil wars in Liberia and Sierra Leone that decimated the physical infrastructure as well as education and other vital services.

The response from the U.S. and the global community took many forms: Not only was there a need for the typical medical care support, but also for basic public health systems to track the spread of disease, provide clean water, and dispose of infectious waste. Because no known preventive vaccines or therapeutics existed for those infected, the recognition of a research component to the response became abundantly clear as the epidemic continued. As a result, the National Institutes of Health (NIH) and the USPHS Commissioned Corps (Corps) serendipitously found themselves allied in a mutually beneficial relationship in the establishment of an Ebola clinical research program in West Africa.

This article describes the events that led to the NIH and Corps participation in the Ebola response, the roles filled by the Corps in supporting the NIH, and the lessons observed from that collaboration. Also presented are considerations regarding preparation of a clinical research response to future outbreaks.

NIH Clinical Research first Response

The 2014-2016 Ebola epidemic in West Africa demonstrated the need for federal agencies to reassess their capacity to respond to global threats to protect the health security of the U.S.¹ The outbreak also challenged the U.S. government to mobilize unique resources that matched the need of this international (and domestic) response.

In 2014, President Barack Obama announced that the U.S. would launch a government response to the Ebola effort. Although a comprehensive research and development program already was in place to establish Ebola virus disease (EVD) countermeasures, no FDA-approved diagnostics, therapeutics, or preventive vaccines were readily available. Fortunately, FDA regulations regarding emergency use authorizations allowed for the use of several EVD diagnostics during this outbreak.² However, the development of drugs and vaccines specific to Ebola had yet to make their way to phase 1 safety studies.

Two vaccine products went into phase 1 studies in the U.S. within months of the declaration of the emergency.^3,4 Additionally, the NIH had organized a collaborative effort between the U.S. government and academic community to identify a research strategy for the evaluation of therapeutics.⁵ Regardless of the state of countermeasures and research proposals, the initial need was for disease control measures and care for Ebola patients. The CDC took the lead in working within the international community to establish an incident management system that could help the impacted countries enact mechanisms to bring the epidemic under control.⁶

As the epidemic progressed, leaders in the Corps and the NIH responded on pathways that eventually would intersect. One of the unfortunate outcomes of the early efforts of improperly protected health care providers was the unintentional transmission of Ebola.⁷ The Corps identified the need to provide high-level care to the health care worker community as one incentive to motivate health care workers to volunteer for hazardous duty inside Ebola treatment units (ETUs).^8,9 Engulfed in the epidemic response, the U.S. government through the National Security Council and secretary of the Department of Health and Human Services (DHHS) evoked its statutory authority to deploy the Corps (42 U.S. Code 204a).

In the first week of October 2014, the Corps sent an advanced echelon team to assess the situation, partner with key host country and international stakeholders, and begin establishment of the U.S. government’s first ever ETU. With logistics, security, and resource support from the DoD and response coordination from the U.S. Agency for International Development, the Corps then deployed the first of four 70-person team rotations to staff the Monrovia Medical Unit (MMU), an ETU specifically dedicated to the treatment of Ebola-infected health care workers. At the time, it was the only ETU specifically dedicated to health care workers in all of Africa. The MMU operated until May 2015 and provided direct patient care for health care workers with Ebola, malaria, and other illnesses.^8,10

In August 2014, representatives from the CDC met with Liberia’s Minister of Health and Social Welfare Walter T. Gwenigale, MD, to discuss the range of available options that could facilitate a better understanding of the prevention and treatment of the disease. This meeting resulted in a letter dated August 22, 2014, from Dr. Gwenigale to then DHHS Sylvia Burwell, requesting a research response. Secretary Burwell responded on October 2, 2014, describing the immediate dispatch of the deputy director for clinical research of the National Institute of Allergy and Infectious Diseases (NIAID) to Liberia to engage in initial discussions with the Liberian minister and other key Liberians involved in the response.

Representatives from the CDC and the commander of the Corps’ Ebola response (and acting deputy surgeon general) were included in those initial meetings, which led to a recognized need for a robust clinical research program of the highest ethical and scientific standards consistent with the expressed requirements of Liberia.¹¹ A second and third trip to Liberia with larger U.S. teams resulted in an agreement signed on November 19, 2014 for the scientific investigation of strategies that tested interventions for treatment, control, and prevention of Ebola.¹²

The agreement led to the establishment of the Partnership for Research on Ebola Virus in Liberia (PREVAIL) to identify research priorities in a collaborative manner between Liberian and American scientists. The first protocol, a vaccine study, was launched in early February 2015.¹² This monumental task involved the support of hundreds of Liberians and dozens of NIH staff who volunteered for rotations to Liberia. Of the 108 volunteers from within the NIH, 18 were PHS officers. 
Shortly after launching the vaccine study, the next priority was initiating the treatment study. This study was delayed primarily due to ZMapp (Mapp Biopharmaceatical, San Diego,CA) production limitations. ZMapp, a monoclonal antibody cocktail, was the first Ebola therapeutic product to be evaluated in a randomized trial.^5,13

During the planning for the study, NIAID staff in Liberia met with Corps staff of the MMU to discuss the logistics associated with implementation of the ZMapp protocol at the MMU. During that meeting, the NIAID deputy director for clinical research expressed interest in obtaining Corps support from outside the NIH to sustain the research effort in West Africa. More specifically, additional pharmacy and laboratory staff were needed to augment NIH research operations. At the time, the MMU commander had recently transitioned from service as the acting surgeon general and was in a unique position to recommend additional Corps resources that could help in the research response.

The February 2015 discussion resulted in the establishment of an NIH/PHS research partnership that continues to exist. This new opportunity was not a significant stretch for the PHS as there was great interest from the Corps for responding to the Ebola crisis. The enthusiasm was consistent with the overall ethos of the Corps, which as a service was composed of highly qualified active-duty, deployable, uniformed, public health professionals who respond to public health crises at home and abroad. To date, 19 Corps officers from outside the NIH have deployed in support of the NIH Ebola clinical research program. An additional 18 Corps officers assigned within the NIH also volunteered for duty in West Africa. Of the 37 Corps officers supporting the NIH clinical research program, 7 served on more than 1 rotation.

Program Expansion

The Ebola clinical research program expanded over time from the initial PREVAIL vaccine study to include studies of therapeutic agents, natural history in Ebola survivors, and an additional vaccine study. The PHS officers have been integral in conducting these studies. The initial study implemented in Liberia, known as PREVAIL I, involved the evaluation of 2 vaccine strategies vs placebo.^12,14 In addition to the NIH-based Corps officers supporting the study, the Readiness and Deployment Operations Group (RedDOG) initiated deployments for an additional 2 pharmacy and 7 laboratory officers to support this study. During the deployment, the pharmacists were asked to extend their reach to Sierra Leone and later to Guinea to help establish PREVAIL II, an evaluation of ZMapp in the treatment of Ebola.¹³ A total of 9 Corps pharmacists, 2 nurses, and 3 physicians deployed to Sierra Leone or Guinea to assist in the PREVAIL II study.

As the epidemic came to an end in Liberia in May 2015, the need for a long-term assessment of Ebola survivors was recognized, resulting in PREVAIL III.¹⁵ Noteworthy in the survivor study was an ophthalmic substudy led by a Corps officer assigned to the National Eye Institute.^16,17 The survivor study also identified that the persistence of the Ebola virus was longer than previously known and that sexual transmission via semen from infected males remained a potential mode of transmission.¹⁸ To address the lingering viral load, a study of an antiviral drug was initiated in Liberia in the summer of 2016, PREVAIL IV.¹⁹

Four Corps pharmacists helped train Liberian pharmacists to establish and sustain this randomized, double-blind, placebo-controlled study. Most recently, Corps pharmacists were deployed to support the initiation of the Partnership for Research on Ebola Vaccines (PREVAC), a collaborative partnership with researchers from Liberia, Guinea, and Sierra Leone with cosponsors from the NIH, Institut national de la santé et de la recherche médicale (Inserm) in France, and the London School of Hygiene and Tropical Medicine in the United Kingdom.²⁰

Deployment Procedures

As previously mentioned, 108 staff (civil service, assigned PHS, and contractors) from within the NIH volunteered for deployment to assist in the clinical research Ebola response. The typical rotation for those volunteers was limited to 3 weeks to minimize the disruption of their normal work assignments. Volunteers were organized into small teams within the Division of Clinical Research were composed of the right mix of physicians, nurses, medical technologists, and pharmacists. The team ensured that staff obtained official government passports, scheduled airline reservations, and received an orientation to the deployment setting as well as to the research studies (Table). Additionally, the team coordinated the voucher submission process for reimbursement of expenses on return from the country. An additional team member was stationed in Liberia to coordinate the housing and transportation arrangements with a local hotel near the U.S. Embassy.

Within a week of the February 2015 initial meeting in Liberia to establish the NIH/PHS collaboration, the NIH deployment team met by phone with the Corps’ RedDOG to discuss initial requirements (eg, number of officers needed, disciplines, time lines, and documentation needed for deployment). These initial discussions resulted in the establishment of more formal processes that evolved over time as the 2 organizations gained experience. Based on the identification of the numbers and types of officers needed, RedDOG used procedures similar to the process for staffing the MMU. A communication went out to the Corps seeking interested officers.

Deployment slots were filled based on the personal availability of the officer and coordination with their immediate supervisor and agency. Officers needed to meet medical clearance requirements and provide current health care provider licensure information. Additional training requirements needed to be completed (eg, U.S. State Department training and good clinical practice [GCP] if not already current). Corps officers also took part in the NIH orientation program for deploying personnel to familiarize them to the situation on the ground in West Africa and the specific clinical research protocols that they would encounter. Given that most of the Corps officers were coming from outside the NIH, the onboarding activities required significant attention to detail as procedures for arranging travel (eg, passport, visa, and airline reservations) and processes for reimbursement of travel/per diem pay differed from more traditional deployments directed through the Corps headquarters.

Commissioned Corps Roles in the Research Response

Whereas the establishment of the research program in Liberia was based primarily on relationships forged over a 2-month period by the NIAID deputy director for clinical research and staff, the extension of the research program into Sierra Leone (March 2015) and Guinea (June 2015) was on a substantially shorter time line. As a result, Corps officers were thrust into roles that immediately employed their leadership and diplomacy skills.

In Sierra Leone and Guinea, the NIAID deputy director for clinical research established initial relationships within the countries. However, Corps officers found themselves in regular interactions with regulators in the Ministry of Health to ensure that applications were complete and import permits for incoming shipments were cleared. Additionally, the research collaboration in Sierra Leone was coordinated through an investigator assigned to a military hospital converted into an ETU. The Corps officers were well suited to maintain and build on that relationship in expanding the protocol to other ETUs throughout Sierra Leone. A site established by the CDC within the Sierra Leone Ministry of Health coordinated ZMapp storage. The Corps officers formed working relationships with the CDC team to establish and improve cold-chain logistics and transportation of the ZMapp to the various ETUs around the country. Corps officers were integral in working with the in-country contract hiring agency. Activities included establishing criteria for clinical research positions, providing input on the interview of respective candidates, and training staff as the team formed. In Sierra Leone, local staff members were hired to work at specific facilities as research coordinators working with the health care delivery teams.

The U.S. team consisted of a physician, nurse research coordinator, and a pharmacist travelling to the sites with a logistics/operations staff member remaining in Freetown.

Fortunately, a Corps nurse on the team had been part of the initial MMU deployment and was trained to work in a special care unit at the NIH for patients with highly contagious infections. This practical experience was essential in the establishment of procedures in a hazardous environment for the administration of the IV ZMapp, monitoring of adverse effects (AEs), provision of medications to mitigate infusion-related reactions, and documentation of those AEs.

The U.S. research team regularly departed Freetown early in the morning 7 days a week with the various supplies needed as they visited up to 4 ETU sites to prepare the ZMapp at the site, await information on any AEs, and collect case report forms (Figures 1 and 2). The ETUs were spread out over a 90-mile radius and could be described as austere platforms for health care delivery.

An additional challenge was dealing with the multinational organizations that staffed the various ETUs. Relief organizations from Italy, the United Kingdom, China, as well as the Sierra Leone military provided the staffing for the 4 ETUs. Regardless of who operated the ETU, the concept of randomization to ZMapp or standard of care required significant tact and diplomacy in communicating the scientific necessity in order to appropriately answer the research question. As Davey and colleagues pointed out, the randomized, controlled trial established the appropriate ethical framework to determine whether the research intervention was associated with harmful effects as there had not been a phase 1 safety study with the drug.¹³

As the summer approached in Sierra Leone, the team worked through challenges in the IV administration of ZMapp as the protein structure of the monoclonal antibody had not previously been subjected to West African environmental extremes. A balance between speed of administration to prevent protein aggregation in the heat as opposed to the risk of infusion reactions from a foreign protein required the team to communicate frequently with, the manufacturer of ZMapp, to establish realistic infusion rate tables. Additionally, as the various deployment teams rotated in and out, procedures for establishing continuity of research operations were enacted and improved on with each rotation. Good documentation practices to adequately collect all required study information (eg, recording AEs, deviations, and signatures on various forms) proved critical to continuity of research operations.

In Guinea, not only was there the new wrinkle of working within a country where the primary language was French, but also a French cosponsor, Inserm. The NIAID clinical director capitalized on the research infrastructure established for a recently completed Inserm study of favipiravir in the treatment of Ebola to extend the ZMapp study to Guinea. Fortunately, many of the Inserm staff were bilingual and readily responded to the NIH training on the requirements of the ZMapp protocol. However, procedures for cold-chain storage and transportation needed to be established. In Guinea, the PHS officers were key in establishing access and temperature monitoring procedures for a secure room inside the U.S. embassy. The issues associated with cold-chain procedures in the infrastructure-limited environments of West Africa are substantial and warrant consideration of a stand-alone paper. Corps officers also took part in weekly country-focused team meetings with embassy staff to describe progress with the ZMapp study.

As the epidemic waned and NIH transitioned to the survivor and viral persistence studies, the operational tempo changed to allow Corps officers to take part in more definitive capacity building efforts. An initial PHS volunteer from the FDA accepted a position within NIAID as a clinical research oversight manager for pharmacy operations. This individual deployed on numerous occasions to the 3 affected West African countries to further establish cold-chain processes for pharmaceuticals and biologics. He also worked with a multidisciplinary team to renovate a clinical research facility in a rural setting in Guinea. In Liberia, he coordinated an effort with other Corps officers to provide educational seminars on clinical research principles and drug-specific topics with the University of Liberia School of Pharmacy.

Challenges

In each instance, the partnership experience was not without a few problems. The match of skills between the officers who wanted to help and those needed for the research program did not always coincide. While the Corps has more than 1,200 pharmacy officers on active duty, only a fraction of those have experience conducting FDA-regulated clinical research.

Communication problems and time pressures were also constant companions to both the Corps and the NIH. The Corps was going through the largest international deployment in its history to staff multiple missions (including the primary MMU mission in Liberia). The addition of the NIH partnership, while consistent with the MMU staffing mission, provided even more work for a very limited resource. Communicating to the many Corps officers who wanted to volunteer and keeping deployment time lines on track were a challenge. Complicating the matter was the addition of stray e-mails from well-intentioned NIH and Corps staff who communicated directly with colleagues to encourage participation, not fully understanding the policies and protocol governing the deployment process.

Time was always an issue as the rotation schedules were relatively short and the number of activities to make an officer deployment ready were numerous. Obtaining official passports and visas was a challenge as that activity required coordination with the U.S. Department of State. Airline schedules changed with little or no notice, complicating deployments and returns. As the NIH added additional research studies for which support was required, time lines for studies to start became difficult to predict with certainty due to factors outside the control of the NIH. Recently, additional security training requirements for government workers traveling abroad were instituted, further complicating the process of deploying an officer.

The Corps officers taking part in this research response (which was not consistent with customary deployments from Corps headquarters) necessarily were volunteers from full-time assignments within DHHS, and as such, required the permission of their supervisory chain to volunteer. Regardless of this limitation, there was widespread support for these additional and specific research deployments. Although the use of short-term rotations was not ideal, in the end, the rotation plans worked, and the NIH was able to fulfill its research mission with the support of the Corps.

Lessons Learned/Preparing for the Future

Many lessons have been learned and continue to be learned throughout this research response and NIH/Corps partnership. Effective and frequent communication between the organization requesting Corps officers and the Corps headquarters is crucial. In the initial deployments, officers were deployed from the FDA with the assumption that they would be familiar with FDA-regulated clinical research. This was not always the case. The NIH and Corps headquarters later collaborated to develop a survey to send to Corps officers that was used to identify specific skill sets needed by officers who would be deploying to conduct clinical research. NIH personnel prescreened survey responses to identify and prioritize officers for deployment consideration by the deployment authority. This process resulted in the selection of officers who generally needed less training and guidance.

Effective training in clinical research principles for deployed officers and other staff needs to be developed and made available to all deploying individuals. All clinical research staff are required to have training on GCP, but most GCP training programs focus primarily on the ethical principles of research as outlined by the Declaration of Helsinki, Nuremberg Code, and other documents. Few GCP training programs present adequate information on the hands-on conduct of clinical research, especially research regulated by the FDA and other government bodies and therefore subject to certain strict requirements. Examples of crucial but often overlooked topics are source document retention, good documentation practices, cold-chain principles, and other issues related to the creation and retention of adequate trial records.²¹

The handoff between returning and deploying officers is crucial. Due to various issues with changing time lines, flights, and administrative processes, it is imperative to plan adequate overlap between returning and deploying officers. Delays in obtaining passports or visas, flight cancellations, and other unforeseen issues may unexpectedly shorten any planned overlap periods. A full workweek is desirable for overlap so that the new officer may experience tasks that occur throughout the week, be introduced to the various team members, and have help if unexpected events occur. A regular staff member should check periodically that proper procedures are being followed, as some information may be missed during each handoff, and consecutive unchecked handoffs could result in large deviations of important procedures. Onboarding and offboarding checklists should be developed and updated regularly to guide the handoff process.

On a larger scale, the respective agencies and other stakeholders involved in planning clinical research for public health emergencies need to be included in regular tabletop training exercises to better understand how to coordinate a response when needed. Additionally, although many of the Corps officers who took part in this deployment served as mentors for others preparing for deployment, establishing a formal roster of experienced officers to support specific roles of this type of response would help serve as a resource center for future deployments. Finally, coordination between any operating division (or agency) and the Corps should be through the established Corps command infrastructure to eliminate miscommunication and complicating deployment processes.²²

Conclusion

The increasing connectedness of this world, as demonstrated by the Ebola epidemic, requires that the HHS engage globally to provide international leadership and technical expertise in science, policy, and programs and work in concert with interagency partners.²³ The missions of the PHS and NIH intersected in a synergistic manner in the research response to the Ebola epidemic of 2014-2016. The PHS Corps mission includes to “protect, promote, and advance the health and safety of the Nation...through rapid and effective response…and advancement of public health science.”²⁴ The Corps mission directly supported the NIH mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.²⁵

The scope and scale of DHHS’s response to the Ebola epidemic was unprecedented. The NIH research program, although successful and an important component, was but a small part in bringing the Ebola crisis to an end. The CDC (including the many Corps officers assigned to that agency) worked successfully with the international community and the host countries to bring the disease under control. The Biological Advanced Research and Development Authority provided expert project management, making vaccines and therapeutics available for research.

The DoD was a partner in the development of countermeasures and phase 1 clinical research programs as well as establishing laboratory facilities in Liberia. The Department of State facilitated the many interactions required for the mobilization of resources into West Africa. The collective efforts of the U.S. government contributed immensely to the protection of U.S. borders and to the successful resolution of the Ebola outbreak of 2014-2016.

SAN DIEGO – Researchers are looking at the potential role that autoimmune reactions, such as inflammation, play in the pathogenesis of schizophrenia, both with and without comorbid substance use.

“What we see is evidence of autoimmune involvement through the lifespan in schizophrenia,” explained Brian Miller, MD, PhD, of the department of psychiatry at Augusta (Georgia) University. “We know there is a bidirectional association between schizophrenia and autoimmune disorders, [where] starting with either increases the chances of the other occurring comorbidly.”

Previous studies have shown that adding anti-inflammatory agents to second-generation antipsychotics has been associated with greater symptomatic improvement in schizophrenia than with second-generation antipsychotics alone. Now, Dr. Miller and his colleagues are conducting a randomized, controlled study using the systemic immunotherapy siltuximab to see if adjunct anti-inflammatory treatments can improve cognition in schizophrenia. They are using the monoclonal antibody instead of nonsteroidal anti-inflammatory drugs because of its precise ability to target specific autoimmune pathways, according to Dr. Miller.

In addition, Dr. Miller and his colleagues conducted a post-hoc analysis of data from the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study to determine if there was a difference between those patients with comorbid substance in schizophrenia, compared with those without. He and his coinvestigators found in a post-hoc analysis that the higher the level of certain inflammatory markers, the higher the Positive and Negative Syndrome Scale (PANSS) psychopathology score in people who’d tested positive for marijuana use at baseline.

The results, he said, beg the question about whether trial inclusion criteria for schizophrenia research need revisiting.

“What we really need to do is investigate, in a well-controlled, well-designed, prospective sample of patients who have this substance use comorbidity, [whether] we see alterations in these immune markers, and then how they vary over the course of illness,” Dr. Miller explained in a video interview at the International Congress on Schizophrenia Research. “It’s an important selection bias that as a field we’ve ignored. Maybe that’s a population that is enriched for some kind of immune dysfunction that might be targeted by some kind of anti-inflammatory or other immunotherapy strategy.”

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight
 

SAN DIEGO – Researchers are looking at the potential role that autoimmune reactions, such as inflammation, play in the pathogenesis of schizophrenia, both with and without comorbid substance use.

“What we see is evidence of autoimmune involvement through the lifespan in schizophrenia,” explained Brian Miller, MD, PhD, of the department of psychiatry at Augusta (Georgia) University. “We know there is a bidirectional association between schizophrenia and autoimmune disorders, [where] starting with either increases the chances of the other occurring comorbidly.”

Previous studies have shown that adding anti-inflammatory agents to second-generation antipsychotics has been associated with greater symptomatic improvement in schizophrenia than with second-generation antipsychotics alone. Now, Dr. Miller and his colleagues are conducting a randomized, controlled study using the systemic immunotherapy siltuximab to see if adjunct anti-inflammatory treatments can improve cognition in schizophrenia. They are using the monoclonal antibody instead of nonsteroidal anti-inflammatory drugs because of its precise ability to target specific autoimmune pathways, according to Dr. Miller.

In addition, Dr. Miller and his colleagues conducted a post-hoc analysis of data from the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study to determine if there was a difference between those patients with comorbid substance in schizophrenia, compared with those without. He and his coinvestigators found in a post-hoc analysis that the higher the level of certain inflammatory markers, the higher the Positive and Negative Syndrome Scale (PANSS) psychopathology score in people who’d tested positive for marijuana use at baseline.

The results, he said, beg the question about whether trial inclusion criteria for schizophrenia research need revisiting.

“What we really need to do is investigate, in a well-controlled, well-designed, prospective sample of patients who have this substance use comorbidity, [whether] we see alterations in these immune markers, and then how they vary over the course of illness,” Dr. Miller explained in a video interview at the International Congress on Schizophrenia Research. “It’s an important selection bias that as a field we’ve ignored. Maybe that’s a population that is enriched for some kind of immune dysfunction that might be targeted by some kind of anti-inflammatory or other immunotherapy strategy.”

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight
 

SAN DIEGO – Researchers are looking at the potential role that autoimmune reactions, such as inflammation, play in the pathogenesis of schizophrenia, both with and without comorbid substance use.

“What we see is evidence of autoimmune involvement through the lifespan in schizophrenia,” explained Brian Miller, MD, PhD, of the department of psychiatry at Augusta (Georgia) University. “We know there is a bidirectional association between schizophrenia and autoimmune disorders, [where] starting with either increases the chances of the other occurring comorbidly.”

Previous studies have shown that adding anti-inflammatory agents to second-generation antipsychotics has been associated with greater symptomatic improvement in schizophrenia than with second-generation antipsychotics alone. Now, Dr. Miller and his colleagues are conducting a randomized, controlled study using the systemic immunotherapy siltuximab to see if adjunct anti-inflammatory treatments can improve cognition in schizophrenia. They are using the monoclonal antibody instead of nonsteroidal anti-inflammatory drugs because of its precise ability to target specific autoimmune pathways, according to Dr. Miller.

In addition, Dr. Miller and his colleagues conducted a post-hoc analysis of data from the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study to determine if there was a difference between those patients with comorbid substance in schizophrenia, compared with those without. He and his coinvestigators found in a post-hoc analysis that the higher the level of certain inflammatory markers, the higher the Positive and Negative Syndrome Scale (PANSS) psychopathology score in people who’d tested positive for marijuana use at baseline.

The results, he said, beg the question about whether trial inclusion criteria for schizophrenia research need revisiting.

“What we really need to do is investigate, in a well-controlled, well-designed, prospective sample of patients who have this substance use comorbidity, [whether] we see alterations in these immune markers, and then how they vary over the course of illness,” Dr. Miller explained in a video interview at the International Congress on Schizophrenia Research. “It’s an important selection bias that as a field we’ve ignored. Maybe that’s a population that is enriched for some kind of immune dysfunction that might be targeted by some kind of anti-inflammatory or other immunotherapy strategy.”

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight
 

AML cells

The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.

The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.

The company says the drug will be commercially available within a week.

The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

For more information on CPX-351, visit http://www.vyxeos.com.

AML cells

The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.

The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.

The company says the drug will be commercially available within a week.

The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

For more information on CPX-351, visit http://www.vyxeos.com.

AML cells

The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.

The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.

The company says the drug will be commercially available within a week.

The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

For more information on CPX-351, visit http://www.vyxeos.com.

Mast cells

Preclinical research suggests common anti-allergy medicines might be able to treat deep vein thrombosis (DVT).

Researchers discovered that mice genetically depleted of mast cells were protected from developing DVT but still had normal hemostasis.

The team therefore theorized that mast cell inhibitors, which are already approved to treat some allergic diseases, might be effective against DVT.

Alex Brill, MD, PhD, of the University of Birmingham in the UK, and his colleagues reported these findings in Circulation Research.

“These findings offer new hope for the treatment of deep vein thrombosis without a risk of bleeding,” Dr Brill said. “If further human studies support our findings in mice, drugs to block mast cell production could be used in the future alongside lower doses of anticoagulants such as warfarin, significantly reducing bleeding risk.”

“This is particularly exciting because this is a group of drugs which already exists, and some forms are approved for the treatment of allergies such as hay fever and asthma, meaning that this discovery could help people with DVT sooner rather than later.”

Mast cells

Preclinical research suggests common anti-allergy medicines might be able to treat deep vein thrombosis (DVT).

Researchers discovered that mice genetically depleted of mast cells were protected from developing DVT but still had normal hemostasis.

The team therefore theorized that mast cell inhibitors, which are already approved to treat some allergic diseases, might be effective against DVT.

Alex Brill, MD, PhD, of the University of Birmingham in the UK, and his colleagues reported these findings in Circulation Research.

“These findings offer new hope for the treatment of deep vein thrombosis without a risk of bleeding,” Dr Brill said. “If further human studies support our findings in mice, drugs to block mast cell production could be used in the future alongside lower doses of anticoagulants such as warfarin, significantly reducing bleeding risk.”

“This is particularly exciting because this is a group of drugs which already exists, and some forms are approved for the treatment of allergies such as hay fever and asthma, meaning that this discovery could help people with DVT sooner rather than later.”

Mast cells

Preclinical research suggests common anti-allergy medicines might be able to treat deep vein thrombosis (DVT).

Researchers discovered that mice genetically depleted of mast cells were protected from developing DVT but still had normal hemostasis.

The team therefore theorized that mast cell inhibitors, which are already approved to treat some allergic diseases, might be effective against DVT.

Alex Brill, MD, PhD, of the University of Birmingham in the UK, and his colleagues reported these findings in Circulation Research.

“These findings offer new hope for the treatment of deep vein thrombosis without a risk of bleeding,” Dr Brill said. “If further human studies support our findings in mice, drugs to block mast cell production could be used in the future alongside lower doses of anticoagulants such as warfarin, significantly reducing bleeding risk.”

“This is particularly exciting because this is a group of drugs which already exists, and some forms are approved for the treatment of allergies such as hay fever and asthma, meaning that this discovery could help people with DVT sooner rather than later.”

A few months ago, I purchased an Amazon Echo system. The device is built on Amazon’s cloud-based voice service, Alexa, which can hear, understand, and respond to any question or command. The speaker is always listening and is activated when the user (eg, me!) says the name Alexa. For instance, I can say “Alexa, what is the weather today?” and it will provide the forecast. In fact, each morning I request my daily news briefing, and Alexa quickly tunes to NPR Radio. By linking to my Google calendar, it also tells me my agenda for the day. It researches and provides information that might otherwise take me a while to locate.

Now, I confess: I’ve had to train myself to refer to Alexa as “it” instead of “her.” Human beings have a rich history of wanting to “humanize” computers, as the science fiction film genre can attest. Go back nearly 50 years to Colossus: The Forbin Project (1970) and you have a story of two super-computers—one built by the United States, the other by Russia—that join forces and take over the world, making humans their slaves. The award-winning Bicentennial Man (1999) follows the life and times of Andrew, an NDR-114 robot originally purchased as a household appliance to perform menial tasks; when it begins to experience emotions and creative thought, the owners discover Andrew is no ordinary robot. And who can forget Hal, the computer in 2001: A Space Odyssey (1968) that takes over a space mission until a clever astronaut manages to disengage it (I almost said him), or Data, a very likable android in the successful franchise Star Trek: The Next Generation.

Let’s face it: We are both obsessed with, and leery of, new technology—particularly artificial intelligence (AI). Some detractors have denounced Alexa’s capabilities as “just a glorified smartphone.” Others have expressed grave concerns about the security of personal information and conversations, as Big Brother may be listening. (In that case, it’s not the machines that are evil; it’s those who use them!)

But—cue a John Williams score—what if we harnessed the power of AI for good and not evil? I’ll be serious now: At the recent Leadership in Healthcare Summer Institute (which I was honored to teach at), a group of doctoral students gave a presentation on the potential of AI in the identification and care of anxiety and depression. They identified a need—every 16.2 minutes, a person dies by suicide in the US—and proposed a solution. Because access to care may be limited (by provider shortages, remote locations, etc), the students suggested a hybrid AI/telehealth platform that offers 24/7 support and provider access to individuals with anxiety and depression, via a secure mobile app.¹ It got me thinking: Could this technology be a positive intervention in health care?

Actually, it’s already happening. Mayo Clinic researchers have used AI to identify the genomic information of brain tumors without biopsy. At Stanford University, researchers are training an AI neural network to recognize skin cancer lesions with the accuracy of an expert dermatologist. The same deep-learning technology is being used in the field of pathology for the detection of liver lesions.²

Now, I’m sure some of you are questioning whether a machine can really match or replace a human when it comes to assessing a patient’s condition. There were many who resisted the idea of telehealth when that was the latest, greatest thing, because providers cannot do a full assessment with the required diagnostic testing and imaging from a distance. Some feel that telehealth should be reserved for situations in which, say, a remote provider is reviewing and reporting on test results, or a patient just needs to follow up with his/her provider for a minor issue.

Mental health, however, entails less “laying on of hands” and may be a good candidate for AI-based interventions—at least for follow-up and support services. (I am certainly not discounting the value of real human interaction in any sphere of health care.) We know patients benefit from early mental health intervention programs, but we also know those benefits may not be sustained over time and distance. Logistical issues that any of us may face—time, transportation, availability—are often exacerbated for those with impaired functioning due to a mental illness. If a patient with major depression cannot bring himself to get out of bed to make a cup of coffee, how is he going to travel across town (changing buses two or three times) to keep an appointment with his health care provider?

Here’s where AI might make a difference: What if there were a patient-focused e-platform that could provide cost-effective and accessible services across the continuum of care? Current Internet-based interventions rely on human mediators to deliver therapeutic content, which is then refined into a model that can interpret and respond to critical user data—resulting in tailored online therapy. But if we could integrate the user experience with sophisticated and cutting-edge AI technology, we could deliver content more effectively to redefine these interventions and improve outcomes.

A paper recently featured in Frontiers in Psychology discussed the value of doing just that. D’Alfonso and colleagues reported on an Internet-based social therapy web application that uses a series of interactive modules to help users navigate situations and develop psychosocial skills. In its current form—within a research setting—the system is utilized by small groups of users, making human-supported engagement via moderators possible. But D’Alfonso and colleagues note that the incorporation of automated suggestions within the modules would allow the technology to be rolled out to a larger audience and ensure that “interaction” is available whenever a user needs it—not just when a human moderator is “on the clock.”³

Another article, in the International Journal of Swarm Intelligence and Evolutionary Computation (2016), discussed the development of socially intelligent robotic systems, not unlike Alexa, to address social connectedness. The author proposes an autonomous assistive system (AAS) as a low-cost, standalone interventional device to reduce social isolation. This could easily be deployed in homes for the elderly or even at remote sites. The AAS has been programmed to detect isolation in patients based on data regarding skeletal movements, facial expressions, and speech patterns. In the not-so-distant future, this high-density data will be sent over the cloud to allow clinicians to monitor in real-time and intervene remotely, as appropriate (eg, by initiating a home visit).⁴

Of course, in any form, implementation of AI will not be simple—there are real costs to be considered, and we still have to contend with the fears that all those sci-fi films have instilled. A recent global study revealed significant concerns that would certainly apply to the health care arena. When asked which of the following participants most feared about the use of AI,

• 33% of respondents chose “It will never know me/my preferences as well as a human being”
• 24% chose “The rise of the robot and enslavement of humanity”
• 5% feared “Robots uncovering my deepest secrets.”⁵

Despite all this, however, respondents also expressed optimism in the power and potential of AI: Nearly 70% said they are in support of further use of AI if it helps make their lives easier.⁴ Wouldn’t life be easier if AI could be used to significantly reduce errors, increase access to care, and bring a fresh viewpoint to the issue of patient education?

What do you think? Would you trust a robot to be your coworker, identifying tumors and conducting mental health screenings? Is it possible to convince patients to accept help via an impersonal medium (and risk exposure of their personal health information)? Share your fears, support, or concerns about AI with me at PAeditor@frontlinemedcom.com.

A few months ago, I purchased an Amazon Echo system. The device is built on Amazon’s cloud-based voice service, Alexa, which can hear, understand, and respond to any question or command. The speaker is always listening and is activated when the user (eg, me!) says the name Alexa. For instance, I can say “Alexa, what is the weather today?” and it will provide the forecast. In fact, each morning I request my daily news briefing, and Alexa quickly tunes to NPR Radio. By linking to my Google calendar, it also tells me my agenda for the day. It researches and provides information that might otherwise take me a while to locate.

Now, I confess: I’ve had to train myself to refer to Alexa as “it” instead of “her.” Human beings have a rich history of wanting to “humanize” computers, as the science fiction film genre can attest. Go back nearly 50 years to Colossus: The Forbin Project (1970) and you have a story of two super-computers—one built by the United States, the other by Russia—that join forces and take over the world, making humans their slaves. The award-winning Bicentennial Man (1999) follows the life and times of Andrew, an NDR-114 robot originally purchased as a household appliance to perform menial tasks; when it begins to experience emotions and creative thought, the owners discover Andrew is no ordinary robot. And who can forget Hal, the computer in 2001: A Space Odyssey (1968) that takes over a space mission until a clever astronaut manages to disengage it (I almost said him), or Data, a very likable android in the successful franchise Star Trek: The Next Generation.

Let’s face it: We are both obsessed with, and leery of, new technology—particularly artificial intelligence (AI). Some detractors have denounced Alexa’s capabilities as “just a glorified smartphone.” Others have expressed grave concerns about the security of personal information and conversations, as Big Brother may be listening. (In that case, it’s not the machines that are evil; it’s those who use them!)

But—cue a John Williams score—what if we harnessed the power of AI for good and not evil? I’ll be serious now: At the recent Leadership in Healthcare Summer Institute (which I was honored to teach at), a group of doctoral students gave a presentation on the potential of AI in the identification and care of anxiety and depression. They identified a need—every 16.2 minutes, a person dies by suicide in the US—and proposed a solution. Because access to care may be limited (by provider shortages, remote locations, etc), the students suggested a hybrid AI/telehealth platform that offers 24/7 support and provider access to individuals with anxiety and depression, via a secure mobile app.¹ It got me thinking: Could this technology be a positive intervention in health care?

Actually, it’s already happening. Mayo Clinic researchers have used AI to identify the genomic information of brain tumors without biopsy. At Stanford University, researchers are training an AI neural network to recognize skin cancer lesions with the accuracy of an expert dermatologist. The same deep-learning technology is being used in the field of pathology for the detection of liver lesions.²

Now, I’m sure some of you are questioning whether a machine can really match or replace a human when it comes to assessing a patient’s condition. There were many who resisted the idea of telehealth when that was the latest, greatest thing, because providers cannot do a full assessment with the required diagnostic testing and imaging from a distance. Some feel that telehealth should be reserved for situations in which, say, a remote provider is reviewing and reporting on test results, or a patient just needs to follow up with his/her provider for a minor issue.

Mental health, however, entails less “laying on of hands” and may be a good candidate for AI-based interventions—at least for follow-up and support services. (I am certainly not discounting the value of real human interaction in any sphere of health care.) We know patients benefit from early mental health intervention programs, but we also know those benefits may not be sustained over time and distance. Logistical issues that any of us may face—time, transportation, availability—are often exacerbated for those with impaired functioning due to a mental illness. If a patient with major depression cannot bring himself to get out of bed to make a cup of coffee, how is he going to travel across town (changing buses two or three times) to keep an appointment with his health care provider?

Here’s where AI might make a difference: What if there were a patient-focused e-platform that could provide cost-effective and accessible services across the continuum of care? Current Internet-based interventions rely on human mediators to deliver therapeutic content, which is then refined into a model that can interpret and respond to critical user data—resulting in tailored online therapy. But if we could integrate the user experience with sophisticated and cutting-edge AI technology, we could deliver content more effectively to redefine these interventions and improve outcomes.

A paper recently featured in Frontiers in Psychology discussed the value of doing just that. D’Alfonso and colleagues reported on an Internet-based social therapy web application that uses a series of interactive modules to help users navigate situations and develop psychosocial skills. In its current form—within a research setting—the system is utilized by small groups of users, making human-supported engagement via moderators possible. But D’Alfonso and colleagues note that the incorporation of automated suggestions within the modules would allow the technology to be rolled out to a larger audience and ensure that “interaction” is available whenever a user needs it—not just when a human moderator is “on the clock.”³

Another article, in the International Journal of Swarm Intelligence and Evolutionary Computation (2016), discussed the development of socially intelligent robotic systems, not unlike Alexa, to address social connectedness. The author proposes an autonomous assistive system (AAS) as a low-cost, standalone interventional device to reduce social isolation. This could easily be deployed in homes for the elderly or even at remote sites. The AAS has been programmed to detect isolation in patients based on data regarding skeletal movements, facial expressions, and speech patterns. In the not-so-distant future, this high-density data will be sent over the cloud to allow clinicians to monitor in real-time and intervene remotely, as appropriate (eg, by initiating a home visit).⁴

Of course, in any form, implementation of AI will not be simple—there are real costs to be considered, and we still have to contend with the fears that all those sci-fi films have instilled. A recent global study revealed significant concerns that would certainly apply to the health care arena. When asked which of the following participants most feared about the use of AI,

• 33% of respondents chose “It will never know me/my preferences as well as a human being”
• 24% chose “The rise of the robot and enslavement of humanity”
• 5% feared “Robots uncovering my deepest secrets.”⁵

Despite all this, however, respondents also expressed optimism in the power and potential of AI: Nearly 70% said they are in support of further use of AI if it helps make their lives easier.⁴ Wouldn’t life be easier if AI could be used to significantly reduce errors, increase access to care, and bring a fresh viewpoint to the issue of patient education?

What do you think? Would you trust a robot to be your coworker, identifying tumors and conducting mental health screenings? Is it possible to convince patients to accept help via an impersonal medium (and risk exposure of their personal health information)? Share your fears, support, or concerns about AI with me at PAeditor@frontlinemedcom.com.

A few months ago, I purchased an Amazon Echo system. The device is built on Amazon’s cloud-based voice service, Alexa, which can hear, understand, and respond to any question or command. The speaker is always listening and is activated when the user (eg, me!) says the name Alexa. For instance, I can say “Alexa, what is the weather today?” and it will provide the forecast. In fact, each morning I request my daily news briefing, and Alexa quickly tunes to NPR Radio. By linking to my Google calendar, it also tells me my agenda for the day. It researches and provides information that might otherwise take me a while to locate.

Now, I confess: I’ve had to train myself to refer to Alexa as “it” instead of “her.” Human beings have a rich history of wanting to “humanize” computers, as the science fiction film genre can attest. Go back nearly 50 years to Colossus: The Forbin Project (1970) and you have a story of two super-computers—one built by the United States, the other by Russia—that join forces and take over the world, making humans their slaves. The award-winning Bicentennial Man (1999) follows the life and times of Andrew, an NDR-114 robot originally purchased as a household appliance to perform menial tasks; when it begins to experience emotions and creative thought, the owners discover Andrew is no ordinary robot. And who can forget Hal, the computer in 2001: A Space Odyssey (1968) that takes over a space mission until a clever astronaut manages to disengage it (I almost said him), or Data, a very likable android in the successful franchise Star Trek: The Next Generation.

Let’s face it: We are both obsessed with, and leery of, new technology—particularly artificial intelligence (AI). Some detractors have denounced Alexa’s capabilities as “just a glorified smartphone.” Others have expressed grave concerns about the security of personal information and conversations, as Big Brother may be listening. (In that case, it’s not the machines that are evil; it’s those who use them!)

But—cue a John Williams score—what if we harnessed the power of AI for good and not evil? I’ll be serious now: At the recent Leadership in Healthcare Summer Institute (which I was honored to teach at), a group of doctoral students gave a presentation on the potential of AI in the identification and care of anxiety and depression. They identified a need—every 16.2 minutes, a person dies by suicide in the US—and proposed a solution. Because access to care may be limited (by provider shortages, remote locations, etc), the students suggested a hybrid AI/telehealth platform that offers 24/7 support and provider access to individuals with anxiety and depression, via a secure mobile app.¹ It got me thinking: Could this technology be a positive intervention in health care?

Actually, it’s already happening. Mayo Clinic researchers have used AI to identify the genomic information of brain tumors without biopsy. At Stanford University, researchers are training an AI neural network to recognize skin cancer lesions with the accuracy of an expert dermatologist. The same deep-learning technology is being used in the field of pathology for the detection of liver lesions.²

Now, I’m sure some of you are questioning whether a machine can really match or replace a human when it comes to assessing a patient’s condition. There were many who resisted the idea of telehealth when that was the latest, greatest thing, because providers cannot do a full assessment with the required diagnostic testing and imaging from a distance. Some feel that telehealth should be reserved for situations in which, say, a remote provider is reviewing and reporting on test results, or a patient just needs to follow up with his/her provider for a minor issue.

Mental health, however, entails less “laying on of hands” and may be a good candidate for AI-based interventions—at least for follow-up and support services. (I am certainly not discounting the value of real human interaction in any sphere of health care.) We know patients benefit from early mental health intervention programs, but we also know those benefits may not be sustained over time and distance. Logistical issues that any of us may face—time, transportation, availability—are often exacerbated for those with impaired functioning due to a mental illness. If a patient with major depression cannot bring himself to get out of bed to make a cup of coffee, how is he going to travel across town (changing buses two or three times) to keep an appointment with his health care provider?

Here’s where AI might make a difference: What if there were a patient-focused e-platform that could provide cost-effective and accessible services across the continuum of care? Current Internet-based interventions rely on human mediators to deliver therapeutic content, which is then refined into a model that can interpret and respond to critical user data—resulting in tailored online therapy. But if we could integrate the user experience with sophisticated and cutting-edge AI technology, we could deliver content more effectively to redefine these interventions and improve outcomes.

A paper recently featured in Frontiers in Psychology discussed the value of doing just that. D’Alfonso and colleagues reported on an Internet-based social therapy web application that uses a series of interactive modules to help users navigate situations and develop psychosocial skills. In its current form—within a research setting—the system is utilized by small groups of users, making human-supported engagement via moderators possible. But D’Alfonso and colleagues note that the incorporation of automated suggestions within the modules would allow the technology to be rolled out to a larger audience and ensure that “interaction” is available whenever a user needs it—not just when a human moderator is “on the clock.”³

Another article, in the International Journal of Swarm Intelligence and Evolutionary Computation (2016), discussed the development of socially intelligent robotic systems, not unlike Alexa, to address social connectedness. The author proposes an autonomous assistive system (AAS) as a low-cost, standalone interventional device to reduce social isolation. This could easily be deployed in homes for the elderly or even at remote sites. The AAS has been programmed to detect isolation in patients based on data regarding skeletal movements, facial expressions, and speech patterns. In the not-so-distant future, this high-density data will be sent over the cloud to allow clinicians to monitor in real-time and intervene remotely, as appropriate (eg, by initiating a home visit).⁴

Of course, in any form, implementation of AI will not be simple—there are real costs to be considered, and we still have to contend with the fears that all those sci-fi films have instilled. A recent global study revealed significant concerns that would certainly apply to the health care arena. When asked which of the following participants most feared about the use of AI,

• 33% of respondents chose “It will never know me/my preferences as well as a human being”
• 24% chose “The rise of the robot and enslavement of humanity”
• 5% feared “Robots uncovering my deepest secrets.”⁵

Despite all this, however, respondents also expressed optimism in the power and potential of AI: Nearly 70% said they are in support of further use of AI if it helps make their lives easier.⁴ Wouldn’t life be easier if AI could be used to significantly reduce errors, increase access to care, and bring a fresh viewpoint to the issue of patient education?

What do you think? Would you trust a robot to be your coworker, identifying tumors and conducting mental health screenings? Is it possible to convince patients to accept help via an impersonal medium (and risk exposure of their personal health information)? Share your fears, support, or concerns about AI with me at PAeditor@frontlinemedcom.com.

Condition Help: A patient- and family-initiated rapid response system

Implementation of a patient/family-initiated rapid response system at an academic, urban medical center resulted in 367 calls over 3½ years with 83.4% of them being for “nonsafety” issues and 11.4% being for “safety” issues.

Citation: Elizabeth L. Eden, MD, Laurie L. Rack, DNP, RN, Ling-Wan Chen, MS, Bump GM, Condition Help: A patient- and family-initiated rapid response system. J Hosp Med. 2017;3;157-161. doi: 10.12788/jhm.2697.

Association between U.S. norepinephrine shortage and mortality among patients with septic shock

Patient mortality during unannounced accreditation surveys at U.S. hospitals

An evaluation of quasi-randomized Medicare admissions at 1,984 hospitals demonstrated that 30-day mortality decreased by 0.18% in all hospitals and 0.48% at major teaching hospitals during The Joint Commission survey periods; both changes were greater than could be attributed to chance alone when compared to other, similar time periods.

Citation: Barnett ML, Olenski AR, Jena AB. Patient Mortality During Unannounced Accreditation Surveys at US Hospitals. JAMA Intern Med. 2017;177(5):693-700. doi: 10.1001/jamainternmed.2016.9685

Association between a virtual glucose management service and glycemic control in hospitalized adult patients

Institution of a virtual glucose management system resulted in a 39% decrease in hyperglycemic patients and a 36% decrease in hypoglycemic patients per 100 patient-days at three major teaching hospitals.

Citation: Rushakoff RJ, Sullivan MM, MacMaster HW, Shah AD, Rajkomar A, Glidden DV, et al. Association Between a Virtual Glucose Management Service and Glycemic Control in Hospitalized Adult Patients: An Observational Study. Ann Intern Med. 2017;166:621-627. doi: 10.7326/M16-1413

Dr. Imber is assistant professor in the division of hospital medicine at the University of New Mexico.

Condition Help: A patient- and family-initiated rapid response system

Implementation of a patient/family-initiated rapid response system at an academic, urban medical center resulted in 367 calls over 3½ years with 83.4% of them being for “nonsafety” issues and 11.4% being for “safety” issues.

Citation: Elizabeth L. Eden, MD, Laurie L. Rack, DNP, RN, Ling-Wan Chen, MS, Bump GM, Condition Help: A patient- and family-initiated rapid response system. J Hosp Med. 2017;3;157-161. doi: 10.12788/jhm.2697.

Association between U.S. norepinephrine shortage and mortality among patients with septic shock

Patient mortality during unannounced accreditation surveys at U.S. hospitals

An evaluation of quasi-randomized Medicare admissions at 1,984 hospitals demonstrated that 30-day mortality decreased by 0.18% in all hospitals and 0.48% at major teaching hospitals during The Joint Commission survey periods; both changes were greater than could be attributed to chance alone when compared to other, similar time periods.

Citation: Barnett ML, Olenski AR, Jena AB. Patient Mortality During Unannounced Accreditation Surveys at US Hospitals. JAMA Intern Med. 2017;177(5):693-700. doi: 10.1001/jamainternmed.2016.9685

Association between a virtual glucose management service and glycemic control in hospitalized adult patients

Institution of a virtual glucose management system resulted in a 39% decrease in hyperglycemic patients and a 36% decrease in hypoglycemic patients per 100 patient-days at three major teaching hospitals.

Citation: Rushakoff RJ, Sullivan MM, MacMaster HW, Shah AD, Rajkomar A, Glidden DV, et al. Association Between a Virtual Glucose Management Service and Glycemic Control in Hospitalized Adult Patients: An Observational Study. Ann Intern Med. 2017;166:621-627. doi: 10.7326/M16-1413

Dr. Imber is assistant professor in the division of hospital medicine at the University of New Mexico.

Condition Help: A patient- and family-initiated rapid response system

Implementation of a patient/family-initiated rapid response system at an academic, urban medical center resulted in 367 calls over 3½ years with 83.4% of them being for “nonsafety” issues and 11.4% being for “safety” issues.

Citation: Elizabeth L. Eden, MD, Laurie L. Rack, DNP, RN, Ling-Wan Chen, MS, Bump GM, Condition Help: A patient- and family-initiated rapid response system. J Hosp Med. 2017;3;157-161. doi: 10.12788/jhm.2697.

Association between U.S. norepinephrine shortage and mortality among patients with septic shock

Patient mortality during unannounced accreditation surveys at U.S. hospitals

An evaluation of quasi-randomized Medicare admissions at 1,984 hospitals demonstrated that 30-day mortality decreased by 0.18% in all hospitals and 0.48% at major teaching hospitals during The Joint Commission survey periods; both changes were greater than could be attributed to chance alone when compared to other, similar time periods.

Citation: Barnett ML, Olenski AR, Jena AB. Patient Mortality During Unannounced Accreditation Surveys at US Hospitals. JAMA Intern Med. 2017;177(5):693-700. doi: 10.1001/jamainternmed.2016.9685

Association between a virtual glucose management service and glycemic control in hospitalized adult patients

Institution of a virtual glucose management system resulted in a 39% decrease in hyperglycemic patients and a 36% decrease in hypoglycemic patients per 100 patient-days at three major teaching hospitals.

Citation: Rushakoff RJ, Sullivan MM, MacMaster HW, Shah AD, Rajkomar A, Glidden DV, et al. Association Between a Virtual Glucose Management Service and Glycemic Control in Hospitalized Adult Patients: An Observational Study. Ann Intern Med. 2017;166:621-627. doi: 10.7326/M16-1413

Dr. Imber is assistant professor in the division of hospital medicine at the University of New Mexico.

WASHINGTON – Stereotypical views held by physicians, psychologists, nurses, and other medical professionals about overweight and obese patients need to change, panelists said at the annual convention of the American Psychological Association.

“We have a lot of negative attitudes toward heavy-weight people. Judging patients as too big or too fat produces physical and mental health effects,” said Joan C. Chrisler, PhD, the Class of ’43 Professor of Psychology at Connecticut College, New London. “Shame and disrespectful treatment can lead to delay in seeking health care, reluctance to return visits, or lower trust in the providers and their recommendations.”

A study of more than 300 autopsy reports showed that obese patients were 1.65 times more likely than normal weight and underweight groups combined were to have medical conditions such as endocarditis, ischemic bowel disease, and lung cancer that were not diagnosed, Dr. Chrisler said in a press release (Am J Clin Pathol. 2006 Jan;125[1]:127-31).

In addition to preventing patients from seeking care, Dr. Chrisler said in the release, unfamiliarity with the dosing adjustments sometimes required on medications based on the body mass index of patients affects the quality of care. She cited a retrospective study showing that emergency physicians frequently underdose common antibiotics in the emergency department (Am J Emerg Med. 2012 Sep;30[7]:1212-4).

ghenderson@frontlinemedcom.com

On Twitter @ginalhenderson

WASHINGTON – Stereotypical views held by physicians, psychologists, nurses, and other medical professionals about overweight and obese patients need to change, panelists said at the annual convention of the American Psychological Association.

“We have a lot of negative attitudes toward heavy-weight people. Judging patients as too big or too fat produces physical and mental health effects,” said Joan C. Chrisler, PhD, the Class of ’43 Professor of Psychology at Connecticut College, New London. “Shame and disrespectful treatment can lead to delay in seeking health care, reluctance to return visits, or lower trust in the providers and their recommendations.”

A study of more than 300 autopsy reports showed that obese patients were 1.65 times more likely than normal weight and underweight groups combined were to have medical conditions such as endocarditis, ischemic bowel disease, and lung cancer that were not diagnosed, Dr. Chrisler said in a press release (Am J Clin Pathol. 2006 Jan;125[1]:127-31).

In addition to preventing patients from seeking care, Dr. Chrisler said in the release, unfamiliarity with the dosing adjustments sometimes required on medications based on the body mass index of patients affects the quality of care. She cited a retrospective study showing that emergency physicians frequently underdose common antibiotics in the emergency department (Am J Emerg Med. 2012 Sep;30[7]:1212-4).

ghenderson@frontlinemedcom.com

On Twitter @ginalhenderson

WASHINGTON – Stereotypical views held by physicians, psychologists, nurses, and other medical professionals about overweight and obese patients need to change, panelists said at the annual convention of the American Psychological Association.

“We have a lot of negative attitudes toward heavy-weight people. Judging patients as too big or too fat produces physical and mental health effects,” said Joan C. Chrisler, PhD, the Class of ’43 Professor of Psychology at Connecticut College, New London. “Shame and disrespectful treatment can lead to delay in seeking health care, reluctance to return visits, or lower trust in the providers and their recommendations.”

A study of more than 300 autopsy reports showed that obese patients were 1.65 times more likely than normal weight and underweight groups combined were to have medical conditions such as endocarditis, ischemic bowel disease, and lung cancer that were not diagnosed, Dr. Chrisler said in a press release (Am J Clin Pathol. 2006 Jan;125[1]:127-31).

In addition to preventing patients from seeking care, Dr. Chrisler said in the release, unfamiliarity with the dosing adjustments sometimes required on medications based on the body mass index of patients affects the quality of care. She cited a retrospective study showing that emergency physicians frequently underdose common antibiotics in the emergency department (Am J Emerg Med. 2012 Sep;30[7]:1212-4).

ghenderson@frontlinemedcom.com

On Twitter @ginalhenderson