Red-haired women were significantly more likely than were women with nonred hair to have elevated levels of C-reactive protein that may increase risk for cardiovascular conditions, according to data from nearly 9,000 women participating in the Nurses’ Health Study.

“Positive associations between red hair and cardiovascular disease and cancer in women, but not men, have been reported,” wrote Rebecca I. Hartman, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

In a study published in the Journal of Investigative Dermatology, they reviewed data from the Nurses’ Health Study, a 1976 cohort study of 121,700 women registered nurses in the United States. They analyzed blood specimens from 8,994 women that were collected between 1989 and 1990. Participants’ natural hair color was determined by asking them their natural hair color at age 21 years, with choices of red, blonde, light brown, dark brown, or black. Overall, dark brown/black hair was the most common color (45%) and 390 of the women (4.3%) had red hair.

The average CRP levels were significantly higher for women with red hair (3.7 mg/L), compared with those with blonde (3.3 mg/L), light brown (3.0 mg/mL), or dark brown/black (3.2 mg/L).

Using the CRP levels for red-haired women as a reference, women with blond, light brown, and dark brown/black hair averaged significantly lower CRP levels than those of red-haired women in an age-adjusted model (–15.2%, –18/1%, and –14.2%, respectively) and in a multivariate analysis (–12.7%, –14.1%, and –10.9%, respectively).

Non-red-haired women had significantly lower odds of high CRP levels compared with red-haired women, with odds ratios of 0.62, 0.60, and 0.67 for women with blonde, light brown, and dark brown/black hair, respectively, in multivariate analysis, the researchers found.

The study was limited by several factors including the use of self-reports for hair color and the relative homogeneity of the Nurses’ Health Study, which has a population of mostly white, female health professionals, the researchers noted.

However, the findings of significantly increased CRP levels “could potentially explain a prior report of increased risks of cardiovascular disease and cancer in red-haired women,” they said. “Although, we observed similar associations in the NHS between red hair and cardiovascular disease and cancer, they were not statistically significant,” they added.

Additional studies are needed to validate and examine the clinical significance of the results, they concluded.

“Elevated CRP levels, a marker of inflammation, have been associated with increased risk for several diseases, including colon cancer and heart disease,” lead author Dr. Hartman said in an interview. “Another study suggested red-haired women have elevated risks of cardiovascular disease and cancer. We wanted to see if different levels of inflammation in red-haired women could possibly explain these findings.”

She said she was not surprised by the findings, “as they were in line with our hypothesis.” In addition, “animal studies suggest that the gene most responsible for red hair, MC1R, may be linked to inflammation,” she said.

While red-haired women were found to have higher CRP levels in the study, “the underlying mechanism and clinical significance remain unknown,” and more research is needed, Dr. Hartman emphasized. “First, our findings need to be validated in women and also examined in men. If our findings are validated, future studies should examine the mechanism of CRP elevation in red-haired women, and whether these women have elevated risks of colon cancer and heart disease,” she said.

“If red-haired women do have increased levels of inflammation, and as a result have elevated risks of colon cancer and heart disease, then future interventions can focus on enhanced screening and possibly chemoprevention in this population,” she added.

The study was supported by the National Institutes of Health. Lead author Dr. Hartman was supported by an American Skin Association Research Grant.
 

SOURCE: Hartman RI et al. J Invest Dermatol. 2020 Oct 12. doi: 10.1016/j.jid.2020.09.015.

Red-haired women were significantly more likely than were women with nonred hair to have elevated levels of C-reactive protein that may increase risk for cardiovascular conditions, according to data from nearly 9,000 women participating in the Nurses’ Health Study.

“Positive associations between red hair and cardiovascular disease and cancer in women, but not men, have been reported,” wrote Rebecca I. Hartman, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

In a study published in the Journal of Investigative Dermatology, they reviewed data from the Nurses’ Health Study, a 1976 cohort study of 121,700 women registered nurses in the United States. They analyzed blood specimens from 8,994 women that were collected between 1989 and 1990. Participants’ natural hair color was determined by asking them their natural hair color at age 21 years, with choices of red, blonde, light brown, dark brown, or black. Overall, dark brown/black hair was the most common color (45%) and 390 of the women (4.3%) had red hair.

The average CRP levels were significantly higher for women with red hair (3.7 mg/L), compared with those with blonde (3.3 mg/L), light brown (3.0 mg/mL), or dark brown/black (3.2 mg/L).

Using the CRP levels for red-haired women as a reference, women with blond, light brown, and dark brown/black hair averaged significantly lower CRP levels than those of red-haired women in an age-adjusted model (–15.2%, –18/1%, and –14.2%, respectively) and in a multivariate analysis (–12.7%, –14.1%, and –10.9%, respectively).

Non-red-haired women had significantly lower odds of high CRP levels compared with red-haired women, with odds ratios of 0.62, 0.60, and 0.67 for women with blonde, light brown, and dark brown/black hair, respectively, in multivariate analysis, the researchers found.

The study was limited by several factors including the use of self-reports for hair color and the relative homogeneity of the Nurses’ Health Study, which has a population of mostly white, female health professionals, the researchers noted.

However, the findings of significantly increased CRP levels “could potentially explain a prior report of increased risks of cardiovascular disease and cancer in red-haired women,” they said. “Although, we observed similar associations in the NHS between red hair and cardiovascular disease and cancer, they were not statistically significant,” they added.

Additional studies are needed to validate and examine the clinical significance of the results, they concluded.

“Elevated CRP levels, a marker of inflammation, have been associated with increased risk for several diseases, including colon cancer and heart disease,” lead author Dr. Hartman said in an interview. “Another study suggested red-haired women have elevated risks of cardiovascular disease and cancer. We wanted to see if different levels of inflammation in red-haired women could possibly explain these findings.”

She said she was not surprised by the findings, “as they were in line with our hypothesis.” In addition, “animal studies suggest that the gene most responsible for red hair, MC1R, may be linked to inflammation,” she said.

While red-haired women were found to have higher CRP levels in the study, “the underlying mechanism and clinical significance remain unknown,” and more research is needed, Dr. Hartman emphasized. “First, our findings need to be validated in women and also examined in men. If our findings are validated, future studies should examine the mechanism of CRP elevation in red-haired women, and whether these women have elevated risks of colon cancer and heart disease,” she said.

“If red-haired women do have increased levels of inflammation, and as a result have elevated risks of colon cancer and heart disease, then future interventions can focus on enhanced screening and possibly chemoprevention in this population,” she added.

The study was supported by the National Institutes of Health. Lead author Dr. Hartman was supported by an American Skin Association Research Grant.
 

SOURCE: Hartman RI et al. J Invest Dermatol. 2020 Oct 12. doi: 10.1016/j.jid.2020.09.015.

Red-haired women were significantly more likely than were women with nonred hair to have elevated levels of C-reactive protein that may increase risk for cardiovascular conditions, according to data from nearly 9,000 women participating in the Nurses’ Health Study.

“Positive associations between red hair and cardiovascular disease and cancer in women, but not men, have been reported,” wrote Rebecca I. Hartman, MD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

In a study published in the Journal of Investigative Dermatology, they reviewed data from the Nurses’ Health Study, a 1976 cohort study of 121,700 women registered nurses in the United States. They analyzed blood specimens from 8,994 women that were collected between 1989 and 1990. Participants’ natural hair color was determined by asking them their natural hair color at age 21 years, with choices of red, blonde, light brown, dark brown, or black. Overall, dark brown/black hair was the most common color (45%) and 390 of the women (4.3%) had red hair.

The average CRP levels were significantly higher for women with red hair (3.7 mg/L), compared with those with blonde (3.3 mg/L), light brown (3.0 mg/mL), or dark brown/black (3.2 mg/L).

Using the CRP levels for red-haired women as a reference, women with blond, light brown, and dark brown/black hair averaged significantly lower CRP levels than those of red-haired women in an age-adjusted model (–15.2%, –18/1%, and –14.2%, respectively) and in a multivariate analysis (–12.7%, –14.1%, and –10.9%, respectively).

Non-red-haired women had significantly lower odds of high CRP levels compared with red-haired women, with odds ratios of 0.62, 0.60, and 0.67 for women with blonde, light brown, and dark brown/black hair, respectively, in multivariate analysis, the researchers found.

The study was limited by several factors including the use of self-reports for hair color and the relative homogeneity of the Nurses’ Health Study, which has a population of mostly white, female health professionals, the researchers noted.

However, the findings of significantly increased CRP levels “could potentially explain a prior report of increased risks of cardiovascular disease and cancer in red-haired women,” they said. “Although, we observed similar associations in the NHS between red hair and cardiovascular disease and cancer, they were not statistically significant,” they added.

Additional studies are needed to validate and examine the clinical significance of the results, they concluded.

“Elevated CRP levels, a marker of inflammation, have been associated with increased risk for several diseases, including colon cancer and heart disease,” lead author Dr. Hartman said in an interview. “Another study suggested red-haired women have elevated risks of cardiovascular disease and cancer. We wanted to see if different levels of inflammation in red-haired women could possibly explain these findings.”

She said she was not surprised by the findings, “as they were in line with our hypothesis.” In addition, “animal studies suggest that the gene most responsible for red hair, MC1R, may be linked to inflammation,” she said.

While red-haired women were found to have higher CRP levels in the study, “the underlying mechanism and clinical significance remain unknown,” and more research is needed, Dr. Hartman emphasized. “First, our findings need to be validated in women and also examined in men. If our findings are validated, future studies should examine the mechanism of CRP elevation in red-haired women, and whether these women have elevated risks of colon cancer and heart disease,” she said.

“If red-haired women do have increased levels of inflammation, and as a result have elevated risks of colon cancer and heart disease, then future interventions can focus on enhanced screening and possibly chemoprevention in this population,” she added.

The study was supported by the National Institutes of Health. Lead author Dr. Hartman was supported by an American Skin Association Research Grant.
 

SOURCE: Hartman RI et al. J Invest Dermatol. 2020 Oct 12. doi: 10.1016/j.jid.2020.09.015.

The Centers for Disease Control and Prevention updated its recommendations for likely person-to-person spread of SARS-CoV-2 to warn about the risk of multiple, brief, “close contact” encounters with others who are positive for COVID-19.

New data suggest each close encounter – coming within 6 feet of an infected person – can increase the risk for transmission, CDC director Robert Redfield, MD, said during a media briefing.

“As we get more data and understand the science of COVID, we’re going to continue to incorporate that in our recommendations,” Dr. Redfield said in response to a reporter’s question about a recent study.

Previously, the CDC cautioned against spending 15 minutes or longer in close proximity to an infected person, particularly in enclosed indoor spaces.

In a new report published online Oct. 21 in Morbidity and Mortality Weekly Report, however, investigators “determined that an individual who had a series of shorter contacts that over time added up to more than 15 minutes became infected.”
 

Beware of brief encounters?

On July 28, a 20-year-old male correctional officer in Vermont had multiple brief encounters with six transferred incarcerated or detained people while their SARS-CoV-2 test results were pending. The six were asymptomatic at the time and were housed in a quarantine unit, reported CDC researcher Julia Pringle, PhD, and colleagues.

The following day, all six inmates tested polymerase chain reaction (PCR) positive for COVID-19. The correctional officer did not spend 15 minutes or more within 6 feet of any of the inmates, according to video surveillance footage, and he continued to work.

On Aug. 4, however, he developed symptoms that included loss of smell and taste, myalgia, runny nose, cough, shortness of breath, headache, loss of appetite, and gastrointestinal symptoms. He stayed home starting the next day and tested PCR positive for COVID-19 on Aug. 11.

Further review of the surveillance video showed that the officer had numerous brief encounters of approximately 1 minute each that cumulatively exceeded 15 minutes over a 24-hour period, the researchers reported.

During all the interactions with inmates, the correctional officer wore a cloth mask, gown, and eye protection. The inmates wore masks while in their cells but did not have them on during brief cell doorway interactions or in the recreation room, according to the report.
 

No interaction is 100% safe

“We know that every activity that involves interacting with others has some degree of risk right now,” said Jay Butler, MD, CDC deputy director for infectious diseases.

“Unfortunately, we’re seeing a distressing trend here in the United States with COVID-19 cases increasing in nearly 75% of the country,” he said. “We’ve confirmed 8.1 million cases and, sadly, over 220,000 deaths since January.

“I know these are numbers, but these are also people,” Dr. Butler added.

“The pandemic is not over,” Dr. Redfield said. “Earlier this week, COVID virus cases reached over 40 million globally. Here in the United States we are approaching a critical phase.”

Four factors associated with higher risk for transmission are the proximity of each encounter, its duration, whether an interaction takes place indoors or outdoors, and the number of people encountered, Dr. Butler said.

Dr. Butler acknowledged widespread fatigue with adherence to personal protection measures, but added that social distancing, mask-wearing, and other measures are more important now than ever. He noted that more Americans will be spending time indoors with the onset of cooler weather and the upcoming holidays.
 

A note of optimism

Dr. Redfield remains optimistic about the limited availability of a vaccine or vaccines by year’s end but added that “it’s important for all of us to remain diligent in our efforts to defeat this virus.”

“There is hope on the way, in the form of safe and effective vaccines in a matter of weeks or months. To bridge to that next phase, we have to take steps to keep ourselves, our families, and our communities safe,” said Alex Azar, secretary of the Department of Health & Human Services.

“I know it’s been a difficult year for Americans, but we are going to come through this on the other side,” Dr. Redfield said.

The Centers for Disease Control and Prevention updated its recommendations for likely person-to-person spread of SARS-CoV-2 to warn about the risk of multiple, brief, “close contact” encounters with others who are positive for COVID-19.

New data suggest each close encounter – coming within 6 feet of an infected person – can increase the risk for transmission, CDC director Robert Redfield, MD, said during a media briefing.

“As we get more data and understand the science of COVID, we’re going to continue to incorporate that in our recommendations,” Dr. Redfield said in response to a reporter’s question about a recent study.

Previously, the CDC cautioned against spending 15 minutes or longer in close proximity to an infected person, particularly in enclosed indoor spaces.

In a new report published online Oct. 21 in Morbidity and Mortality Weekly Report, however, investigators “determined that an individual who had a series of shorter contacts that over time added up to more than 15 minutes became infected.”
 

Beware of brief encounters?

On July 28, a 20-year-old male correctional officer in Vermont had multiple brief encounters with six transferred incarcerated or detained people while their SARS-CoV-2 test results were pending. The six were asymptomatic at the time and were housed in a quarantine unit, reported CDC researcher Julia Pringle, PhD, and colleagues.

The following day, all six inmates tested polymerase chain reaction (PCR) positive for COVID-19. The correctional officer did not spend 15 minutes or more within 6 feet of any of the inmates, according to video surveillance footage, and he continued to work.

On Aug. 4, however, he developed symptoms that included loss of smell and taste, myalgia, runny nose, cough, shortness of breath, headache, loss of appetite, and gastrointestinal symptoms. He stayed home starting the next day and tested PCR positive for COVID-19 on Aug. 11.

Further review of the surveillance video showed that the officer had numerous brief encounters of approximately 1 minute each that cumulatively exceeded 15 minutes over a 24-hour period, the researchers reported.

During all the interactions with inmates, the correctional officer wore a cloth mask, gown, and eye protection. The inmates wore masks while in their cells but did not have them on during brief cell doorway interactions or in the recreation room, according to the report.
 

No interaction is 100% safe

“We know that every activity that involves interacting with others has some degree of risk right now,” said Jay Butler, MD, CDC deputy director for infectious diseases.

“Unfortunately, we’re seeing a distressing trend here in the United States with COVID-19 cases increasing in nearly 75% of the country,” he said. “We’ve confirmed 8.1 million cases and, sadly, over 220,000 deaths since January.

“I know these are numbers, but these are also people,” Dr. Butler added.

“The pandemic is not over,” Dr. Redfield said. “Earlier this week, COVID virus cases reached over 40 million globally. Here in the United States we are approaching a critical phase.”

Four factors associated with higher risk for transmission are the proximity of each encounter, its duration, whether an interaction takes place indoors or outdoors, and the number of people encountered, Dr. Butler said.

Dr. Butler acknowledged widespread fatigue with adherence to personal protection measures, but added that social distancing, mask-wearing, and other measures are more important now than ever. He noted that more Americans will be spending time indoors with the onset of cooler weather and the upcoming holidays.
 

A note of optimism

Dr. Redfield remains optimistic about the limited availability of a vaccine or vaccines by year’s end but added that “it’s important for all of us to remain diligent in our efforts to defeat this virus.”

“There is hope on the way, in the form of safe and effective vaccines in a matter of weeks or months. To bridge to that next phase, we have to take steps to keep ourselves, our families, and our communities safe,” said Alex Azar, secretary of the Department of Health & Human Services.

“I know it’s been a difficult year for Americans, but we are going to come through this on the other side,” Dr. Redfield said.

The Centers for Disease Control and Prevention updated its recommendations for likely person-to-person spread of SARS-CoV-2 to warn about the risk of multiple, brief, “close contact” encounters with others who are positive for COVID-19.

New data suggest each close encounter – coming within 6 feet of an infected person – can increase the risk for transmission, CDC director Robert Redfield, MD, said during a media briefing.

“As we get more data and understand the science of COVID, we’re going to continue to incorporate that in our recommendations,” Dr. Redfield said in response to a reporter’s question about a recent study.

Previously, the CDC cautioned against spending 15 minutes or longer in close proximity to an infected person, particularly in enclosed indoor spaces.

In a new report published online Oct. 21 in Morbidity and Mortality Weekly Report, however, investigators “determined that an individual who had a series of shorter contacts that over time added up to more than 15 minutes became infected.”
 

Beware of brief encounters?

On July 28, a 20-year-old male correctional officer in Vermont had multiple brief encounters with six transferred incarcerated or detained people while their SARS-CoV-2 test results were pending. The six were asymptomatic at the time and were housed in a quarantine unit, reported CDC researcher Julia Pringle, PhD, and colleagues.

The following day, all six inmates tested polymerase chain reaction (PCR) positive for COVID-19. The correctional officer did not spend 15 minutes or more within 6 feet of any of the inmates, according to video surveillance footage, and he continued to work.

On Aug. 4, however, he developed symptoms that included loss of smell and taste, myalgia, runny nose, cough, shortness of breath, headache, loss of appetite, and gastrointestinal symptoms. He stayed home starting the next day and tested PCR positive for COVID-19 on Aug. 11.

Further review of the surveillance video showed that the officer had numerous brief encounters of approximately 1 minute each that cumulatively exceeded 15 minutes over a 24-hour period, the researchers reported.

During all the interactions with inmates, the correctional officer wore a cloth mask, gown, and eye protection. The inmates wore masks while in their cells but did not have them on during brief cell doorway interactions or in the recreation room, according to the report.
 

No interaction is 100% safe

“We know that every activity that involves interacting with others has some degree of risk right now,” said Jay Butler, MD, CDC deputy director for infectious diseases.

“Unfortunately, we’re seeing a distressing trend here in the United States with COVID-19 cases increasing in nearly 75% of the country,” he said. “We’ve confirmed 8.1 million cases and, sadly, over 220,000 deaths since January.

“I know these are numbers, but these are also people,” Dr. Butler added.

“The pandemic is not over,” Dr. Redfield said. “Earlier this week, COVID virus cases reached over 40 million globally. Here in the United States we are approaching a critical phase.”

Four factors associated with higher risk for transmission are the proximity of each encounter, its duration, whether an interaction takes place indoors or outdoors, and the number of people encountered, Dr. Butler said.

Dr. Butler acknowledged widespread fatigue with adherence to personal protection measures, but added that social distancing, mask-wearing, and other measures are more important now than ever. He noted that more Americans will be spending time indoors with the onset of cooler weather and the upcoming holidays.
 

A note of optimism

Dr. Redfield remains optimistic about the limited availability of a vaccine or vaccines by year’s end but added that “it’s important for all of us to remain diligent in our efforts to defeat this virus.”

“There is hope on the way, in the form of safe and effective vaccines in a matter of weeks or months. To bridge to that next phase, we have to take steps to keep ourselves, our families, and our communities safe,” said Alex Azar, secretary of the Department of Health & Human Services.

“I know it’s been a difficult year for Americans, but we are going to come through this on the other side,” Dr. Redfield said.

Convalescent plasma may not prevent progression to severe disease or reduce mortality risk in hospitalized patients with moderate COVID-19, based on a phase 2 trial involving more than 400 patients in India.

The PLACID trial offers real-world data with “high generalizability,” according to lead author Anup Agarwal, MD, of the Indian Council of Medical Research, New Delhi, and colleagues.

“Evidence suggests that convalescent plasma collected from survivors of COVID-19 contains receptor binding domain specific antibodies with potent antiviral activity,” the investigators wrote in the BMJ. “However, effective titers of antiviral neutralizing antibodies, optimal timing for convalescent plasma treatment, optimal timing for plasma donation, and the severity class of patients who are likely to benefit from convalescent plasma remain unclear.”

According to Dr. Agarwal and colleagues, case series and observational studies have suggested that convalescent plasma may reduce viral load, hospital stay, and mortality, but randomized controlled trials to date have ended prematurely because of issues with enrollment and design, making PLACID the first randomized controlled trial of its kind to reach completion.

The open-label, multicenter study involved 464 hospitalized adults who tested positive for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR). Enrollment also required a respiratory rate of more than 24 breaths/min with an oxygen saturation (SpO₂) of 93% or less on room air, or a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO₂ /FiO₂ ) ratio between 200 and 300 mm Hg.

Patients were randomly assigned in a 1:1 ratio to receive either best standard of care (control), or best standard of care plus convalescent plasma, which was given in two doses of 200 mL, 24 hours apart. Patients were assessed via clinical examination, chest imaging, and serial laboratory testing, the latter of which included neutralizing antibody titers on days 0, 3, and 7.

The primary outcome was a 28-day composite of progression to severe disease (PaO₂/FiO₂ ratio < 100 mm Hg) and all-cause mortality. An array of secondary outcomes were also reported, including symptom resolution, total duration of respiratory support, change in oxygen requirement, and others.

In the convalescent plasma group, 19% of patients progressed to severe disease or died within 28 days, compared with 18% of those in the control group (risk ratio, 1.04; 95% confidence interval, 0.71-1.54), suggesting no statistically significant benefit from the intervention. This lack of benefit was also found in a subgroup analysis of patients with detectable titers of antibodies to SARS-CoV-2, and when progression to severe disease and all-cause mortality were analyzed independently across all patients.

Still, at day 7, patients treated with convalescent plasma were significantly more likely to have resolution of fatigue (RR, 1.21; 95% CI, 1.02-1.42) and shortness of breath (RR, 1.16; 95% CI, 1.02-1.32). And at the same time point, patients treated with convalescent plasma were 20% more likely to test negative for SARS-CoV-2 RNA (RR, 1.2; 95% CI, 1.04-1.5).

In an accompanying editorial, Elizabeth B. Pathak, PhD, of the Women’s Institute for Independent Social Enquiry, Olney, Md., suggested that the reported symptom improvements need to be viewed with skepticism.

“These results should be interpreted with caution, because the trial was not blinded, so knowledge of treatment status could have influenced the reporting of subjective symptoms by patients who survived to day 7,” Dr. Pathak wrote.

Dr. Pathak noted that convalescent plasma did appear to have an antiviral effect, based on the higher rate of negative RNA test results at day 7. She hypothesized that the lack of major corresponding clinical benefit could be explained by detrimental thrombotic processes.

“The net effect of plasma is prothrombotic,” Dr. Pathak wrote, which should raise safety concerns, since “COVID-19 is a life-threatening thrombotic disorder.”

According to Dr. Pathak, large-scale datasets may be giving a false sense of security. She cited a recent safety analysis of 20,000 U.S. patients who received convalescent plasma, in which the investigators excluded 88.2% of cardiac events and 66.3% of thrombotic events, as these were deemed unrelated to transfusion; but this decision was made by the treating physician, without independent review or a defined protocol.

Michael J. Joyner, MD, of the Mayo Clinic in Rochester, Minn., was the lead author of the above safety study, and is leading the Food and Drug Administration expanded access program for convalescent plasma in patients with COVID-19. He suggested that the study by Dr. Agarwal and colleagues was admirable, but flaws in the treatment protocol cast doubt upon the efficacy findings.

“It is very impressive that these investigators performed a large trial of convalescent plasma in the midst of a pandemic,” Dr. Joyner said. “Unfortunately it is unclear how generalizable the findings are because many of the units of plasma had either very low or no antibody titers and because the plasma was given late in the course of the disease. It has been known since at least the 1930s that antibody therapy works best when enough product is given either prophylactically or early in the course of disease.”

Dr. Joyner had a more positive interpretation of the reported symptom improvements.

“It is also interesting to note that while there was no mortality benefit, that – even with the limitations of the study – there was some evidence of improved patient physiology at 7 days,” he said. “So, at one level, [this is] a negative study, but at least [there are] some hints of efficacy given the suboptimal use case in the patients studied.”

The study was funded by the Indian Council of Medical Research, which employs several of the authors and PLACID Trial Collaborators. Dr. Pathak and Dr. Joyner reported no conflicts of interest.

SOURCE: Agarwal A et al. BMJ. 2020 Oct 23. doi: 10.1136/bmj.m3939 .

Convalescent plasma may not prevent progression to severe disease or reduce mortality risk in hospitalized patients with moderate COVID-19, based on a phase 2 trial involving more than 400 patients in India.

The PLACID trial offers real-world data with “high generalizability,” according to lead author Anup Agarwal, MD, of the Indian Council of Medical Research, New Delhi, and colleagues.

“Evidence suggests that convalescent plasma collected from survivors of COVID-19 contains receptor binding domain specific antibodies with potent antiviral activity,” the investigators wrote in the BMJ. “However, effective titers of antiviral neutralizing antibodies, optimal timing for convalescent plasma treatment, optimal timing for plasma donation, and the severity class of patients who are likely to benefit from convalescent plasma remain unclear.”

According to Dr. Agarwal and colleagues, case series and observational studies have suggested that convalescent plasma may reduce viral load, hospital stay, and mortality, but randomized controlled trials to date have ended prematurely because of issues with enrollment and design, making PLACID the first randomized controlled trial of its kind to reach completion.

The open-label, multicenter study involved 464 hospitalized adults who tested positive for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR). Enrollment also required a respiratory rate of more than 24 breaths/min with an oxygen saturation (SpO₂) of 93% or less on room air, or a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO₂ /FiO₂ ) ratio between 200 and 300 mm Hg.

Patients were randomly assigned in a 1:1 ratio to receive either best standard of care (control), or best standard of care plus convalescent plasma, which was given in two doses of 200 mL, 24 hours apart. Patients were assessed via clinical examination, chest imaging, and serial laboratory testing, the latter of which included neutralizing antibody titers on days 0, 3, and 7.

The primary outcome was a 28-day composite of progression to severe disease (PaO₂/FiO₂ ratio < 100 mm Hg) and all-cause mortality. An array of secondary outcomes were also reported, including symptom resolution, total duration of respiratory support, change in oxygen requirement, and others.

In the convalescent plasma group, 19% of patients progressed to severe disease or died within 28 days, compared with 18% of those in the control group (risk ratio, 1.04; 95% confidence interval, 0.71-1.54), suggesting no statistically significant benefit from the intervention. This lack of benefit was also found in a subgroup analysis of patients with detectable titers of antibodies to SARS-CoV-2, and when progression to severe disease and all-cause mortality were analyzed independently across all patients.

Still, at day 7, patients treated with convalescent plasma were significantly more likely to have resolution of fatigue (RR, 1.21; 95% CI, 1.02-1.42) and shortness of breath (RR, 1.16; 95% CI, 1.02-1.32). And at the same time point, patients treated with convalescent plasma were 20% more likely to test negative for SARS-CoV-2 RNA (RR, 1.2; 95% CI, 1.04-1.5).

In an accompanying editorial, Elizabeth B. Pathak, PhD, of the Women’s Institute for Independent Social Enquiry, Olney, Md., suggested that the reported symptom improvements need to be viewed with skepticism.

“These results should be interpreted with caution, because the trial was not blinded, so knowledge of treatment status could have influenced the reporting of subjective symptoms by patients who survived to day 7,” Dr. Pathak wrote.

Dr. Pathak noted that convalescent plasma did appear to have an antiviral effect, based on the higher rate of negative RNA test results at day 7. She hypothesized that the lack of major corresponding clinical benefit could be explained by detrimental thrombotic processes.

“The net effect of plasma is prothrombotic,” Dr. Pathak wrote, which should raise safety concerns, since “COVID-19 is a life-threatening thrombotic disorder.”

According to Dr. Pathak, large-scale datasets may be giving a false sense of security. She cited a recent safety analysis of 20,000 U.S. patients who received convalescent plasma, in which the investigators excluded 88.2% of cardiac events and 66.3% of thrombotic events, as these were deemed unrelated to transfusion; but this decision was made by the treating physician, without independent review or a defined protocol.

Michael J. Joyner, MD, of the Mayo Clinic in Rochester, Minn., was the lead author of the above safety study, and is leading the Food and Drug Administration expanded access program for convalescent plasma in patients with COVID-19. He suggested that the study by Dr. Agarwal and colleagues was admirable, but flaws in the treatment protocol cast doubt upon the efficacy findings.

“It is very impressive that these investigators performed a large trial of convalescent plasma in the midst of a pandemic,” Dr. Joyner said. “Unfortunately it is unclear how generalizable the findings are because many of the units of plasma had either very low or no antibody titers and because the plasma was given late in the course of the disease. It has been known since at least the 1930s that antibody therapy works best when enough product is given either prophylactically or early in the course of disease.”

Dr. Joyner had a more positive interpretation of the reported symptom improvements.

“It is also interesting to note that while there was no mortality benefit, that – even with the limitations of the study – there was some evidence of improved patient physiology at 7 days,” he said. “So, at one level, [this is] a negative study, but at least [there are] some hints of efficacy given the suboptimal use case in the patients studied.”

The study was funded by the Indian Council of Medical Research, which employs several of the authors and PLACID Trial Collaborators. Dr. Pathak and Dr. Joyner reported no conflicts of interest.

SOURCE: Agarwal A et al. BMJ. 2020 Oct 23. doi: 10.1136/bmj.m3939 .

Convalescent plasma may not prevent progression to severe disease or reduce mortality risk in hospitalized patients with moderate COVID-19, based on a phase 2 trial involving more than 400 patients in India.

The PLACID trial offers real-world data with “high generalizability,” according to lead author Anup Agarwal, MD, of the Indian Council of Medical Research, New Delhi, and colleagues.

“Evidence suggests that convalescent plasma collected from survivors of COVID-19 contains receptor binding domain specific antibodies with potent antiviral activity,” the investigators wrote in the BMJ. “However, effective titers of antiviral neutralizing antibodies, optimal timing for convalescent plasma treatment, optimal timing for plasma donation, and the severity class of patients who are likely to benefit from convalescent plasma remain unclear.”

According to Dr. Agarwal and colleagues, case series and observational studies have suggested that convalescent plasma may reduce viral load, hospital stay, and mortality, but randomized controlled trials to date have ended prematurely because of issues with enrollment and design, making PLACID the first randomized controlled trial of its kind to reach completion.

The open-label, multicenter study involved 464 hospitalized adults who tested positive for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR). Enrollment also required a respiratory rate of more than 24 breaths/min with an oxygen saturation (SpO₂) of 93% or less on room air, or a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO₂ /FiO₂ ) ratio between 200 and 300 mm Hg.

Patients were randomly assigned in a 1:1 ratio to receive either best standard of care (control), or best standard of care plus convalescent plasma, which was given in two doses of 200 mL, 24 hours apart. Patients were assessed via clinical examination, chest imaging, and serial laboratory testing, the latter of which included neutralizing antibody titers on days 0, 3, and 7.

The primary outcome was a 28-day composite of progression to severe disease (PaO₂/FiO₂ ratio < 100 mm Hg) and all-cause mortality. An array of secondary outcomes were also reported, including symptom resolution, total duration of respiratory support, change in oxygen requirement, and others.

In the convalescent plasma group, 19% of patients progressed to severe disease or died within 28 days, compared with 18% of those in the control group (risk ratio, 1.04; 95% confidence interval, 0.71-1.54), suggesting no statistically significant benefit from the intervention. This lack of benefit was also found in a subgroup analysis of patients with detectable titers of antibodies to SARS-CoV-2, and when progression to severe disease and all-cause mortality were analyzed independently across all patients.

Still, at day 7, patients treated with convalescent plasma were significantly more likely to have resolution of fatigue (RR, 1.21; 95% CI, 1.02-1.42) and shortness of breath (RR, 1.16; 95% CI, 1.02-1.32). And at the same time point, patients treated with convalescent plasma were 20% more likely to test negative for SARS-CoV-2 RNA (RR, 1.2; 95% CI, 1.04-1.5).

In an accompanying editorial, Elizabeth B. Pathak, PhD, of the Women’s Institute for Independent Social Enquiry, Olney, Md., suggested that the reported symptom improvements need to be viewed with skepticism.

“These results should be interpreted with caution, because the trial was not blinded, so knowledge of treatment status could have influenced the reporting of subjective symptoms by patients who survived to day 7,” Dr. Pathak wrote.

Dr. Pathak noted that convalescent plasma did appear to have an antiviral effect, based on the higher rate of negative RNA test results at day 7. She hypothesized that the lack of major corresponding clinical benefit could be explained by detrimental thrombotic processes.

“The net effect of plasma is prothrombotic,” Dr. Pathak wrote, which should raise safety concerns, since “COVID-19 is a life-threatening thrombotic disorder.”

According to Dr. Pathak, large-scale datasets may be giving a false sense of security. She cited a recent safety analysis of 20,000 U.S. patients who received convalescent plasma, in which the investigators excluded 88.2% of cardiac events and 66.3% of thrombotic events, as these were deemed unrelated to transfusion; but this decision was made by the treating physician, without independent review or a defined protocol.

Michael J. Joyner, MD, of the Mayo Clinic in Rochester, Minn., was the lead author of the above safety study, and is leading the Food and Drug Administration expanded access program for convalescent plasma in patients with COVID-19. He suggested that the study by Dr. Agarwal and colleagues was admirable, but flaws in the treatment protocol cast doubt upon the efficacy findings.

“It is very impressive that these investigators performed a large trial of convalescent plasma in the midst of a pandemic,” Dr. Joyner said. “Unfortunately it is unclear how generalizable the findings are because many of the units of plasma had either very low or no antibody titers and because the plasma was given late in the course of the disease. It has been known since at least the 1930s that antibody therapy works best when enough product is given either prophylactically or early in the course of disease.”

Dr. Joyner had a more positive interpretation of the reported symptom improvements.

“It is also interesting to note that while there was no mortality benefit, that – even with the limitations of the study – there was some evidence of improved patient physiology at 7 days,” he said. “So, at one level, [this is] a negative study, but at least [there are] some hints of efficacy given the suboptimal use case in the patients studied.”

The study was funded by the Indian Council of Medical Research, which employs several of the authors and PLACID Trial Collaborators. Dr. Pathak and Dr. Joyner reported no conflicts of interest.

SOURCE: Agarwal A et al. BMJ. 2020 Oct 23. doi: 10.1136/bmj.m3939 .

The U.S. Food and Drug Administration approved remdesivir (Veklury) Oct. 22 as a treatment for hospitalized COVID-19 patients aged 12 and up, making it the first and only approved treatment for COVID-19, according to a release from drug manufacturer Gilead Sciences.

The FDA’s initial Emergency Use Authorization (EUA) of the antiviral, issued in May, allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who needed oxygen therapy or mechanical ventilation.

An August EUA expanded treatment to include all adult and pediatric hospitalized COVID-19 patients, regardless of the severity of their disease. The FDA also issued a new EUA for remdesivir Oct. 22 allowing treatment of hospitalized pediatric patients younger than 12 weighing at least 3.5 kg.

Today’s approval is based on three randomized controlled trials, according to Gilead.

Final trial results from one of them, the National Institute of Allergy and Infectious Disease–funded ACTT-1 trial, published earlier in October, showed that hospitalized patients with COVID-19 who received remdesivir had a shorter median recovery time than those who received a placebo – 10 days versus 15 days.

This difference and some related secondary endpoints were statistically significant in the randomized trial, but there was not a statistically significant difference in mortality between the treatment and placebo groups.

The other two trials used for the approval, the SIMPLE trials, were open-label phase 3 trials conducted in countries with a high prevalence of COVID-19 infections, according to Gilead.

The SIMPLE-Severe trial was a randomized, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing plus standard of care in 397 hospitalized adult patients with severe COVID-19. The primary endpoint was clinical status on day 14 assessed on a 7-point ordinal scale, according to Gilead.

The trial found that a 5-day or a 10-day treatment course of Veklury achieved similar clinical outcomes to the ACTT-1 trial (odds ratio, 0.75; 95% confidence interval, 0.51-1.12).

The SIMPLE-Moderate trial was a randomized, controlled, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing durations of Veklury plus standard of care, compared with standard of care alone in 600 hospitalized adult patients with moderate COVID-19, Gilead stated in its release.

The primary endpoint was clinical status on day 11 assessed on a 7-point ordinal scale.

The results showed statistically improved clinical outcomes with a 5-day treatment course of Veklury, compared with standard of care (OR, 1.65; 95% CI, 1.0-2.48; P = .017), according to Gilead.

This article first appeared on Medscape.com.

The U.S. Food and Drug Administration approved remdesivir (Veklury) Oct. 22 as a treatment for hospitalized COVID-19 patients aged 12 and up, making it the first and only approved treatment for COVID-19, according to a release from drug manufacturer Gilead Sciences.

The FDA’s initial Emergency Use Authorization (EUA) of the antiviral, issued in May, allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who needed oxygen therapy or mechanical ventilation.

An August EUA expanded treatment to include all adult and pediatric hospitalized COVID-19 patients, regardless of the severity of their disease. The FDA also issued a new EUA for remdesivir Oct. 22 allowing treatment of hospitalized pediatric patients younger than 12 weighing at least 3.5 kg.

Today’s approval is based on three randomized controlled trials, according to Gilead.

Final trial results from one of them, the National Institute of Allergy and Infectious Disease–funded ACTT-1 trial, published earlier in October, showed that hospitalized patients with COVID-19 who received remdesivir had a shorter median recovery time than those who received a placebo – 10 days versus 15 days.

This difference and some related secondary endpoints were statistically significant in the randomized trial, but there was not a statistically significant difference in mortality between the treatment and placebo groups.

The other two trials used for the approval, the SIMPLE trials, were open-label phase 3 trials conducted in countries with a high prevalence of COVID-19 infections, according to Gilead.

The SIMPLE-Severe trial was a randomized, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing plus standard of care in 397 hospitalized adult patients with severe COVID-19. The primary endpoint was clinical status on day 14 assessed on a 7-point ordinal scale, according to Gilead.

The trial found that a 5-day or a 10-day treatment course of Veklury achieved similar clinical outcomes to the ACTT-1 trial (odds ratio, 0.75; 95% confidence interval, 0.51-1.12).

The SIMPLE-Moderate trial was a randomized, controlled, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing durations of Veklury plus standard of care, compared with standard of care alone in 600 hospitalized adult patients with moderate COVID-19, Gilead stated in its release.

The primary endpoint was clinical status on day 11 assessed on a 7-point ordinal scale.

The results showed statistically improved clinical outcomes with a 5-day treatment course of Veklury, compared with standard of care (OR, 1.65; 95% CI, 1.0-2.48; P = .017), according to Gilead.

This article first appeared on Medscape.com.

The U.S. Food and Drug Administration approved remdesivir (Veklury) Oct. 22 as a treatment for hospitalized COVID-19 patients aged 12 and up, making it the first and only approved treatment for COVID-19, according to a release from drug manufacturer Gilead Sciences.

The FDA’s initial Emergency Use Authorization (EUA) of the antiviral, issued in May, allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who needed oxygen therapy or mechanical ventilation.

An August EUA expanded treatment to include all adult and pediatric hospitalized COVID-19 patients, regardless of the severity of their disease. The FDA also issued a new EUA for remdesivir Oct. 22 allowing treatment of hospitalized pediatric patients younger than 12 weighing at least 3.5 kg.

Today’s approval is based on three randomized controlled trials, according to Gilead.

Final trial results from one of them, the National Institute of Allergy and Infectious Disease–funded ACTT-1 trial, published earlier in October, showed that hospitalized patients with COVID-19 who received remdesivir had a shorter median recovery time than those who received a placebo – 10 days versus 15 days.

This difference and some related secondary endpoints were statistically significant in the randomized trial, but there was not a statistically significant difference in mortality between the treatment and placebo groups.

The other two trials used for the approval, the SIMPLE trials, were open-label phase 3 trials conducted in countries with a high prevalence of COVID-19 infections, according to Gilead.

The SIMPLE-Severe trial was a randomized, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing plus standard of care in 397 hospitalized adult patients with severe COVID-19. The primary endpoint was clinical status on day 14 assessed on a 7-point ordinal scale, according to Gilead.

The trial found that a 5-day or a 10-day treatment course of Veklury achieved similar clinical outcomes to the ACTT-1 trial (odds ratio, 0.75; 95% confidence interval, 0.51-1.12).

The SIMPLE-Moderate trial was a randomized, controlled, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing durations of Veklury plus standard of care, compared with standard of care alone in 600 hospitalized adult patients with moderate COVID-19, Gilead stated in its release.

The primary endpoint was clinical status on day 11 assessed on a 7-point ordinal scale.

The results showed statistically improved clinical outcomes with a 5-day treatment course of Veklury, compared with standard of care (OR, 1.65; 95% CI, 1.0-2.48; P = .017), according to Gilead.

This article first appeared on Medscape.com.

This is the third in a series of columns discussing the important roles that dermatologists have played in the skin care industry. This section will discuss those dermatologists who worked behind the scenes with the cosmetic industry, rather than developing their own skin care lines.
 

Norman Orentreich, MD

Dr. Orentreich was a successful New York City dermatologist and the first to perform hair transplants. This new technique brought him fame and notoriety and arguably made him the first “celebrity dermatologist.” (He was also a member of the original advisory board of Dermatology News, at that time Skin & Allergy News, in January 1970.) Dr. Orentreich was a seminal figure in the trend to link the cosmetic industry and dermatology. In August 1967, Vogue magazine¹ published an article on him, titled “Can Great Skin be Created?” This popular article caught the attention of Leonard Lauder, of Estée Lauder, who recruited Dr. Orentreich to help create the skin care line Clinique. Clinique was intended to be a brand with a medical look that promoted its products as “allergy tested,” with packaging that has an antiseptic look and beauty counter salespeople wearing white coats.

Dr. Orentreich’s input into the development of a skin type–based skin care line was fundamental to the development of this brand. The four-question questionnaire with an iconic plastic lever that customers slide left or right instantly provided them with an assessment of their skin type at the beauty counter, with one of four skin types: Very Dry to Dry Skin (Skin Type 1), Dry Combination (Skin Type 2), Combination Oily (Skin Type 3), and Oily (Skin Type 4).

Although this skin-typing system was not scientifically accurate (there is no scientific definition of combination skin), it was reminiscent of the system developed by cosmetic company tycoon Helena Rubinstein in the 1940s that classified people into four skin types: oily, dry, combination, and sensitive. Clinique became a blockbuster skin care brand and was one of the first developed by a dermatologist – although Dr. Orentreich did not put his name on it.

In 1972, Dr. Orentreich filed a patent² for an exfoliating pad for the skin that later became known as the “Buf-Puf.” I heard years ago that he got the idea from the machines used to buff the floors in the hospital. The buffing pad had a hole in the center where the machine attached. Dr. Orentreich purportedly thought “I wonder what they do with the cut-out centers?” He looked into this, and subsequently used the centers to create the Buf-Puf. I cannot find a reference for this, but I love this story and hope it’s true. If any readers have any knowledge of this, please let me know, so I can amend my story if it is incorrect.
 

Almay

Almay, an amalgamation of the founders’ names, Alfred and Fanny May Woititz, was the first hypoallergenic brand, established in 1931, and the first to provide hypoallergenic cosmetics, long before Clinique. In addition, the company was the first skin care brand to become available by prescription only (as it was initially), fully disclose all individual ingredients in its products (well before this became mandatory in 1976), provide totally fragrance-free products, develop a hypoallergenic fragrance – and provide patch tests and other materials to physicians to identify contact allergens.

Over 90 years, the company was also the first among skin care brands to do the following:

• Provide custom formulations to individuals proven to be allergic to a specific ingredient, through their physicians.
• Perform a full range of premarket safety testing on all products for allergy and irritation, and test all its products for comedogenicity.
• Formulate cosmetics for use around the eye area (eye shadows and eyeliners) specifically for contact lens wearers.
• Formulate hypoallergenic regimens for specific skin types in the mass market.
• Provide a specific cosmetic regimen for acne-prone women, including a silicone-based makeup and active ingredients for treatment in cosmetics and skin care.

I recently interviewed Stanley Levy, MD, who was one of the consultants to Almay, and practices in Chapel Hill, N.C., where he has an academic niche related to skin care formulation and safety. He told me how Almay provided patch test materials to dermatologists to help identify contact dermatitis to cosmetic ingredients, and described Almay’s relationship with the dermatology field as follows: “From the outset, Almay was linked to dermatology. In 1930, a chemist and pharmacist in New York City, Al Woititz, was looking to compound cosmetics for his wife suffering from cosmetic allergies, Fannie May. He enlisted the counsel of the preeminent dermatologic expert in contact dermatitis at the time, Dr. Marion Sulzberger, to suggest ingredients to avoid. [Dr. Sulzberger was also a member of the original Dermatology News editorial advisory board.] Soon, dermatologists around New York City were recommending these formulations. This led to a product line free of the known allergens and a fledgling company trademarked as Almay. For the past 90 years, [the company] has kept a close relationship with dermatologists, well before that was the norm.”

The Almay research overseen by Dr. Levy and others contributed greatly to our understanding of the allergenicity of skin care.
 

Albert Kligman, MD

The turning point for the interface of dermatology with the cosmetic industry was the shift from a safety-based approach (hypoallergenic and noncomedogenic) to an emphasis on efficacy claims in the 1980s. Part of the impetus for this was the Dr. Kligman’s observation that retinoids could improve photoaging.

Dr. Kligman, a well-known dermatologist at the University of Pennsylvania, Philadelphia, showed that retinoids were an effective treatment for acne. For more about this, listen to my interview on the Dermatology Weekly podcast, with James Leyden, MD, about his work at the University of Pennsylvania with Dr. Kligman on the development of oral and topical retinoids. During Dr. Kligman’s research on acne, he noticed that wrinkles improved after treatment with tretinoin, and in 1986, he and Dr. Leyden (and several other authors) published the first article about tretinoin’s use for photoaged skin.³ This led to a double-blind study⁴ conducted by John J. Voorhees, MD, University of Michigan, Ann Arbor, and coauthors that showed statistically significant improvement of photoaged skin when treated with topical tretinoin. Dr. Voorhees and his group did many more studies on retinoids^5,6 and photoaging⁷ – so many that, at one time, he was (and maybe still is) the most widely published dermatologist in the United States. These studies showed that, not only did prescription tretinoin improve the appearance of wrinkles, but so did over-the-counter retinol.⁸ Retinoids remain the most efficacious prescription and cosmeceutical ingredients to treat wrinkled skin.

When studies conducted by Dr. Kligman, Dr. Voorhees, and by Barbara Gilcrest, MD, ^9,10 showed that retinoids improved wrinkles, a major change in the focus in the skin care industry occurred.

During the same time period, the studies on alpha hydroxy acids by Chérie Ditre, MD, Eugene Van Scott, MD, and colleages^11,12; and studies by Sheldon Pinnell, MD, on Vitamin C (see part 1 of this series) all demonstrated the efficacy of cosmetic ingredients on photoaged skin. This triggered a major change in how skin care products were marketed, with an efficacy approach rather than a safety approach.

With the shift from safety (hypoallergenic and noncomedogenic issues) to efficacy claims in the 1980s, and as nondrug active ingredients like retinol were shown to have biologic effects, the lines between the Food and Drug Administration’s definition of a drug versus a cosmetic became blurred. In 1984, Dr. Kligman suggested a new classification for the ingredients that fell in the middle, proposing the term “cosmeceutical” and thus, the concept of a cosmeceutical was introduced. To this day, cosmeceutical is not an official definition and the FDA has yet to deal with it as a quasi-drug category. FDA regulations as to what constitutes a drug versus a cosmetic date back to the 1938 Food, Drug and Cosmetic Act.

Once marketing focused on efficacy, many companies made outrageous claims. During the second half of the 1980s, the FDA issued some warning letters to some companies in an effort to control these claims.

Now efficacy claims abound and we, as dermatologists, should be the experts who back up these claims with scientific data. As the cosmeceutical market has evolved and grown, consumers are bewildered by the myriad of active ingredients being promoted and the number of products in the marketplace. As dermatologic innovation has led to more efficacious active ingredients, our patients look to us as knowledgeable and credible sources of information and for recommendations about the best skin care routines for their skin issues. This is all reflected in the fact that physician-dispensed skin care is becoming the fastest growing segment in this market. It is incumbent upon dermatologists to be knowledgeable and conversant about skin care products and skin care routines, and is particularly true for those of us who sell skin care products in our offices.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Burt’s Bees, Evolus, Galderma, and Revance. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at dermnews@mdedge.com.

References

1. Vogue Magazine, 1967 Aug 15. “Can Great Skin be Created?”

2. https://patents.google.com/patent/US3910284.

3. Kligman AM et al. J Am Acad Dermatol. 1986 Oct;15(4 Pt 2):836-59.

4. Weiss JS et al. JAMA. 1988 Jan 22-29;259(4):527-32.

5. Goldfarb MT et al. J Am Acad Dermatol. 1989 Sep;21(3 Pt 2):645-50.

6. Ellis CN et al. J Am Acad Dermatol. 1990 Oct;23(4 Pt 1):629-37.

7. Kang S; Voorhees JJ. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S55-61.

8. Kafi R et al. Arch Dermatol. 2007 May;143(5):606-12.

9. Gilchrest BA. J Am Acad Dermatol. 1989 Sep;21(3 Pt 2):610-3.

10. Bhawan J et al. Arch Dermatol. 1991 May;127(5):666-72.

11. Griffin TD et al. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):196-203.

12. Ditre CM et al. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):187-95.
 

This is the third in a series of columns discussing the important roles that dermatologists have played in the skin care industry. This section will discuss those dermatologists who worked behind the scenes with the cosmetic industry, rather than developing their own skin care lines.
 

Norman Orentreich, MD

Dr. Orentreich was a successful New York City dermatologist and the first to perform hair transplants. This new technique brought him fame and notoriety and arguably made him the first “celebrity dermatologist.” (He was also a member of the original advisory board of Dermatology News, at that time Skin & Allergy News, in January 1970.) Dr. Orentreich was a seminal figure in the trend to link the cosmetic industry and dermatology. In August 1967, Vogue magazine¹ published an article on him, titled “Can Great Skin be Created?” This popular article caught the attention of Leonard Lauder, of Estée Lauder, who recruited Dr. Orentreich to help create the skin care line Clinique. Clinique was intended to be a brand with a medical look that promoted its products as “allergy tested,” with packaging that has an antiseptic look and beauty counter salespeople wearing white coats.

Dr. Orentreich’s input into the development of a skin type–based skin care line was fundamental to the development of this brand. The four-question questionnaire with an iconic plastic lever that customers slide left or right instantly provided them with an assessment of their skin type at the beauty counter, with one of four skin types: Very Dry to Dry Skin (Skin Type 1), Dry Combination (Skin Type 2), Combination Oily (Skin Type 3), and Oily (Skin Type 4).

Although this skin-typing system was not scientifically accurate (there is no scientific definition of combination skin), it was reminiscent of the system developed by cosmetic company tycoon Helena Rubinstein in the 1940s that classified people into four skin types: oily, dry, combination, and sensitive. Clinique became a blockbuster skin care brand and was one of the first developed by a dermatologist – although Dr. Orentreich did not put his name on it.

In 1972, Dr. Orentreich filed a patent² for an exfoliating pad for the skin that later became known as the “Buf-Puf.” I heard years ago that he got the idea from the machines used to buff the floors in the hospital. The buffing pad had a hole in the center where the machine attached. Dr. Orentreich purportedly thought “I wonder what they do with the cut-out centers?” He looked into this, and subsequently used the centers to create the Buf-Puf. I cannot find a reference for this, but I love this story and hope it’s true. If any readers have any knowledge of this, please let me know, so I can amend my story if it is incorrect.
 

Almay

Almay, an amalgamation of the founders’ names, Alfred and Fanny May Woititz, was the first hypoallergenic brand, established in 1931, and the first to provide hypoallergenic cosmetics, long before Clinique. In addition, the company was the first skin care brand to become available by prescription only (as it was initially), fully disclose all individual ingredients in its products (well before this became mandatory in 1976), provide totally fragrance-free products, develop a hypoallergenic fragrance – and provide patch tests and other materials to physicians to identify contact allergens.

Over 90 years, the company was also the first among skin care brands to do the following:

• Provide custom formulations to individuals proven to be allergic to a specific ingredient, through their physicians.
• Perform a full range of premarket safety testing on all products for allergy and irritation, and test all its products for comedogenicity.
• Formulate cosmetics for use around the eye area (eye shadows and eyeliners) specifically for contact lens wearers.
• Formulate hypoallergenic regimens for specific skin types in the mass market.
• Provide a specific cosmetic regimen for acne-prone women, including a silicone-based makeup and active ingredients for treatment in cosmetics and skin care.

I recently interviewed Stanley Levy, MD, who was one of the consultants to Almay, and practices in Chapel Hill, N.C., where he has an academic niche related to skin care formulation and safety. He told me how Almay provided patch test materials to dermatologists to help identify contact dermatitis to cosmetic ingredients, and described Almay’s relationship with the dermatology field as follows: “From the outset, Almay was linked to dermatology. In 1930, a chemist and pharmacist in New York City, Al Woititz, was looking to compound cosmetics for his wife suffering from cosmetic allergies, Fannie May. He enlisted the counsel of the preeminent dermatologic expert in contact dermatitis at the time, Dr. Marion Sulzberger, to suggest ingredients to avoid. [Dr. Sulzberger was also a member of the original Dermatology News editorial advisory board.] Soon, dermatologists around New York City were recommending these formulations. This led to a product line free of the known allergens and a fledgling company trademarked as Almay. For the past 90 years, [the company] has kept a close relationship with dermatologists, well before that was the norm.”

The Almay research overseen by Dr. Levy and others contributed greatly to our understanding of the allergenicity of skin care.
 

Albert Kligman, MD

The turning point for the interface of dermatology with the cosmetic industry was the shift from a safety-based approach (hypoallergenic and noncomedogenic) to an emphasis on efficacy claims in the 1980s. Part of the impetus for this was the Dr. Kligman’s observation that retinoids could improve photoaging.

Dr. Kligman, a well-known dermatologist at the University of Pennsylvania, Philadelphia, showed that retinoids were an effective treatment for acne. For more about this, listen to my interview on the Dermatology Weekly podcast, with James Leyden, MD, about his work at the University of Pennsylvania with Dr. Kligman on the development of oral and topical retinoids. During Dr. Kligman’s research on acne, he noticed that wrinkles improved after treatment with tretinoin, and in 1986, he and Dr. Leyden (and several other authors) published the first article about tretinoin’s use for photoaged skin.³ This led to a double-blind study⁴ conducted by John J. Voorhees, MD, University of Michigan, Ann Arbor, and coauthors that showed statistically significant improvement of photoaged skin when treated with topical tretinoin. Dr. Voorhees and his group did many more studies on retinoids^5,6 and photoaging⁷ – so many that, at one time, he was (and maybe still is) the most widely published dermatologist in the United States. These studies showed that, not only did prescription tretinoin improve the appearance of wrinkles, but so did over-the-counter retinol.⁸ Retinoids remain the most efficacious prescription and cosmeceutical ingredients to treat wrinkled skin.

When studies conducted by Dr. Kligman, Dr. Voorhees, and by Barbara Gilcrest, MD, ^9,10 showed that retinoids improved wrinkles, a major change in the focus in the skin care industry occurred.

During the same time period, the studies on alpha hydroxy acids by Chérie Ditre, MD, Eugene Van Scott, MD, and colleages^11,12; and studies by Sheldon Pinnell, MD, on Vitamin C (see part 1 of this series) all demonstrated the efficacy of cosmetic ingredients on photoaged skin. This triggered a major change in how skin care products were marketed, with an efficacy approach rather than a safety approach.

With the shift from safety (hypoallergenic and noncomedogenic issues) to efficacy claims in the 1980s, and as nondrug active ingredients like retinol were shown to have biologic effects, the lines between the Food and Drug Administration’s definition of a drug versus a cosmetic became blurred. In 1984, Dr. Kligman suggested a new classification for the ingredients that fell in the middle, proposing the term “cosmeceutical” and thus, the concept of a cosmeceutical was introduced. To this day, cosmeceutical is not an official definition and the FDA has yet to deal with it as a quasi-drug category. FDA regulations as to what constitutes a drug versus a cosmetic date back to the 1938 Food, Drug and Cosmetic Act.

Once marketing focused on efficacy, many companies made outrageous claims. During the second half of the 1980s, the FDA issued some warning letters to some companies in an effort to control these claims.

Now efficacy claims abound and we, as dermatologists, should be the experts who back up these claims with scientific data. As the cosmeceutical market has evolved and grown, consumers are bewildered by the myriad of active ingredients being promoted and the number of products in the marketplace. As dermatologic innovation has led to more efficacious active ingredients, our patients look to us as knowledgeable and credible sources of information and for recommendations about the best skin care routines for their skin issues. This is all reflected in the fact that physician-dispensed skin care is becoming the fastest growing segment in this market. It is incumbent upon dermatologists to be knowledgeable and conversant about skin care products and skin care routines, and is particularly true for those of us who sell skin care products in our offices.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Burt’s Bees, Evolus, Galderma, and Revance. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at dermnews@mdedge.com.

References

1. Vogue Magazine, 1967 Aug 15. “Can Great Skin be Created?”

2. https://patents.google.com/patent/US3910284.

3. Kligman AM et al. J Am Acad Dermatol. 1986 Oct;15(4 Pt 2):836-59.

4. Weiss JS et al. JAMA. 1988 Jan 22-29;259(4):527-32.

5. Goldfarb MT et al. J Am Acad Dermatol. 1989 Sep;21(3 Pt 2):645-50.

6. Ellis CN et al. J Am Acad Dermatol. 1990 Oct;23(4 Pt 1):629-37.

7. Kang S; Voorhees JJ. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S55-61.

8. Kafi R et al. Arch Dermatol. 2007 May;143(5):606-12.

9. Gilchrest BA. J Am Acad Dermatol. 1989 Sep;21(3 Pt 2):610-3.

10. Bhawan J et al. Arch Dermatol. 1991 May;127(5):666-72.

11. Griffin TD et al. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):196-203.

12. Ditre CM et al. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):187-95.
 

This is the third in a series of columns discussing the important roles that dermatologists have played in the skin care industry. This section will discuss those dermatologists who worked behind the scenes with the cosmetic industry, rather than developing their own skin care lines.
 

Norman Orentreich, MD

Dr. Orentreich was a successful New York City dermatologist and the first to perform hair transplants. This new technique brought him fame and notoriety and arguably made him the first “celebrity dermatologist.” (He was also a member of the original advisory board of Dermatology News, at that time Skin & Allergy News, in January 1970.) Dr. Orentreich was a seminal figure in the trend to link the cosmetic industry and dermatology. In August 1967, Vogue magazine¹ published an article on him, titled “Can Great Skin be Created?” This popular article caught the attention of Leonard Lauder, of Estée Lauder, who recruited Dr. Orentreich to help create the skin care line Clinique. Clinique was intended to be a brand with a medical look that promoted its products as “allergy tested,” with packaging that has an antiseptic look and beauty counter salespeople wearing white coats.

Dr. Orentreich’s input into the development of a skin type–based skin care line was fundamental to the development of this brand. The four-question questionnaire with an iconic plastic lever that customers slide left or right instantly provided them with an assessment of their skin type at the beauty counter, with one of four skin types: Very Dry to Dry Skin (Skin Type 1), Dry Combination (Skin Type 2), Combination Oily (Skin Type 3), and Oily (Skin Type 4).

Although this skin-typing system was not scientifically accurate (there is no scientific definition of combination skin), it was reminiscent of the system developed by cosmetic company tycoon Helena Rubinstein in the 1940s that classified people into four skin types: oily, dry, combination, and sensitive. Clinique became a blockbuster skin care brand and was one of the first developed by a dermatologist – although Dr. Orentreich did not put his name on it.

In 1972, Dr. Orentreich filed a patent² for an exfoliating pad for the skin that later became known as the “Buf-Puf.” I heard years ago that he got the idea from the machines used to buff the floors in the hospital. The buffing pad had a hole in the center where the machine attached. Dr. Orentreich purportedly thought “I wonder what they do with the cut-out centers?” He looked into this, and subsequently used the centers to create the Buf-Puf. I cannot find a reference for this, but I love this story and hope it’s true. If any readers have any knowledge of this, please let me know, so I can amend my story if it is incorrect.
 

Almay

Almay, an amalgamation of the founders’ names, Alfred and Fanny May Woititz, was the first hypoallergenic brand, established in 1931, and the first to provide hypoallergenic cosmetics, long before Clinique. In addition, the company was the first skin care brand to become available by prescription only (as it was initially), fully disclose all individual ingredients in its products (well before this became mandatory in 1976), provide totally fragrance-free products, develop a hypoallergenic fragrance – and provide patch tests and other materials to physicians to identify contact allergens.

Over 90 years, the company was also the first among skin care brands to do the following:

• Provide custom formulations to individuals proven to be allergic to a specific ingredient, through their physicians.
• Perform a full range of premarket safety testing on all products for allergy and irritation, and test all its products for comedogenicity.
• Formulate cosmetics for use around the eye area (eye shadows and eyeliners) specifically for contact lens wearers.
• Formulate hypoallergenic regimens for specific skin types in the mass market.
• Provide a specific cosmetic regimen for acne-prone women, including a silicone-based makeup and active ingredients for treatment in cosmetics and skin care.

I recently interviewed Stanley Levy, MD, who was one of the consultants to Almay, and practices in Chapel Hill, N.C., where he has an academic niche related to skin care formulation and safety. He told me how Almay provided patch test materials to dermatologists to help identify contact dermatitis to cosmetic ingredients, and described Almay’s relationship with the dermatology field as follows: “From the outset, Almay was linked to dermatology. In 1930, a chemist and pharmacist in New York City, Al Woititz, was looking to compound cosmetics for his wife suffering from cosmetic allergies, Fannie May. He enlisted the counsel of the preeminent dermatologic expert in contact dermatitis at the time, Dr. Marion Sulzberger, to suggest ingredients to avoid. [Dr. Sulzberger was also a member of the original Dermatology News editorial advisory board.] Soon, dermatologists around New York City were recommending these formulations. This led to a product line free of the known allergens and a fledgling company trademarked as Almay. For the past 90 years, [the company] has kept a close relationship with dermatologists, well before that was the norm.”

The Almay research overseen by Dr. Levy and others contributed greatly to our understanding of the allergenicity of skin care.
 

Albert Kligman, MD

The turning point for the interface of dermatology with the cosmetic industry was the shift from a safety-based approach (hypoallergenic and noncomedogenic) to an emphasis on efficacy claims in the 1980s. Part of the impetus for this was the Dr. Kligman’s observation that retinoids could improve photoaging.

Dr. Kligman, a well-known dermatologist at the University of Pennsylvania, Philadelphia, showed that retinoids were an effective treatment for acne. For more about this, listen to my interview on the Dermatology Weekly podcast, with James Leyden, MD, about his work at the University of Pennsylvania with Dr. Kligman on the development of oral and topical retinoids. During Dr. Kligman’s research on acne, he noticed that wrinkles improved after treatment with tretinoin, and in 1986, he and Dr. Leyden (and several other authors) published the first article about tretinoin’s use for photoaged skin.³ This led to a double-blind study⁴ conducted by John J. Voorhees, MD, University of Michigan, Ann Arbor, and coauthors that showed statistically significant improvement of photoaged skin when treated with topical tretinoin. Dr. Voorhees and his group did many more studies on retinoids^5,6 and photoaging⁷ – so many that, at one time, he was (and maybe still is) the most widely published dermatologist in the United States. These studies showed that, not only did prescription tretinoin improve the appearance of wrinkles, but so did over-the-counter retinol.⁸ Retinoids remain the most efficacious prescription and cosmeceutical ingredients to treat wrinkled skin.

When studies conducted by Dr. Kligman, Dr. Voorhees, and by Barbara Gilcrest, MD, ^9,10 showed that retinoids improved wrinkles, a major change in the focus in the skin care industry occurred.

During the same time period, the studies on alpha hydroxy acids by Chérie Ditre, MD, Eugene Van Scott, MD, and colleages^11,12; and studies by Sheldon Pinnell, MD, on Vitamin C (see part 1 of this series) all demonstrated the efficacy of cosmetic ingredients on photoaged skin. This triggered a major change in how skin care products were marketed, with an efficacy approach rather than a safety approach.

With the shift from safety (hypoallergenic and noncomedogenic issues) to efficacy claims in the 1980s, and as nondrug active ingredients like retinol were shown to have biologic effects, the lines between the Food and Drug Administration’s definition of a drug versus a cosmetic became blurred. In 1984, Dr. Kligman suggested a new classification for the ingredients that fell in the middle, proposing the term “cosmeceutical” and thus, the concept of a cosmeceutical was introduced. To this day, cosmeceutical is not an official definition and the FDA has yet to deal with it as a quasi-drug category. FDA regulations as to what constitutes a drug versus a cosmetic date back to the 1938 Food, Drug and Cosmetic Act.

Once marketing focused on efficacy, many companies made outrageous claims. During the second half of the 1980s, the FDA issued some warning letters to some companies in an effort to control these claims.

Now efficacy claims abound and we, as dermatologists, should be the experts who back up these claims with scientific data. As the cosmeceutical market has evolved and grown, consumers are bewildered by the myriad of active ingredients being promoted and the number of products in the marketplace. As dermatologic innovation has led to more efficacious active ingredients, our patients look to us as knowledgeable and credible sources of information and for recommendations about the best skin care routines for their skin issues. This is all reflected in the fact that physician-dispensed skin care is becoming the fastest growing segment in this market. It is incumbent upon dermatologists to be knowledgeable and conversant about skin care products and skin care routines, and is particularly true for those of us who sell skin care products in our offices.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Burt’s Bees, Evolus, Galderma, and Revance. She is the CEO of Skin Type Solutions, a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at dermnews@mdedge.com.

References

1. Vogue Magazine, 1967 Aug 15. “Can Great Skin be Created?”

2. https://patents.google.com/patent/US3910284.

3. Kligman AM et al. J Am Acad Dermatol. 1986 Oct;15(4 Pt 2):836-59.

4. Weiss JS et al. JAMA. 1988 Jan 22-29;259(4):527-32.

5. Goldfarb MT et al. J Am Acad Dermatol. 1989 Sep;21(3 Pt 2):645-50.

6. Ellis CN et al. J Am Acad Dermatol. 1990 Oct;23(4 Pt 1):629-37.

7. Kang S; Voorhees JJ. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S55-61.

8. Kafi R et al. Arch Dermatol. 2007 May;143(5):606-12.

9. Gilchrest BA. J Am Acad Dermatol. 1989 Sep;21(3 Pt 2):610-3.

10. Bhawan J et al. Arch Dermatol. 1991 May;127(5):666-72.

11. Griffin TD et al. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):196-203.

12. Ditre CM et al. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):187-95.
 

I. Finding a mentor

Case

You are a 27-year-old first-year resident who is seeking mentorship. You are halfway through the year and are thinking about your goals and future. You have a general interest in hematology/oncology but have limited experience and would like to gain more experience with clinically relevant scholarship. However, you do not know anyone in the field and are not sure who to ask for guidance.

Stage 1: Seeking the right mentor

Start first with your area of interest and then look broadly. In this case the resident is interested in heme/onc. The first place to look is on the heme/onc department website or in the faculty directory. It can be helpful to look at what the potential mentor has published recently and/or look at a version of their CV on the faculty directory or website. This can help determine how productive they are and help assess whether you share similar interests, and whether they have worked with many learners in the past.

It is also important to do some background work and ask around about potential mentors. Often resident colleagues and fellows have a good sense of current projects and which faculty work well with learners. Lastly, it is important to also look at non–heme/onc physicians as there may be internal medicine physicians or surgeons who are doing hematology or oncology research that more align with your interests.

After you have assessed whether you think this person would be a strong mentor for you, it is time to reach out. People are flattered to be asked and part of their promotion criteria is their ability to mentor. Do not assume that a potential mentor is too busy! Let him or her make that decision. Remember the worst a mentor can say is “no.” Even if they do not have time or the need for a mentee at the present time, they generally will offer some assistance or direction on who to ask.

Start with a straightforward, but pleasant email. Waiting up to 2 weeks for a response is reasonable. If after 2 weeks you have not received word, feel free to reach out again asking politely if he or she would be willing to work with you. Do not be afraid to ask bluntly for their guidance and mentorship and have a specific project or area of research that you would like their assistance with.
 

II. Optimizing the mentor/mentee relationship

Case continued

Success! Your email was received with interest by a hematologist who has done several projects, comes highly recommended by other residents, and worked with students and residents in the past. The project involves anticoagulation on the inpatient service. You are set to meet with her next month.

Stage 2: Establishing expectations and goals

Now comes the hard work in establishing an excellent mentor/mentee relationship. Before you meet with your mentor, brainstorm first. What do you want out of the relationship? A publication? Career advice? Attaining a fellowship position? You should feel empowered in knowing that you as the mentee are in the driver seat, but this relationship should be mutually beneficial. Consider basing the relationship and initial discussions on these key questions:

1. My goals

• What are my goals? It is okay not to know but be ready to communicate some information to your mentor.
• Remember to also ask your mentor what their goals are for you as well.

2. Outcome

• What type of outcome are both you and your mentor looking for from the relationship?

3. Expectations

• What mentorship expectations do you have?
• What are your mentor’s expectations of you?

Once you feel you have a sense of what you are looking for out of the relationship, it is important to communicate this with the mentor to establish congruent expectations of one another. For example, think about asking your mentor if the two of you can establish a mentor/mentee contract. This is a written document that can be found online and establishes a mutual agreement of roles, responsibilities, and expectations of one another for the relationship. It can further help to open a line for honest and consistent feedback. This can also give you a formalized endpoint and agreed upon scope for the mentoring relationship. Having a check-in preestablished in a contract reduces any potentially awkward conversations about redefining the relationship down the road. (For example, what if our case resident decides to pursue GI? It could happen.)
 

Stage 3: Establishing a common goal

After you have determined the goals and expectations of the relationship together (remember, this is a relationship), it is time to start exploring possible projects and establishing goals for those projects. Having a quality improvement or research project will determine a common goal to work towards and help establish and define the relationship.

Once you have delineated broadly what the project(s) should be, develop smaller SMART (specific, measurable, achievable, relevant, time-bound) goals to move the project forward. These goals determine stopping points for evaluation and feedback, which further establish the relationship and keep the project(s) progressing. For example, one goal could be to write the first draft of the proposal for your quality improvement project within 3 weeks.
 

Stage 4: Continued communication

With any project it is important to stay on the same page as your mentor and be clear to establish “who is doing what by when.” Do not expect accountability to be the mentor’s job. Remember that you are in the driver’s seat and that you should propose how often you need to meet and what those meetings look like by developing an agenda. You can have an open discussion and allow your mentor to help determine a reasonable timeline. Remember, the more you communicate your goals, the better your mentor will be able to address them.

One pro tip is to always exceed your mentor’s expectations – if you think you need 2 weeks to complete a task, ask for 3-4 weeks. This gives you extra padding in case of unforeseen circumstances and makes you look like a “rockstar” if you hit a deadline 1-2 weeks earlier than planned.
 

III. Ending and/or redefining the relationship

Case continued

You are now a senior resident who’s published multiple articles in the past year, and have completed an anticoagulation project for inpatients with pulmonary emboli. You look back on your experience and what stands out is the extent of your gratitude and appreciation for your incredible mentor. Not only do you feel that your mentor has guided you in your career and with your scholarship, but you feel that he or she has shaped your character and talent set. At this point your mentor is both a teacher and guide, but now also a friend. While you feel there is always more that you can learn from her, you are ready to explore new interests. How do you effectively end or redefine this relationship?

Stage 5: Redefining your mentoring relationship

First, go back to the expectations or contract established early in the relationship. The check-in is a key time in the relationship to reevaluate goals and priorities. At this point you may decide to amicably end the relationship or project, or move on to a new project with a change in your role. For example, the quality improvement project may change to research, or you as the mentee have a change in focus (e.g., change in specialty or scholarly focus).

In summary, the interaction between you and your mentor should be a relationship. And the keys to a great relationship are:

1. Establish clear expectations from the beginning. This clarifies the relationship and helps the mentee and mentor to become more successful.

2. Maintain clear and open communication throughout the relationship.3. Define your goals and discuss them with your mentor early. (Have we mentioned the importance of goals enough?) After all, your goal is the reason you started pursuing this relationship in the first place.

In clinical training having guidance can greatly enhance your experience and direct your future career in unexpected ways. We hope that using these tools will guide you towards forging a strong mentor/mentee relationship.

Dr. Zimmerberg-Helms is a resident physician at the University of New Mexico, Albuquerque. Dr. Rendon is an attending hospitalist at the University of New Mexico.

I. Finding a mentor

Case

You are a 27-year-old first-year resident who is seeking mentorship. You are halfway through the year and are thinking about your goals and future. You have a general interest in hematology/oncology but have limited experience and would like to gain more experience with clinically relevant scholarship. However, you do not know anyone in the field and are not sure who to ask for guidance.

Stage 1: Seeking the right mentor

Start first with your area of interest and then look broadly. In this case the resident is interested in heme/onc. The first place to look is on the heme/onc department website or in the faculty directory. It can be helpful to look at what the potential mentor has published recently and/or look at a version of their CV on the faculty directory or website. This can help determine how productive they are and help assess whether you share similar interests, and whether they have worked with many learners in the past.

It is also important to do some background work and ask around about potential mentors. Often resident colleagues and fellows have a good sense of current projects and which faculty work well with learners. Lastly, it is important to also look at non–heme/onc physicians as there may be internal medicine physicians or surgeons who are doing hematology or oncology research that more align with your interests.

After you have assessed whether you think this person would be a strong mentor for you, it is time to reach out. People are flattered to be asked and part of their promotion criteria is their ability to mentor. Do not assume that a potential mentor is too busy! Let him or her make that decision. Remember the worst a mentor can say is “no.” Even if they do not have time or the need for a mentee at the present time, they generally will offer some assistance or direction on who to ask.

Start with a straightforward, but pleasant email. Waiting up to 2 weeks for a response is reasonable. If after 2 weeks you have not received word, feel free to reach out again asking politely if he or she would be willing to work with you. Do not be afraid to ask bluntly for their guidance and mentorship and have a specific project or area of research that you would like their assistance with.
 

II. Optimizing the mentor/mentee relationship

Case continued

Success! Your email was received with interest by a hematologist who has done several projects, comes highly recommended by other residents, and worked with students and residents in the past. The project involves anticoagulation on the inpatient service. You are set to meet with her next month.

Stage 2: Establishing expectations and goals

Now comes the hard work in establishing an excellent mentor/mentee relationship. Before you meet with your mentor, brainstorm first. What do you want out of the relationship? A publication? Career advice? Attaining a fellowship position? You should feel empowered in knowing that you as the mentee are in the driver seat, but this relationship should be mutually beneficial. Consider basing the relationship and initial discussions on these key questions:

1. My goals

• What are my goals? It is okay not to know but be ready to communicate some information to your mentor.
• Remember to also ask your mentor what their goals are for you as well.

2. Outcome

• What type of outcome are both you and your mentor looking for from the relationship?

3. Expectations

• What mentorship expectations do you have?
• What are your mentor’s expectations of you?

Once you feel you have a sense of what you are looking for out of the relationship, it is important to communicate this with the mentor to establish congruent expectations of one another. For example, think about asking your mentor if the two of you can establish a mentor/mentee contract. This is a written document that can be found online and establishes a mutual agreement of roles, responsibilities, and expectations of one another for the relationship. It can further help to open a line for honest and consistent feedback. This can also give you a formalized endpoint and agreed upon scope for the mentoring relationship. Having a check-in preestablished in a contract reduces any potentially awkward conversations about redefining the relationship down the road. (For example, what if our case resident decides to pursue GI? It could happen.)
 

Stage 3: Establishing a common goal

After you have determined the goals and expectations of the relationship together (remember, this is a relationship), it is time to start exploring possible projects and establishing goals for those projects. Having a quality improvement or research project will determine a common goal to work towards and help establish and define the relationship.

Once you have delineated broadly what the project(s) should be, develop smaller SMART (specific, measurable, achievable, relevant, time-bound) goals to move the project forward. These goals determine stopping points for evaluation and feedback, which further establish the relationship and keep the project(s) progressing. For example, one goal could be to write the first draft of the proposal for your quality improvement project within 3 weeks.
 

Stage 4: Continued communication

With any project it is important to stay on the same page as your mentor and be clear to establish “who is doing what by when.” Do not expect accountability to be the mentor’s job. Remember that you are in the driver’s seat and that you should propose how often you need to meet and what those meetings look like by developing an agenda. You can have an open discussion and allow your mentor to help determine a reasonable timeline. Remember, the more you communicate your goals, the better your mentor will be able to address them.

One pro tip is to always exceed your mentor’s expectations – if you think you need 2 weeks to complete a task, ask for 3-4 weeks. This gives you extra padding in case of unforeseen circumstances and makes you look like a “rockstar” if you hit a deadline 1-2 weeks earlier than planned.
 

III. Ending and/or redefining the relationship

Case continued

You are now a senior resident who’s published multiple articles in the past year, and have completed an anticoagulation project for inpatients with pulmonary emboli. You look back on your experience and what stands out is the extent of your gratitude and appreciation for your incredible mentor. Not only do you feel that your mentor has guided you in your career and with your scholarship, but you feel that he or she has shaped your character and talent set. At this point your mentor is both a teacher and guide, but now also a friend. While you feel there is always more that you can learn from her, you are ready to explore new interests. How do you effectively end or redefine this relationship?

Stage 5: Redefining your mentoring relationship

First, go back to the expectations or contract established early in the relationship. The check-in is a key time in the relationship to reevaluate goals and priorities. At this point you may decide to amicably end the relationship or project, or move on to a new project with a change in your role. For example, the quality improvement project may change to research, or you as the mentee have a change in focus (e.g., change in specialty or scholarly focus).

In summary, the interaction between you and your mentor should be a relationship. And the keys to a great relationship are:

1. Establish clear expectations from the beginning. This clarifies the relationship and helps the mentee and mentor to become more successful.

2. Maintain clear and open communication throughout the relationship.3. Define your goals and discuss them with your mentor early. (Have we mentioned the importance of goals enough?) After all, your goal is the reason you started pursuing this relationship in the first place.

In clinical training having guidance can greatly enhance your experience and direct your future career in unexpected ways. We hope that using these tools will guide you towards forging a strong mentor/mentee relationship.

Dr. Zimmerberg-Helms is a resident physician at the University of New Mexico, Albuquerque. Dr. Rendon is an attending hospitalist at the University of New Mexico.

I. Finding a mentor

Case

You are a 27-year-old first-year resident who is seeking mentorship. You are halfway through the year and are thinking about your goals and future. You have a general interest in hematology/oncology but have limited experience and would like to gain more experience with clinically relevant scholarship. However, you do not know anyone in the field and are not sure who to ask for guidance.

Stage 1: Seeking the right mentor

Start first with your area of interest and then look broadly. In this case the resident is interested in heme/onc. The first place to look is on the heme/onc department website or in the faculty directory. It can be helpful to look at what the potential mentor has published recently and/or look at a version of their CV on the faculty directory or website. This can help determine how productive they are and help assess whether you share similar interests, and whether they have worked with many learners in the past.

It is also important to do some background work and ask around about potential mentors. Often resident colleagues and fellows have a good sense of current projects and which faculty work well with learners. Lastly, it is important to also look at non–heme/onc physicians as there may be internal medicine physicians or surgeons who are doing hematology or oncology research that more align with your interests.

After you have assessed whether you think this person would be a strong mentor for you, it is time to reach out. People are flattered to be asked and part of their promotion criteria is their ability to mentor. Do not assume that a potential mentor is too busy! Let him or her make that decision. Remember the worst a mentor can say is “no.” Even if they do not have time or the need for a mentee at the present time, they generally will offer some assistance or direction on who to ask.

Start with a straightforward, but pleasant email. Waiting up to 2 weeks for a response is reasonable. If after 2 weeks you have not received word, feel free to reach out again asking politely if he or she would be willing to work with you. Do not be afraid to ask bluntly for their guidance and mentorship and have a specific project or area of research that you would like their assistance with.
 

II. Optimizing the mentor/mentee relationship

Case continued

Success! Your email was received with interest by a hematologist who has done several projects, comes highly recommended by other residents, and worked with students and residents in the past. The project involves anticoagulation on the inpatient service. You are set to meet with her next month.

Stage 2: Establishing expectations and goals

Now comes the hard work in establishing an excellent mentor/mentee relationship. Before you meet with your mentor, brainstorm first. What do you want out of the relationship? A publication? Career advice? Attaining a fellowship position? You should feel empowered in knowing that you as the mentee are in the driver seat, but this relationship should be mutually beneficial. Consider basing the relationship and initial discussions on these key questions:

1. My goals

• What are my goals? It is okay not to know but be ready to communicate some information to your mentor.
• Remember to also ask your mentor what their goals are for you as well.

2. Outcome

• What type of outcome are both you and your mentor looking for from the relationship?

3. Expectations

• What mentorship expectations do you have?
• What are your mentor’s expectations of you?

Once you feel you have a sense of what you are looking for out of the relationship, it is important to communicate this with the mentor to establish congruent expectations of one another. For example, think about asking your mentor if the two of you can establish a mentor/mentee contract. This is a written document that can be found online and establishes a mutual agreement of roles, responsibilities, and expectations of one another for the relationship. It can further help to open a line for honest and consistent feedback. This can also give you a formalized endpoint and agreed upon scope for the mentoring relationship. Having a check-in preestablished in a contract reduces any potentially awkward conversations about redefining the relationship down the road. (For example, what if our case resident decides to pursue GI? It could happen.)
 

Stage 3: Establishing a common goal

After you have determined the goals and expectations of the relationship together (remember, this is a relationship), it is time to start exploring possible projects and establishing goals for those projects. Having a quality improvement or research project will determine a common goal to work towards and help establish and define the relationship.

Once you have delineated broadly what the project(s) should be, develop smaller SMART (specific, measurable, achievable, relevant, time-bound) goals to move the project forward. These goals determine stopping points for evaluation and feedback, which further establish the relationship and keep the project(s) progressing. For example, one goal could be to write the first draft of the proposal for your quality improvement project within 3 weeks.
 

Stage 4: Continued communication

With any project it is important to stay on the same page as your mentor and be clear to establish “who is doing what by when.” Do not expect accountability to be the mentor’s job. Remember that you are in the driver’s seat and that you should propose how often you need to meet and what those meetings look like by developing an agenda. You can have an open discussion and allow your mentor to help determine a reasonable timeline. Remember, the more you communicate your goals, the better your mentor will be able to address them.

One pro tip is to always exceed your mentor’s expectations – if you think you need 2 weeks to complete a task, ask for 3-4 weeks. This gives you extra padding in case of unforeseen circumstances and makes you look like a “rockstar” if you hit a deadline 1-2 weeks earlier than planned.
 

III. Ending and/or redefining the relationship

Case continued

You are now a senior resident who’s published multiple articles in the past year, and have completed an anticoagulation project for inpatients with pulmonary emboli. You look back on your experience and what stands out is the extent of your gratitude and appreciation for your incredible mentor. Not only do you feel that your mentor has guided you in your career and with your scholarship, but you feel that he or she has shaped your character and talent set. At this point your mentor is both a teacher and guide, but now also a friend. While you feel there is always more that you can learn from her, you are ready to explore new interests. How do you effectively end or redefine this relationship?

Stage 5: Redefining your mentoring relationship

First, go back to the expectations or contract established early in the relationship. The check-in is a key time in the relationship to reevaluate goals and priorities. At this point you may decide to amicably end the relationship or project, or move on to a new project with a change in your role. For example, the quality improvement project may change to research, or you as the mentee have a change in focus (e.g., change in specialty or scholarly focus).

In summary, the interaction between you and your mentor should be a relationship. And the keys to a great relationship are:

1. Establish clear expectations from the beginning. This clarifies the relationship and helps the mentee and mentor to become more successful.

2. Maintain clear and open communication throughout the relationship.3. Define your goals and discuss them with your mentor early. (Have we mentioned the importance of goals enough?) After all, your goal is the reason you started pursuing this relationship in the first place.

In clinical training having guidance can greatly enhance your experience and direct your future career in unexpected ways. We hope that using these tools will guide you towards forging a strong mentor/mentee relationship.

Dr. Zimmerberg-Helms is a resident physician at the University of New Mexico, Albuquerque. Dr. Rendon is an attending hospitalist at the University of New Mexico.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

egreb@mdedge.com

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

egreb@mdedge.com

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

egreb@mdedge.com

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Among individuals admitted to hospitals with sepsis, statin users had a lower mortality, compared with nonstatin users, according to a recent analysis focused on a large and diverse cohort of patients in California.

Mortality hazard ratios at 30 and 90 days were lower by about 20% for statin users admitted for sepsis, compared with nonstatin users, according to results of the retrospective cohort study.

Hydrophilic and synthetic statins had more favorable mortality outcomes, compared with lipophilic and fungal-derived statins, respectively, added investigator Brannen Liang, MD, a third-year internal medicine resident at Kaiser Permanente Los Angeles Medical Center.

These findings suggest a potential benefit of statins in patients with sepsis, with certain types of statins having a greater protective effect than others, according to Dr. Liang, who presented the original research in a presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

“I think there’s potential for extending the use of statins to other indications, such as sepsis,” Dr. Liang said in an interview, though he also cautioned that the present study is hypothesis generating and more research is necessary.

Using a certain statin type over another (i.e., a hydrophilic, synthetic statin) might be a consideration for populations who are at greater risk for sepsis, such as the immunocompromised, patients with diabetes, or elderly and who also require a statin for an indication such as hyperlipidemia, he added.

While the link between statin use and sepsis mortality outcomes is not new, this study is unique in that it replicates results of earlier studies in a large and diverse real-world population, Dr. Liang said.

“Numerous studies seem to suggest that statins may play a role in attenuating the mortality of patients admitted to the hospital with sepsis, for whatever reason – whether this is due to their anti-inflammatory effects, their lipid-lowering effects, or if they truly have an antimicrobial effect, which has been studied in vitro and in animal studies,” he said in an interview.

It’s impossible to definitively conclude from retrospective studies such as this whether statins reduce sepsis-related mortality risk, but the present study at least makes the case for using certain types of statins when they are indicated in high-risk patients, said Steven Q. Simpson, MD, FCCP, professor of medicine in the division of pulmonary and critical care medicine at the University of Kansas, Kansas City.

“If you have patients at high risk for sepsis and they need a statin, you could give consideration to using a hydrophilic and synthetic statin, rather than either of the other choices,” said Dr. Simpson, CHEST president-elect and senior advisor to the Solving Sepsis initiative of the Biomedical Advanced Research and Development Authority of the Department of Health & Human Services.

The retrospective cohort study by Dr. Liang and colleagues included a total of 137,019 individuals admitted for sepsis within the Kaiser Permanente Southern California health system between 2008 and 2018. Of that group, 36,908 were taking a statin.

Overall, the mean age of patients admitted for sepsis was 66.9 years, and 50.4% were female. Nearly 50% were White, about 12% were Black, 28% were Hispanic, and 8% were Asian. A diagnosis of ischemic heart disease was reported for 43% of statin users and 23% of nonusers, while diabetes mellitus was reported for 60% of statin users and 37% of nonusers (P < .0001 for both comparisons).

Differences in mortality favored statin users, compared with nonusers, with hazard ratios of 0.79 (95% confidence interval, 0.77-0.82) at 30 days and similarly, 0.79 (95% CI, 0.77-0.81) at 90 days, Dr. Liang reported, noting that the models were adjusted for age, race, sex, and comorbidities.

Further analysis suggested a mortality advantage of lipophilic, compared with hydrophilic statins, and an advantage of fungal-derived statins over synthetic-derived statins, the investigator added.

In the comparison of lipophilic statin users and hydrophilic statin users, the 30- and 90-day mortality HRs were 1.13 (95% CI, 1.02-1.26) and 1.17 (95% CI, 1.07-1.28), respectively, the data show. For fungal-derived statin users, compared with synthetic derived statin users, 30- and 90-day mortality HRs were 1.12 (95% CI, 1.06-1.19) and 1.14 (95% CI, 1.09-1.20), respectively.

Dr. Liang and coauthors disclosed no relevant relationships with respect to the work presented at the CHEST meeting.

SOURCE: Liang B et al. CHEST 2020, Abstract A589.

Among individuals admitted to hospitals with sepsis, statin users had a lower mortality, compared with nonstatin users, according to a recent analysis focused on a large and diverse cohort of patients in California.

Mortality hazard ratios at 30 and 90 days were lower by about 20% for statin users admitted for sepsis, compared with nonstatin users, according to results of the retrospective cohort study.

Hydrophilic and synthetic statins had more favorable mortality outcomes, compared with lipophilic and fungal-derived statins, respectively, added investigator Brannen Liang, MD, a third-year internal medicine resident at Kaiser Permanente Los Angeles Medical Center.

These findings suggest a potential benefit of statins in patients with sepsis, with certain types of statins having a greater protective effect than others, according to Dr. Liang, who presented the original research in a presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

“I think there’s potential for extending the use of statins to other indications, such as sepsis,” Dr. Liang said in an interview, though he also cautioned that the present study is hypothesis generating and more research is necessary.

Using a certain statin type over another (i.e., a hydrophilic, synthetic statin) might be a consideration for populations who are at greater risk for sepsis, such as the immunocompromised, patients with diabetes, or elderly and who also require a statin for an indication such as hyperlipidemia, he added.

While the link between statin use and sepsis mortality outcomes is not new, this study is unique in that it replicates results of earlier studies in a large and diverse real-world population, Dr. Liang said.

“Numerous studies seem to suggest that statins may play a role in attenuating the mortality of patients admitted to the hospital with sepsis, for whatever reason – whether this is due to their anti-inflammatory effects, their lipid-lowering effects, or if they truly have an antimicrobial effect, which has been studied in vitro and in animal studies,” he said in an interview.

It’s impossible to definitively conclude from retrospective studies such as this whether statins reduce sepsis-related mortality risk, but the present study at least makes the case for using certain types of statins when they are indicated in high-risk patients, said Steven Q. Simpson, MD, FCCP, professor of medicine in the division of pulmonary and critical care medicine at the University of Kansas, Kansas City.

“If you have patients at high risk for sepsis and they need a statin, you could give consideration to using a hydrophilic and synthetic statin, rather than either of the other choices,” said Dr. Simpson, CHEST president-elect and senior advisor to the Solving Sepsis initiative of the Biomedical Advanced Research and Development Authority of the Department of Health & Human Services.

The retrospective cohort study by Dr. Liang and colleagues included a total of 137,019 individuals admitted for sepsis within the Kaiser Permanente Southern California health system between 2008 and 2018. Of that group, 36,908 were taking a statin.

Overall, the mean age of patients admitted for sepsis was 66.9 years, and 50.4% were female. Nearly 50% were White, about 12% were Black, 28% were Hispanic, and 8% were Asian. A diagnosis of ischemic heart disease was reported for 43% of statin users and 23% of nonusers, while diabetes mellitus was reported for 60% of statin users and 37% of nonusers (P < .0001 for both comparisons).

Differences in mortality favored statin users, compared with nonusers, with hazard ratios of 0.79 (95% confidence interval, 0.77-0.82) at 30 days and similarly, 0.79 (95% CI, 0.77-0.81) at 90 days, Dr. Liang reported, noting that the models were adjusted for age, race, sex, and comorbidities.

Further analysis suggested a mortality advantage of lipophilic, compared with hydrophilic statins, and an advantage of fungal-derived statins over synthetic-derived statins, the investigator added.

In the comparison of lipophilic statin users and hydrophilic statin users, the 30- and 90-day mortality HRs were 1.13 (95% CI, 1.02-1.26) and 1.17 (95% CI, 1.07-1.28), respectively, the data show. For fungal-derived statin users, compared with synthetic derived statin users, 30- and 90-day mortality HRs were 1.12 (95% CI, 1.06-1.19) and 1.14 (95% CI, 1.09-1.20), respectively.

Dr. Liang and coauthors disclosed no relevant relationships with respect to the work presented at the CHEST meeting.

SOURCE: Liang B et al. CHEST 2020, Abstract A589.

Among individuals admitted to hospitals with sepsis, statin users had a lower mortality, compared with nonstatin users, according to a recent analysis focused on a large and diverse cohort of patients in California.

Mortality hazard ratios at 30 and 90 days were lower by about 20% for statin users admitted for sepsis, compared with nonstatin users, according to results of the retrospective cohort study.

Hydrophilic and synthetic statins had more favorable mortality outcomes, compared with lipophilic and fungal-derived statins, respectively, added investigator Brannen Liang, MD, a third-year internal medicine resident at Kaiser Permanente Los Angeles Medical Center.

These findings suggest a potential benefit of statins in patients with sepsis, with certain types of statins having a greater protective effect than others, according to Dr. Liang, who presented the original research in a presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

“I think there’s potential for extending the use of statins to other indications, such as sepsis,” Dr. Liang said in an interview, though he also cautioned that the present study is hypothesis generating and more research is necessary.

Using a certain statin type over another (i.e., a hydrophilic, synthetic statin) might be a consideration for populations who are at greater risk for sepsis, such as the immunocompromised, patients with diabetes, or elderly and who also require a statin for an indication such as hyperlipidemia, he added.

While the link between statin use and sepsis mortality outcomes is not new, this study is unique in that it replicates results of earlier studies in a large and diverse real-world population, Dr. Liang said.

“Numerous studies seem to suggest that statins may play a role in attenuating the mortality of patients admitted to the hospital with sepsis, for whatever reason – whether this is due to their anti-inflammatory effects, their lipid-lowering effects, or if they truly have an antimicrobial effect, which has been studied in vitro and in animal studies,” he said in an interview.

It’s impossible to definitively conclude from retrospective studies such as this whether statins reduce sepsis-related mortality risk, but the present study at least makes the case for using certain types of statins when they are indicated in high-risk patients, said Steven Q. Simpson, MD, FCCP, professor of medicine in the division of pulmonary and critical care medicine at the University of Kansas, Kansas City.

“If you have patients at high risk for sepsis and they need a statin, you could give consideration to using a hydrophilic and synthetic statin, rather than either of the other choices,” said Dr. Simpson, CHEST president-elect and senior advisor to the Solving Sepsis initiative of the Biomedical Advanced Research and Development Authority of the Department of Health & Human Services.

The retrospective cohort study by Dr. Liang and colleagues included a total of 137,019 individuals admitted for sepsis within the Kaiser Permanente Southern California health system between 2008 and 2018. Of that group, 36,908 were taking a statin.

Overall, the mean age of patients admitted for sepsis was 66.9 years, and 50.4% were female. Nearly 50% were White, about 12% were Black, 28% were Hispanic, and 8% were Asian. A diagnosis of ischemic heart disease was reported for 43% of statin users and 23% of nonusers, while diabetes mellitus was reported for 60% of statin users and 37% of nonusers (P < .0001 for both comparisons).

Differences in mortality favored statin users, compared with nonusers, with hazard ratios of 0.79 (95% confidence interval, 0.77-0.82) at 30 days and similarly, 0.79 (95% CI, 0.77-0.81) at 90 days, Dr. Liang reported, noting that the models were adjusted for age, race, sex, and comorbidities.

Further analysis suggested a mortality advantage of lipophilic, compared with hydrophilic statins, and an advantage of fungal-derived statins over synthetic-derived statins, the investigator added.

In the comparison of lipophilic statin users and hydrophilic statin users, the 30- and 90-day mortality HRs were 1.13 (95% CI, 1.02-1.26) and 1.17 (95% CI, 1.07-1.28), respectively, the data show. For fungal-derived statin users, compared with synthetic derived statin users, 30- and 90-day mortality HRs were 1.12 (95% CI, 1.06-1.19) and 1.14 (95% CI, 1.09-1.20), respectively.

Dr. Liang and coauthors disclosed no relevant relationships with respect to the work presented at the CHEST meeting.

SOURCE: Liang B et al. CHEST 2020, Abstract A589.

Two recently completed analyses of highly purified cannabidiol (CBD) used to reduce seizures in Lennox Gastaut syndrome (LGS) have shown the formulation as an add-on treatment is effective in reducing seizures out to 3 years but that it can also cause thrombocytopenia in children on concurrent valproic acid therapy.

At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Anul Patel, MD, section chief of Pediatric neurology at Nationwide Children’s and associate professor of clinical pediatrics and neurology at the Ohio State University, both in Columbus, Ohio, reported 156-week results of an open-label extension trial called GWPCARE5 that showed patients with LGS taking Epidiolex had a 60% or greater average reduction in seizures, compared with baseline. Epidiolex, a highly purified form of CBD, was approved by the Food and Drug Administration in 2018 for LGS and Dravet syndrome.

In a separate presentation, Nancy A. McNamara, MD, an assistant professor at the C.S. Mott Children’s Hospital at the University of Michigan, Ann Arbor, said that more than one-third of patients taking both Epidiolex and valproic acid (VPA) developed thrombocytopenia after starting CBD therapy. The single-center chart review she reported on included 83 patients.

Daniel Friedman, MD, an epilepsy specialist at New York University who’s researched CBD in children with autism spectrum disorder, said, “These studies show that, while purified CBD has durable effects on the most disabling seizures in children and adults with LGS, like all treatments, it is not without risks that warrant attention and monitoring.” 
 

Open-label extension study

The open-label extension study included 366 patients who participated in the two previous clinical trials. They were given varying doses of CBD titrated over 2 weeks with 20 mg/kg as the target dose, Dr. Patel said. The most common concurrent therapies they were taking were clobazam, valproate or VPA, lamotrigine, levetiracetam, and rufinamide. At weeks 145-156, 67% of patients had a 50% or greater reduction in seizures, 44% had a 75% or greater reduction, and 9% stopped having seizures altogether, Dr. Patel said.

“CBD treatment had a similar safety profile to what was observed in the completed parent randomized clinical trials,” Dr. Patel said. “Sustained reductions in drop and total seizures were observed up to the 156-week follow-up point. So these results demonstrate the potential long-term benefits of CBD treatment for patients with LGS as it relates to reduction of their seizures.”

Adverse event profiles in this analysis were similar to previous clinical trials, he noted. The three most common adverse events were diarrhea (38%), convulsion (38%) and pyrexia (34%), but high percentages of those adverse events resolved during follow-up: 78%, 80%, and 96%, respectively.

Dr. Patel also noted that 31% of patients had elevated liver enzymes (alanine aminotransferase or aspartate aminotransferase), but most of these patients – 78 of 113, or 69% – were on concomitant VPA. “Importantly, no patient met the standard criteria for severe drug-induced liver injury, known as Hy’s law,” he said.

Retention rates for patients were 81% at 1 year, 69% at 2 years and 65% at 3 years, Dr. Patel said.
 

“An urgent systemic review”

Dr. McNamara’s research drilled down into the interaction of CBD and VPA. “Over the past several months we have made observations that several patients that had been started on CBD, also known as Epidiolex, had developed thrombocytopenia, some of which were symptomatic,” she said. Symptoms included hematuria, easy bruising, and gingival bleeding.

That prompted what Dr. McNamara called “an urgent systemic review” of all patients on CBD. Of 83 patients started on CBD for LGS from January to August 2019, 9 (11%) developed thrombocytopenia. “All of these patients were on concurrent VPA and no patients started on CBD without VPA developed thrombocytopenia,” she said. In all, 23 patients were taking CBD concurrently with VPA. Four of nine cases were symptomatic.

“The thrombocytopenia was reversible in all patients with reduction of medication and one patient recovered spontaneously without intervention,” Dr. McNamara noted.

“This was an important finding because this was not something that had come out of the clinical trials prior to FDA approval,” Dr. McNamara said. “This requires closer monitoring for patients who are started on CBD who are already on VPA.”

Of the 23 patients taking concurrent VPA, 10 had low platelet counts after starting CBD. In six patients, platelet counts dropped from normal before CBD therapy to low afterward.

The study used a McNemar test to determine if an observed adverse event occurred by chance or was related to starting a drug, which yielded a P value of .125, Dr. McNamara said. “While this did not achieve statistical significance, we suggest that prescribers closely monitor platelet levels after starting CBD, particularly when a patient is also on concurrent VPA,” she said.

Her group obtained a complete blood count at baseline and then at 1, 3, and 6 months after starting the patient on CBD, along with evaluation of alanine aminotransferase and aspartate aminotransferase. “We believe that this is helpful because most of the patients that develop low platelets did so within 3 months of starting cannabidiol,” Dr. McNamara said.

She acknowledged the limits of the single-center study. “Future research will need to be done with larger cohorts with standardized surveillance labs,” she said in an interview.

Dr. Patel disclosed financial relationships with GW Research and Greenwich Biosciences. Dr. McNamara has no relevant disclosures.

Two recently completed analyses of highly purified cannabidiol (CBD) used to reduce seizures in Lennox Gastaut syndrome (LGS) have shown the formulation as an add-on treatment is effective in reducing seizures out to 3 years but that it can also cause thrombocytopenia in children on concurrent valproic acid therapy.

At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Anul Patel, MD, section chief of Pediatric neurology at Nationwide Children’s and associate professor of clinical pediatrics and neurology at the Ohio State University, both in Columbus, Ohio, reported 156-week results of an open-label extension trial called GWPCARE5 that showed patients with LGS taking Epidiolex had a 60% or greater average reduction in seizures, compared with baseline. Epidiolex, a highly purified form of CBD, was approved by the Food and Drug Administration in 2018 for LGS and Dravet syndrome.

In a separate presentation, Nancy A. McNamara, MD, an assistant professor at the C.S. Mott Children’s Hospital at the University of Michigan, Ann Arbor, said that more than one-third of patients taking both Epidiolex and valproic acid (VPA) developed thrombocytopenia after starting CBD therapy. The single-center chart review she reported on included 83 patients.

Daniel Friedman, MD, an epilepsy specialist at New York University who’s researched CBD in children with autism spectrum disorder, said, “These studies show that, while purified CBD has durable effects on the most disabling seizures in children and adults with LGS, like all treatments, it is not without risks that warrant attention and monitoring.” 
 

Open-label extension study

The open-label extension study included 366 patients who participated in the two previous clinical trials. They were given varying doses of CBD titrated over 2 weeks with 20 mg/kg as the target dose, Dr. Patel said. The most common concurrent therapies they were taking were clobazam, valproate or VPA, lamotrigine, levetiracetam, and rufinamide. At weeks 145-156, 67% of patients had a 50% or greater reduction in seizures, 44% had a 75% or greater reduction, and 9% stopped having seizures altogether, Dr. Patel said.

“CBD treatment had a similar safety profile to what was observed in the completed parent randomized clinical trials,” Dr. Patel said. “Sustained reductions in drop and total seizures were observed up to the 156-week follow-up point. So these results demonstrate the potential long-term benefits of CBD treatment for patients with LGS as it relates to reduction of their seizures.”

Adverse event profiles in this analysis were similar to previous clinical trials, he noted. The three most common adverse events were diarrhea (38%), convulsion (38%) and pyrexia (34%), but high percentages of those adverse events resolved during follow-up: 78%, 80%, and 96%, respectively.

Dr. Patel also noted that 31% of patients had elevated liver enzymes (alanine aminotransferase or aspartate aminotransferase), but most of these patients – 78 of 113, or 69% – were on concomitant VPA. “Importantly, no patient met the standard criteria for severe drug-induced liver injury, known as Hy’s law,” he said.

Retention rates for patients were 81% at 1 year, 69% at 2 years and 65% at 3 years, Dr. Patel said.
 

“An urgent systemic review”

Dr. McNamara’s research drilled down into the interaction of CBD and VPA. “Over the past several months we have made observations that several patients that had been started on CBD, also known as Epidiolex, had developed thrombocytopenia, some of which were symptomatic,” she said. Symptoms included hematuria, easy bruising, and gingival bleeding.

That prompted what Dr. McNamara called “an urgent systemic review” of all patients on CBD. Of 83 patients started on CBD for LGS from January to August 2019, 9 (11%) developed thrombocytopenia. “All of these patients were on concurrent VPA and no patients started on CBD without VPA developed thrombocytopenia,” she said. In all, 23 patients were taking CBD concurrently with VPA. Four of nine cases were symptomatic.

“The thrombocytopenia was reversible in all patients with reduction of medication and one patient recovered spontaneously without intervention,” Dr. McNamara noted.

“This was an important finding because this was not something that had come out of the clinical trials prior to FDA approval,” Dr. McNamara said. “This requires closer monitoring for patients who are started on CBD who are already on VPA.”

Of the 23 patients taking concurrent VPA, 10 had low platelet counts after starting CBD. In six patients, platelet counts dropped from normal before CBD therapy to low afterward.

The study used a McNemar test to determine if an observed adverse event occurred by chance or was related to starting a drug, which yielded a P value of .125, Dr. McNamara said. “While this did not achieve statistical significance, we suggest that prescribers closely monitor platelet levels after starting CBD, particularly when a patient is also on concurrent VPA,” she said.

Her group obtained a complete blood count at baseline and then at 1, 3, and 6 months after starting the patient on CBD, along with evaluation of alanine aminotransferase and aspartate aminotransferase. “We believe that this is helpful because most of the patients that develop low platelets did so within 3 months of starting cannabidiol,” Dr. McNamara said.

She acknowledged the limits of the single-center study. “Future research will need to be done with larger cohorts with standardized surveillance labs,” she said in an interview.

Dr. Patel disclosed financial relationships with GW Research and Greenwich Biosciences. Dr. McNamara has no relevant disclosures.

Two recently completed analyses of highly purified cannabidiol (CBD) used to reduce seizures in Lennox Gastaut syndrome (LGS) have shown the formulation as an add-on treatment is effective in reducing seizures out to 3 years but that it can also cause thrombocytopenia in children on concurrent valproic acid therapy.

At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Anul Patel, MD, section chief of Pediatric neurology at Nationwide Children’s and associate professor of clinical pediatrics and neurology at the Ohio State University, both in Columbus, Ohio, reported 156-week results of an open-label extension trial called GWPCARE5 that showed patients with LGS taking Epidiolex had a 60% or greater average reduction in seizures, compared with baseline. Epidiolex, a highly purified form of CBD, was approved by the Food and Drug Administration in 2018 for LGS and Dravet syndrome.

In a separate presentation, Nancy A. McNamara, MD, an assistant professor at the C.S. Mott Children’s Hospital at the University of Michigan, Ann Arbor, said that more than one-third of patients taking both Epidiolex and valproic acid (VPA) developed thrombocytopenia after starting CBD therapy. The single-center chart review she reported on included 83 patients.

Daniel Friedman, MD, an epilepsy specialist at New York University who’s researched CBD in children with autism spectrum disorder, said, “These studies show that, while purified CBD has durable effects on the most disabling seizures in children and adults with LGS, like all treatments, it is not without risks that warrant attention and monitoring.” 
 

Open-label extension study

The open-label extension study included 366 patients who participated in the two previous clinical trials. They were given varying doses of CBD titrated over 2 weeks with 20 mg/kg as the target dose, Dr. Patel said. The most common concurrent therapies they were taking were clobazam, valproate or VPA, lamotrigine, levetiracetam, and rufinamide. At weeks 145-156, 67% of patients had a 50% or greater reduction in seizures, 44% had a 75% or greater reduction, and 9% stopped having seizures altogether, Dr. Patel said.

“CBD treatment had a similar safety profile to what was observed in the completed parent randomized clinical trials,” Dr. Patel said. “Sustained reductions in drop and total seizures were observed up to the 156-week follow-up point. So these results demonstrate the potential long-term benefits of CBD treatment for patients with LGS as it relates to reduction of their seizures.”

Adverse event profiles in this analysis were similar to previous clinical trials, he noted. The three most common adverse events were diarrhea (38%), convulsion (38%) and pyrexia (34%), but high percentages of those adverse events resolved during follow-up: 78%, 80%, and 96%, respectively.

Dr. Patel also noted that 31% of patients had elevated liver enzymes (alanine aminotransferase or aspartate aminotransferase), but most of these patients – 78 of 113, or 69% – were on concomitant VPA. “Importantly, no patient met the standard criteria for severe drug-induced liver injury, known as Hy’s law,” he said.

Retention rates for patients were 81% at 1 year, 69% at 2 years and 65% at 3 years, Dr. Patel said.
 

“An urgent systemic review”

Dr. McNamara’s research drilled down into the interaction of CBD and VPA. “Over the past several months we have made observations that several patients that had been started on CBD, also known as Epidiolex, had developed thrombocytopenia, some of which were symptomatic,” she said. Symptoms included hematuria, easy bruising, and gingival bleeding.

That prompted what Dr. McNamara called “an urgent systemic review” of all patients on CBD. Of 83 patients started on CBD for LGS from January to August 2019, 9 (11%) developed thrombocytopenia. “All of these patients were on concurrent VPA and no patients started on CBD without VPA developed thrombocytopenia,” she said. In all, 23 patients were taking CBD concurrently with VPA. Four of nine cases were symptomatic.

“The thrombocytopenia was reversible in all patients with reduction of medication and one patient recovered spontaneously without intervention,” Dr. McNamara noted.

“This was an important finding because this was not something that had come out of the clinical trials prior to FDA approval,” Dr. McNamara said. “This requires closer monitoring for patients who are started on CBD who are already on VPA.”

Of the 23 patients taking concurrent VPA, 10 had low platelet counts after starting CBD. In six patients, platelet counts dropped from normal before CBD therapy to low afterward.

The study used a McNemar test to determine if an observed adverse event occurred by chance or was related to starting a drug, which yielded a P value of .125, Dr. McNamara said. “While this did not achieve statistical significance, we suggest that prescribers closely monitor platelet levels after starting CBD, particularly when a patient is also on concurrent VPA,” she said.

Her group obtained a complete blood count at baseline and then at 1, 3, and 6 months after starting the patient on CBD, along with evaluation of alanine aminotransferase and aspartate aminotransferase. “We believe that this is helpful because most of the patients that develop low platelets did so within 3 months of starting cannabidiol,” Dr. McNamara said.

She acknowledged the limits of the single-center study. “Future research will need to be done with larger cohorts with standardized surveillance labs,” she said in an interview.

Dr. Patel disclosed financial relationships with GW Research and Greenwich Biosciences. Dr. McNamara has no relevant disclosures.

In addition to screening adolescent patients at least once a year for substance use, it’s important that pediatricians build relationships with other behavioral health providers and develop a strategy for ensuring that teens with substance use issues continue returning to your practice as their medical home, according to Lucien Gonzalez, MD, assistant professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis.

In a presentation at the annual meeting of the American Academy of Pediatrics, held virtually this year, Dr. Gonzalez discussed some of the common challenges pediatricians face in appropriately screening, diagnosing, and managing or referring youth when it comes to substance use.
 

Substance use screening

One of these included picking the right assessment tool and frequency for screening patients for substance use. A number of validated tools are out there, including the Screening to Brief Intervention (S2BI) and CRAFFT Screening Tool for Adolescent Substance Abuse. Regardless of which screening tool providers choose, “the important thing is to use a tool that is validated in the pediatric population and ideally has frequency results in it,” Dr. Gonzalez said.

In terms of frequency, screening young people at least once a year is fairly standard, but it may be necessary to screen adolescents more often or to screen them at acute visits.

“As many of you who work with adolescents know, you can’t always rely on the yearly well child visit because after a certain age, you start to see drop-off,” Dr. Gonzalez said. “They often aren’t coming for well child visits, and they often are then only showing up for acute visits.”

That means doctors need to think about how their clinics operate, how often they see their teen patients, and other factors – including how much can happen in a single year of adolescence – to ensure that screening captures these patients at least once a year, but more if that works within the practice.
 

Screening vs. diagnosis

Dr. Gonzalez also addressed the difference between screening and diagnosis, a very familiar distinction to physicians in other areas of medicine but often a source of confusion in the area of substance use.

“Screening is the presumptive identification of unrecognized disease in apparently healthy people who don’t have symptoms, using assessments that can be used rapidly,” Dr. Gonzalez said. “When we move into the diagnostic realm, these are people who present with symptoms or they have positive results on our screening test prompting further investigation.”

Sonia Khan, MD, a pediatrician and the medical director of the substance use disorder counseling program in the department of health and human services in Fremont, Calif., who heard the talk, particularly appreciated this point about screening versus diagnosis.

“As soon as you get a hint that there’s a problem with the kid, you’re no longer screening. You’re doing diagnostic investigation,” Dr. Khan, also the human relations commissioner for the city of Fremont, Calif., said in an interview. “Screening is about the kids you don’t know about. It seems like a small point to make a big deal out of, but it’s not.”

Sometimes a screening tool can serve as an introductory interview guide when beginning a clinical investigation with a patient who already shows symptoms, but that doesn’t mean it’s a screen.

Dr. Gonzalez emphasized the importance of not prescreening.

“A prescreener looks at a kid and decides whether or not they need to be screened,” Dr. Gonzalez said. “We have research that demonstrates that that doesn’t work. Physicians are not good at determining this by eyeballing it, and it’s fraught with bias. Universal screening with a validated screening tool is what works.”

Again, the idea of confronting one’s own personal biases and how they could interfere with screening really resonated with Dr. Khan.

“When it comes to the prescreening, if you’re only screening the ones you [think you] need to screen, you’re introducing bias into your screening,” she said. “It’s usually judgmental. It’s important to focus on really getting the bias out of what you’re doing because it’s a field fraught with bias and expectations.”


 

Brief interventions

Another area of confusion for many providers is what qualifies as a brief intervention and how to deliver it. The brief intervention needs to focus on increasing the patient’s knowledge, insights, and awareness when it comes to their own substance use and how it affects others. It should also support motivation in the patient to make behavioral changes. “It is always given in a nonjudgmental, supportive manner,” Dr. Gonzalez said.

Though motivational interviewing is often discussed as though it’s a brief intervention, it is actually the mechanism for delivering the intervention – not the intervention itself.

Dr. Gonzalez highly recommended that providers seek motivational interviewing training if they haven’t already. He went on to caution attendees about behavior goals in interventions: They should be the patient’s change goals, not the provider’s, and the provider is there to facilitate the teen’s clarification of those goals.

“It’s very important to use those listening skills that we have and honor their decision-making and listen to their language in establishing their own goals,” he said. It’s also important to keep cultural relevance and respect in mind when delivering the intervention. He shared a chart showing the dominant and nondominant groups along various demographic cultural influences, including age, disability status, faith, race/ethnicity, indigenous heritage, socioeconomic status, national origin, gender and sexuality.

For example, the dominant age groups are the young and middle-aged while the nondominant are children and elderly. The dominant faith in the United States is Christian or secular, and the dominant sexuality is heterosexual; the corresponding nondominant groups would be non-Christian and nonheterosexual. It’s important for providers to consider the child’s needs within that entire behavioral context to understand where they’re coming from.

“Have you ever characterized a kid’s situation with regard to substance use and diagnoses based on certain characteristics?” Dr. Gonzalez asked attendees. “We like to think that we don’t, but research on diagnostic disparities indicates otherwise.”

A way to help avoid this is to know who you are in the room and who you’re with in terms of dominant and nondominant groups. “Oftentimes a kid’s cultural make-up holds a big part of the answer to what they need,” Dr. Gonzalez said. He provided the example of a patient who was witnessing domestic violence in the home. A key part to helping him meet his goal of reducing cannabis and alcohol use was understanding his relationship with his dad, his response to trauma, and his depression, all within his cultural and religious background.
 

Preserving the medical home

Finally, when it comes to referrals, consider what are you referring a patient for and whom are you referring them to because not all programs and all clinicians are created equal. Create, build, and maintain relationships with as many behavioral health clinicians and practices as you can, he advised.

Further, it’s important to preserve the medical home, though that can require extra effort, particularly with children who have seen a lot of providers. Each physician will need to develop their own strategy for how to do this. Sometimes kids feel passed around and there’s poor communication within programs, leaving kids and their families feeling unwelcome at your practice.

“No child is a hot potato,” he said. Because they may feel like they’re being bounced around among different providers, programs, emergency departments, facilities, and such, it’s important to convey strongly that you want to continue to care for them.

“Whether we’ve been part of that or not, we become part of that,” Dr. Gonzalez said. “They may think that you don’t want to see them again. You want to keep them, and you might have to continue giving repeated messages. Sometimes we need to be very overt and repeat ourselves and say no, ‘I really, really, really want you to come back. This is your home and I want you to come back.’ ”

Dr. Gonzalez and Dr. Khan have no disclosures.

In addition to screening adolescent patients at least once a year for substance use, it’s important that pediatricians build relationships with other behavioral health providers and develop a strategy for ensuring that teens with substance use issues continue returning to your practice as their medical home, according to Lucien Gonzalez, MD, assistant professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis.

In a presentation at the annual meeting of the American Academy of Pediatrics, held virtually this year, Dr. Gonzalez discussed some of the common challenges pediatricians face in appropriately screening, diagnosing, and managing or referring youth when it comes to substance use.
 

Substance use screening

One of these included picking the right assessment tool and frequency for screening patients for substance use. A number of validated tools are out there, including the Screening to Brief Intervention (S2BI) and CRAFFT Screening Tool for Adolescent Substance Abuse. Regardless of which screening tool providers choose, “the important thing is to use a tool that is validated in the pediatric population and ideally has frequency results in it,” Dr. Gonzalez said.

In terms of frequency, screening young people at least once a year is fairly standard, but it may be necessary to screen adolescents more often or to screen them at acute visits.

“As many of you who work with adolescents know, you can’t always rely on the yearly well child visit because after a certain age, you start to see drop-off,” Dr. Gonzalez said. “They often aren’t coming for well child visits, and they often are then only showing up for acute visits.”

That means doctors need to think about how their clinics operate, how often they see their teen patients, and other factors – including how much can happen in a single year of adolescence – to ensure that screening captures these patients at least once a year, but more if that works within the practice.
 

Screening vs. diagnosis

Dr. Gonzalez also addressed the difference between screening and diagnosis, a very familiar distinction to physicians in other areas of medicine but often a source of confusion in the area of substance use.

“Screening is the presumptive identification of unrecognized disease in apparently healthy people who don’t have symptoms, using assessments that can be used rapidly,” Dr. Gonzalez said. “When we move into the diagnostic realm, these are people who present with symptoms or they have positive results on our screening test prompting further investigation.”

Sonia Khan, MD, a pediatrician and the medical director of the substance use disorder counseling program in the department of health and human services in Fremont, Calif., who heard the talk, particularly appreciated this point about screening versus diagnosis.

“As soon as you get a hint that there’s a problem with the kid, you’re no longer screening. You’re doing diagnostic investigation,” Dr. Khan, also the human relations commissioner for the city of Fremont, Calif., said in an interview. “Screening is about the kids you don’t know about. It seems like a small point to make a big deal out of, but it’s not.”

Sometimes a screening tool can serve as an introductory interview guide when beginning a clinical investigation with a patient who already shows symptoms, but that doesn’t mean it’s a screen.

Dr. Gonzalez emphasized the importance of not prescreening.

“A prescreener looks at a kid and decides whether or not they need to be screened,” Dr. Gonzalez said. “We have research that demonstrates that that doesn’t work. Physicians are not good at determining this by eyeballing it, and it’s fraught with bias. Universal screening with a validated screening tool is what works.”

Again, the idea of confronting one’s own personal biases and how they could interfere with screening really resonated with Dr. Khan.

“When it comes to the prescreening, if you’re only screening the ones you [think you] need to screen, you’re introducing bias into your screening,” she said. “It’s usually judgmental. It’s important to focus on really getting the bias out of what you’re doing because it’s a field fraught with bias and expectations.”


 

Brief interventions

Another area of confusion for many providers is what qualifies as a brief intervention and how to deliver it. The brief intervention needs to focus on increasing the patient’s knowledge, insights, and awareness when it comes to their own substance use and how it affects others. It should also support motivation in the patient to make behavioral changes. “It is always given in a nonjudgmental, supportive manner,” Dr. Gonzalez said.

Though motivational interviewing is often discussed as though it’s a brief intervention, it is actually the mechanism for delivering the intervention – not the intervention itself.

Dr. Gonzalez highly recommended that providers seek motivational interviewing training if they haven’t already. He went on to caution attendees about behavior goals in interventions: They should be the patient’s change goals, not the provider’s, and the provider is there to facilitate the teen’s clarification of those goals.

“It’s very important to use those listening skills that we have and honor their decision-making and listen to their language in establishing their own goals,” he said. It’s also important to keep cultural relevance and respect in mind when delivering the intervention. He shared a chart showing the dominant and nondominant groups along various demographic cultural influences, including age, disability status, faith, race/ethnicity, indigenous heritage, socioeconomic status, national origin, gender and sexuality.

For example, the dominant age groups are the young and middle-aged while the nondominant are children and elderly. The dominant faith in the United States is Christian or secular, and the dominant sexuality is heterosexual; the corresponding nondominant groups would be non-Christian and nonheterosexual. It’s important for providers to consider the child’s needs within that entire behavioral context to understand where they’re coming from.

“Have you ever characterized a kid’s situation with regard to substance use and diagnoses based on certain characteristics?” Dr. Gonzalez asked attendees. “We like to think that we don’t, but research on diagnostic disparities indicates otherwise.”

A way to help avoid this is to know who you are in the room and who you’re with in terms of dominant and nondominant groups. “Oftentimes a kid’s cultural make-up holds a big part of the answer to what they need,” Dr. Gonzalez said. He provided the example of a patient who was witnessing domestic violence in the home. A key part to helping him meet his goal of reducing cannabis and alcohol use was understanding his relationship with his dad, his response to trauma, and his depression, all within his cultural and religious background.
 

Preserving the medical home

Finally, when it comes to referrals, consider what are you referring a patient for and whom are you referring them to because not all programs and all clinicians are created equal. Create, build, and maintain relationships with as many behavioral health clinicians and practices as you can, he advised.

Further, it’s important to preserve the medical home, though that can require extra effort, particularly with children who have seen a lot of providers. Each physician will need to develop their own strategy for how to do this. Sometimes kids feel passed around and there’s poor communication within programs, leaving kids and their families feeling unwelcome at your practice.

“No child is a hot potato,” he said. Because they may feel like they’re being bounced around among different providers, programs, emergency departments, facilities, and such, it’s important to convey strongly that you want to continue to care for them.

“Whether we’ve been part of that or not, we become part of that,” Dr. Gonzalez said. “They may think that you don’t want to see them again. You want to keep them, and you might have to continue giving repeated messages. Sometimes we need to be very overt and repeat ourselves and say no, ‘I really, really, really want you to come back. This is your home and I want you to come back.’ ”

Dr. Gonzalez and Dr. Khan have no disclosures.

In addition to screening adolescent patients at least once a year for substance use, it’s important that pediatricians build relationships with other behavioral health providers and develop a strategy for ensuring that teens with substance use issues continue returning to your practice as their medical home, according to Lucien Gonzalez, MD, assistant professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis.

In a presentation at the annual meeting of the American Academy of Pediatrics, held virtually this year, Dr. Gonzalez discussed some of the common challenges pediatricians face in appropriately screening, diagnosing, and managing or referring youth when it comes to substance use.
 

Substance use screening

One of these included picking the right assessment tool and frequency for screening patients for substance use. A number of validated tools are out there, including the Screening to Brief Intervention (S2BI) and CRAFFT Screening Tool for Adolescent Substance Abuse. Regardless of which screening tool providers choose, “the important thing is to use a tool that is validated in the pediatric population and ideally has frequency results in it,” Dr. Gonzalez said.

In terms of frequency, screening young people at least once a year is fairly standard, but it may be necessary to screen adolescents more often or to screen them at acute visits.

“As many of you who work with adolescents know, you can’t always rely on the yearly well child visit because after a certain age, you start to see drop-off,” Dr. Gonzalez said. “They often aren’t coming for well child visits, and they often are then only showing up for acute visits.”

That means doctors need to think about how their clinics operate, how often they see their teen patients, and other factors – including how much can happen in a single year of adolescence – to ensure that screening captures these patients at least once a year, but more if that works within the practice.
 

Screening vs. diagnosis

Dr. Gonzalez also addressed the difference between screening and diagnosis, a very familiar distinction to physicians in other areas of medicine but often a source of confusion in the area of substance use.

“Screening is the presumptive identification of unrecognized disease in apparently healthy people who don’t have symptoms, using assessments that can be used rapidly,” Dr. Gonzalez said. “When we move into the diagnostic realm, these are people who present with symptoms or they have positive results on our screening test prompting further investigation.”

Sonia Khan, MD, a pediatrician and the medical director of the substance use disorder counseling program in the department of health and human services in Fremont, Calif., who heard the talk, particularly appreciated this point about screening versus diagnosis.

“As soon as you get a hint that there’s a problem with the kid, you’re no longer screening. You’re doing diagnostic investigation,” Dr. Khan, also the human relations commissioner for the city of Fremont, Calif., said in an interview. “Screening is about the kids you don’t know about. It seems like a small point to make a big deal out of, but it’s not.”

Sometimes a screening tool can serve as an introductory interview guide when beginning a clinical investigation with a patient who already shows symptoms, but that doesn’t mean it’s a screen.

Dr. Gonzalez emphasized the importance of not prescreening.

“A prescreener looks at a kid and decides whether or not they need to be screened,” Dr. Gonzalez said. “We have research that demonstrates that that doesn’t work. Physicians are not good at determining this by eyeballing it, and it’s fraught with bias. Universal screening with a validated screening tool is what works.”

Again, the idea of confronting one’s own personal biases and how they could interfere with screening really resonated with Dr. Khan.

“When it comes to the prescreening, if you’re only screening the ones you [think you] need to screen, you’re introducing bias into your screening,” she said. “It’s usually judgmental. It’s important to focus on really getting the bias out of what you’re doing because it’s a field fraught with bias and expectations.”


 

Brief interventions

Another area of confusion for many providers is what qualifies as a brief intervention and how to deliver it. The brief intervention needs to focus on increasing the patient’s knowledge, insights, and awareness when it comes to their own substance use and how it affects others. It should also support motivation in the patient to make behavioral changes. “It is always given in a nonjudgmental, supportive manner,” Dr. Gonzalez said.

Though motivational interviewing is often discussed as though it’s a brief intervention, it is actually the mechanism for delivering the intervention – not the intervention itself.

Dr. Gonzalez highly recommended that providers seek motivational interviewing training if they haven’t already. He went on to caution attendees about behavior goals in interventions: They should be the patient’s change goals, not the provider’s, and the provider is there to facilitate the teen’s clarification of those goals.

“It’s very important to use those listening skills that we have and honor their decision-making and listen to their language in establishing their own goals,” he said. It’s also important to keep cultural relevance and respect in mind when delivering the intervention. He shared a chart showing the dominant and nondominant groups along various demographic cultural influences, including age, disability status, faith, race/ethnicity, indigenous heritage, socioeconomic status, national origin, gender and sexuality.

For example, the dominant age groups are the young and middle-aged while the nondominant are children and elderly. The dominant faith in the United States is Christian or secular, and the dominant sexuality is heterosexual; the corresponding nondominant groups would be non-Christian and nonheterosexual. It’s important for providers to consider the child’s needs within that entire behavioral context to understand where they’re coming from.

“Have you ever characterized a kid’s situation with regard to substance use and diagnoses based on certain characteristics?” Dr. Gonzalez asked attendees. “We like to think that we don’t, but research on diagnostic disparities indicates otherwise.”

A way to help avoid this is to know who you are in the room and who you’re with in terms of dominant and nondominant groups. “Oftentimes a kid’s cultural make-up holds a big part of the answer to what they need,” Dr. Gonzalez said. He provided the example of a patient who was witnessing domestic violence in the home. A key part to helping him meet his goal of reducing cannabis and alcohol use was understanding his relationship with his dad, his response to trauma, and his depression, all within his cultural and religious background.
 

Preserving the medical home

Finally, when it comes to referrals, consider what are you referring a patient for and whom are you referring them to because not all programs and all clinicians are created equal. Create, build, and maintain relationships with as many behavioral health clinicians and practices as you can, he advised.

Further, it’s important to preserve the medical home, though that can require extra effort, particularly with children who have seen a lot of providers. Each physician will need to develop their own strategy for how to do this. Sometimes kids feel passed around and there’s poor communication within programs, leaving kids and their families feeling unwelcome at your practice.

“No child is a hot potato,” he said. Because they may feel like they’re being bounced around among different providers, programs, emergency departments, facilities, and such, it’s important to convey strongly that you want to continue to care for them.

“Whether we’ve been part of that or not, we become part of that,” Dr. Gonzalez said. “They may think that you don’t want to see them again. You want to keep them, and you might have to continue giving repeated messages. Sometimes we need to be very overt and repeat ourselves and say no, ‘I really, really, really want you to come back. This is your home and I want you to come back.’ ”

Dr. Gonzalez and Dr. Khan have no disclosures.