A panel of advisers to the Food and Drug Administration unanimously supported an effort to simplify COVID-19 vaccinations, with the aim of developing a one-dose approach – perhaps annually – for the general population.

The FDA is looking to give clearer direction to vaccine makers about future development of COVID-19 vaccines. The plan is to narrow down the current complex landscape of options for vaccinations, and thus help increase use of these shots. 

COVID remains a serious threat, causing about 4,000 deaths a week recently, according to the Centers for Disease Control and Prevention. The 21 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26 voted unanimously “yes” on a single question posed by the FDA: 

“Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (Original plus Omicron BA.4/BA.5)?”

In other words, would it be better to have one vaccine potentially combining multiple strains of the virus, instead of multiple vaccines – such as a two-shot primary series then a booster containing different combinations of viral strains.

The FDA will consider the panel’s advice as it outlines new strategies for keeping ahead of the evolving virus.

In explaining their support for the FDA plan, panel members said they hoped that a simpler regime would aid in persuading more people to get COVID vaccines.

Pamela McInnes, DDS, MSc, noted that it’s difficult to explain to many people that the vaccine works to protect them from more severe illness if they contract COVID after getting vaccinated. 

“That is a real challenge,” said Dr. McInness, retired deputy director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

“The message that you would have gotten more sick and landed in the hospital resonates with me, but I’m not sure if it resonates with” many people who become infected, she said.
 

The plan

In the briefing document for the meeting, the FDA outlined a plan for transitioning from the current complex landscape of COVID-19 vaccines to a single vaccine composition for the primary series and booster vaccination. 

This would require harmonizing the strain composition of all COVID-19 vaccines; simplifying the immunization schedule for future vaccination campaigns to administer a two-dose series in certain young children and in older adults and persons with compromised immunity, and only one dose in all other individuals; and establishing a process for vaccine strain selection recommendations, similar in many ways to that used for seasonal influenza vaccines, based on prevailing and predicted variants that would take place by June to allow for vaccine production by September.

During the discussion, though, questions arose about the June target date. Given the production schedule for some vaccines, that date might need to shift, said Jerry Weir, PhD, director of the division of viral products at FDA’s Center for Biologics Evaluation and Research. 

“We’re all just going to have to maintain flexibility,” Dr. Weir said, adding that there is not yet a “good pattern” established for updating these vaccines. 
 

Increasing vaccination rates

There was broad consensus about the need to boost public support for COVID-19 vaccinations. While about 81% of the U.S. population has had at least one dose of this vaccine, only 15.3% have had an updated bivalent booster dose, according to the CDC.

“Anything that results in better public communication would be extremely valuable,” said committee member Henry H. Bernstein, DO, MHCM, of the Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

But it’s unclear what expectations will be prioritized for the COVID vaccine program, he said. 

“Realistically, I don’t think we can have it all – less infection, less transmission, less severe disease, and less long COVID,” Dr. Bernstein said. “And that seems to be a major challenge for public messaging.” 
 

Panelists press for more data 

Other committee members also pressed for clearer targets in evaluating the goals for COVID vaccines, and for more robust data. 

Like his fellow VRBPAC members, Cody Meissner, MD, of Dartmouth’s Geisel School of Medicine, Hanover, N.H., supported a move toward harmonizing the strains used in different companies’ vaccines. But he added that it wasn’t clear yet how frequently they should be administered. 

“We need to see what happens with disease burden,” Dr. Meissner said. “We may or may not need annual vaccination. It’s just awfully early, it seems to me, in this process to answer that question.”

Among those serving on VRBPAC was one of the FDA’s more vocal critics on these points, Paul A. Offit, MD, a vaccine expert from Children’s Hospital of Philadelphia. Dr. Offit, for example, joined former FDA officials in writing a November opinion article for the Washington Post, arguing that the evidence for boosters for healthy younger adults was not strong.

At the Jan. 26 meeting, he supported the drive toward simplification of COVID vaccine schedules, while arguing for more data about how well these products are working.

“This virus is going to be with us for years, if not decades, and there will always be vulnerable groups who are going to be hospitalized and killed by the virus,” Dr. Offit said.

The CDC needs to provide more information about the characteristics of people being hospitalized with COVID infections, including their ages and comorbidities as well as details about their vaccine history, he said. In addition, academic researchers should provide a clearer picture of what immunological predictors are at play in increasing people’s risk from COVID.

“Then and only then can we really best make the decision about who gets vaccinated with what and when,” Dr. Offit said. 

VRBPAC member Ofer Levy, MD, PhD, also urged the FDA to press for a collection of more robust and detailed information about the immune response to COVID-19 vaccinations, such as a deeper look at what’s happening with antibodies.

“I hope FDA will continue to reflect on how to best take this information forward, and encourage – or require – sponsors to gather more information in a standardized way across these different arms of the human immune system,” Dr. Levy said. “So we keep learning and keep doing this better.”

In recapping the panel’s suggestions at the end of the meeting, Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research, addressed the requests made during the day’s meeting about better data on how the vaccines work. 

“We heard loud and clear that we need to use a data-driven approach to get to the simplest possible scheme that we can for vaccination,” Dr. Marks said. “And it should be as simple as possible but not oversimplified, a little bit like they say about Mozart’s music.”

A version of this article first appeared on WebMD.com.

A panel of advisers to the Food and Drug Administration unanimously supported an effort to simplify COVID-19 vaccinations, with the aim of developing a one-dose approach – perhaps annually – for the general population.

The FDA is looking to give clearer direction to vaccine makers about future development of COVID-19 vaccines. The plan is to narrow down the current complex landscape of options for vaccinations, and thus help increase use of these shots. 

COVID remains a serious threat, causing about 4,000 deaths a week recently, according to the Centers for Disease Control and Prevention. The 21 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26 voted unanimously “yes” on a single question posed by the FDA: 

“Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (Original plus Omicron BA.4/BA.5)?”

In other words, would it be better to have one vaccine potentially combining multiple strains of the virus, instead of multiple vaccines – such as a two-shot primary series then a booster containing different combinations of viral strains.

The FDA will consider the panel’s advice as it outlines new strategies for keeping ahead of the evolving virus.

In explaining their support for the FDA plan, panel members said they hoped that a simpler regime would aid in persuading more people to get COVID vaccines.

Pamela McInnes, DDS, MSc, noted that it’s difficult to explain to many people that the vaccine works to protect them from more severe illness if they contract COVID after getting vaccinated. 

“That is a real challenge,” said Dr. McInness, retired deputy director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

“The message that you would have gotten more sick and landed in the hospital resonates with me, but I’m not sure if it resonates with” many people who become infected, she said.
 

The plan

In the briefing document for the meeting, the FDA outlined a plan for transitioning from the current complex landscape of COVID-19 vaccines to a single vaccine composition for the primary series and booster vaccination. 

This would require harmonizing the strain composition of all COVID-19 vaccines; simplifying the immunization schedule for future vaccination campaigns to administer a two-dose series in certain young children and in older adults and persons with compromised immunity, and only one dose in all other individuals; and establishing a process for vaccine strain selection recommendations, similar in many ways to that used for seasonal influenza vaccines, based on prevailing and predicted variants that would take place by June to allow for vaccine production by September.

During the discussion, though, questions arose about the June target date. Given the production schedule for some vaccines, that date might need to shift, said Jerry Weir, PhD, director of the division of viral products at FDA’s Center for Biologics Evaluation and Research. 

“We’re all just going to have to maintain flexibility,” Dr. Weir said, adding that there is not yet a “good pattern” established for updating these vaccines. 
 

Increasing vaccination rates

There was broad consensus about the need to boost public support for COVID-19 vaccinations. While about 81% of the U.S. population has had at least one dose of this vaccine, only 15.3% have had an updated bivalent booster dose, according to the CDC.

“Anything that results in better public communication would be extremely valuable,” said committee member Henry H. Bernstein, DO, MHCM, of the Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

But it’s unclear what expectations will be prioritized for the COVID vaccine program, he said. 

“Realistically, I don’t think we can have it all – less infection, less transmission, less severe disease, and less long COVID,” Dr. Bernstein said. “And that seems to be a major challenge for public messaging.” 
 

Panelists press for more data 

Other committee members also pressed for clearer targets in evaluating the goals for COVID vaccines, and for more robust data. 

Like his fellow VRBPAC members, Cody Meissner, MD, of Dartmouth’s Geisel School of Medicine, Hanover, N.H., supported a move toward harmonizing the strains used in different companies’ vaccines. But he added that it wasn’t clear yet how frequently they should be administered. 

“We need to see what happens with disease burden,” Dr. Meissner said. “We may or may not need annual vaccination. It’s just awfully early, it seems to me, in this process to answer that question.”

Among those serving on VRBPAC was one of the FDA’s more vocal critics on these points, Paul A. Offit, MD, a vaccine expert from Children’s Hospital of Philadelphia. Dr. Offit, for example, joined former FDA officials in writing a November opinion article for the Washington Post, arguing that the evidence for boosters for healthy younger adults was not strong.

At the Jan. 26 meeting, he supported the drive toward simplification of COVID vaccine schedules, while arguing for more data about how well these products are working.

“This virus is going to be with us for years, if not decades, and there will always be vulnerable groups who are going to be hospitalized and killed by the virus,” Dr. Offit said.

The CDC needs to provide more information about the characteristics of people being hospitalized with COVID infections, including their ages and comorbidities as well as details about their vaccine history, he said. In addition, academic researchers should provide a clearer picture of what immunological predictors are at play in increasing people’s risk from COVID.

“Then and only then can we really best make the decision about who gets vaccinated with what and when,” Dr. Offit said. 

VRBPAC member Ofer Levy, MD, PhD, also urged the FDA to press for a collection of more robust and detailed information about the immune response to COVID-19 vaccinations, such as a deeper look at what’s happening with antibodies.

“I hope FDA will continue to reflect on how to best take this information forward, and encourage – or require – sponsors to gather more information in a standardized way across these different arms of the human immune system,” Dr. Levy said. “So we keep learning and keep doing this better.”

In recapping the panel’s suggestions at the end of the meeting, Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research, addressed the requests made during the day’s meeting about better data on how the vaccines work. 

“We heard loud and clear that we need to use a data-driven approach to get to the simplest possible scheme that we can for vaccination,” Dr. Marks said. “And it should be as simple as possible but not oversimplified, a little bit like they say about Mozart’s music.”

A version of this article first appeared on WebMD.com.

A panel of advisers to the Food and Drug Administration unanimously supported an effort to simplify COVID-19 vaccinations, with the aim of developing a one-dose approach – perhaps annually – for the general population.

The FDA is looking to give clearer direction to vaccine makers about future development of COVID-19 vaccines. The plan is to narrow down the current complex landscape of options for vaccinations, and thus help increase use of these shots. 

COVID remains a serious threat, causing about 4,000 deaths a week recently, according to the Centers for Disease Control and Prevention. The 21 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26 voted unanimously “yes” on a single question posed by the FDA: 

“Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (Original plus Omicron BA.4/BA.5)?”

In other words, would it be better to have one vaccine potentially combining multiple strains of the virus, instead of multiple vaccines – such as a two-shot primary series then a booster containing different combinations of viral strains.

The FDA will consider the panel’s advice as it outlines new strategies for keeping ahead of the evolving virus.

In explaining their support for the FDA plan, panel members said they hoped that a simpler regime would aid in persuading more people to get COVID vaccines.

Pamela McInnes, DDS, MSc, noted that it’s difficult to explain to many people that the vaccine works to protect them from more severe illness if they contract COVID after getting vaccinated. 

“That is a real challenge,” said Dr. McInness, retired deputy director of the National Center for Advancing Translational Sciences at the National Institutes of Health.

“The message that you would have gotten more sick and landed in the hospital resonates with me, but I’m not sure if it resonates with” many people who become infected, she said.
 

The plan

In the briefing document for the meeting, the FDA outlined a plan for transitioning from the current complex landscape of COVID-19 vaccines to a single vaccine composition for the primary series and booster vaccination. 

This would require harmonizing the strain composition of all COVID-19 vaccines; simplifying the immunization schedule for future vaccination campaigns to administer a two-dose series in certain young children and in older adults and persons with compromised immunity, and only one dose in all other individuals; and establishing a process for vaccine strain selection recommendations, similar in many ways to that used for seasonal influenza vaccines, based on prevailing and predicted variants that would take place by June to allow for vaccine production by September.

During the discussion, though, questions arose about the June target date. Given the production schedule for some vaccines, that date might need to shift, said Jerry Weir, PhD, director of the division of viral products at FDA’s Center for Biologics Evaluation and Research. 

“We’re all just going to have to maintain flexibility,” Dr. Weir said, adding that there is not yet a “good pattern” established for updating these vaccines. 
 

Increasing vaccination rates

There was broad consensus about the need to boost public support for COVID-19 vaccinations. While about 81% of the U.S. population has had at least one dose of this vaccine, only 15.3% have had an updated bivalent booster dose, according to the CDC.

“Anything that results in better public communication would be extremely valuable,” said committee member Henry H. Bernstein, DO, MHCM, of the Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

But it’s unclear what expectations will be prioritized for the COVID vaccine program, he said. 

“Realistically, I don’t think we can have it all – less infection, less transmission, less severe disease, and less long COVID,” Dr. Bernstein said. “And that seems to be a major challenge for public messaging.” 
 

Panelists press for more data 

Other committee members also pressed for clearer targets in evaluating the goals for COVID vaccines, and for more robust data. 

Like his fellow VRBPAC members, Cody Meissner, MD, of Dartmouth’s Geisel School of Medicine, Hanover, N.H., supported a move toward harmonizing the strains used in different companies’ vaccines. But he added that it wasn’t clear yet how frequently they should be administered. 

“We need to see what happens with disease burden,” Dr. Meissner said. “We may or may not need annual vaccination. It’s just awfully early, it seems to me, in this process to answer that question.”

Among those serving on VRBPAC was one of the FDA’s more vocal critics on these points, Paul A. Offit, MD, a vaccine expert from Children’s Hospital of Philadelphia. Dr. Offit, for example, joined former FDA officials in writing a November opinion article for the Washington Post, arguing that the evidence for boosters for healthy younger adults was not strong.

At the Jan. 26 meeting, he supported the drive toward simplification of COVID vaccine schedules, while arguing for more data about how well these products are working.

“This virus is going to be with us for years, if not decades, and there will always be vulnerable groups who are going to be hospitalized and killed by the virus,” Dr. Offit said.

The CDC needs to provide more information about the characteristics of people being hospitalized with COVID infections, including their ages and comorbidities as well as details about their vaccine history, he said. In addition, academic researchers should provide a clearer picture of what immunological predictors are at play in increasing people’s risk from COVID.

“Then and only then can we really best make the decision about who gets vaccinated with what and when,” Dr. Offit said. 

VRBPAC member Ofer Levy, MD, PhD, also urged the FDA to press for a collection of more robust and detailed information about the immune response to COVID-19 vaccinations, such as a deeper look at what’s happening with antibodies.

“I hope FDA will continue to reflect on how to best take this information forward, and encourage – or require – sponsors to gather more information in a standardized way across these different arms of the human immune system,” Dr. Levy said. “So we keep learning and keep doing this better.”

In recapping the panel’s suggestions at the end of the meeting, Peter Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation and Research, addressed the requests made during the day’s meeting about better data on how the vaccines work. 

“We heard loud and clear that we need to use a data-driven approach to get to the simplest possible scheme that we can for vaccination,” Dr. Marks said. “And it should be as simple as possible but not oversimplified, a little bit like they say about Mozart’s music.”

A version of this article first appeared on WebMD.com.

The Society of Thoracic Surgeons (STS) and its newly installed president have posted an apology for a speech delivered by its outgoing president that appeared, in part, to disparage affirmative action as a means to promote diversity, equity, and inclusion in the field.

The speech, entitled “Three Score & More,” presented Jan. 22 at the STS 58th annual meeting in San Diego by John H. Calhoon, MD, University of Texas Health Science Center at San Antonio, unleashed a cascade of tweets, some circumspect but many expressing outrage and dismay.

Many of the tweets were from individuals who acknowledged not hearing the speech but who had seen at least one accompanying slide which, by then, had been widely circulated on the platform. It contained phrases such as “Affirmative Action is not equal opportunity” and “Defining people by color, gender, religion only tends to ingrain bias and discrimination,” all under the heading of “Virtuous Ideals.”

Reactions on Twitter included comments such as “This is bad beyond description” and a description of the slide’s content as “the blueprint & thought process for those actively maintaining Whiteness & the Patriarchy in medicine.”

Following an early onslaught of such tweets, the STS and new president Thomas E. MacGillivray, MD, MedStar Health, Washington, issued a statement disowning at least the controversial parts of Dr. Calhoon’s presentation, stating they were “inconsistent with STS’s core values of diversity, equity, and inclusion.”

The post continues, “The STS apologizes for these remarks. We know these comments were hurtful and we regret the pain they have caused to so many valued colleagues.” It then states, “Diversity, equity, and inclusion are central principles of our Society, and what we strive for in our profession and our practice. STS is committed to learning from this experience and taking action to reinforce our commitment to these values.”

“I believe that either the slide and/or my remarks were misinterpreted by some. I don’t want to hurt anybody. I’m profoundly sorry and apologize,” Dr. Calhoon said in an interview.

“I’m proud of my own group’s record on diversity and using equity and inclusion to get there,” he said. “We’re committed to it. We’ve had a wonderfully diverse group. I tried to highlight that in my remarks.”

About the Twitter response to the slide in question, Dr. Calhoon said, “I have no idea how they were thinking.” He added, “I can only comment that I’m really proud of our record and, for that matter, the STS’s record on diversity, equity, and inclusion.”

A version of this article first appeared on Medscape.com.

The Society of Thoracic Surgeons (STS) and its newly installed president have posted an apology for a speech delivered by its outgoing president that appeared, in part, to disparage affirmative action as a means to promote diversity, equity, and inclusion in the field.

The speech, entitled “Three Score & More,” presented Jan. 22 at the STS 58th annual meeting in San Diego by John H. Calhoon, MD, University of Texas Health Science Center at San Antonio, unleashed a cascade of tweets, some circumspect but many expressing outrage and dismay.

Many of the tweets were from individuals who acknowledged not hearing the speech but who had seen at least one accompanying slide which, by then, had been widely circulated on the platform. It contained phrases such as “Affirmative Action is not equal opportunity” and “Defining people by color, gender, religion only tends to ingrain bias and discrimination,” all under the heading of “Virtuous Ideals.”

Reactions on Twitter included comments such as “This is bad beyond description” and a description of the slide’s content as “the blueprint & thought process for those actively maintaining Whiteness & the Patriarchy in medicine.”

Following an early onslaught of such tweets, the STS and new president Thomas E. MacGillivray, MD, MedStar Health, Washington, issued a statement disowning at least the controversial parts of Dr. Calhoon’s presentation, stating they were “inconsistent with STS’s core values of diversity, equity, and inclusion.”

The post continues, “The STS apologizes for these remarks. We know these comments were hurtful and we regret the pain they have caused to so many valued colleagues.” It then states, “Diversity, equity, and inclusion are central principles of our Society, and what we strive for in our profession and our practice. STS is committed to learning from this experience and taking action to reinforce our commitment to these values.”

“I believe that either the slide and/or my remarks were misinterpreted by some. I don’t want to hurt anybody. I’m profoundly sorry and apologize,” Dr. Calhoon said in an interview.

“I’m proud of my own group’s record on diversity and using equity and inclusion to get there,” he said. “We’re committed to it. We’ve had a wonderfully diverse group. I tried to highlight that in my remarks.”

About the Twitter response to the slide in question, Dr. Calhoon said, “I have no idea how they were thinking.” He added, “I can only comment that I’m really proud of our record and, for that matter, the STS’s record on diversity, equity, and inclusion.”

A version of this article first appeared on Medscape.com.

The Society of Thoracic Surgeons (STS) and its newly installed president have posted an apology for a speech delivered by its outgoing president that appeared, in part, to disparage affirmative action as a means to promote diversity, equity, and inclusion in the field.

The speech, entitled “Three Score & More,” presented Jan. 22 at the STS 58th annual meeting in San Diego by John H. Calhoon, MD, University of Texas Health Science Center at San Antonio, unleashed a cascade of tweets, some circumspect but many expressing outrage and dismay.

Many of the tweets were from individuals who acknowledged not hearing the speech but who had seen at least one accompanying slide which, by then, had been widely circulated on the platform. It contained phrases such as “Affirmative Action is not equal opportunity” and “Defining people by color, gender, religion only tends to ingrain bias and discrimination,” all under the heading of “Virtuous Ideals.”

Reactions on Twitter included comments such as “This is bad beyond description” and a description of the slide’s content as “the blueprint & thought process for those actively maintaining Whiteness & the Patriarchy in medicine.”

Following an early onslaught of such tweets, the STS and new president Thomas E. MacGillivray, MD, MedStar Health, Washington, issued a statement disowning at least the controversial parts of Dr. Calhoon’s presentation, stating they were “inconsistent with STS’s core values of diversity, equity, and inclusion.”

The post continues, “The STS apologizes for these remarks. We know these comments were hurtful and we regret the pain they have caused to so many valued colleagues.” It then states, “Diversity, equity, and inclusion are central principles of our Society, and what we strive for in our profession and our practice. STS is committed to learning from this experience and taking action to reinforce our commitment to these values.”

“I believe that either the slide and/or my remarks were misinterpreted by some. I don’t want to hurt anybody. I’m profoundly sorry and apologize,” Dr. Calhoon said in an interview.

“I’m proud of my own group’s record on diversity and using equity and inclusion to get there,” he said. “We’re committed to it. We’ve had a wonderfully diverse group. I tried to highlight that in my remarks.”

About the Twitter response to the slide in question, Dr. Calhoon said, “I have no idea how they were thinking.” He added, “I can only comment that I’m really proud of our record and, for that matter, the STS’s record on diversity, equity, and inclusion.”

A version of this article first appeared on Medscape.com.

Women who experience preeclampsia during pregnancy are almost twice as likely to have a heart attack or stroke within 20 years of giving birth as pregnant women who did not, according to a new study published in the European Journal of Preventive Cardiology. The risks are especially high in the first decade after giving birth, the researchers found.
 

Preeclampsia is the onset of high blood pressure after the 20th week of pregnancy combined with signs of organ damage, such as excess protein in the urine. It can occur in up to 8% of pregnancies, and the association between preeclampsia and long-term cardiac risks is well-known. But new research suggests these risks appear much earlier in life than expected – as early as age 30 – at a time when women are often not screened for signs of heart trouble

“Targeted interventions cannot wait until women with preeclampsia become eligible for conventional screening programs in middle age,” Sara Hallum, PhD, a coauthor of the study, told this news organization.

Dr. Hallum, who was an epidemiologist at the University of Copenhagen at the time of the study, and colleagues evaluated the medical histories of more than 1.1 million women in Denmark who became pregnant once or twice between 1978 and 2017. Of this group, 3% had experienced preeclampsia. They compared rates of heart attack and stroke between the two groups over time.

While 1.2% of the entire study population had experienced a heart attack or stroke within 20 years of giving birth, 2% of the women with a history of preeclampsia had such an event. Within the first decade after delivery, women with a history of preeclampsia were four times as likely to have a heart attack and three times as likely to have a stroke as other women.

Women aged 30-39 with a history of preeclampsia were nearly five times as likely to have a heart attack and three times as likely to have a stroke as similar-aged women. And if a woman gave birth twice and had preeclampsia only during the second pregnancy, she was at especially high risk for a heart attack, the researchers found.

“Women with a history of preeclampsia should be monitored routinely for modifiable risk factors, particularly for increased blood pressure,” Dr. Hallum said.

The Danish study population is racially homogeneous, so the researchers were not able to distinguish the effects of preeclampsia by racial group. In the United States, strong evidence shows that Black women experience the effects of preeclampsia more than others.
 

A useful clue to cardiac risk

Ellen Seely, MD, an endocrinologist at Brigham and Women’s Hospital in Boston, who specializes in preeclampsia, said physicians are less likely to ask women who have been pregnant if they had experienced preeclampsia than to ask if they smoke or have a family history of heart attacks. As a result, they may miss a looming cardiovascular event, especially in younger women who appear healthy.

“Emerging high blood pressure shouldn’t be ignored” in a seemingly healthy young woman, Dr. Seely said, particularly if that woman has divulged a history of preeclampsia. The doctor’s first step should be to verify hypertension, Dr. Seely said. If high blood pressure is evident, immediate treatment – such as encouraging more physical activity and a healthier diet – should follow. Watchful waiting in such cases is inappropriate, she added.

Although the experience of having preeclampsia is unpleasant and scary, Dr. Seely noted that in at least one way it can prove advantageous. Some women who did not experience preeclampsia will end up having a heart attack, sometimes with no prior warning that anything was amiss. At least a history of preeclampsia provides a clue that women should take care of their hearts.

“The patient carries their history with them wherever they go,” Dr. Seely said. For now, this reality often requires women to mention their pregnancy history even if a provider doesn’t ask. Someday, Dr. Seely said, asking about that history will become just as routine for providers as asking about family history.

The study was funded by the Danish Heart Foundation. Dr. Hallum and Dr. Seely have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Women who experience preeclampsia during pregnancy are almost twice as likely to have a heart attack or stroke within 20 years of giving birth as pregnant women who did not, according to a new study published in the European Journal of Preventive Cardiology. The risks are especially high in the first decade after giving birth, the researchers found.
 

Preeclampsia is the onset of high blood pressure after the 20th week of pregnancy combined with signs of organ damage, such as excess protein in the urine. It can occur in up to 8% of pregnancies, and the association between preeclampsia and long-term cardiac risks is well-known. But new research suggests these risks appear much earlier in life than expected – as early as age 30 – at a time when women are often not screened for signs of heart trouble

“Targeted interventions cannot wait until women with preeclampsia become eligible for conventional screening programs in middle age,” Sara Hallum, PhD, a coauthor of the study, told this news organization.

Dr. Hallum, who was an epidemiologist at the University of Copenhagen at the time of the study, and colleagues evaluated the medical histories of more than 1.1 million women in Denmark who became pregnant once or twice between 1978 and 2017. Of this group, 3% had experienced preeclampsia. They compared rates of heart attack and stroke between the two groups over time.

While 1.2% of the entire study population had experienced a heart attack or stroke within 20 years of giving birth, 2% of the women with a history of preeclampsia had such an event. Within the first decade after delivery, women with a history of preeclampsia were four times as likely to have a heart attack and three times as likely to have a stroke as other women.

Women aged 30-39 with a history of preeclampsia were nearly five times as likely to have a heart attack and three times as likely to have a stroke as similar-aged women. And if a woman gave birth twice and had preeclampsia only during the second pregnancy, she was at especially high risk for a heart attack, the researchers found.

“Women with a history of preeclampsia should be monitored routinely for modifiable risk factors, particularly for increased blood pressure,” Dr. Hallum said.

The Danish study population is racially homogeneous, so the researchers were not able to distinguish the effects of preeclampsia by racial group. In the United States, strong evidence shows that Black women experience the effects of preeclampsia more than others.
 

A useful clue to cardiac risk

Ellen Seely, MD, an endocrinologist at Brigham and Women’s Hospital in Boston, who specializes in preeclampsia, said physicians are less likely to ask women who have been pregnant if they had experienced preeclampsia than to ask if they smoke or have a family history of heart attacks. As a result, they may miss a looming cardiovascular event, especially in younger women who appear healthy.

“Emerging high blood pressure shouldn’t be ignored” in a seemingly healthy young woman, Dr. Seely said, particularly if that woman has divulged a history of preeclampsia. The doctor’s first step should be to verify hypertension, Dr. Seely said. If high blood pressure is evident, immediate treatment – such as encouraging more physical activity and a healthier diet – should follow. Watchful waiting in such cases is inappropriate, she added.

Although the experience of having preeclampsia is unpleasant and scary, Dr. Seely noted that in at least one way it can prove advantageous. Some women who did not experience preeclampsia will end up having a heart attack, sometimes with no prior warning that anything was amiss. At least a history of preeclampsia provides a clue that women should take care of their hearts.

“The patient carries their history with them wherever they go,” Dr. Seely said. For now, this reality often requires women to mention their pregnancy history even if a provider doesn’t ask. Someday, Dr. Seely said, asking about that history will become just as routine for providers as asking about family history.

The study was funded by the Danish Heart Foundation. Dr. Hallum and Dr. Seely have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Women who experience preeclampsia during pregnancy are almost twice as likely to have a heart attack or stroke within 20 years of giving birth as pregnant women who did not, according to a new study published in the European Journal of Preventive Cardiology. The risks are especially high in the first decade after giving birth, the researchers found.
 

Preeclampsia is the onset of high blood pressure after the 20th week of pregnancy combined with signs of organ damage, such as excess protein in the urine. It can occur in up to 8% of pregnancies, and the association between preeclampsia and long-term cardiac risks is well-known. But new research suggests these risks appear much earlier in life than expected – as early as age 30 – at a time when women are often not screened for signs of heart trouble

“Targeted interventions cannot wait until women with preeclampsia become eligible for conventional screening programs in middle age,” Sara Hallum, PhD, a coauthor of the study, told this news organization.

Dr. Hallum, who was an epidemiologist at the University of Copenhagen at the time of the study, and colleagues evaluated the medical histories of more than 1.1 million women in Denmark who became pregnant once or twice between 1978 and 2017. Of this group, 3% had experienced preeclampsia. They compared rates of heart attack and stroke between the two groups over time.

While 1.2% of the entire study population had experienced a heart attack or stroke within 20 years of giving birth, 2% of the women with a history of preeclampsia had such an event. Within the first decade after delivery, women with a history of preeclampsia were four times as likely to have a heart attack and three times as likely to have a stroke as other women.

Women aged 30-39 with a history of preeclampsia were nearly five times as likely to have a heart attack and three times as likely to have a stroke as similar-aged women. And if a woman gave birth twice and had preeclampsia only during the second pregnancy, she was at especially high risk for a heart attack, the researchers found.

“Women with a history of preeclampsia should be monitored routinely for modifiable risk factors, particularly for increased blood pressure,” Dr. Hallum said.

The Danish study population is racially homogeneous, so the researchers were not able to distinguish the effects of preeclampsia by racial group. In the United States, strong evidence shows that Black women experience the effects of preeclampsia more than others.
 

A useful clue to cardiac risk

Ellen Seely, MD, an endocrinologist at Brigham and Women’s Hospital in Boston, who specializes in preeclampsia, said physicians are less likely to ask women who have been pregnant if they had experienced preeclampsia than to ask if they smoke or have a family history of heart attacks. As a result, they may miss a looming cardiovascular event, especially in younger women who appear healthy.

“Emerging high blood pressure shouldn’t be ignored” in a seemingly healthy young woman, Dr. Seely said, particularly if that woman has divulged a history of preeclampsia. The doctor’s first step should be to verify hypertension, Dr. Seely said. If high blood pressure is evident, immediate treatment – such as encouraging more physical activity and a healthier diet – should follow. Watchful waiting in such cases is inappropriate, she added.

Although the experience of having preeclampsia is unpleasant and scary, Dr. Seely noted that in at least one way it can prove advantageous. Some women who did not experience preeclampsia will end up having a heart attack, sometimes with no prior warning that anything was amiss. At least a history of preeclampsia provides a clue that women should take care of their hearts.

“The patient carries their history with them wherever they go,” Dr. Seely said. For now, this reality often requires women to mention their pregnancy history even if a provider doesn’t ask. Someday, Dr. Seely said, asking about that history will become just as routine for providers as asking about family history.

The study was funded by the Danish Heart Foundation. Dr. Hallum and Dr. Seely have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

A version of this article first appeared on Medscape.com.

General pediatricians and a multidisciplinary team of specialists agreed most of the time on which children should be diagnosed with autism spectrum disorder (ASD), data from a new study suggest.

But when it came to ruling out ASD, the agreement rate was much lower.

The study by Melanie Penner, MSc, MD, with the Autism Research Centre at Bloorview Research Institute, Toronto, and colleagues found that 89% of the time when a physician determined a child had ASD, the multidisciplinary team agreed. But when a pediatrician thought a child did not have ASD, the multidisciplinary team agreed only 60% of the time. The study was published in JAMA Network Open.

Multidisciplinary team model can’t keep up with demand

The findings are important as many guidelines recommend multidisciplinary teams (MDTs) for all ASD diagnostic assessment. However, the resources for this model can’t meet the demand of children needing a diagnosis and can lead to long waits for ASD therapies.

In Canada, the researchers note, the average wait time from referral to receipt of ASD diagnosis has been reported as 7 months and “has likely lengthened since the COVID-19 pandemic.”

Jennifer Gerdts, PhD, an attending psychologist at the Seattle Children’s Autism Center, said in an interview that the wait there for diagnosis in children older than 4 is “multiple years,” a length of time that’s common across the United States. Meanwhile, in many states families can’t access services without a diagnosis.

Expanding capacity with diagnoses by general pediatricians may improve access, but the diagnostic accuracy is critical.

Dr. Gerdts, who was not part of the study, said this research is “hugely important in the work that is under way to build community capacity for diagnostic evaluation.”

She said this study shows that not all diagnoses need the resources of a multiple-disciplinary team and that “pediatricians can do it, too, and they can do it pretty accurately.” Dr. Gerdts evaluates children for autism and helps train pediatricians to make diagnoses.
 

Pediatricians, specialist team completed blinded assessments

The 17 pediatricians in the study and the specialist team independently completed blinded assessment and each recorded a decision on whether the child had ASD. The prospective diagnostic study was conducted in a specialist assessment center in Toronto and in general pediatrician practices in Ontario from June 2016 to March 2020.

Children were younger than 5.5 years, did not have an ASD diagnosis and were referred because there was a development concern. The pediatricians referred 106 children (75% boys; average age, 3.5 years). More than half (57%) of the participating children were from minority racial and ethnic groups.

The children were randomly assigned to two groups: One included children who had their MDT visits before their pediatrician assessment and the other group included those who had their MDT visits after their pediatrician assessment.

The MDT diagnosed more than two-thirds of the children (68%) with ASD.

Sensitivity and specificity of the pediatrician assessments, compared with that of the specialist team, were 0.75 (95% confidence interval, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively.
 

A look at pediatricians’ accuracy

Pediatricians reported the decisions they would have made had the child not been in the study.

• In 69% of the true-positive cases, pediatricians would have given an ASD diagnosis.
• In 44% of true-negative cases, they would have told the family the child did not have autism; in 30% of those case, they would give alternative diagnoses (most commonly ADHD and language delay).
• The pediatrician would have diagnosed ASD in only one of the seven false-positive cases and would refer those patients to a subspecialist 71% of the time.
• In false-negative cases, the pediatrician would incorrectly tell the family the child does not have autism 44% of the time.

Regarding the false-negative cases, the authors wrote, “more caution is needed for pediatricians when definitively ruling out ASD, which might result in diagnostic delays.”
 

Confidence is key

Physician confidence was also correlated with accuracy.

The authors wrote: “Among true-positive cases (MDT and pediatrician agree the child has ASD), the pediatrician was certain or very certain 80% of the time (43 cases) and the MDT was certain or very certain 96% of the time (52 cases). As such, if pediatricians conferred ASD diagnoses when feeling certain or very certain, they would make 46 correct diagnoses and 2 incorrect diagnoses.”

The high accuracy of diagnosis when physicians are confident suggests “listening to that sense of certainty is important,” Dr. Gerdts said. Conversely, these numbers show when a physician is uncertain about diagnosing ASD, they should listen to that instinct, too, and refer.

The results of the study support having general pediatricians diagnose and move forward with their patients when the signs of ASD are more definitive, saving the less-certain cases for the more resource-intensive teams to diagnose. Many states are moving toward that “tiered” system, Dr. Gerdts said.

“For many, and in fact most children, general pediatricians are pretty accurate when making an autism diagnosis,” she said.

“Let’s get [general pediatricians] confident in recognizing when this is outside their skill and ability level,” she said. “If you’re not sure, it is better to refer them on than to misdiagnose them.”

The important missing piece she said is how to support them “so they don’t feel pressure to make that call,” Dr. Gerdts said.

This project was funded by a grant from the Bloorview Research Institute, a grant from the Canadian Institutes of Health Research and a grant from the Canadian Institutes of Health. Three coauthors consult for and receive grants from several pharmaceutical companies and other organizations. Dr. Gerdts declared no relevant financial relationships.

General pediatricians and a multidisciplinary team of specialists agreed most of the time on which children should be diagnosed with autism spectrum disorder (ASD), data from a new study suggest.

But when it came to ruling out ASD, the agreement rate was much lower.

The study by Melanie Penner, MSc, MD, with the Autism Research Centre at Bloorview Research Institute, Toronto, and colleagues found that 89% of the time when a physician determined a child had ASD, the multidisciplinary team agreed. But when a pediatrician thought a child did not have ASD, the multidisciplinary team agreed only 60% of the time. The study was published in JAMA Network Open.

Multidisciplinary team model can’t keep up with demand

The findings are important as many guidelines recommend multidisciplinary teams (MDTs) for all ASD diagnostic assessment. However, the resources for this model can’t meet the demand of children needing a diagnosis and can lead to long waits for ASD therapies.

In Canada, the researchers note, the average wait time from referral to receipt of ASD diagnosis has been reported as 7 months and “has likely lengthened since the COVID-19 pandemic.”

Jennifer Gerdts, PhD, an attending psychologist at the Seattle Children’s Autism Center, said in an interview that the wait there for diagnosis in children older than 4 is “multiple years,” a length of time that’s common across the United States. Meanwhile, in many states families can’t access services without a diagnosis.

Expanding capacity with diagnoses by general pediatricians may improve access, but the diagnostic accuracy is critical.

Dr. Gerdts, who was not part of the study, said this research is “hugely important in the work that is under way to build community capacity for diagnostic evaluation.”

She said this study shows that not all diagnoses need the resources of a multiple-disciplinary team and that “pediatricians can do it, too, and they can do it pretty accurately.” Dr. Gerdts evaluates children for autism and helps train pediatricians to make diagnoses.
 

Pediatricians, specialist team completed blinded assessments

The 17 pediatricians in the study and the specialist team independently completed blinded assessment and each recorded a decision on whether the child had ASD. The prospective diagnostic study was conducted in a specialist assessment center in Toronto and in general pediatrician practices in Ontario from June 2016 to March 2020.

Children were younger than 5.5 years, did not have an ASD diagnosis and were referred because there was a development concern. The pediatricians referred 106 children (75% boys; average age, 3.5 years). More than half (57%) of the participating children were from minority racial and ethnic groups.

The children were randomly assigned to two groups: One included children who had their MDT visits before their pediatrician assessment and the other group included those who had their MDT visits after their pediatrician assessment.

The MDT diagnosed more than two-thirds of the children (68%) with ASD.

Sensitivity and specificity of the pediatrician assessments, compared with that of the specialist team, were 0.75 (95% confidence interval, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively.
 

A look at pediatricians’ accuracy

Pediatricians reported the decisions they would have made had the child not been in the study.

• In 69% of the true-positive cases, pediatricians would have given an ASD diagnosis.
• In 44% of true-negative cases, they would have told the family the child did not have autism; in 30% of those case, they would give alternative diagnoses (most commonly ADHD and language delay).
• The pediatrician would have diagnosed ASD in only one of the seven false-positive cases and would refer those patients to a subspecialist 71% of the time.
• In false-negative cases, the pediatrician would incorrectly tell the family the child does not have autism 44% of the time.

Regarding the false-negative cases, the authors wrote, “more caution is needed for pediatricians when definitively ruling out ASD, which might result in diagnostic delays.”
 

Confidence is key

Physician confidence was also correlated with accuracy.

The authors wrote: “Among true-positive cases (MDT and pediatrician agree the child has ASD), the pediatrician was certain or very certain 80% of the time (43 cases) and the MDT was certain or very certain 96% of the time (52 cases). As such, if pediatricians conferred ASD diagnoses when feeling certain or very certain, they would make 46 correct diagnoses and 2 incorrect diagnoses.”

The high accuracy of diagnosis when physicians are confident suggests “listening to that sense of certainty is important,” Dr. Gerdts said. Conversely, these numbers show when a physician is uncertain about diagnosing ASD, they should listen to that instinct, too, and refer.

The results of the study support having general pediatricians diagnose and move forward with their patients when the signs of ASD are more definitive, saving the less-certain cases for the more resource-intensive teams to diagnose. Many states are moving toward that “tiered” system, Dr. Gerdts said.

“For many, and in fact most children, general pediatricians are pretty accurate when making an autism diagnosis,” she said.

“Let’s get [general pediatricians] confident in recognizing when this is outside their skill and ability level,” she said. “If you’re not sure, it is better to refer them on than to misdiagnose them.”

The important missing piece she said is how to support them “so they don’t feel pressure to make that call,” Dr. Gerdts said.

This project was funded by a grant from the Bloorview Research Institute, a grant from the Canadian Institutes of Health Research and a grant from the Canadian Institutes of Health. Three coauthors consult for and receive grants from several pharmaceutical companies and other organizations. Dr. Gerdts declared no relevant financial relationships.

General pediatricians and a multidisciplinary team of specialists agreed most of the time on which children should be diagnosed with autism spectrum disorder (ASD), data from a new study suggest.

But when it came to ruling out ASD, the agreement rate was much lower.

The study by Melanie Penner, MSc, MD, with the Autism Research Centre at Bloorview Research Institute, Toronto, and colleagues found that 89% of the time when a physician determined a child had ASD, the multidisciplinary team agreed. But when a pediatrician thought a child did not have ASD, the multidisciplinary team agreed only 60% of the time. The study was published in JAMA Network Open.

Multidisciplinary team model can’t keep up with demand

The findings are important as many guidelines recommend multidisciplinary teams (MDTs) for all ASD diagnostic assessment. However, the resources for this model can’t meet the demand of children needing a diagnosis and can lead to long waits for ASD therapies.

In Canada, the researchers note, the average wait time from referral to receipt of ASD diagnosis has been reported as 7 months and “has likely lengthened since the COVID-19 pandemic.”

Jennifer Gerdts, PhD, an attending psychologist at the Seattle Children’s Autism Center, said in an interview that the wait there for diagnosis in children older than 4 is “multiple years,” a length of time that’s common across the United States. Meanwhile, in many states families can’t access services without a diagnosis.

Expanding capacity with diagnoses by general pediatricians may improve access, but the diagnostic accuracy is critical.

Dr. Gerdts, who was not part of the study, said this research is “hugely important in the work that is under way to build community capacity for diagnostic evaluation.”

She said this study shows that not all diagnoses need the resources of a multiple-disciplinary team and that “pediatricians can do it, too, and they can do it pretty accurately.” Dr. Gerdts evaluates children for autism and helps train pediatricians to make diagnoses.
 

Pediatricians, specialist team completed blinded assessments

The 17 pediatricians in the study and the specialist team independently completed blinded assessment and each recorded a decision on whether the child had ASD. The prospective diagnostic study was conducted in a specialist assessment center in Toronto and in general pediatrician practices in Ontario from June 2016 to March 2020.

Children were younger than 5.5 years, did not have an ASD diagnosis and were referred because there was a development concern. The pediatricians referred 106 children (75% boys; average age, 3.5 years). More than half (57%) of the participating children were from minority racial and ethnic groups.

The children were randomly assigned to two groups: One included children who had their MDT visits before their pediatrician assessment and the other group included those who had their MDT visits after their pediatrician assessment.

The MDT diagnosed more than two-thirds of the children (68%) with ASD.

Sensitivity and specificity of the pediatrician assessments, compared with that of the specialist team, were 0.75 (95% confidence interval, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively.
 

A look at pediatricians’ accuracy

Pediatricians reported the decisions they would have made had the child not been in the study.

• In 69% of the true-positive cases, pediatricians would have given an ASD diagnosis.
• In 44% of true-negative cases, they would have told the family the child did not have autism; in 30% of those case, they would give alternative diagnoses (most commonly ADHD and language delay).
• The pediatrician would have diagnosed ASD in only one of the seven false-positive cases and would refer those patients to a subspecialist 71% of the time.
• In false-negative cases, the pediatrician would incorrectly tell the family the child does not have autism 44% of the time.

Regarding the false-negative cases, the authors wrote, “more caution is needed for pediatricians when definitively ruling out ASD, which might result in diagnostic delays.”
 

Confidence is key

Physician confidence was also correlated with accuracy.

The authors wrote: “Among true-positive cases (MDT and pediatrician agree the child has ASD), the pediatrician was certain or very certain 80% of the time (43 cases) and the MDT was certain or very certain 96% of the time (52 cases). As such, if pediatricians conferred ASD diagnoses when feeling certain or very certain, they would make 46 correct diagnoses and 2 incorrect diagnoses.”

The high accuracy of diagnosis when physicians are confident suggests “listening to that sense of certainty is important,” Dr. Gerdts said. Conversely, these numbers show when a physician is uncertain about diagnosing ASD, they should listen to that instinct, too, and refer.

The results of the study support having general pediatricians diagnose and move forward with their patients when the signs of ASD are more definitive, saving the less-certain cases for the more resource-intensive teams to diagnose. Many states are moving toward that “tiered” system, Dr. Gerdts said.

“For many, and in fact most children, general pediatricians are pretty accurate when making an autism diagnosis,” she said.

“Let’s get [general pediatricians] confident in recognizing when this is outside their skill and ability level,” she said. “If you’re not sure, it is better to refer them on than to misdiagnose them.”

The important missing piece she said is how to support them “so they don’t feel pressure to make that call,” Dr. Gerdts said.

This project was funded by a grant from the Bloorview Research Institute, a grant from the Canadian Institutes of Health Research and a grant from the Canadian Institutes of Health. Three coauthors consult for and receive grants from several pharmaceutical companies and other organizations. Dr. Gerdts declared no relevant financial relationships.

For Julia Moore Vogel, PhD, a cup of peppermint tea marked the moment her life would change forever.

One morning in early July 2020, she took a sip of her favorite strongly flavored pick-me-up and couldn’t taste it. She knew loss of taste and smell were symptoms of COVID-19, and she suspected she had contracted the virus. A doctor’s visit confirmed her fears.

“I remember trying the tea and just being so shocked and thinking: How can this be happening to me?” said Dr. Moore Vogel, a COVID-19 researcher with the Scripps Research Translational Institute in San Diego. “I’d been so incredibly careful.”

Her physician assured her that as a healthy woman in her mid-30s, she’d be “back to normal” in 2 weeks’ time and that her loss of taste and smell “very likely will be your only symptom,” she recalled.

But within a week, Dr. Moore Vogel started having trouble breathing. She couldn’t work, and she experienced crushing fatigue, brain fog, and migraines. Now, 2½ years later, Dr. Moore Vogel is among the tens of millions of Americans with long COVID.

As a COVID-19 patient-researcher who still struggles with fatigue and migraines, she has learned to cope with her condition. She directs the Participant Center for the All of Us Research Program, a National Institutes of Health collaboration to build the largest, most diverse health database in history. She relies on a practice called pacing, which helps conserve physical, mental, and emotional energy, to avoid making her symptoms worse.

And she is a coauthor of a landmark 200-study review of long COVID published Jan. 13 in the journal Nature, with Scripps Executive Vice President and Medscape Editor-in-Chief Eric Topol, MD. Two other institute long COVID researchers and patient advocates who have the condition coauthored the review – Lisa McCorkell and Hannah E. Davis, cofounders of the Patient-Led Research Collaborative , a group of long COVID patients who study the virus.

Dr. Moore Vogel discussed the key findings of the new review and her personal experiences with this news organization.
 

Q: When you contracted COVID, no treatments or vaccines existed. Can you talk about what the experience was like for you?

A: “It was July 2020. The loss of taste and smell was the first symptom, and what was interesting was that was my only symptom for a little bit. Being the goal-oriented, work-oriented person that I am, I just worked the rest of the week and hoped that it wasn’t real.

“But that was a Wednesday, and by Friday, I was just getting really tired, and it was really hard to finish my workday. I ended up taking 3 weeks off to recover from the acute phase. At the time, I had read early discussions about long COVID, and it was always on my [mind] – how long was it going to take to recover?”
 

Q: You went to see a doctor that first week?

A: “I called them when I had the loss of taste and smell, and they said, ‘It’s very likely this will be your only symptom.’ And when I first talked to a physician, they were saying, ‘Oh, you’re young and healthy, in 2 weeks you’ll be back to normal.’ But of course that turned out not to be true.

“It’s hard to remember what it was like at that time. There were so few treatments, it was all about rationing ventilators, and it was absolutely terrifying at the time to just not know what was going to happen.”
 

Q: How are you managing your condition today?

A: “I have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), one of the really common diagnoses that come out of long COVID. So, that’s the biggest thing for me to manage now, and the main management is pacing.

“I also have medications for migraine management. I’ve always had some degree of migraines, like 2 a month, but now it’s like 15 a month, so it’s a totally different scale of management.”
 

Q: It must be frustrating, personally and professionally, that long COVID treatments remain elusive.

A: “I’m disappointed at the pace of testing things in clinical trials. There was so much progress made, so much innovation in the early stages of the pandemic to treat the acute phase, and it led to amazing things. We have all these monoclonal antibodies, the steroids are really effective, not to mention the antivirals and the vaccines, of course, on the prevention side. It’s been amazing.

“But for some reason, long COVID treatment is really lagging. What I hypothesize as part of the reason for that is that it doesn’t feel as dramatic. When you see someone on a ventilator or hear about death, it feels very dramatic, and people really worry about that.”
 

Q: So, let’s talk about the research. How did your personal experiences – and those of the two other coauthors with long COVID – help inform this review?

A: “I work with Eric Topol on a regular basis, and it was amazing that he invited patients to work with him on this review ... I have to say of my other long COVID patient coauthors, Hannah Davis and Lisa McCorkell, it was amazing to work with them.

“It was my first time working with people who have long COVID on a big project. The understanding that we had of each other [where] one of us might say, Oh, I’m crashing today, I can’t work on this. Can you help get us across the finish line for this deadline? That was really amazing to me in terms of how a workplace can be with real disability accommodations.

“It’s really changed my personal outlook on how important it is to have patients involved in the process.”
 

Q: What was the most surprising or significant finding of the review, in your view?

A: “I would say the most impactful thing to me in the process of writing this review is how much research has been done in such a short time. We started with over 250 studies that we wanted to reference in the review, and we actually had to cut out 50 in the editorial process, which was really hard!

“There’s just been so much progress that’s been made in the past couple of years. And then thinking about the progress on long COVID in general, the other things that’s important to acknowledge is all the work that’s been done on other postviral illnesses that present very similarly to long COVID in many patients, ME/CFS, and postural orthostatic tachycardia syndrome (POTS).”
 

Q: One thing that stood out is the review’s finding that long COVID is potentially lifelong COVID and, in some ways, is closer to HIV-AIDS than, say, influenza. Is that right?

A: “Yes. I’m really glad you took that point away from the review because that was one of the things that I felt the most strongly about incorporating. For many people, based on the treatments that we have today, this is likely to lead to lifelong disability. And that’s something, from my personal experience, for sure. I’m seeing no improvement on the horizon.

“That’s part of why I’m so passionate about there being clinical trials because I know there are millions and millions of us. So for me, that wasn’t so surprising, because I’m living it, but I can see how for the general public that was a really surprising finding.”
 

Q: The review breaks down long COVID’s effects on various organs/systems, and it includes the most comprehensive look to date at the effects on pregnant women. Anything you’d care to stress about that?

A: “It really underlies the importance of vaccination, given that it can affect both the pregnant person and child. There is early evidence of development delays if there’s infection while the child is still gestating. So, I think it underscores the need for vaccination to reduce that risk.

“You know, pregnancy is a stressful and terrifying time anyway. So, if there’s anything you can do to reduce the risk to yourself and your unborn child, I think it’s really worthwhile.”
 

Q: Why do you think this exhaustive review was needed?

A: “Because of the massive amount of literature that’s out there, it’s so hard for anybody to sift through. Eric Topol and Hannah Davis, two of the coauthors, are two people who have done it, and they keep up with all the literature, and they are always tweeting about it.

“But most people don’t have the time to be able to sift through it, so what we did was take all of that literature, organize it into sections, and summarize the key findings. Then the other thing that I think is really important for the field right now is the recommendations piece.”
 

Q: What impact do you think the new long COVID review in Nature will have?

A: “The response to our review is way beyond what I expected, and I think that’s in part a sign that there is growing awareness of the issue of long COVID.

“I hope that helps spiral toward more treatment trials. Because there are a lot of great candidates out there. We have a whole table in the review about the different potential treatments that should be tested.”
 

Q: What’s the take-home message for physicians?

A: “One of the key recommendations is about physician education. We know that it is so hard for physicians to keep up with this massive amount of literature, and we really need more physician education that’s meant for busy physicians who really don’t have time to read all of the primary literature themselves.

“So many folks are not getting the care that they need. Because these types of conditions haven’t been seen as much by primary care providers, physical therapists, etc., there’s so much more education that’s needed.

“I think the basic tenets probably could be taught in a weekend course, [including] listening to the patients, believing patients. There are so many times patient symptoms are [dismissed and not] really being taken seriously by their physicians.

“I think part of the challenge behind that is the conflating of mental health issues with these other physiological symptoms. There’s a tendency to say, ‘Oh, all this is this caused by mental health issues’ and that mental health is the root cause, when actually it’s the illness that’s the root cause.”
 

Q: What’s the big picture: How significant is the public health crisis that long COVID represents?

A: “I believe it’s a massive crisis, a massive emergency. A lot of people in the long COVID community are calling it a mass-disabling event. There is concern that if we let the pandemic run unmitigated for long enough – given that we expect about 10% of folks that get COVID will end up with long COVID – we could end up eventually with a majority-disabled society.

“That would be devasting – to individuals, to the economy, the medical system. So, it’s absolutely a public health emergency in my view, and that’s part of why I’ve been so surprised by the lack of trials, the lack of awareness in the public. There hasn’t been as much public education about long COVID as there has about acute COVID. I think we can do more from a public health perspective.”
 

Q: What are the main challenges in combating long COVID?

A: “I think the lack of treatments is the most devastating part because it’s such a hard disease to contract, and there’s no end in sight, and so that time horizon can be really difficult. That’s part of why I’m pushing the treatments so much, because I want to offer hope to the community, you know, I want there to be hope around the corner.

“My hope is that within 5 years we’ll have treatments that can really improve quality of life for the community. And I know that that may seem like a long time for those who are suffering, and I hope that there will be some clinical trials of treatments that improve symptom management within 1-2 years. But I think for really more novel things, it’s really going to take at least 5.”
 

Q: Any advice you’d give to someone with long COVID today?

A: “Connecting with others that are going through the experience is extremely valuable and can really help with that mental component which can be really draining.

“The other thing, in terms of what’s important for the lives of people who are living with long COVID, I would say to everyone who doesn’t have long COVID but knows someone who does, being able to offer support is crucial and can make such a difference in quality of life.

“It is really crucial, for those who don’t have long COVID, to take it into account when you’re making your risk calculations. When you’re thinking: Am I going to wear a mask here? or Am I going to go to that bar?

“Really consider the possibility that if you get COVID, you have a 10% chance of getting long COVID. And if you get long COVID, you have a 25% chance of not being able to work anymore or being so ill that you can’t work anymore and you may lose your health insurance.

“The compounding effects are absolutely devastating, and I think that’s under-factored-in to the general risk calculations of the public.”

A version of this article first appeared on Medscape.com.

For Julia Moore Vogel, PhD, a cup of peppermint tea marked the moment her life would change forever.

One morning in early July 2020, she took a sip of her favorite strongly flavored pick-me-up and couldn’t taste it. She knew loss of taste and smell were symptoms of COVID-19, and she suspected she had contracted the virus. A doctor’s visit confirmed her fears.

“I remember trying the tea and just being so shocked and thinking: How can this be happening to me?” said Dr. Moore Vogel, a COVID-19 researcher with the Scripps Research Translational Institute in San Diego. “I’d been so incredibly careful.”

Her physician assured her that as a healthy woman in her mid-30s, she’d be “back to normal” in 2 weeks’ time and that her loss of taste and smell “very likely will be your only symptom,” she recalled.

But within a week, Dr. Moore Vogel started having trouble breathing. She couldn’t work, and she experienced crushing fatigue, brain fog, and migraines. Now, 2½ years later, Dr. Moore Vogel is among the tens of millions of Americans with long COVID.

As a COVID-19 patient-researcher who still struggles with fatigue and migraines, she has learned to cope with her condition. She directs the Participant Center for the All of Us Research Program, a National Institutes of Health collaboration to build the largest, most diverse health database in history. She relies on a practice called pacing, which helps conserve physical, mental, and emotional energy, to avoid making her symptoms worse.

And she is a coauthor of a landmark 200-study review of long COVID published Jan. 13 in the journal Nature, with Scripps Executive Vice President and Medscape Editor-in-Chief Eric Topol, MD. Two other institute long COVID researchers and patient advocates who have the condition coauthored the review – Lisa McCorkell and Hannah E. Davis, cofounders of the Patient-Led Research Collaborative , a group of long COVID patients who study the virus.

Dr. Moore Vogel discussed the key findings of the new review and her personal experiences with this news organization.
 

Q: When you contracted COVID, no treatments or vaccines existed. Can you talk about what the experience was like for you?

A: “It was July 2020. The loss of taste and smell was the first symptom, and what was interesting was that was my only symptom for a little bit. Being the goal-oriented, work-oriented person that I am, I just worked the rest of the week and hoped that it wasn’t real.

“But that was a Wednesday, and by Friday, I was just getting really tired, and it was really hard to finish my workday. I ended up taking 3 weeks off to recover from the acute phase. At the time, I had read early discussions about long COVID, and it was always on my [mind] – how long was it going to take to recover?”
 

Q: You went to see a doctor that first week?

A: “I called them when I had the loss of taste and smell, and they said, ‘It’s very likely this will be your only symptom.’ And when I first talked to a physician, they were saying, ‘Oh, you’re young and healthy, in 2 weeks you’ll be back to normal.’ But of course that turned out not to be true.

“It’s hard to remember what it was like at that time. There were so few treatments, it was all about rationing ventilators, and it was absolutely terrifying at the time to just not know what was going to happen.”
 

Q: How are you managing your condition today?

A: “I have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), one of the really common diagnoses that come out of long COVID. So, that’s the biggest thing for me to manage now, and the main management is pacing.

“I also have medications for migraine management. I’ve always had some degree of migraines, like 2 a month, but now it’s like 15 a month, so it’s a totally different scale of management.”
 

Q: It must be frustrating, personally and professionally, that long COVID treatments remain elusive.

A: “I’m disappointed at the pace of testing things in clinical trials. There was so much progress made, so much innovation in the early stages of the pandemic to treat the acute phase, and it led to amazing things. We have all these monoclonal antibodies, the steroids are really effective, not to mention the antivirals and the vaccines, of course, on the prevention side. It’s been amazing.

“But for some reason, long COVID treatment is really lagging. What I hypothesize as part of the reason for that is that it doesn’t feel as dramatic. When you see someone on a ventilator or hear about death, it feels very dramatic, and people really worry about that.”
 

Q: So, let’s talk about the research. How did your personal experiences – and those of the two other coauthors with long COVID – help inform this review?

A: “I work with Eric Topol on a regular basis, and it was amazing that he invited patients to work with him on this review ... I have to say of my other long COVID patient coauthors, Hannah Davis and Lisa McCorkell, it was amazing to work with them.

“It was my first time working with people who have long COVID on a big project. The understanding that we had of each other [where] one of us might say, Oh, I’m crashing today, I can’t work on this. Can you help get us across the finish line for this deadline? That was really amazing to me in terms of how a workplace can be with real disability accommodations.

“It’s really changed my personal outlook on how important it is to have patients involved in the process.”
 

Q: What was the most surprising or significant finding of the review, in your view?

A: “I would say the most impactful thing to me in the process of writing this review is how much research has been done in such a short time. We started with over 250 studies that we wanted to reference in the review, and we actually had to cut out 50 in the editorial process, which was really hard!

“There’s just been so much progress that’s been made in the past couple of years. And then thinking about the progress on long COVID in general, the other things that’s important to acknowledge is all the work that’s been done on other postviral illnesses that present very similarly to long COVID in many patients, ME/CFS, and postural orthostatic tachycardia syndrome (POTS).”
 

Q: One thing that stood out is the review’s finding that long COVID is potentially lifelong COVID and, in some ways, is closer to HIV-AIDS than, say, influenza. Is that right?

A: “Yes. I’m really glad you took that point away from the review because that was one of the things that I felt the most strongly about incorporating. For many people, based on the treatments that we have today, this is likely to lead to lifelong disability. And that’s something, from my personal experience, for sure. I’m seeing no improvement on the horizon.

“That’s part of why I’m so passionate about there being clinical trials because I know there are millions and millions of us. So for me, that wasn’t so surprising, because I’m living it, but I can see how for the general public that was a really surprising finding.”
 

Q: The review breaks down long COVID’s effects on various organs/systems, and it includes the most comprehensive look to date at the effects on pregnant women. Anything you’d care to stress about that?

A: “It really underlies the importance of vaccination, given that it can affect both the pregnant person and child. There is early evidence of development delays if there’s infection while the child is still gestating. So, I think it underscores the need for vaccination to reduce that risk.

“You know, pregnancy is a stressful and terrifying time anyway. So, if there’s anything you can do to reduce the risk to yourself and your unborn child, I think it’s really worthwhile.”
 

Q: Why do you think this exhaustive review was needed?

A: “Because of the massive amount of literature that’s out there, it’s so hard for anybody to sift through. Eric Topol and Hannah Davis, two of the coauthors, are two people who have done it, and they keep up with all the literature, and they are always tweeting about it.

“But most people don’t have the time to be able to sift through it, so what we did was take all of that literature, organize it into sections, and summarize the key findings. Then the other thing that I think is really important for the field right now is the recommendations piece.”
 

Q: What impact do you think the new long COVID review in Nature will have?

A: “The response to our review is way beyond what I expected, and I think that’s in part a sign that there is growing awareness of the issue of long COVID.

“I hope that helps spiral toward more treatment trials. Because there are a lot of great candidates out there. We have a whole table in the review about the different potential treatments that should be tested.”
 

Q: What’s the take-home message for physicians?

A: “One of the key recommendations is about physician education. We know that it is so hard for physicians to keep up with this massive amount of literature, and we really need more physician education that’s meant for busy physicians who really don’t have time to read all of the primary literature themselves.

“So many folks are not getting the care that they need. Because these types of conditions haven’t been seen as much by primary care providers, physical therapists, etc., there’s so much more education that’s needed.

“I think the basic tenets probably could be taught in a weekend course, [including] listening to the patients, believing patients. There are so many times patient symptoms are [dismissed and not] really being taken seriously by their physicians.

“I think part of the challenge behind that is the conflating of mental health issues with these other physiological symptoms. There’s a tendency to say, ‘Oh, all this is this caused by mental health issues’ and that mental health is the root cause, when actually it’s the illness that’s the root cause.”
 

Q: What’s the big picture: How significant is the public health crisis that long COVID represents?

A: “I believe it’s a massive crisis, a massive emergency. A lot of people in the long COVID community are calling it a mass-disabling event. There is concern that if we let the pandemic run unmitigated for long enough – given that we expect about 10% of folks that get COVID will end up with long COVID – we could end up eventually with a majority-disabled society.

“That would be devasting – to individuals, to the economy, the medical system. So, it’s absolutely a public health emergency in my view, and that’s part of why I’ve been so surprised by the lack of trials, the lack of awareness in the public. There hasn’t been as much public education about long COVID as there has about acute COVID. I think we can do more from a public health perspective.”
 

Q: What are the main challenges in combating long COVID?

A: “I think the lack of treatments is the most devastating part because it’s such a hard disease to contract, and there’s no end in sight, and so that time horizon can be really difficult. That’s part of why I’m pushing the treatments so much, because I want to offer hope to the community, you know, I want there to be hope around the corner.

“My hope is that within 5 years we’ll have treatments that can really improve quality of life for the community. And I know that that may seem like a long time for those who are suffering, and I hope that there will be some clinical trials of treatments that improve symptom management within 1-2 years. But I think for really more novel things, it’s really going to take at least 5.”
 

Q: Any advice you’d give to someone with long COVID today?

A: “Connecting with others that are going through the experience is extremely valuable and can really help with that mental component which can be really draining.

“The other thing, in terms of what’s important for the lives of people who are living with long COVID, I would say to everyone who doesn’t have long COVID but knows someone who does, being able to offer support is crucial and can make such a difference in quality of life.

“It is really crucial, for those who don’t have long COVID, to take it into account when you’re making your risk calculations. When you’re thinking: Am I going to wear a mask here? or Am I going to go to that bar?

“Really consider the possibility that if you get COVID, you have a 10% chance of getting long COVID. And if you get long COVID, you have a 25% chance of not being able to work anymore or being so ill that you can’t work anymore and you may lose your health insurance.

“The compounding effects are absolutely devastating, and I think that’s under-factored-in to the general risk calculations of the public.”

A version of this article first appeared on Medscape.com.

For Julia Moore Vogel, PhD, a cup of peppermint tea marked the moment her life would change forever.

One morning in early July 2020, she took a sip of her favorite strongly flavored pick-me-up and couldn’t taste it. She knew loss of taste and smell were symptoms of COVID-19, and she suspected she had contracted the virus. A doctor’s visit confirmed her fears.

“I remember trying the tea and just being so shocked and thinking: How can this be happening to me?” said Dr. Moore Vogel, a COVID-19 researcher with the Scripps Research Translational Institute in San Diego. “I’d been so incredibly careful.”

Her physician assured her that as a healthy woman in her mid-30s, she’d be “back to normal” in 2 weeks’ time and that her loss of taste and smell “very likely will be your only symptom,” she recalled.

But within a week, Dr. Moore Vogel started having trouble breathing. She couldn’t work, and she experienced crushing fatigue, brain fog, and migraines. Now, 2½ years later, Dr. Moore Vogel is among the tens of millions of Americans with long COVID.

As a COVID-19 patient-researcher who still struggles with fatigue and migraines, she has learned to cope with her condition. She directs the Participant Center for the All of Us Research Program, a National Institutes of Health collaboration to build the largest, most diverse health database in history. She relies on a practice called pacing, which helps conserve physical, mental, and emotional energy, to avoid making her symptoms worse.

And she is a coauthor of a landmark 200-study review of long COVID published Jan. 13 in the journal Nature, with Scripps Executive Vice President and Medscape Editor-in-Chief Eric Topol, MD. Two other institute long COVID researchers and patient advocates who have the condition coauthored the review – Lisa McCorkell and Hannah E. Davis, cofounders of the Patient-Led Research Collaborative , a group of long COVID patients who study the virus.

Dr. Moore Vogel discussed the key findings of the new review and her personal experiences with this news organization.
 

Q: When you contracted COVID, no treatments or vaccines existed. Can you talk about what the experience was like for you?

A: “It was July 2020. The loss of taste and smell was the first symptom, and what was interesting was that was my only symptom for a little bit. Being the goal-oriented, work-oriented person that I am, I just worked the rest of the week and hoped that it wasn’t real.

“But that was a Wednesday, and by Friday, I was just getting really tired, and it was really hard to finish my workday. I ended up taking 3 weeks off to recover from the acute phase. At the time, I had read early discussions about long COVID, and it was always on my [mind] – how long was it going to take to recover?”
 

Q: You went to see a doctor that first week?

A: “I called them when I had the loss of taste and smell, and they said, ‘It’s very likely this will be your only symptom.’ And when I first talked to a physician, they were saying, ‘Oh, you’re young and healthy, in 2 weeks you’ll be back to normal.’ But of course that turned out not to be true.

“It’s hard to remember what it was like at that time. There were so few treatments, it was all about rationing ventilators, and it was absolutely terrifying at the time to just not know what was going to happen.”
 

Q: How are you managing your condition today?

A: “I have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), one of the really common diagnoses that come out of long COVID. So, that’s the biggest thing for me to manage now, and the main management is pacing.

“I also have medications for migraine management. I’ve always had some degree of migraines, like 2 a month, but now it’s like 15 a month, so it’s a totally different scale of management.”
 

Q: It must be frustrating, personally and professionally, that long COVID treatments remain elusive.

A: “I’m disappointed at the pace of testing things in clinical trials. There was so much progress made, so much innovation in the early stages of the pandemic to treat the acute phase, and it led to amazing things. We have all these monoclonal antibodies, the steroids are really effective, not to mention the antivirals and the vaccines, of course, on the prevention side. It’s been amazing.

“But for some reason, long COVID treatment is really lagging. What I hypothesize as part of the reason for that is that it doesn’t feel as dramatic. When you see someone on a ventilator or hear about death, it feels very dramatic, and people really worry about that.”
 

Q: So, let’s talk about the research. How did your personal experiences – and those of the two other coauthors with long COVID – help inform this review?

A: “I work with Eric Topol on a regular basis, and it was amazing that he invited patients to work with him on this review ... I have to say of my other long COVID patient coauthors, Hannah Davis and Lisa McCorkell, it was amazing to work with them.

“It was my first time working with people who have long COVID on a big project. The understanding that we had of each other [where] one of us might say, Oh, I’m crashing today, I can’t work on this. Can you help get us across the finish line for this deadline? That was really amazing to me in terms of how a workplace can be with real disability accommodations.

“It’s really changed my personal outlook on how important it is to have patients involved in the process.”
 

Q: What was the most surprising or significant finding of the review, in your view?

A: “I would say the most impactful thing to me in the process of writing this review is how much research has been done in such a short time. We started with over 250 studies that we wanted to reference in the review, and we actually had to cut out 50 in the editorial process, which was really hard!

“There’s just been so much progress that’s been made in the past couple of years. And then thinking about the progress on long COVID in general, the other things that’s important to acknowledge is all the work that’s been done on other postviral illnesses that present very similarly to long COVID in many patients, ME/CFS, and postural orthostatic tachycardia syndrome (POTS).”
 

Q: One thing that stood out is the review’s finding that long COVID is potentially lifelong COVID and, in some ways, is closer to HIV-AIDS than, say, influenza. Is that right?

A: “Yes. I’m really glad you took that point away from the review because that was one of the things that I felt the most strongly about incorporating. For many people, based on the treatments that we have today, this is likely to lead to lifelong disability. And that’s something, from my personal experience, for sure. I’m seeing no improvement on the horizon.

“That’s part of why I’m so passionate about there being clinical trials because I know there are millions and millions of us. So for me, that wasn’t so surprising, because I’m living it, but I can see how for the general public that was a really surprising finding.”
 

Q: The review breaks down long COVID’s effects on various organs/systems, and it includes the most comprehensive look to date at the effects on pregnant women. Anything you’d care to stress about that?

A: “It really underlies the importance of vaccination, given that it can affect both the pregnant person and child. There is early evidence of development delays if there’s infection while the child is still gestating. So, I think it underscores the need for vaccination to reduce that risk.

“You know, pregnancy is a stressful and terrifying time anyway. So, if there’s anything you can do to reduce the risk to yourself and your unborn child, I think it’s really worthwhile.”
 

Q: Why do you think this exhaustive review was needed?

A: “Because of the massive amount of literature that’s out there, it’s so hard for anybody to sift through. Eric Topol and Hannah Davis, two of the coauthors, are two people who have done it, and they keep up with all the literature, and they are always tweeting about it.

“But most people don’t have the time to be able to sift through it, so what we did was take all of that literature, organize it into sections, and summarize the key findings. Then the other thing that I think is really important for the field right now is the recommendations piece.”
 

Q: What impact do you think the new long COVID review in Nature will have?

A: “The response to our review is way beyond what I expected, and I think that’s in part a sign that there is growing awareness of the issue of long COVID.

“I hope that helps spiral toward more treatment trials. Because there are a lot of great candidates out there. We have a whole table in the review about the different potential treatments that should be tested.”
 

Q: What’s the take-home message for physicians?

A: “One of the key recommendations is about physician education. We know that it is so hard for physicians to keep up with this massive amount of literature, and we really need more physician education that’s meant for busy physicians who really don’t have time to read all of the primary literature themselves.

“So many folks are not getting the care that they need. Because these types of conditions haven’t been seen as much by primary care providers, physical therapists, etc., there’s so much more education that’s needed.

“I think the basic tenets probably could be taught in a weekend course, [including] listening to the patients, believing patients. There are so many times patient symptoms are [dismissed and not] really being taken seriously by their physicians.

“I think part of the challenge behind that is the conflating of mental health issues with these other physiological symptoms. There’s a tendency to say, ‘Oh, all this is this caused by mental health issues’ and that mental health is the root cause, when actually it’s the illness that’s the root cause.”
 

Q: What’s the big picture: How significant is the public health crisis that long COVID represents?

A: “I believe it’s a massive crisis, a massive emergency. A lot of people in the long COVID community are calling it a mass-disabling event. There is concern that if we let the pandemic run unmitigated for long enough – given that we expect about 10% of folks that get COVID will end up with long COVID – we could end up eventually with a majority-disabled society.

“That would be devasting – to individuals, to the economy, the medical system. So, it’s absolutely a public health emergency in my view, and that’s part of why I’ve been so surprised by the lack of trials, the lack of awareness in the public. There hasn’t been as much public education about long COVID as there has about acute COVID. I think we can do more from a public health perspective.”
 

Q: What are the main challenges in combating long COVID?

A: “I think the lack of treatments is the most devastating part because it’s such a hard disease to contract, and there’s no end in sight, and so that time horizon can be really difficult. That’s part of why I’m pushing the treatments so much, because I want to offer hope to the community, you know, I want there to be hope around the corner.

“My hope is that within 5 years we’ll have treatments that can really improve quality of life for the community. And I know that that may seem like a long time for those who are suffering, and I hope that there will be some clinical trials of treatments that improve symptom management within 1-2 years. But I think for really more novel things, it’s really going to take at least 5.”
 

Q: Any advice you’d give to someone with long COVID today?

A: “Connecting with others that are going through the experience is extremely valuable and can really help with that mental component which can be really draining.

“The other thing, in terms of what’s important for the lives of people who are living with long COVID, I would say to everyone who doesn’t have long COVID but knows someone who does, being able to offer support is crucial and can make such a difference in quality of life.

“It is really crucial, for those who don’t have long COVID, to take it into account when you’re making your risk calculations. When you’re thinking: Am I going to wear a mask here? or Am I going to go to that bar?

“Really consider the possibility that if you get COVID, you have a 10% chance of getting long COVID. And if you get long COVID, you have a 25% chance of not being able to work anymore or being so ill that you can’t work anymore and you may lose your health insurance.

“The compounding effects are absolutely devastating, and I think that’s under-factored-in to the general risk calculations of the public.”

A version of this article first appeared on Medscape.com.

Middle-aged adults who spend just 9 additional minutes a day participating in moderate to vigorous physical activity (MVPA) experience improved cognition in new findings that underscore the critical role brisk exercise, such as running and cycling, plays in brain health.

“Even minor differences in daily behavior appeared meaningful for cognition in this study,” researcher John J. Mitchell, MSci and PhD candidate, Medical Research Council, London, told this news organization.

The findings were published online in the Journal of Epidemiology and Community Health.
 

Research gap

Previous research has linked physical activity (PA) with increased cognitive reserve, which delays the onset of cognitive decline in later life. But disentangling the most important components of PA for cognition – such as intensity and volume – has not been well researched.

Previous studies didn’t capture sleep time, which typically takes up the largest component of the day. Sleep is “acutely relevant” when examining cognition, the investigators noted.

In addition, studies in this area often focus on just one or two activity components of the day, which “neglects the growing awareness” that movements “are all tightly interlinked,” said Mr. Mitchell.

The new study included 4,481 participants in the British Cohort Study who were born in 1970 across England, Scotland, and Wales. The participants were followed throughout childhood and adulthood.

The median age of the participants was 47 years, and they were predominantly White, female (52%), married (66%), and well educated. Most were occasional or nonrisky alcohol consumers, and half had never smoked.

The researchers collected biometric measurements and health, demographic, and lifestyle information. Participants wore a thigh-mounted accelerometer at least 7 consecutive hours a day for up to 7 days to track PA, sedentary behavior (SB), and sleep time.

The device used in the study could detect subtle movements as well as speed of accelerations, said Mr. Mitchell. “From this, we can distinguish MVPA from slow walking, standing, and sitting. It’s the current best practice for detecting the more subtle movements we make, such as brisk walking and stair climbing, beyond just ‘exercise,’ “ he added.

Light intensity PA (LIPA) describes movement such as walking and moving around the house or office, while MVPA includes activities such as brisk walking and running that accelerate the heart rate. SB, defined as time spent sitting or lying, is distinguished from standing by the thigh inclination.

On an average day, the cohort spent 51 minutes in MVPA; 5 hours, 42 minutes in LIPA; 9 hours, 16 minutes in SB; and 8 hours, 11 minutes sleeping.

Researchers calculated an overall global score for verbal memory and executive function.

The study used “compositional data analysis,” a statistical method that can examine the associations of cognition and PA in the context of all components of daily movement.

The analysis revealed a positive association between MVPA and cognition relative to all other behaviors, after adjustment for sociodemographic factors that included sex, age, education, and marital status. But the relationship lessened after further adjustment for health status – for example, cardiovascular disease or disability – and lifestyle factors, such as alcohol consumption and smoking status.

SB relative to all other movements remained positively associated with cognition after full adjustment. This, the authors speculated, may reflect engagement in cognitively stimulating activities such as reading.

To better understand the associations, the researchers used a statistical method to reallocate time in the cohort’s average day from one activity component to another.

“We held two of the components static but moved time between the other two and monitored the theoretical ramifications of that change for cognition,” said Mr. Mitchell.
 

Real cognitive change

There was a 1.31% improvement in cognition ranking compared to the sample average after replacing 9 minutes of sedentary activity with MVPA (1.31; 95% confidence interval [CI], 0.09-2.50). There was a 1.27% improvement after replacing 7 minutes of LIPA with MVPA, and a 1.2% improvement after replacing 7 minutes of sleep with MVPA.

Individuals might move up from about the 50th percentile to the 51st or 52nd percentile after just 9 minutes of more moderate to vigorous movement in place of sitting, said Mr. Mitchell. “This highlights how even very modest differences in people’s daily movement – less than 10 minutes – is linked to quite real changes in our cognitive health.”

The impact of physical activity appeared greatest on working memory and mental processes, such as planning and organization.

On the other hand, cognition declined by 1%-2% after replacing MVPA with 8 minutes of SB, 6 minutes of LIPA, or 7 minutes of sleep.

The activity tracking device couldn’t determine how well participants slept, which is “a clear limitation” of the study, said Mr. Mitchell. “We have to be cautious when trying to interpret our findings surrounding sleep.”

Another limitation is that despite a large sample size, people of color were underrepresented, limiting the generalizability of the findings. As well, other healthy pursuits – for example, reading – might have contributed to improved cognition.
 

Important findings

In a comment, Jennifer J. Heisz, PhD, associate professor and Canada research chair in brain health and aging, department of kinesiology, McMaster University, Hamilton, Ont., said the findings from the study are important.

“Through the statistical modelling, the authors demonstrate that swapping just 9 minutes of sedentary behavior with moderate to vigorous physical activity, such as a brisk walk or bike ride, was associated with an increase in cognition.”

She added that this seemed to be especially true for people who sit while at work.

The findings “confer with the growing consensus” that some exercise is better than none when it comes to brain health, said Dr. Heisz.

“Clinicians should encourage their patients to add a brisk, 10-minute walk to their daily routine and break up prolonged sitting with short movement breaks.”

She noted the study was cross-sectional, “so it is not possible to infer causation.”

The study received funding from the Medical Research Council and the British Heart Foundation. Mr. Mitchell and Dr. Heisz have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Middle-aged adults who spend just 9 additional minutes a day participating in moderate to vigorous physical activity (MVPA) experience improved cognition in new findings that underscore the critical role brisk exercise, such as running and cycling, plays in brain health.

“Even minor differences in daily behavior appeared meaningful for cognition in this study,” researcher John J. Mitchell, MSci and PhD candidate, Medical Research Council, London, told this news organization.

The findings were published online in the Journal of Epidemiology and Community Health.
 

Research gap

Previous research has linked physical activity (PA) with increased cognitive reserve, which delays the onset of cognitive decline in later life. But disentangling the most important components of PA for cognition – such as intensity and volume – has not been well researched.

Previous studies didn’t capture sleep time, which typically takes up the largest component of the day. Sleep is “acutely relevant” when examining cognition, the investigators noted.

In addition, studies in this area often focus on just one or two activity components of the day, which “neglects the growing awareness” that movements “are all tightly interlinked,” said Mr. Mitchell.

The new study included 4,481 participants in the British Cohort Study who were born in 1970 across England, Scotland, and Wales. The participants were followed throughout childhood and adulthood.

The median age of the participants was 47 years, and they were predominantly White, female (52%), married (66%), and well educated. Most were occasional or nonrisky alcohol consumers, and half had never smoked.

The researchers collected biometric measurements and health, demographic, and lifestyle information. Participants wore a thigh-mounted accelerometer at least 7 consecutive hours a day for up to 7 days to track PA, sedentary behavior (SB), and sleep time.

The device used in the study could detect subtle movements as well as speed of accelerations, said Mr. Mitchell. “From this, we can distinguish MVPA from slow walking, standing, and sitting. It’s the current best practice for detecting the more subtle movements we make, such as brisk walking and stair climbing, beyond just ‘exercise,’ “ he added.

Light intensity PA (LIPA) describes movement such as walking and moving around the house or office, while MVPA includes activities such as brisk walking and running that accelerate the heart rate. SB, defined as time spent sitting or lying, is distinguished from standing by the thigh inclination.

On an average day, the cohort spent 51 minutes in MVPA; 5 hours, 42 minutes in LIPA; 9 hours, 16 minutes in SB; and 8 hours, 11 minutes sleeping.

Researchers calculated an overall global score for verbal memory and executive function.

The study used “compositional data analysis,” a statistical method that can examine the associations of cognition and PA in the context of all components of daily movement.

The analysis revealed a positive association between MVPA and cognition relative to all other behaviors, after adjustment for sociodemographic factors that included sex, age, education, and marital status. But the relationship lessened after further adjustment for health status – for example, cardiovascular disease or disability – and lifestyle factors, such as alcohol consumption and smoking status.

SB relative to all other movements remained positively associated with cognition after full adjustment. This, the authors speculated, may reflect engagement in cognitively stimulating activities such as reading.

To better understand the associations, the researchers used a statistical method to reallocate time in the cohort’s average day from one activity component to another.

“We held two of the components static but moved time between the other two and monitored the theoretical ramifications of that change for cognition,” said Mr. Mitchell.
 

Real cognitive change

There was a 1.31% improvement in cognition ranking compared to the sample average after replacing 9 minutes of sedentary activity with MVPA (1.31; 95% confidence interval [CI], 0.09-2.50). There was a 1.27% improvement after replacing 7 minutes of LIPA with MVPA, and a 1.2% improvement after replacing 7 minutes of sleep with MVPA.

Individuals might move up from about the 50th percentile to the 51st or 52nd percentile after just 9 minutes of more moderate to vigorous movement in place of sitting, said Mr. Mitchell. “This highlights how even very modest differences in people’s daily movement – less than 10 minutes – is linked to quite real changes in our cognitive health.”

The impact of physical activity appeared greatest on working memory and mental processes, such as planning and organization.

On the other hand, cognition declined by 1%-2% after replacing MVPA with 8 minutes of SB, 6 minutes of LIPA, or 7 minutes of sleep.

The activity tracking device couldn’t determine how well participants slept, which is “a clear limitation” of the study, said Mr. Mitchell. “We have to be cautious when trying to interpret our findings surrounding sleep.”

Another limitation is that despite a large sample size, people of color were underrepresented, limiting the generalizability of the findings. As well, other healthy pursuits – for example, reading – might have contributed to improved cognition.
 

Important findings

In a comment, Jennifer J. Heisz, PhD, associate professor and Canada research chair in brain health and aging, department of kinesiology, McMaster University, Hamilton, Ont., said the findings from the study are important.

“Through the statistical modelling, the authors demonstrate that swapping just 9 minutes of sedentary behavior with moderate to vigorous physical activity, such as a brisk walk or bike ride, was associated with an increase in cognition.”

She added that this seemed to be especially true for people who sit while at work.

The findings “confer with the growing consensus” that some exercise is better than none when it comes to brain health, said Dr. Heisz.

“Clinicians should encourage their patients to add a brisk, 10-minute walk to their daily routine and break up prolonged sitting with short movement breaks.”

She noted the study was cross-sectional, “so it is not possible to infer causation.”

The study received funding from the Medical Research Council and the British Heart Foundation. Mr. Mitchell and Dr. Heisz have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Middle-aged adults who spend just 9 additional minutes a day participating in moderate to vigorous physical activity (MVPA) experience improved cognition in new findings that underscore the critical role brisk exercise, such as running and cycling, plays in brain health.

“Even minor differences in daily behavior appeared meaningful for cognition in this study,” researcher John J. Mitchell, MSci and PhD candidate, Medical Research Council, London, told this news organization.

The findings were published online in the Journal of Epidemiology and Community Health.
 

Research gap

Previous research has linked physical activity (PA) with increased cognitive reserve, which delays the onset of cognitive decline in later life. But disentangling the most important components of PA for cognition – such as intensity and volume – has not been well researched.

Previous studies didn’t capture sleep time, which typically takes up the largest component of the day. Sleep is “acutely relevant” when examining cognition, the investigators noted.

In addition, studies in this area often focus on just one or two activity components of the day, which “neglects the growing awareness” that movements “are all tightly interlinked,” said Mr. Mitchell.

The new study included 4,481 participants in the British Cohort Study who were born in 1970 across England, Scotland, and Wales. The participants were followed throughout childhood and adulthood.

The median age of the participants was 47 years, and they were predominantly White, female (52%), married (66%), and well educated. Most were occasional or nonrisky alcohol consumers, and half had never smoked.

The researchers collected biometric measurements and health, demographic, and lifestyle information. Participants wore a thigh-mounted accelerometer at least 7 consecutive hours a day for up to 7 days to track PA, sedentary behavior (SB), and sleep time.

The device used in the study could detect subtle movements as well as speed of accelerations, said Mr. Mitchell. “From this, we can distinguish MVPA from slow walking, standing, and sitting. It’s the current best practice for detecting the more subtle movements we make, such as brisk walking and stair climbing, beyond just ‘exercise,’ “ he added.

Light intensity PA (LIPA) describes movement such as walking and moving around the house or office, while MVPA includes activities such as brisk walking and running that accelerate the heart rate. SB, defined as time spent sitting or lying, is distinguished from standing by the thigh inclination.

On an average day, the cohort spent 51 minutes in MVPA; 5 hours, 42 minutes in LIPA; 9 hours, 16 minutes in SB; and 8 hours, 11 minutes sleeping.

Researchers calculated an overall global score for verbal memory and executive function.

The study used “compositional data analysis,” a statistical method that can examine the associations of cognition and PA in the context of all components of daily movement.

The analysis revealed a positive association between MVPA and cognition relative to all other behaviors, after adjustment for sociodemographic factors that included sex, age, education, and marital status. But the relationship lessened after further adjustment for health status – for example, cardiovascular disease or disability – and lifestyle factors, such as alcohol consumption and smoking status.

SB relative to all other movements remained positively associated with cognition after full adjustment. This, the authors speculated, may reflect engagement in cognitively stimulating activities such as reading.

To better understand the associations, the researchers used a statistical method to reallocate time in the cohort’s average day from one activity component to another.

“We held two of the components static but moved time between the other two and monitored the theoretical ramifications of that change for cognition,” said Mr. Mitchell.
 

Real cognitive change

There was a 1.31% improvement in cognition ranking compared to the sample average after replacing 9 minutes of sedentary activity with MVPA (1.31; 95% confidence interval [CI], 0.09-2.50). There was a 1.27% improvement after replacing 7 minutes of LIPA with MVPA, and a 1.2% improvement after replacing 7 minutes of sleep with MVPA.

Individuals might move up from about the 50th percentile to the 51st or 52nd percentile after just 9 minutes of more moderate to vigorous movement in place of sitting, said Mr. Mitchell. “This highlights how even very modest differences in people’s daily movement – less than 10 minutes – is linked to quite real changes in our cognitive health.”

The impact of physical activity appeared greatest on working memory and mental processes, such as planning and organization.

On the other hand, cognition declined by 1%-2% after replacing MVPA with 8 minutes of SB, 6 minutes of LIPA, or 7 minutes of sleep.

The activity tracking device couldn’t determine how well participants slept, which is “a clear limitation” of the study, said Mr. Mitchell. “We have to be cautious when trying to interpret our findings surrounding sleep.”

Another limitation is that despite a large sample size, people of color were underrepresented, limiting the generalizability of the findings. As well, other healthy pursuits – for example, reading – might have contributed to improved cognition.
 

Important findings

In a comment, Jennifer J. Heisz, PhD, associate professor and Canada research chair in brain health and aging, department of kinesiology, McMaster University, Hamilton, Ont., said the findings from the study are important.

“Through the statistical modelling, the authors demonstrate that swapping just 9 minutes of sedentary behavior with moderate to vigorous physical activity, such as a brisk walk or bike ride, was associated with an increase in cognition.”

She added that this seemed to be especially true for people who sit while at work.

The findings “confer with the growing consensus” that some exercise is better than none when it comes to brain health, said Dr. Heisz.

“Clinicians should encourage their patients to add a brisk, 10-minute walk to their daily routine and break up prolonged sitting with short movement breaks.”

She noted the study was cross-sectional, “so it is not possible to infer causation.”

The study received funding from the Medical Research Council and the British Heart Foundation. Mr. Mitchell and Dr. Heisz have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.