Feature

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). "Medical gallery of Blausen Medical Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). "Medical gallery of Blausen Medical Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

In 1938, the year that cystic fibrosis (CF) was first described clinically, four of five children born with the disease did not live past their first birthdays.

In 2019, the median age at death for patients enrolled in the Cystic Fibrosis Foundation (CFF) registry was 32 years, and the predicted life expectancy for patients with CF who were born from 2015 through 2019 was 46 years.

Blausen.com staff (2014). "Medical gallery of Blausen Medical Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.

Those numbers reflect the remarkable progress made in the past 4 decades in the care of patients with CF, but also highlight the obstacles ahead, given that the predicted life expectancy for the overall U.S. population in 2019 (pre–COVID-19) was 78.9 years.

Julie Desch, MD, is a CF survivor who has beaten the odds and then some. At age 61, the retired surgical pathologist is a CF patient advocate, speaker, and a board member of the Cystic Fibrosis Research Institute, a not-for-profit organization that funds CF research and offers education, advocacy, and psychosocial support for persons with CF and their families and caregivers.

In an interview, Dr. Desch said that while there has been remarkable progress in her lifetime in the field of CF research and treatment, particularly in the development of drugs that modulate function of the underlying cause of approximately 90% of CF cases, there are still many CF patients who cannot benefit from these therapies.

“There are still 10% of people who don’t make a protein to be modified, so that’s a huge unmet need,” she said.
 

Genetic disorder

CF is a chronic autosomal recessive disorder with multiorgan and multisystem manifestations. It is caused by mutations in the CFTR gene, which codes for the protein CF transmembrane conductance regulator. CFTR controls transport of chloride ions across cell membranes, specifically the apical membrane of epithelial cells in tissues of the airways, intestinal tract, pancreas, kidneys, sweat glands, and the reproductive system, notably the vas deferens in males.

Emw/Wikimedia Commons/CC BY-SA 3.0

The F508 deletion (F508del) mutation is the most common, occurring in approximately 70% of persons with CF. It is a class 2-type protein processing mutation, leading to defects in cellular processing, protein stability, and chloride channel gating defects.

The CFTR protein also secretes bicarbonate to regulate the pH of airway surface liquid, and inhibits the epithelial sodium channel, which mediates passive sodium transport across apical membranes of sodium-absorbing epithelial cells in the kidneys, intestine, and airways.

CF typically presents with the buildup in the lungs of abnormally viscous and sticky mucus leading to frequent, severe infections, particularly with Pseudomonas aeruginosa, progressive lung damage and, prior to the development of effective disease management, to premature death. The phenotype often includes malnutrition due to malabsorption, and failure to thrive.
 

Diagnosis

In all 50 U.S. states and the District of Columbia, newborns are screened for CF with an assay for immunoreactive trypsinogen (IRT) an indirect marker for pancreatic injury that is elevated in serum in most newborns with CF, but also detected in premature infants or those delivered under stressful circumstances. In some states newborns are tested only for IRT, with a diagnosis confirmed with a sweat chloride test and/or a CFTR mutation panel.

Treatment

There is no cure for CF, but the discovery of the gene in 1989 by Canadian and U.S. investigators has led to life-prolonging therapeutic interventions, specifically the development of CFTR modulators.

CFTR modulators include potentiators such as ivacaftor (Kalydeco), and correctors such as lumacaftor and tezacaftor (available in the combination Orkambi), and most recently in the triple combination of elexacaftor, tezacaftor, and ivacaftor (Trikafta; ETI).

Neil Sweezey, MD, FRCPC, a CF expert at The Hospital for Sick Children (SickKids) in Toronto, told this news organization that the ideal therapy for CF, genetic correction of the underlying mutations, is still not feasible, but that CFTR modulators are a close second.

“For 90% of patients, the three-drug combination Trikafta has been shown to be quite safe, quite tolerable, and quite remarkably beneficial,” he said.

In a study reported at CHEST 2021 by investigators from Nationwide Children’s Hospital in Columbus, Ohio, 32 adults who were started on the triple combination had significantly improved in forced expiratory volume in 1 second (FEV₁), gain in body mass index, decreased sweat chloride and decreased colonization by Pseudomonas species. In addition, patients had significant improvements in blood inflammatory markers.

Christopher H. Goss, MD, FCCP, professor of pulmonary critical care and sleep medicine and professor of pediatrics at the University of Washington in Seattle, agreed that with the availability of the triple combination, “these are extraordinary times. An astounding fact is that most patients have complete resolution of cough, and the exacerbation rates have just plummeted,” he said in an interview.

Some of the reductions in exacerbations may be attributable to the COVID-19 pandemic, he noted, because patients in isolation have less exposure to circulating respiratory viruses.

“But it has been miraculous, and the clinical effect is certainly still more astounding than the effects of ivacaftor, which was the first truly breakthrough drug. Weight goes up, well-being increases, and the population lung function has shifted up to better grade lung function, in the entire population,” he said.

In addition, the need for lung and heart transplantation has sharply declined.

“I had a patient who had decided to forgo transplantation, despite absolutely horrible lung function, and he’s now bowling and leading a very productive life, when before he had been preparing for end of life,” Dr. Goss said.

Dr. Sweezey emphasized that as with all medications, patients being started on the triple combination require close monitoring for potential adverse events that might require dose modification or, for a small number of patients, withdrawal.


 

Burden of care

CFTR modulators have reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease (DNase) that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. This can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

The complex nature of CF often requires a combination of other therapies to address comorbidities. These therapies may include infection prophylaxis and treatment with antibiotics and antifungals, nutrition support, and therapy for CF-related complications, including gastrointestinal issues, liver diseases, diabetes, and osteopenia that may be related to poor nutrient absorption, chronic inflammation, or other sequelae of CF.

In addition, patients often require frequent CF care center visits – ideally a minimum of every 3 months – which can result in significant loss of work or school time.

“Outcomes for patients in the long run have been absolutely proven to be best if they’re followed in big, established, multidisciplinary well-organized CF centers,” Dr. Sweezey said. “In the United States and Canada if you’re looked after on a regular basis, which means quarterly, every 3 months – whether you need it or not, you really do need it – and if the patients are seen and assessed and checked every 3 months all of their lives, they have small changes caught early, whether it’s an infection you can slap down with medication or a nutrition problem that may be affecting a child’s growth and development.”

“We’re really kind of at a pivotal moment in CF, where we realize things are changing,” said A. Whitney Brown, MD, senior director for clinical affairs at the Cystic Fibrosis Foundation, and an adult CF and lung transplant physician in the Inova Advanced Lung Disease Program in Falls Church, Va.

“Patient needs and interest have evolved, because of the pandemic and because of the highly effective modulator therapy, but we want to take great effort to study it in a rigorous way, to make sure that as we are agile and adapt the care model, that we can maintain the same quality outcomes that we have traditionally done,” she said in an interview.

The Lancet Respiratory Medicine Commission on the future of CF care states that models of care “need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation, while minimizing the burden of care for patients and their families.”
 

‘A great problem to have’

One of the most significant changes in CF care has been the growing population of CF patients like Dr. Desch who are living well into adulthood, with some approaching Medicare eligibility.

With the advent of triple therapy and CFTR modulators being started earlier in life, lung function can be preserved, damage to other organs can be minimized, and life expectancy for patients with CF will continue to improve.

“We’re anticipating that there may be some needs in the aging CF population that are different than what we have historically had,” Dr. Brown said. “Will there be geriatric providers that need to become experts in CF care? That’s a great problem to have,” she said.

Dr. Goss agreed, noting that CF is steadily shifting from a near uniformly fatal disease to a chronic disorder that in many cases can be managed “with a complex regimen of novel drugs, much like HIV.”

He noted that there are multiple drug interactions with the triple combination, “so it’s really important that people don’t start a CF patient on a drug without consulting a pharmacist, because you can totally inactivate ETI, or augment it dramatically, and we’ve seen both happen.”
 

Cost and access

All experts interviewed for this article agreed that while the care of patients with CF has improved exponentially over the last few decades, there are still troubling inequities in care.

One of the largest impediments is the cost of care, with the triple combination costing more than $300,000 per year.

“Clearly patients aren’t paying that, but insurance companies are, and that’s causing all kinds of trickle-down effects that definitely affect patients. The patients like myself who are able to have insurance that covers it benefit, but there are so many people that don’t,” Dr. Desch said.

Dr. Sweezey noted that prior to the advent of ETI, patients with CF in Canada had better outcomes and longer life expectancy than did similar patients in the United States because of universal access to care and coordinated services under Canada’s health care system, compared with the highly fragmented and inefficient U.S. system. He added that the wider availability of ETI in the United States vs. Canada may begin to narrow that gap, however.

As noted before, there is a substantial proportion of patients – an estimated 10% – who have CFTR mutations that are not correctable by currently available CFTR modulators, and these patients are at significant risk for irreversible airway complications and lung damage.

In addition, although CF occurs most frequently among people of White ancestry, the disease does not respect distinctions of race or ethnicity.

“It’s not just [Whites] – a lot of people from different racial backgrounds, ethnic backgrounds, are not being diagnosed or are not being diagnosed soon enough to have effective care early enough,” Dr. Desch said.

That statement is supported by the Lancet Respiratory Medicine Commission on the future of cystic fibrosis care, whose members noted in 2019 that “epidemiological studies in the past 2 decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognized in many regions of the world.”

The commission members noted that the costs of adequate CF care may be beyond the reach of many patients in developing nations.

Still, if the substantial barriers of cost and access can be overcome, the future will continue to look brighter for patients with CF. As Dr. Sweezey put it: “There are studies that are pushing lower age limits for using these modulators, and as the evidence builds for the efficacy and safety at younger ages, I think all of us are hoping that we’ll end up being able to use either the current or future modulators to actually prevent trouble in CF, rather than trying to come along and fix it after it’s been there.”

Dr. Brown disclosed advisory board activity for Vertex that ended prior to her joining the CF Foundation. Dr. Desch, Dr. Goss, and Dr. Sweezey reported no relevant conflicts of interest.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Long COVID continues to be a moving target – continuously evolving and still surprising doctors and patients who have sometimes incapacitating long-term symptoms.

Little about the disorder seems predictable at this point. People can have long COVID after asymptomatic, mild, or severe COVID-19, for example. And when a person gets long COVID – also known as long-haul COVID – symptoms can vary widely.

To address all the uncertainty, the New York State Department of Health gathered experts in primary care, pediatrics, physical medicine, rehabilitation, and pulmonology to answer some pressing questions.

New York in 2020 was the first epicenter of the pandemic in the United States, making it also the center of the long COVID epidemic, says Emily Lutterloh, MD, director of the Division of Epidemiology at the New York State Department of Health.
 

What do you do when you’re seeing a patient with long COVID for the first time?

The first exam varies because there are so many different ways long COVID presents itself, says Benjamin Abramoff, MD, a physical medicine and rehabilitation specialist at Penn Medicine in Philadelphia.

I’ve now been seriously ill with #LongCovid for 11 months. I was never hospitalized. I didn’t even have a “mild” covid case. Instead, I developed Long Covid from an asymptomatic infection.

I’m far from unique. Up to 1/5 of asymptomatic patients go on to have long-term symptoms.

— Ravi Veriah Jacques (@RaviHVJ) February 3, 2022

Assessing their previous and current care also helps to direct their ongoing management, says Zijian Chen, MD, medical director of the Center for Post-COVID Care at Mount Sinai Health System in New York.
 

Can vaccination help people with long COVID?

Anything that we can do to help prevent people from being critically ill or being hospitalized with COVID-19 is helpful to prevent long COVID, says Dr. Abramoff, who is also director of the long COVID clinic at the University of Pennsylvania, Philadelphia.

“So that’s something I always discuss with patients. In some research, sometimes patients do feel better after the vaccine,” he says.
 

What kind of therapies do you find helpful for your patients?

Rehabilitation is a key part of recovery from long COVID, Dr. Abramoff says. “It is very important to make this very patient-specific.”

“We have patients that are working. They’re already going to the gym in some cases but don’t feel like they have the same endurance,” he says. “And then we have patients who are so crippled by their fatigue that they can’t get out of bed.”
 

1/ What is #LongCOVID?!

A disabling malady from ongoing inflammation, autoimmunity, & potential viral reservoirs (GI, brain?)

NEW DATA: The Lungs “light up” on special MRI Scans 3 to 9 months later in patients never hospitalized for COVID.https://t.co/I2kyZ4cK5F pic.twitter.com/dL1P67L2DK

— WesElyMD (@WesElyMD) February 2, 2022

An exercise program can help people who have long COVID.

“There’s a big role for therapy services in the recovery of these patients,” says John Baratta, MD, of the department of physical medicine and rehabilitation at the University of North Carolina at Chapel Hill.

But the limited number of long COVID clinics can mean some people are unable to get to therapists trained on the needs of patients with lingering COVID symptoms. Educating community physical and occupational therapists is one solution.
 

How long does it take for people with long COVID to recover and get back to 100% if they can?

Specific numbers aren’t really available, Dr. Baratta says.

“But I can tell you the general trend that I see is that a lot of patients have a gradual improvement of symptoms. The slow but steady improvement with time may be the body’s natural healing process, a result of medical interventions, or both.”

It can help to reassure people with long COVID that they will not be discharged from care until they feel they’ve maximized their health, says Sharagim Kemp, DO, medical director of the COVID Recovery Program for Nuvance Health, a health system in New York and Connecticut.

It’s essential to set realistic recovery expectations and tell patients that not everyone will return to 100% of their pre-COVID functioning, she says.

“Once we are able to help them reset their expectations, there’s almost an accelerated recovery because they are not putting that pressure on themselves anymore,” Dr. Kemp says.
 

What are the most common symptoms you’re seeing in long COVID?

It’s helpful to think of long COVID as a very broad umbrella term, Dr. Abramoff says.

Echoing what many others have observed, fatigue, cognitive dysfunction or “brain fog,“ and shortness of breath or troubled breathing appear to be the most common symptoms, he says.

Some reported vague symptoms, Dr. Kemp says.

People may go to the doctor “not even realizing that they had COVID. That’s one of the important points here – to have a high index of suspicion for patients who come in with multiple symptoms,” she says.

For this reason, patients can report symptoms that don’t necessarily fit into any specialty, says Sarah J. Ryan, MD, an internal medicine doctor at Columbia University Irving Medical Center in New York. People say they are “just not themselves” or they are tired after their COVID-19 recovery.
 

Is there a connection between severe COVID cases and severe long COVID?

“It’s not like that at all. I would say that more than 80% of the patients that we see had mild to moderate illness and they were not hospitalized,” Dr. Baratta says.

Long COVID is a bit different in children and teenagers, says Ixsy Ramirez, MD, a pediatric pulmonologist at University of Michigan Health, Ann Arbor. Most patients in the long COVID clinic at the University of Michigan were previously healthy, and not children with asthma or other lung conditions as one might expect. In fact, many are student athletes, or were before they had long COVID.

In this population, shortness of breath is most common, followed by chest pain and fatigue. Unfortunately, the symptoms are so serious for many kids that their performance is limited, even if they can return to competitive play.
 

Are there defined criteria you use to diagnose long COVID? How do you give someone a diagnosis?

That’s an ever-evolving question, Dr. Kemp says. The generally accepted definition centers on persistent or new symptoms 4 weeks or more after the original COVID-19 illness, but there are exceptions.

Researchers are working on lab tests to help confirm the diagnosis. But without a definitive blood biomarker, getting to the diagnosis requires “some thorough detective work,” Dr. Ryan says.
 

Do you bring in mental health providers to help with treatment?

“We focus on mental health quite a bit actually,” says, Dr. Chen, cofounder of his institution’s COVID recovery clinic. Mount Sinai offers one-on-one and group mental health services, for example.

“Personally, I’ve seen patients that I did not expect to have such severe mental health changes” with long COVID.
 

One of the most powerful accounts and testimonies I have seen on what most #LongCovid patients experience when interacting with their doctors.

“I did not fit in a box, so they chose not to see me, even worse they made me feel like it was my fault for not fitting in their box” pic.twitter.com/7GQLBucuO5

— charlos (@loscharlos) February 3, 2022

Examples include severe depression, cases of acute psychosis, hallucinations, and other problems “that are really unexpected after a viral illness.”

Stony Brook University Hospital in New York has a long COVID clinic staffed by multiple primary care doctors who do exams and refer patients to services. A bonus of offering psychological services to all post-COVID patients is doctors get a more complete picture of each person and a better understanding of what they are going through, says Abigail Chua, MD, a pulmonologist at Stony Brook.

Some empathy is essential, Dr. Baratta says. “It’s important to recognize that a lot of these patients present with a sense of grief or loss for their prior life.”
 

What does the future hold?

A simple test to diagnose long COVID, combined with an effective treatment that helps people feel better within a week, would be ideal, Dr. Abramoff says.

“That would be lovely. But you know, we’re just not at that point.”

And it would be helpful to start identifying subtypes of long COVID so diagnosis and treatment can be more targeted, Dr. Abramoff says. Otherwise, “It’s going to be a very challenging approach to try to treat all of our patients with long COVID symptoms the same way.”

Good clinical trials likewise are needed to address all the subtleties of long COVID.

A number of long COVID centers are collaborating on research to find out more, Dr. Chen says. Actions include setting up a bank of tissue samples from people with long COVID so researchers can continue to figure out the condition.

One goal, Dr. Chen says, would be the ability to treat long COVID rather than just its symptoms.

Long COVID emphasizes the need to prevent people from getting COVID in the first place, Dr. Ramirez says. This will continue to be important, particularly when some people dismiss the seriousness of COVID, comparing it to a cold if they get it. That attitude discounts the large number of people who unfortunately go on to develop long-term, often debilitating, symptoms.

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

Long COVID continues to be a moving target – continuously evolving and still surprising doctors and patients who have sometimes incapacitating long-term symptoms.

Little about the disorder seems predictable at this point. People can have long COVID after asymptomatic, mild, or severe COVID-19, for example. And when a person gets long COVID – also known as long-haul COVID – symptoms can vary widely.

To address all the uncertainty, the New York State Department of Health gathered experts in primary care, pediatrics, physical medicine, rehabilitation, and pulmonology to answer some pressing questions.

New York in 2020 was the first epicenter of the pandemic in the United States, making it also the center of the long COVID epidemic, says Emily Lutterloh, MD, director of the Division of Epidemiology at the New York State Department of Health.
 

What do you do when you’re seeing a patient with long COVID for the first time?

The first exam varies because there are so many different ways long COVID presents itself, says Benjamin Abramoff, MD, a physical medicine and rehabilitation specialist at Penn Medicine in Philadelphia.

I’ve now been seriously ill with #LongCovid for 11 months. I was never hospitalized. I didn’t even have a “mild” covid case. Instead, I developed Long Covid from an asymptomatic infection.

I’m far from unique. Up to 1/5 of asymptomatic patients go on to have long-term symptoms.

— Ravi Veriah Jacques (@RaviHVJ) February 3, 2022

Assessing their previous and current care also helps to direct their ongoing management, says Zijian Chen, MD, medical director of the Center for Post-COVID Care at Mount Sinai Health System in New York.
 

Can vaccination help people with long COVID?

Anything that we can do to help prevent people from being critically ill or being hospitalized with COVID-19 is helpful to prevent long COVID, says Dr. Abramoff, who is also director of the long COVID clinic at the University of Pennsylvania, Philadelphia.

“So that’s something I always discuss with patients. In some research, sometimes patients do feel better after the vaccine,” he says.
 

What kind of therapies do you find helpful for your patients?

Rehabilitation is a key part of recovery from long COVID, Dr. Abramoff says. “It is very important to make this very patient-specific.”

“We have patients that are working. They’re already going to the gym in some cases but don’t feel like they have the same endurance,” he says. “And then we have patients who are so crippled by their fatigue that they can’t get out of bed.”
 

1/ What is #LongCOVID?!

A disabling malady from ongoing inflammation, autoimmunity, & potential viral reservoirs (GI, brain?)

NEW DATA: The Lungs “light up” on special MRI Scans 3 to 9 months later in patients never hospitalized for COVID.https://t.co/I2kyZ4cK5F pic.twitter.com/dL1P67L2DK

— WesElyMD (@WesElyMD) February 2, 2022

An exercise program can help people who have long COVID.

“There’s a big role for therapy services in the recovery of these patients,” says John Baratta, MD, of the department of physical medicine and rehabilitation at the University of North Carolina at Chapel Hill.

But the limited number of long COVID clinics can mean some people are unable to get to therapists trained on the needs of patients with lingering COVID symptoms. Educating community physical and occupational therapists is one solution.
 

How long does it take for people with long COVID to recover and get back to 100% if they can?

Specific numbers aren’t really available, Dr. Baratta says.

“But I can tell you the general trend that I see is that a lot of patients have a gradual improvement of symptoms. The slow but steady improvement with time may be the body’s natural healing process, a result of medical interventions, or both.”

It can help to reassure people with long COVID that they will not be discharged from care until they feel they’ve maximized their health, says Sharagim Kemp, DO, medical director of the COVID Recovery Program for Nuvance Health, a health system in New York and Connecticut.

It’s essential to set realistic recovery expectations and tell patients that not everyone will return to 100% of their pre-COVID functioning, she says.

“Once we are able to help them reset their expectations, there’s almost an accelerated recovery because they are not putting that pressure on themselves anymore,” Dr. Kemp says.
 

What are the most common symptoms you’re seeing in long COVID?

It’s helpful to think of long COVID as a very broad umbrella term, Dr. Abramoff says.

Echoing what many others have observed, fatigue, cognitive dysfunction or “brain fog,“ and shortness of breath or troubled breathing appear to be the most common symptoms, he says.

Some reported vague symptoms, Dr. Kemp says.

People may go to the doctor “not even realizing that they had COVID. That’s one of the important points here – to have a high index of suspicion for patients who come in with multiple symptoms,” she says.

For this reason, patients can report symptoms that don’t necessarily fit into any specialty, says Sarah J. Ryan, MD, an internal medicine doctor at Columbia University Irving Medical Center in New York. People say they are “just not themselves” or they are tired after their COVID-19 recovery.
 

Is there a connection between severe COVID cases and severe long COVID?

“It’s not like that at all. I would say that more than 80% of the patients that we see had mild to moderate illness and they were not hospitalized,” Dr. Baratta says.

Long COVID is a bit different in children and teenagers, says Ixsy Ramirez, MD, a pediatric pulmonologist at University of Michigan Health, Ann Arbor. Most patients in the long COVID clinic at the University of Michigan were previously healthy, and not children with asthma or other lung conditions as one might expect. In fact, many are student athletes, or were before they had long COVID.

In this population, shortness of breath is most common, followed by chest pain and fatigue. Unfortunately, the symptoms are so serious for many kids that their performance is limited, even if they can return to competitive play.
 

Are there defined criteria you use to diagnose long COVID? How do you give someone a diagnosis?

That’s an ever-evolving question, Dr. Kemp says. The generally accepted definition centers on persistent or new symptoms 4 weeks or more after the original COVID-19 illness, but there are exceptions.

Researchers are working on lab tests to help confirm the diagnosis. But without a definitive blood biomarker, getting to the diagnosis requires “some thorough detective work,” Dr. Ryan says.
 

Do you bring in mental health providers to help with treatment?

“We focus on mental health quite a bit actually,” says, Dr. Chen, cofounder of his institution’s COVID recovery clinic. Mount Sinai offers one-on-one and group mental health services, for example.

“Personally, I’ve seen patients that I did not expect to have such severe mental health changes” with long COVID.
 

One of the most powerful accounts and testimonies I have seen on what most #LongCovid patients experience when interacting with their doctors.

“I did not fit in a box, so they chose not to see me, even worse they made me feel like it was my fault for not fitting in their box” pic.twitter.com/7GQLBucuO5

— charlos (@loscharlos) February 3, 2022

Examples include severe depression, cases of acute psychosis, hallucinations, and other problems “that are really unexpected after a viral illness.”

Stony Brook University Hospital in New York has a long COVID clinic staffed by multiple primary care doctors who do exams and refer patients to services. A bonus of offering psychological services to all post-COVID patients is doctors get a more complete picture of each person and a better understanding of what they are going through, says Abigail Chua, MD, a pulmonologist at Stony Brook.

Some empathy is essential, Dr. Baratta says. “It’s important to recognize that a lot of these patients present with a sense of grief or loss for their prior life.”
 

What does the future hold?

A simple test to diagnose long COVID, combined with an effective treatment that helps people feel better within a week, would be ideal, Dr. Abramoff says.

“That would be lovely. But you know, we’re just not at that point.”

And it would be helpful to start identifying subtypes of long COVID so diagnosis and treatment can be more targeted, Dr. Abramoff says. Otherwise, “It’s going to be a very challenging approach to try to treat all of our patients with long COVID symptoms the same way.”

Good clinical trials likewise are needed to address all the subtleties of long COVID.

A number of long COVID centers are collaborating on research to find out more, Dr. Chen says. Actions include setting up a bank of tissue samples from people with long COVID so researchers can continue to figure out the condition.

One goal, Dr. Chen says, would be the ability to treat long COVID rather than just its symptoms.

Long COVID emphasizes the need to prevent people from getting COVID in the first place, Dr. Ramirez says. This will continue to be important, particularly when some people dismiss the seriousness of COVID, comparing it to a cold if they get it. That attitude discounts the large number of people who unfortunately go on to develop long-term, often debilitating, symptoms.

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

Long COVID continues to be a moving target – continuously evolving and still surprising doctors and patients who have sometimes incapacitating long-term symptoms.

Little about the disorder seems predictable at this point. People can have long COVID after asymptomatic, mild, or severe COVID-19, for example. And when a person gets long COVID – also known as long-haul COVID – symptoms can vary widely.

To address all the uncertainty, the New York State Department of Health gathered experts in primary care, pediatrics, physical medicine, rehabilitation, and pulmonology to answer some pressing questions.

New York in 2020 was the first epicenter of the pandemic in the United States, making it also the center of the long COVID epidemic, says Emily Lutterloh, MD, director of the Division of Epidemiology at the New York State Department of Health.
 

What do you do when you’re seeing a patient with long COVID for the first time?

The first exam varies because there are so many different ways long COVID presents itself, says Benjamin Abramoff, MD, a physical medicine and rehabilitation specialist at Penn Medicine in Philadelphia.

I’ve now been seriously ill with #LongCovid for 11 months. I was never hospitalized. I didn’t even have a “mild” covid case. Instead, I developed Long Covid from an asymptomatic infection.

I’m far from unique. Up to 1/5 of asymptomatic patients go on to have long-term symptoms.

— Ravi Veriah Jacques (@RaviHVJ) February 3, 2022

Assessing their previous and current care also helps to direct their ongoing management, says Zijian Chen, MD, medical director of the Center for Post-COVID Care at Mount Sinai Health System in New York.
 

Can vaccination help people with long COVID?

Anything that we can do to help prevent people from being critically ill or being hospitalized with COVID-19 is helpful to prevent long COVID, says Dr. Abramoff, who is also director of the long COVID clinic at the University of Pennsylvania, Philadelphia.

“So that’s something I always discuss with patients. In some research, sometimes patients do feel better after the vaccine,” he says.
 

What kind of therapies do you find helpful for your patients?

Rehabilitation is a key part of recovery from long COVID, Dr. Abramoff says. “It is very important to make this very patient-specific.”

“We have patients that are working. They’re already going to the gym in some cases but don’t feel like they have the same endurance,” he says. “And then we have patients who are so crippled by their fatigue that they can’t get out of bed.”
 

1/ What is #LongCOVID?!

A disabling malady from ongoing inflammation, autoimmunity, & potential viral reservoirs (GI, brain?)

NEW DATA: The Lungs “light up” on special MRI Scans 3 to 9 months later in patients never hospitalized for COVID.https://t.co/I2kyZ4cK5F pic.twitter.com/dL1P67L2DK

— WesElyMD (@WesElyMD) February 2, 2022

An exercise program can help people who have long COVID.

“There’s a big role for therapy services in the recovery of these patients,” says John Baratta, MD, of the department of physical medicine and rehabilitation at the University of North Carolina at Chapel Hill.

But the limited number of long COVID clinics can mean some people are unable to get to therapists trained on the needs of patients with lingering COVID symptoms. Educating community physical and occupational therapists is one solution.
 

How long does it take for people with long COVID to recover and get back to 100% if they can?

Specific numbers aren’t really available, Dr. Baratta says.

“But I can tell you the general trend that I see is that a lot of patients have a gradual improvement of symptoms. The slow but steady improvement with time may be the body’s natural healing process, a result of medical interventions, or both.”

It can help to reassure people with long COVID that they will not be discharged from care until they feel they’ve maximized their health, says Sharagim Kemp, DO, medical director of the COVID Recovery Program for Nuvance Health, a health system in New York and Connecticut.

It’s essential to set realistic recovery expectations and tell patients that not everyone will return to 100% of their pre-COVID functioning, she says.

“Once we are able to help them reset their expectations, there’s almost an accelerated recovery because they are not putting that pressure on themselves anymore,” Dr. Kemp says.
 

What are the most common symptoms you’re seeing in long COVID?

It’s helpful to think of long COVID as a very broad umbrella term, Dr. Abramoff says.

Echoing what many others have observed, fatigue, cognitive dysfunction or “brain fog,“ and shortness of breath or troubled breathing appear to be the most common symptoms, he says.

Some reported vague symptoms, Dr. Kemp says.

People may go to the doctor “not even realizing that they had COVID. That’s one of the important points here – to have a high index of suspicion for patients who come in with multiple symptoms,” she says.

For this reason, patients can report symptoms that don’t necessarily fit into any specialty, says Sarah J. Ryan, MD, an internal medicine doctor at Columbia University Irving Medical Center in New York. People say they are “just not themselves” or they are tired after their COVID-19 recovery.
 

Is there a connection between severe COVID cases and severe long COVID?

“It’s not like that at all. I would say that more than 80% of the patients that we see had mild to moderate illness and they were not hospitalized,” Dr. Baratta says.

Long COVID is a bit different in children and teenagers, says Ixsy Ramirez, MD, a pediatric pulmonologist at University of Michigan Health, Ann Arbor. Most patients in the long COVID clinic at the University of Michigan were previously healthy, and not children with asthma or other lung conditions as one might expect. In fact, many are student athletes, or were before they had long COVID.

In this population, shortness of breath is most common, followed by chest pain and fatigue. Unfortunately, the symptoms are so serious for many kids that their performance is limited, even if they can return to competitive play.
 

Are there defined criteria you use to diagnose long COVID? How do you give someone a diagnosis?

That’s an ever-evolving question, Dr. Kemp says. The generally accepted definition centers on persistent or new symptoms 4 weeks or more after the original COVID-19 illness, but there are exceptions.

Researchers are working on lab tests to help confirm the diagnosis. But without a definitive blood biomarker, getting to the diagnosis requires “some thorough detective work,” Dr. Ryan says.
 

Do you bring in mental health providers to help with treatment?

“We focus on mental health quite a bit actually,” says, Dr. Chen, cofounder of his institution’s COVID recovery clinic. Mount Sinai offers one-on-one and group mental health services, for example.

“Personally, I’ve seen patients that I did not expect to have such severe mental health changes” with long COVID.
 

One of the most powerful accounts and testimonies I have seen on what most #LongCovid patients experience when interacting with their doctors.

“I did not fit in a box, so they chose not to see me, even worse they made me feel like it was my fault for not fitting in their box” pic.twitter.com/7GQLBucuO5

— charlos (@loscharlos) February 3, 2022

Examples include severe depression, cases of acute psychosis, hallucinations, and other problems “that are really unexpected after a viral illness.”

Stony Brook University Hospital in New York has a long COVID clinic staffed by multiple primary care doctors who do exams and refer patients to services. A bonus of offering psychological services to all post-COVID patients is doctors get a more complete picture of each person and a better understanding of what they are going through, says Abigail Chua, MD, a pulmonologist at Stony Brook.

Some empathy is essential, Dr. Baratta says. “It’s important to recognize that a lot of these patients present with a sense of grief or loss for their prior life.”
 

What does the future hold?

A simple test to diagnose long COVID, combined with an effective treatment that helps people feel better within a week, would be ideal, Dr. Abramoff says.

“That would be lovely. But you know, we’re just not at that point.”

And it would be helpful to start identifying subtypes of long COVID so diagnosis and treatment can be more targeted, Dr. Abramoff says. Otherwise, “It’s going to be a very challenging approach to try to treat all of our patients with long COVID symptoms the same way.”

Good clinical trials likewise are needed to address all the subtleties of long COVID.

A number of long COVID centers are collaborating on research to find out more, Dr. Chen says. Actions include setting up a bank of tissue samples from people with long COVID so researchers can continue to figure out the condition.

One goal, Dr. Chen says, would be the ability to treat long COVID rather than just its symptoms.

Long COVID emphasizes the need to prevent people from getting COVID in the first place, Dr. Ramirez says. This will continue to be important, particularly when some people dismiss the seriousness of COVID, comparing it to a cold if they get it. That attitude discounts the large number of people who unfortunately go on to develop long-term, often debilitating, symptoms.

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

Media coverage of transgender health care judged to be “negative” was associated with a drop of around 30% in referral rates to gender identity clinics in Sweden among young people under age 19, a new study indicates.

Malin Indremo, MS, from the department of neuroscience, Uppsala (Sweden) University, and colleagues explored the effect of the documentaries, “The Trans Train and Teenage Girls,” which they explain was a “Swedish public service television show” representing “investigative journalism.” The two-part documentary series was aired in Sweden in April 2019 and October 2019, respectively, and is now available in English on YouTube.

In their article, published online in JAMA Network Open, the authors said they consider “The Trans Train” programs to be “negative” media coverage because the “documentaries addressed the distinct increase among adolescents referred to gender identity clinics in recent years. Two young adults who regretted their transition and parents of transgender individuals who questioned the clinics’ assessments of their children were interviewed, and concerns were raised about whether gender-confirming treatments are based on sufficient scientific evidence.”

The programs, they suggest, may have influenced and jeopardized young transgender individuals’ access to transgender-specific health care.

Stella O’Malley, a U.K.-based psychotherapist specializing in transgender care and executive director of Genspect, an international organization that provides support to the parents of young people who are questioning their gender, expressed her disappointment with the study’s conclusions.

“I’m really surprised and disappointed that the researchers believe that negative coverage is the reason for a drop in referrals when it is more accurate to say that the information provided by ‘The Trans Train’ documentaries was concerning and suggests that further critical analysis and a review needs to be carried out on the clinics in question,” she said in an interview.

Ms. O’Malley herself made a documentary for Channel 4 in the United Kingdom, broadcast in 2018, called: “Trans Kids: It’s Time to Talk.”
 

Rapidly increasing numbers of youth, especially girls, question gender

As Ms. Indremo and coauthors explained – and as has been widely reported by this news organization – “the number of referrals to gender identity clinics have rapidly increased worldwide” in recent years, and this “has been especially prominent in adolescents and young adults.”

In addition, they acknowledged, “there has been a shift in gender ratio, with a preponderance toward individuals who were assigned female at birth (AFAB).”

This was the topic of “The Trans Train” programs, and in fact, following their broadcast, Ms. Indremo and colleagues noted that “an intense debate in national media [in Sweden] arose from the documentaries.”

Their research aimed to explore the association between both “positive” and “negative” media coverage and the number of referrals to gender identity clinics for young people (under aged 19) respectively. Data from the six gender clinics in Sweden were included between January 2017 and December 2019.

In the period studied, the clinics received 1,784 referrals, including 613 referrals in 2017, 663 referrals in 2018, and 508 referrals in 2019.

From the age-specific data that included 1,674 referrals, 359 individuals (21.4%) were younger than 13 years and 1,315 individuals (78.6%) were aged 13-18 years. From the assigned sex-specific data that included 1,435 referrals, 1,034 individuals (72.1%) were AFAB and 401 individuals (27.9%) were assigned male at birth (AMAB). Information on sex assigned at birth was lacking from one clinic, which was excluded from the analysis.

When they examined data for the 3 months following the airing of the first part of “The Trans Train” documentary series (in April 2019), they found that referrals to gender clinics fell by 25.4% overall, compared with the 3 months before part 1 was screened. Specifically, they fell by 25.3% for young people aged 13-18 years and by 32.2% for those born female.

In the extended analyses of 6 months following part 1, a decrease of total referrals by 30.7% was observed, while referrals for AFAB individuals decreased by 37.4% and referrals for individuals aged 13-18 years decreased by 27.7%. A decrease of referrals by 41.7% for children aged younger than 13 years was observed in the 6-month analysis, as well as a decrease of 8.2% among AMAB individuals.

“The Trans Train” documentaries, Ms. Indremo and colleagues said, “were criticized for being negatively biased and giving an oversimplified picture of transgender health care.”
 

Did the nature of the trans train documentaries influence referrals?

In an invited commentary published in JAMA Network Open, Ken C. Pang, PhD, from the Murdoch Children’s Research Institute, Melbourne, and colleagues noted: “Although the mechanisms underlying this decrease [in referrals] were not formally explored in their study, the authors reasonably speculated that both parents and referring health professionals may have been less likely to support a child or adolescent’s attendance at a specialist pediatric gender clinic following the documentaries.”

Dr. Pang and colleagues went on to say it is “the ... responsibility of media organizations in ensuring that stories depicting health care for transgender and gender diverse (TGD) young people are fair, balanced, nuanced, and accurate.”

Often, media reports have “fallen short of these standards and lacked the voices of TGD young people who have benefited from gender-affirming care or the perspectives of health professionals with expertise in providing such care,” they added.

“For example, some [media reports] have suggested that the growing number of referrals to such clinics is not owing to greater awareness of gender diversity and empowerment of TGD young people but is instead being driven by other factors such as peer influence, while others have warned that the use of gender-affirming hormonal interventions in TGD young people represents an undue risk,” they continue.

Ms. Indremo and colleagues didn’t see any drop-in referrals after the second part of the series, aired in October 2019, but they say this was likely because referrals were “already lowered” by the airing of the first part of the documentaries.

Nor did they see an increase in referrals following what they say was a “positive” media event in the form of a story about a professional Swedish handball player who announced the decision to quit his career to seek care for gender dysphoria.

“One may assume that a single news event is not significant enough to influence referral counts,” they suggested, noting also that Sweden represents “a society where there is already a relatively high level of awareness of gender identity issues.”

“Our results point to a differential association of media attention depending on the tone of the media content,” they observed.

Dr. Pang and coauthors noted it would be “helpful to examine whether similar media coverage in other countries has been associated with similar decreases in referral numbers and whether particular types of media stories are more prone to having this association.”
 

Parents and doctors debate treatment of gender dysphoria

In Sweden, custodians’ permission as well as custodians’ help is needed for minors to access care for gender dysphoria, said Ms. Indremo and coauthors. “It is possible that the content of the documentaries contributed to a higher custodian barrier to having their children referred for assessment, believing it may not be in the best interest of their child. This would highly impact young transgender individuals’ possibilities to access care.” 

They also acknowledge that health care practitioners who refer young people to specialist clinics might also have been influenced by the documentaries, noting “some commentators argued that all treatments for gender dysphoria be stopped, and that ‘all health care given at the gender identity clinics was an experiment lacking scientific basis.’ ”

In April 2021, Angela Sämfjord, MD, child and adolescent psychiatrist at Sahlgrenska University Hospital, Gothenburg, Sweden, who started a child and adolescent clinic – the Lundstrom Gender Clinic – told this news organization she had reevaluated her approach even prior to “The Trans Train” documentaries and had resigned in 2018 because of her own fears about the lack of evidence for hormonal and surgical treatments of youth with gender dysphoria.

Following the debate that ensued after the airing of “The Trans Train” programs, the Swedish National Board of Health and Welfare published new recommendations in March 2021, which reflected a significant change in direction for the evaluation of gender dysphoria in minors, emphasizing the requirement for a thorough mental health assessment.

And in May 2021, Karolinska Children’s Hospital, which houses one of the leading gender identity clinics in Sweden, announced it would stop the routine medical treatment of children with gender dysphoria under the age of 18, which meant a total ban on the prescribing of puberty blockers and cross-sex hormones to minors. Such treatment could henceforth only be carried out within the setting of a clinical trial approved by the EPM (Ethical Review Agency/Swedish Institutional Review Board), it said.

The remaining five gender identity clinics in Sweden decided upon their own rules, but in general, they have become much more cautious regarding medical treatment of minors within the past year. Also, there is a desire in Sweden to reduce the number of gender identity clinics for minors from the current six to perhaps a maximum of three nationwide.

However, neither Ms. Indremo and colleagues nor Dr. Pang and colleagues mentioned the subsequent change to the Swedish NBHW recommendations on evaluation of gender dysphoria in minors in JAMA articles.

New NBHW recommendations about medical treatment of gender dysphoria with puberty blockers and cross-sex hormones for minors were due to be issued in 2021 but have been delayed.
 

Debate in other countries

Sweden is not alone in discussing this issue. In 2020, Finland became the first country in the world to issue new guidelines that concluded there is a lack of quality evidence to support the use of hormonal interventions in adolescents with gender dysphoria.

This issue has been hotly debated in the United Kingdom – not least with the Keira Bell court case and two National Institute for Health and Clinical Excellence evidence reviews concluding there is a lack of data to support the use of puberty-blocking agents and “cross-sex” hormones in youth with gender dysphoria.

And a number of U.S. states are attempting to outlaw the medical and surgical treatment of gender dysphoria in minors. Even health care professionals who have been treating young people with gender dysphoria for years – some of whom are transgender themselves – have started to speak out and are questioning what they call “sloppy care” given to many such youth.

Indeed, a recent survey shows that detransitioners – individuals who suffer from gender dysphoria, transition to the opposite sex but then regret their decision and detransition – are getting short shrift when it comes to care, with over half of the 100 surveyed saying they feel they did not receive adequate evaluation from a doctor or mental health professional before starting to transition.

And new draft standards of care for treating people with gender dysphoria by the World Professional Association for Transgender Health have drawn criticism from experts.
 

‘First do no harm’

In their conclusion, Dr. Pang and coauthors said that, with respect to the media coverage of young people with gender dysphoria, “who are, after all, one of the most vulnerable subgroups within our society, perhaps our media should recall one of the core tenets of health care and ensure their stories ‘first, do no harm.’”

However, in a commentary recently published in Child and Adolescent Mental Health, Alison Clayton, MBBS, from the University of Melbourne, and coauthors again pointed out that evidence reviews of the use of puberty blockers in young people with gender dysphoria show “there is very low certainty of the benefits of puberty blockers, an unknown risk of harm, and there is need for more rigorous research.”

“The clinically prudent thing to do, if we aim to ‘first, do no harm,’ is to proceed with extreme caution, especially given the rapidly rising case numbers and novel gender dysphoria presentations,” Clayton and colleagues concluded.

Ms. Indremo and coauthors reported no relevant financial relationships. Dr. Pang reported being a member of the Australian Professional Association for Trans Health and its research committee. One commentary coauthor has reported being a member of WPATH.

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

Media coverage of transgender health care judged to be “negative” was associated with a drop of around 30% in referral rates to gender identity clinics in Sweden among young people under age 19, a new study indicates.

Malin Indremo, MS, from the department of neuroscience, Uppsala (Sweden) University, and colleagues explored the effect of the documentaries, “The Trans Train and Teenage Girls,” which they explain was a “Swedish public service television show” representing “investigative journalism.” The two-part documentary series was aired in Sweden in April 2019 and October 2019, respectively, and is now available in English on YouTube.

In their article, published online in JAMA Network Open, the authors said they consider “The Trans Train” programs to be “negative” media coverage because the “documentaries addressed the distinct increase among adolescents referred to gender identity clinics in recent years. Two young adults who regretted their transition and parents of transgender individuals who questioned the clinics’ assessments of their children were interviewed, and concerns were raised about whether gender-confirming treatments are based on sufficient scientific evidence.”

The programs, they suggest, may have influenced and jeopardized young transgender individuals’ access to transgender-specific health care.

Stella O’Malley, a U.K.-based psychotherapist specializing in transgender care and executive director of Genspect, an international organization that provides support to the parents of young people who are questioning their gender, expressed her disappointment with the study’s conclusions.

“I’m really surprised and disappointed that the researchers believe that negative coverage is the reason for a drop in referrals when it is more accurate to say that the information provided by ‘The Trans Train’ documentaries was concerning and suggests that further critical analysis and a review needs to be carried out on the clinics in question,” she said in an interview.

Ms. O’Malley herself made a documentary for Channel 4 in the United Kingdom, broadcast in 2018, called: “Trans Kids: It’s Time to Talk.”
 

Rapidly increasing numbers of youth, especially girls, question gender

As Ms. Indremo and coauthors explained – and as has been widely reported by this news organization – “the number of referrals to gender identity clinics have rapidly increased worldwide” in recent years, and this “has been especially prominent in adolescents and young adults.”

In addition, they acknowledged, “there has been a shift in gender ratio, with a preponderance toward individuals who were assigned female at birth (AFAB).”

This was the topic of “The Trans Train” programs, and in fact, following their broadcast, Ms. Indremo and colleagues noted that “an intense debate in national media [in Sweden] arose from the documentaries.”

Their research aimed to explore the association between both “positive” and “negative” media coverage and the number of referrals to gender identity clinics for young people (under aged 19) respectively. Data from the six gender clinics in Sweden were included between January 2017 and December 2019.

In the period studied, the clinics received 1,784 referrals, including 613 referrals in 2017, 663 referrals in 2018, and 508 referrals in 2019.

From the age-specific data that included 1,674 referrals, 359 individuals (21.4%) were younger than 13 years and 1,315 individuals (78.6%) were aged 13-18 years. From the assigned sex-specific data that included 1,435 referrals, 1,034 individuals (72.1%) were AFAB and 401 individuals (27.9%) were assigned male at birth (AMAB). Information on sex assigned at birth was lacking from one clinic, which was excluded from the analysis.

When they examined data for the 3 months following the airing of the first part of “The Trans Train” documentary series (in April 2019), they found that referrals to gender clinics fell by 25.4% overall, compared with the 3 months before part 1 was screened. Specifically, they fell by 25.3% for young people aged 13-18 years and by 32.2% for those born female.

In the extended analyses of 6 months following part 1, a decrease of total referrals by 30.7% was observed, while referrals for AFAB individuals decreased by 37.4% and referrals for individuals aged 13-18 years decreased by 27.7%. A decrease of referrals by 41.7% for children aged younger than 13 years was observed in the 6-month analysis, as well as a decrease of 8.2% among AMAB individuals.

“The Trans Train” documentaries, Ms. Indremo and colleagues said, “were criticized for being negatively biased and giving an oversimplified picture of transgender health care.”
 

Did the nature of the trans train documentaries influence referrals?

In an invited commentary published in JAMA Network Open, Ken C. Pang, PhD, from the Murdoch Children’s Research Institute, Melbourne, and colleagues noted: “Although the mechanisms underlying this decrease [in referrals] were not formally explored in their study, the authors reasonably speculated that both parents and referring health professionals may have been less likely to support a child or adolescent’s attendance at a specialist pediatric gender clinic following the documentaries.”

Dr. Pang and colleagues went on to say it is “the ... responsibility of media organizations in ensuring that stories depicting health care for transgender and gender diverse (TGD) young people are fair, balanced, nuanced, and accurate.”

Often, media reports have “fallen short of these standards and lacked the voices of TGD young people who have benefited from gender-affirming care or the perspectives of health professionals with expertise in providing such care,” they added.

“For example, some [media reports] have suggested that the growing number of referrals to such clinics is not owing to greater awareness of gender diversity and empowerment of TGD young people but is instead being driven by other factors such as peer influence, while others have warned that the use of gender-affirming hormonal interventions in TGD young people represents an undue risk,” they continue.

Ms. Indremo and colleagues didn’t see any drop-in referrals after the second part of the series, aired in October 2019, but they say this was likely because referrals were “already lowered” by the airing of the first part of the documentaries.

Nor did they see an increase in referrals following what they say was a “positive” media event in the form of a story about a professional Swedish handball player who announced the decision to quit his career to seek care for gender dysphoria.

“One may assume that a single news event is not significant enough to influence referral counts,” they suggested, noting also that Sweden represents “a society where there is already a relatively high level of awareness of gender identity issues.”

“Our results point to a differential association of media attention depending on the tone of the media content,” they observed.

Dr. Pang and coauthors noted it would be “helpful to examine whether similar media coverage in other countries has been associated with similar decreases in referral numbers and whether particular types of media stories are more prone to having this association.”
 

Parents and doctors debate treatment of gender dysphoria

In Sweden, custodians’ permission as well as custodians’ help is needed for minors to access care for gender dysphoria, said Ms. Indremo and coauthors. “It is possible that the content of the documentaries contributed to a higher custodian barrier to having their children referred for assessment, believing it may not be in the best interest of their child. This would highly impact young transgender individuals’ possibilities to access care.” 

They also acknowledge that health care practitioners who refer young people to specialist clinics might also have been influenced by the documentaries, noting “some commentators argued that all treatments for gender dysphoria be stopped, and that ‘all health care given at the gender identity clinics was an experiment lacking scientific basis.’ ”

In April 2021, Angela Sämfjord, MD, child and adolescent psychiatrist at Sahlgrenska University Hospital, Gothenburg, Sweden, who started a child and adolescent clinic – the Lundstrom Gender Clinic – told this news organization she had reevaluated her approach even prior to “The Trans Train” documentaries and had resigned in 2018 because of her own fears about the lack of evidence for hormonal and surgical treatments of youth with gender dysphoria.

Following the debate that ensued after the airing of “The Trans Train” programs, the Swedish National Board of Health and Welfare published new recommendations in March 2021, which reflected a significant change in direction for the evaluation of gender dysphoria in minors, emphasizing the requirement for a thorough mental health assessment.

And in May 2021, Karolinska Children’s Hospital, which houses one of the leading gender identity clinics in Sweden, announced it would stop the routine medical treatment of children with gender dysphoria under the age of 18, which meant a total ban on the prescribing of puberty blockers and cross-sex hormones to minors. Such treatment could henceforth only be carried out within the setting of a clinical trial approved by the EPM (Ethical Review Agency/Swedish Institutional Review Board), it said.

The remaining five gender identity clinics in Sweden decided upon their own rules, but in general, they have become much more cautious regarding medical treatment of minors within the past year. Also, there is a desire in Sweden to reduce the number of gender identity clinics for minors from the current six to perhaps a maximum of three nationwide.

However, neither Ms. Indremo and colleagues nor Dr. Pang and colleagues mentioned the subsequent change to the Swedish NBHW recommendations on evaluation of gender dysphoria in minors in JAMA articles.

New NBHW recommendations about medical treatment of gender dysphoria with puberty blockers and cross-sex hormones for minors were due to be issued in 2021 but have been delayed.
 

Debate in other countries

Sweden is not alone in discussing this issue. In 2020, Finland became the first country in the world to issue new guidelines that concluded there is a lack of quality evidence to support the use of hormonal interventions in adolescents with gender dysphoria.

This issue has been hotly debated in the United Kingdom – not least with the Keira Bell court case and two National Institute for Health and Clinical Excellence evidence reviews concluding there is a lack of data to support the use of puberty-blocking agents and “cross-sex” hormones in youth with gender dysphoria.

And a number of U.S. states are attempting to outlaw the medical and surgical treatment of gender dysphoria in minors. Even health care professionals who have been treating young people with gender dysphoria for years – some of whom are transgender themselves – have started to speak out and are questioning what they call “sloppy care” given to many such youth.

Indeed, a recent survey shows that detransitioners – individuals who suffer from gender dysphoria, transition to the opposite sex but then regret their decision and detransition – are getting short shrift when it comes to care, with over half of the 100 surveyed saying they feel they did not receive adequate evaluation from a doctor or mental health professional before starting to transition.

And new draft standards of care for treating people with gender dysphoria by the World Professional Association for Transgender Health have drawn criticism from experts.
 

‘First do no harm’

In their conclusion, Dr. Pang and coauthors said that, with respect to the media coverage of young people with gender dysphoria, “who are, after all, one of the most vulnerable subgroups within our society, perhaps our media should recall one of the core tenets of health care and ensure their stories ‘first, do no harm.’”

However, in a commentary recently published in Child and Adolescent Mental Health, Alison Clayton, MBBS, from the University of Melbourne, and coauthors again pointed out that evidence reviews of the use of puberty blockers in young people with gender dysphoria show “there is very low certainty of the benefits of puberty blockers, an unknown risk of harm, and there is need for more rigorous research.”

“The clinically prudent thing to do, if we aim to ‘first, do no harm,’ is to proceed with extreme caution, especially given the rapidly rising case numbers and novel gender dysphoria presentations,” Clayton and colleagues concluded.

Ms. Indremo and coauthors reported no relevant financial relationships. Dr. Pang reported being a member of the Australian Professional Association for Trans Health and its research committee. One commentary coauthor has reported being a member of WPATH.

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

Media coverage of transgender health care judged to be “negative” was associated with a drop of around 30% in referral rates to gender identity clinics in Sweden among young people under age 19, a new study indicates.

Malin Indremo, MS, from the department of neuroscience, Uppsala (Sweden) University, and colleagues explored the effect of the documentaries, “The Trans Train and Teenage Girls,” which they explain was a “Swedish public service television show” representing “investigative journalism.” The two-part documentary series was aired in Sweden in April 2019 and October 2019, respectively, and is now available in English on YouTube.

In their article, published online in JAMA Network Open, the authors said they consider “The Trans Train” programs to be “negative” media coverage because the “documentaries addressed the distinct increase among adolescents referred to gender identity clinics in recent years. Two young adults who regretted their transition and parents of transgender individuals who questioned the clinics’ assessments of their children were interviewed, and concerns were raised about whether gender-confirming treatments are based on sufficient scientific evidence.”

The programs, they suggest, may have influenced and jeopardized young transgender individuals’ access to transgender-specific health care.

Stella O’Malley, a U.K.-based psychotherapist specializing in transgender care and executive director of Genspect, an international organization that provides support to the parents of young people who are questioning their gender, expressed her disappointment with the study’s conclusions.

“I’m really surprised and disappointed that the researchers believe that negative coverage is the reason for a drop in referrals when it is more accurate to say that the information provided by ‘The Trans Train’ documentaries was concerning and suggests that further critical analysis and a review needs to be carried out on the clinics in question,” she said in an interview.

Ms. O’Malley herself made a documentary for Channel 4 in the United Kingdom, broadcast in 2018, called: “Trans Kids: It’s Time to Talk.”
 

Rapidly increasing numbers of youth, especially girls, question gender

As Ms. Indremo and coauthors explained – and as has been widely reported by this news organization – “the number of referrals to gender identity clinics have rapidly increased worldwide” in recent years, and this “has been especially prominent in adolescents and young adults.”

In addition, they acknowledged, “there has been a shift in gender ratio, with a preponderance toward individuals who were assigned female at birth (AFAB).”

This was the topic of “The Trans Train” programs, and in fact, following their broadcast, Ms. Indremo and colleagues noted that “an intense debate in national media [in Sweden] arose from the documentaries.”

Their research aimed to explore the association between both “positive” and “negative” media coverage and the number of referrals to gender identity clinics for young people (under aged 19) respectively. Data from the six gender clinics in Sweden were included between January 2017 and December 2019.

In the period studied, the clinics received 1,784 referrals, including 613 referrals in 2017, 663 referrals in 2018, and 508 referrals in 2019.

From the age-specific data that included 1,674 referrals, 359 individuals (21.4%) were younger than 13 years and 1,315 individuals (78.6%) were aged 13-18 years. From the assigned sex-specific data that included 1,435 referrals, 1,034 individuals (72.1%) were AFAB and 401 individuals (27.9%) were assigned male at birth (AMAB). Information on sex assigned at birth was lacking from one clinic, which was excluded from the analysis.

When they examined data for the 3 months following the airing of the first part of “The Trans Train” documentary series (in April 2019), they found that referrals to gender clinics fell by 25.4% overall, compared with the 3 months before part 1 was screened. Specifically, they fell by 25.3% for young people aged 13-18 years and by 32.2% for those born female.

In the extended analyses of 6 months following part 1, a decrease of total referrals by 30.7% was observed, while referrals for AFAB individuals decreased by 37.4% and referrals for individuals aged 13-18 years decreased by 27.7%. A decrease of referrals by 41.7% for children aged younger than 13 years was observed in the 6-month analysis, as well as a decrease of 8.2% among AMAB individuals.

“The Trans Train” documentaries, Ms. Indremo and colleagues said, “were criticized for being negatively biased and giving an oversimplified picture of transgender health care.”
 

Did the nature of the trans train documentaries influence referrals?

In an invited commentary published in JAMA Network Open, Ken C. Pang, PhD, from the Murdoch Children’s Research Institute, Melbourne, and colleagues noted: “Although the mechanisms underlying this decrease [in referrals] were not formally explored in their study, the authors reasonably speculated that both parents and referring health professionals may have been less likely to support a child or adolescent’s attendance at a specialist pediatric gender clinic following the documentaries.”

Dr. Pang and colleagues went on to say it is “the ... responsibility of media organizations in ensuring that stories depicting health care for transgender and gender diverse (TGD) young people are fair, balanced, nuanced, and accurate.”

Often, media reports have “fallen short of these standards and lacked the voices of TGD young people who have benefited from gender-affirming care or the perspectives of health professionals with expertise in providing such care,” they added.

“For example, some [media reports] have suggested that the growing number of referrals to such clinics is not owing to greater awareness of gender diversity and empowerment of TGD young people but is instead being driven by other factors such as peer influence, while others have warned that the use of gender-affirming hormonal interventions in TGD young people represents an undue risk,” they continue.

Ms. Indremo and colleagues didn’t see any drop-in referrals after the second part of the series, aired in October 2019, but they say this was likely because referrals were “already lowered” by the airing of the first part of the documentaries.

Nor did they see an increase in referrals following what they say was a “positive” media event in the form of a story about a professional Swedish handball player who announced the decision to quit his career to seek care for gender dysphoria.

“One may assume that a single news event is not significant enough to influence referral counts,” they suggested, noting also that Sweden represents “a society where there is already a relatively high level of awareness of gender identity issues.”

“Our results point to a differential association of media attention depending on the tone of the media content,” they observed.

Dr. Pang and coauthors noted it would be “helpful to examine whether similar media coverage in other countries has been associated with similar decreases in referral numbers and whether particular types of media stories are more prone to having this association.”
 

Parents and doctors debate treatment of gender dysphoria

In Sweden, custodians’ permission as well as custodians’ help is needed for minors to access care for gender dysphoria, said Ms. Indremo and coauthors. “It is possible that the content of the documentaries contributed to a higher custodian barrier to having their children referred for assessment, believing it may not be in the best interest of their child. This would highly impact young transgender individuals’ possibilities to access care.” 

They also acknowledge that health care practitioners who refer young people to specialist clinics might also have been influenced by the documentaries, noting “some commentators argued that all treatments for gender dysphoria be stopped, and that ‘all health care given at the gender identity clinics was an experiment lacking scientific basis.’ ”

In April 2021, Angela Sämfjord, MD, child and adolescent psychiatrist at Sahlgrenska University Hospital, Gothenburg, Sweden, who started a child and adolescent clinic – the Lundstrom Gender Clinic – told this news organization she had reevaluated her approach even prior to “The Trans Train” documentaries and had resigned in 2018 because of her own fears about the lack of evidence for hormonal and surgical treatments of youth with gender dysphoria.

Following the debate that ensued after the airing of “The Trans Train” programs, the Swedish National Board of Health and Welfare published new recommendations in March 2021, which reflected a significant change in direction for the evaluation of gender dysphoria in minors, emphasizing the requirement for a thorough mental health assessment.

And in May 2021, Karolinska Children’s Hospital, which houses one of the leading gender identity clinics in Sweden, announced it would stop the routine medical treatment of children with gender dysphoria under the age of 18, which meant a total ban on the prescribing of puberty blockers and cross-sex hormones to minors. Such treatment could henceforth only be carried out within the setting of a clinical trial approved by the EPM (Ethical Review Agency/Swedish Institutional Review Board), it said.

The remaining five gender identity clinics in Sweden decided upon their own rules, but in general, they have become much more cautious regarding medical treatment of minors within the past year. Also, there is a desire in Sweden to reduce the number of gender identity clinics for minors from the current six to perhaps a maximum of three nationwide.

However, neither Ms. Indremo and colleagues nor Dr. Pang and colleagues mentioned the subsequent change to the Swedish NBHW recommendations on evaluation of gender dysphoria in minors in JAMA articles.

New NBHW recommendations about medical treatment of gender dysphoria with puberty blockers and cross-sex hormones for minors were due to be issued in 2021 but have been delayed.
 

Debate in other countries

Sweden is not alone in discussing this issue. In 2020, Finland became the first country in the world to issue new guidelines that concluded there is a lack of quality evidence to support the use of hormonal interventions in adolescents with gender dysphoria.

This issue has been hotly debated in the United Kingdom – not least with the Keira Bell court case and two National Institute for Health and Clinical Excellence evidence reviews concluding there is a lack of data to support the use of puberty-blocking agents and “cross-sex” hormones in youth with gender dysphoria.

And a number of U.S. states are attempting to outlaw the medical and surgical treatment of gender dysphoria in minors. Even health care professionals who have been treating young people with gender dysphoria for years – some of whom are transgender themselves – have started to speak out and are questioning what they call “sloppy care” given to many such youth.

Indeed, a recent survey shows that detransitioners – individuals who suffer from gender dysphoria, transition to the opposite sex but then regret their decision and detransition – are getting short shrift when it comes to care, with over half of the 100 surveyed saying they feel they did not receive adequate evaluation from a doctor or mental health professional before starting to transition.

And new draft standards of care for treating people with gender dysphoria by the World Professional Association for Transgender Health have drawn criticism from experts.
 

‘First do no harm’

In their conclusion, Dr. Pang and coauthors said that, with respect to the media coverage of young people with gender dysphoria, “who are, after all, one of the most vulnerable subgroups within our society, perhaps our media should recall one of the core tenets of health care and ensure their stories ‘first, do no harm.’”

However, in a commentary recently published in Child and Adolescent Mental Health, Alison Clayton, MBBS, from the University of Melbourne, and coauthors again pointed out that evidence reviews of the use of puberty blockers in young people with gender dysphoria show “there is very low certainty of the benefits of puberty blockers, an unknown risk of harm, and there is need for more rigorous research.”

“The clinically prudent thing to do, if we aim to ‘first, do no harm,’ is to proceed with extreme caution, especially given the rapidly rising case numbers and novel gender dysphoria presentations,” Clayton and colleagues concluded.

Ms. Indremo and coauthors reported no relevant financial relationships. Dr. Pang reported being a member of the Australian Professional Association for Trans Health and its research committee. One commentary coauthor has reported being a member of WPATH.

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

It is a great mystery of infectious disease: Why are some people seemingly unaffected by illness that harms others? During the COVID-19 pandemic, we’ve seen this play out time and time again when whole families get sick except for one or two fortunate family members. And at so-called superspreader events that infect many, a lucky few typically walk away with their health intact. Did the virus never enter their bodies? Or do some people have natural resistance to pathogens they’ve never been exposed to before encoded in their genes?

Resistance to infectious disease is much more than a scientific curiosity and studying how it works can be a path to curb future outbreaks.

“In the event that we could identify what makes some people resistant, that immediately opens avenues for therapeutics that we could apply in all those other people who do suffer from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York.

Dr. Spaan is part of an international effort to identify genetic variations that spare people from becoming infected with SARS-CoV-2, the virus that causes COVID-19.

There’s far more research on what drives the tendency to get infectious diseases than on resistance to them. But a few researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases, they’ve already translated these insights into treatments.

Perhaps the strongest example of how odd genes of just a few people can inspire treatments to help many comes from research on the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS).
 

A genetic quirk

In the mid-1990s, several groups of researchers independently identified a mutation in a gene called CCR5 linked to resistance to HIV infection.

The gene encodes a protein on the surface of some white blood cells that helps set up the movement of other immune cells to fight infections. HIV, meanwhile, uses the CCR5 protein to help it enter the white blood cells that it infects.

The mutation, known as delta 32, results in a shorter than usual protein that doesn’t reach the surface of the cell. People who carry two copies of the delta 32 form of CCR5 do not have any CCR5 protein on the outside of their white blood cells.

Researchers, led by molecular immunologist Philip Murphy, MD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md, showed in 1997 that people with two copies of the mutation were unusually common among a group of men who were at especially high risk of HIV exposure, but had never contracted the virus. And out of more than 700 HIV-positive people, none carried two copies of CCR5 delta 32.

Pharmaceutical companies used these insights to develop drugs to block CCR5 and delay the development of AIDS. For instance, the drug maraviroc, marketed by Pfizer, was approved for use in HIV-positive people in 2007.

Only a few examples of this kind of inborn, genetically determined complete resistance to infection have ever been heard of. All of them involve cell-surface molecules that are believed to help a virus or other pathogen gain entry to the cell.
 

Locking out illness

“The first step for any intracellular pathogen is getting inside the cell. And if you’re missing the doorway, then the virus can’t accomplish the first step in its life cycle,” Dr. Murphy says. “Getting inside is fundamental.”

Changes in cell-surface molecules can also make someone more likely to have an infection or severe disease. One such group of cell-surface molecules that have been linked to both increasing and decreasing the risk of various infections are histo-blood group antigens. The most familiar members of this group are the molecules that define blood types A, B, and O.

Scientists have also identified one example of total resistance to infection involving these molecules. In 2003, researchers showed that people who lack a functional copy of a gene known as FUT2 cannot be infected with Norwalk virus, one of more than 30 viruses in the norovirus family that cause illness in the digestive tract.

The gene FUT2 encodes an enzyme that determines whether or not blood group antigens are found in a person’s saliva and other body fluids as well as on their red blood cells.

“It didn’t matter how many virus particles we challenged an individual with, if they did not have that first enzyme, they did not get infected,” says researcher Lisa Lindesmith, a virologist at the University of North Carolina in Chapel Hill.
 

No norovirus

Norwalk is a relatively rare type of norovirus. But FUT2 deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have periodically swept across the world over the past quarter-century. These illnesses take an especially heavy toll on children in the developing world, causing malnutrition and contributing to infant and child deaths.

But progress in translating these insights about genetic resistance into drugs or other things that could reduce the burden of noroviruses has been slow.

“The biggest barrier here is lack of ability to study the virus outside of humans,” Lindesmith says.

Noroviruses are very difficult to grow in the lab, “and there’s no small animal model of gastrointestinal illness caused by the viruses.”

We are clearly making giant strides in improving those skills,” says Lindesmith. “But we are just not quite there yet.”

In the years before COVID-19 emerged, tuberculosis was responsible for the largest number of annual worldwide deaths from an infectious disease. It’s a lung disease caused by the bacterium Mycobacterium tuberculosis, and it has been a pandemic for thousands of years.

Some 85%-95% of people with intact immune systems who are infected with TB control the infection and never get active lung disease. And some people who have intense, continuing exposure to the bacterium, which is spread through droplets and aerosols from people with active lung disease, apparently never become infected at all.
 

Thwarting uberculosis

Understanding the ways of these different forms of resistance could help in the search for vaccines, treatments, and other ways to fight tuberculosis, says Elouise Kroon, MD, a graduate student at Stellenbosch University in Cape Town, South Africa.

“What makes it particularly hard to study is the fact that there is no gold standard to measure infection,” she says. “So, what we do is infer infection from two different types of tests” -- a skin test and a blood test that measure different kinds of immune response to molecules from the bacterium.

Dr. Kroon and other researchers have studied resistance to infection by following people living in the same household as those with active lung disease or people who live and work in crowded conditions in high-risk communities. But not all such studies have used the same definition of so-called resisters, documented exposure in the same way, or followed up to ensure that people continue to test negative over the long term.

The best clue that has emerged from studies so far links resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Marlo Möller, PhD, a professor in the TB Host Genetics Research Group at Stellenbosch University.

“That always seems to pop up everywhere. But the rest is not so obvious,” she says. “A lot of the studies don’t find the same thing. It’s different in different populations,” which may be a result of the long evolutionary history between tuberculosis and humans, as well as the fact that different strains of the bacterium are prevalent in different parts of the world.

COVID-19 is a much newer infectious disease, but teasing out how it contributes to both severe illness and resistance to infection is still a major task.
 

Overcoming COVID

Early in the pandemic, research by the COVID Human Genetic Effort, the international consortium that Dr. Spaan is part of, linked severe COVID-19 pneumonia to the lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy these molecules. Together, these mechanisms explain about one-fifth of severe COVID-19 cases, the researchers reported in 2021.

A few studies by other groups have explored resistance to COVID-19 infection, suggesting that reduced risk of contracting the virus is tied to certain blood group factors. People with Type O blood appear to be at slightly reduced risk of infection, for example.

But the studies done so far are designed to find common genetic variations, which generally have a small effect on resistance. Now, genetic researchers are launching an effort to identify genetic resistance factors with a big effect, even if they are vanishingly rare.

The group is recruiting people who did not become infected with COVID-19 despite heavy exposure, such as those living in households where all the other members got sick or people who were exposed to a superspreader event but did not become ill. As with tuberculosis, being certain that someone has not been infected with the virus can be tricky, but the team is using several blood tests to home in on the people most likely to have escaped infection.

They plan to sequence the genomes of these people to identify things that strongly affect infection risk, then do more laboratory studies to try to tease out the means of resistance.

Their work is inspired by earlier efforts to uncover inborn resistance to infections, Dr. Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. Those earlier efforts took place in “a different epoch,” before there were rapid sequencing technologies, Dr. Spaan says.

“Now we have modern technologies to do this more systematically.”

The emergence of viral variants such as the Delta and Omicron COVID strains raises the stakes of the work, he continues.

“The need to unravel these inborn mechanisms of resistance to COVID has become even more important because of these new variants and the anticipation that we will have COVID with us for years.”

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

It is a great mystery of infectious disease: Why are some people seemingly unaffected by illness that harms others? During the COVID-19 pandemic, we’ve seen this play out time and time again when whole families get sick except for one or two fortunate family members. And at so-called superspreader events that infect many, a lucky few typically walk away with their health intact. Did the virus never enter their bodies? Or do some people have natural resistance to pathogens they’ve never been exposed to before encoded in their genes?

Resistance to infectious disease is much more than a scientific curiosity and studying how it works can be a path to curb future outbreaks.

“In the event that we could identify what makes some people resistant, that immediately opens avenues for therapeutics that we could apply in all those other people who do suffer from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York.

Dr. Spaan is part of an international effort to identify genetic variations that spare people from becoming infected with SARS-CoV-2, the virus that causes COVID-19.

There’s far more research on what drives the tendency to get infectious diseases than on resistance to them. But a few researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases, they’ve already translated these insights into treatments.

Perhaps the strongest example of how odd genes of just a few people can inspire treatments to help many comes from research on the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS).
 

A genetic quirk

In the mid-1990s, several groups of researchers independently identified a mutation in a gene called CCR5 linked to resistance to HIV infection.

The gene encodes a protein on the surface of some white blood cells that helps set up the movement of other immune cells to fight infections. HIV, meanwhile, uses the CCR5 protein to help it enter the white blood cells that it infects.

The mutation, known as delta 32, results in a shorter than usual protein that doesn’t reach the surface of the cell. People who carry two copies of the delta 32 form of CCR5 do not have any CCR5 protein on the outside of their white blood cells.

Researchers, led by molecular immunologist Philip Murphy, MD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md, showed in 1997 that people with two copies of the mutation were unusually common among a group of men who were at especially high risk of HIV exposure, but had never contracted the virus. And out of more than 700 HIV-positive people, none carried two copies of CCR5 delta 32.

Pharmaceutical companies used these insights to develop drugs to block CCR5 and delay the development of AIDS. For instance, the drug maraviroc, marketed by Pfizer, was approved for use in HIV-positive people in 2007.

Only a few examples of this kind of inborn, genetically determined complete resistance to infection have ever been heard of. All of them involve cell-surface molecules that are believed to help a virus or other pathogen gain entry to the cell.
 

Locking out illness

“The first step for any intracellular pathogen is getting inside the cell. And if you’re missing the doorway, then the virus can’t accomplish the first step in its life cycle,” Dr. Murphy says. “Getting inside is fundamental.”

Changes in cell-surface molecules can also make someone more likely to have an infection or severe disease. One such group of cell-surface molecules that have been linked to both increasing and decreasing the risk of various infections are histo-blood group antigens. The most familiar members of this group are the molecules that define blood types A, B, and O.

Scientists have also identified one example of total resistance to infection involving these molecules. In 2003, researchers showed that people who lack a functional copy of a gene known as FUT2 cannot be infected with Norwalk virus, one of more than 30 viruses in the norovirus family that cause illness in the digestive tract.

The gene FUT2 encodes an enzyme that determines whether or not blood group antigens are found in a person’s saliva and other body fluids as well as on their red blood cells.

“It didn’t matter how many virus particles we challenged an individual with, if they did not have that first enzyme, they did not get infected,” says researcher Lisa Lindesmith, a virologist at the University of North Carolina in Chapel Hill.
 

No norovirus

Norwalk is a relatively rare type of norovirus. But FUT2 deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have periodically swept across the world over the past quarter-century. These illnesses take an especially heavy toll on children in the developing world, causing malnutrition and contributing to infant and child deaths.

But progress in translating these insights about genetic resistance into drugs or other things that could reduce the burden of noroviruses has been slow.

“The biggest barrier here is lack of ability to study the virus outside of humans,” Lindesmith says.

Noroviruses are very difficult to grow in the lab, “and there’s no small animal model of gastrointestinal illness caused by the viruses.”

We are clearly making giant strides in improving those skills,” says Lindesmith. “But we are just not quite there yet.”

In the years before COVID-19 emerged, tuberculosis was responsible for the largest number of annual worldwide deaths from an infectious disease. It’s a lung disease caused by the bacterium Mycobacterium tuberculosis, and it has been a pandemic for thousands of years.

Some 85%-95% of people with intact immune systems who are infected with TB control the infection and never get active lung disease. And some people who have intense, continuing exposure to the bacterium, which is spread through droplets and aerosols from people with active lung disease, apparently never become infected at all.
 

Thwarting uberculosis

Understanding the ways of these different forms of resistance could help in the search for vaccines, treatments, and other ways to fight tuberculosis, says Elouise Kroon, MD, a graduate student at Stellenbosch University in Cape Town, South Africa.

“What makes it particularly hard to study is the fact that there is no gold standard to measure infection,” she says. “So, what we do is infer infection from two different types of tests” -- a skin test and a blood test that measure different kinds of immune response to molecules from the bacterium.

Dr. Kroon and other researchers have studied resistance to infection by following people living in the same household as those with active lung disease or people who live and work in crowded conditions in high-risk communities. But not all such studies have used the same definition of so-called resisters, documented exposure in the same way, or followed up to ensure that people continue to test negative over the long term.

The best clue that has emerged from studies so far links resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Marlo Möller, PhD, a professor in the TB Host Genetics Research Group at Stellenbosch University.

“That always seems to pop up everywhere. But the rest is not so obvious,” she says. “A lot of the studies don’t find the same thing. It’s different in different populations,” which may be a result of the long evolutionary history between tuberculosis and humans, as well as the fact that different strains of the bacterium are prevalent in different parts of the world.

COVID-19 is a much newer infectious disease, but teasing out how it contributes to both severe illness and resistance to infection is still a major task.
 

Overcoming COVID

Early in the pandemic, research by the COVID Human Genetic Effort, the international consortium that Dr. Spaan is part of, linked severe COVID-19 pneumonia to the lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy these molecules. Together, these mechanisms explain about one-fifth of severe COVID-19 cases, the researchers reported in 2021.

A few studies by other groups have explored resistance to COVID-19 infection, suggesting that reduced risk of contracting the virus is tied to certain blood group factors. People with Type O blood appear to be at slightly reduced risk of infection, for example.

But the studies done so far are designed to find common genetic variations, which generally have a small effect on resistance. Now, genetic researchers are launching an effort to identify genetic resistance factors with a big effect, even if they are vanishingly rare.

The group is recruiting people who did not become infected with COVID-19 despite heavy exposure, such as those living in households where all the other members got sick or people who were exposed to a superspreader event but did not become ill. As with tuberculosis, being certain that someone has not been infected with the virus can be tricky, but the team is using several blood tests to home in on the people most likely to have escaped infection.

They plan to sequence the genomes of these people to identify things that strongly affect infection risk, then do more laboratory studies to try to tease out the means of resistance.

Their work is inspired by earlier efforts to uncover inborn resistance to infections, Dr. Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. Those earlier efforts took place in “a different epoch,” before there were rapid sequencing technologies, Dr. Spaan says.

“Now we have modern technologies to do this more systematically.”

The emergence of viral variants such as the Delta and Omicron COVID strains raises the stakes of the work, he continues.

“The need to unravel these inborn mechanisms of resistance to COVID has become even more important because of these new variants and the anticipation that we will have COVID with us for years.”

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

It is a great mystery of infectious disease: Why are some people seemingly unaffected by illness that harms others? During the COVID-19 pandemic, we’ve seen this play out time and time again when whole families get sick except for one or two fortunate family members. And at so-called superspreader events that infect many, a lucky few typically walk away with their health intact. Did the virus never enter their bodies? Or do some people have natural resistance to pathogens they’ve never been exposed to before encoded in their genes?

Resistance to infectious disease is much more than a scientific curiosity and studying how it works can be a path to curb future outbreaks.

“In the event that we could identify what makes some people resistant, that immediately opens avenues for therapeutics that we could apply in all those other people who do suffer from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York.

Dr. Spaan is part of an international effort to identify genetic variations that spare people from becoming infected with SARS-CoV-2, the virus that causes COVID-19.

There’s far more research on what drives the tendency to get infectious diseases than on resistance to them. But a few researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases, they’ve already translated these insights into treatments.

Perhaps the strongest example of how odd genes of just a few people can inspire treatments to help many comes from research on the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS).
 

A genetic quirk

In the mid-1990s, several groups of researchers independently identified a mutation in a gene called CCR5 linked to resistance to HIV infection.

The gene encodes a protein on the surface of some white blood cells that helps set up the movement of other immune cells to fight infections. HIV, meanwhile, uses the CCR5 protein to help it enter the white blood cells that it infects.

The mutation, known as delta 32, results in a shorter than usual protein that doesn’t reach the surface of the cell. People who carry two copies of the delta 32 form of CCR5 do not have any CCR5 protein on the outside of their white blood cells.

Researchers, led by molecular immunologist Philip Murphy, MD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md, showed in 1997 that people with two copies of the mutation were unusually common among a group of men who were at especially high risk of HIV exposure, but had never contracted the virus. And out of more than 700 HIV-positive people, none carried two copies of CCR5 delta 32.

Pharmaceutical companies used these insights to develop drugs to block CCR5 and delay the development of AIDS. For instance, the drug maraviroc, marketed by Pfizer, was approved for use in HIV-positive people in 2007.

Only a few examples of this kind of inborn, genetically determined complete resistance to infection have ever been heard of. All of them involve cell-surface molecules that are believed to help a virus or other pathogen gain entry to the cell.
 

Locking out illness

“The first step for any intracellular pathogen is getting inside the cell. And if you’re missing the doorway, then the virus can’t accomplish the first step in its life cycle,” Dr. Murphy says. “Getting inside is fundamental.”

Changes in cell-surface molecules can also make someone more likely to have an infection or severe disease. One such group of cell-surface molecules that have been linked to both increasing and decreasing the risk of various infections are histo-blood group antigens. The most familiar members of this group are the molecules that define blood types A, B, and O.

Scientists have also identified one example of total resistance to infection involving these molecules. In 2003, researchers showed that people who lack a functional copy of a gene known as FUT2 cannot be infected with Norwalk virus, one of more than 30 viruses in the norovirus family that cause illness in the digestive tract.

The gene FUT2 encodes an enzyme that determines whether or not blood group antigens are found in a person’s saliva and other body fluids as well as on their red blood cells.

“It didn’t matter how many virus particles we challenged an individual with, if they did not have that first enzyme, they did not get infected,” says researcher Lisa Lindesmith, a virologist at the University of North Carolina in Chapel Hill.
 

No norovirus

Norwalk is a relatively rare type of norovirus. But FUT2 deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have periodically swept across the world over the past quarter-century. These illnesses take an especially heavy toll on children in the developing world, causing malnutrition and contributing to infant and child deaths.

But progress in translating these insights about genetic resistance into drugs or other things that could reduce the burden of noroviruses has been slow.

“The biggest barrier here is lack of ability to study the virus outside of humans,” Lindesmith says.

Noroviruses are very difficult to grow in the lab, “and there’s no small animal model of gastrointestinal illness caused by the viruses.”

We are clearly making giant strides in improving those skills,” says Lindesmith. “But we are just not quite there yet.”

In the years before COVID-19 emerged, tuberculosis was responsible for the largest number of annual worldwide deaths from an infectious disease. It’s a lung disease caused by the bacterium Mycobacterium tuberculosis, and it has been a pandemic for thousands of years.

Some 85%-95% of people with intact immune systems who are infected with TB control the infection and never get active lung disease. And some people who have intense, continuing exposure to the bacterium, which is spread through droplets and aerosols from people with active lung disease, apparently never become infected at all.
 

Thwarting uberculosis

Understanding the ways of these different forms of resistance could help in the search for vaccines, treatments, and other ways to fight tuberculosis, says Elouise Kroon, MD, a graduate student at Stellenbosch University in Cape Town, South Africa.

“What makes it particularly hard to study is the fact that there is no gold standard to measure infection,” she says. “So, what we do is infer infection from two different types of tests” -- a skin test and a blood test that measure different kinds of immune response to molecules from the bacterium.

Dr. Kroon and other researchers have studied resistance to infection by following people living in the same household as those with active lung disease or people who live and work in crowded conditions in high-risk communities. But not all such studies have used the same definition of so-called resisters, documented exposure in the same way, or followed up to ensure that people continue to test negative over the long term.

The best clue that has emerged from studies so far links resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Marlo Möller, PhD, a professor in the TB Host Genetics Research Group at Stellenbosch University.

“That always seems to pop up everywhere. But the rest is not so obvious,” she says. “A lot of the studies don’t find the same thing. It’s different in different populations,” which may be a result of the long evolutionary history between tuberculosis and humans, as well as the fact that different strains of the bacterium are prevalent in different parts of the world.

COVID-19 is a much newer infectious disease, but teasing out how it contributes to both severe illness and resistance to infection is still a major task.
 

Overcoming COVID

Early in the pandemic, research by the COVID Human Genetic Effort, the international consortium that Dr. Spaan is part of, linked severe COVID-19 pneumonia to the lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy these molecules. Together, these mechanisms explain about one-fifth of severe COVID-19 cases, the researchers reported in 2021.

A few studies by other groups have explored resistance to COVID-19 infection, suggesting that reduced risk of contracting the virus is tied to certain blood group factors. People with Type O blood appear to be at slightly reduced risk of infection, for example.

But the studies done so far are designed to find common genetic variations, which generally have a small effect on resistance. Now, genetic researchers are launching an effort to identify genetic resistance factors with a big effect, even if they are vanishingly rare.

The group is recruiting people who did not become infected with COVID-19 despite heavy exposure, such as those living in households where all the other members got sick or people who were exposed to a superspreader event but did not become ill. As with tuberculosis, being certain that someone has not been infected with the virus can be tricky, but the team is using several blood tests to home in on the people most likely to have escaped infection.

They plan to sequence the genomes of these people to identify things that strongly affect infection risk, then do more laboratory studies to try to tease out the means of resistance.

Their work is inspired by earlier efforts to uncover inborn resistance to infections, Dr. Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. Those earlier efforts took place in “a different epoch,” before there were rapid sequencing technologies, Dr. Spaan says.

“Now we have modern technologies to do this more systematically.”

The emergence of viral variants such as the Delta and Omicron COVID strains raises the stakes of the work, he continues.

“The need to unravel these inborn mechanisms of resistance to COVID has become even more important because of these new variants and the anticipation that we will have COVID with us for years.”

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

The investigational, next-generation cardiac myosin inhibitor aficamten (previously CK-274, Cytokinetics) continues to show promise as a potential treatment for hypertrophic cardiomyopathy (HCM).

Today, the company announced positive topline results from cohort 3 of the REDWOOD-HCM phase 2 clinical trial, which included 13 patients with symptomatic obstructive HCM and a resting or post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) of 50 mm Hg or greater whose background therapy included disopyramide.

Treatment with aficamten led to substantial reductions in the average resting LVOT-G, as well as the post-Valsalva LVOT-G (defined as resting gradient less than 30 mm Hg and post-Valsalva gradient less than 50 mm Hg), the company reported.

These “clinically relevant” decreases in pressure gradients were achieved with only modest decreases in average left ventricular ejection fraction (LVEF), the company said. 

In no patient did LVEF fall below the prespecified safety threshold of 50%.

New York Heart Association (NYHA) functional class was improved in most patients.

The safety and tolerability of aficamten in cohort 3 were consistent with previous experience in the REDWOOD-HCM trial, with no treatment interruptions and no serious treatment-related adverse events.

The pharmacokinetic data from cohort 3 are similar to those observed in REDWOOD-HCM cohorts 1 and 2, which included HCM patients taking background medications exclusive of disopyramide, as reported previously by this news organization.

“We are encouraged by the clinically relevant reductions in the LVOT gradient observed in these medically refractory patients and are pleased with the safety profile of aficamten when administered in combination with disopyramide,” Fady Malik, MD, PhD, Cytokinetics’ executive vice president of research and development, said in a news release.

“These results represent the first report of patients with obstructive HCM treated with a combination of a cardiac myosin inhibitor and disopyramide and support our plan to include this patient population in SEQUOIA-HCM, our phase 3 trial, which is important, given these patients have exhausted other available medical therapies,” Dr. Malik said.

The results from cohort 3 of the REDWOOD-HCM trial will be presented at the upcoming American College of Cardiology Annual Meeting in April.

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

The investigational, next-generation cardiac myosin inhibitor aficamten (previously CK-274, Cytokinetics) continues to show promise as a potential treatment for hypertrophic cardiomyopathy (HCM).

Today, the company announced positive topline results from cohort 3 of the REDWOOD-HCM phase 2 clinical trial, which included 13 patients with symptomatic obstructive HCM and a resting or post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) of 50 mm Hg or greater whose background therapy included disopyramide.

Treatment with aficamten led to substantial reductions in the average resting LVOT-G, as well as the post-Valsalva LVOT-G (defined as resting gradient less than 30 mm Hg and post-Valsalva gradient less than 50 mm Hg), the company reported.

These “clinically relevant” decreases in pressure gradients were achieved with only modest decreases in average left ventricular ejection fraction (LVEF), the company said. 

In no patient did LVEF fall below the prespecified safety threshold of 50%.

New York Heart Association (NYHA) functional class was improved in most patients.

The safety and tolerability of aficamten in cohort 3 were consistent with previous experience in the REDWOOD-HCM trial, with no treatment interruptions and no serious treatment-related adverse events.

The pharmacokinetic data from cohort 3 are similar to those observed in REDWOOD-HCM cohorts 1 and 2, which included HCM patients taking background medications exclusive of disopyramide, as reported previously by this news organization.

“We are encouraged by the clinically relevant reductions in the LVOT gradient observed in these medically refractory patients and are pleased with the safety profile of aficamten when administered in combination with disopyramide,” Fady Malik, MD, PhD, Cytokinetics’ executive vice president of research and development, said in a news release.

“These results represent the first report of patients with obstructive HCM treated with a combination of a cardiac myosin inhibitor and disopyramide and support our plan to include this patient population in SEQUOIA-HCM, our phase 3 trial, which is important, given these patients have exhausted other available medical therapies,” Dr. Malik said.

The results from cohort 3 of the REDWOOD-HCM trial will be presented at the upcoming American College of Cardiology Annual Meeting in April.

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

The investigational, next-generation cardiac myosin inhibitor aficamten (previously CK-274, Cytokinetics) continues to show promise as a potential treatment for hypertrophic cardiomyopathy (HCM).

Today, the company announced positive topline results from cohort 3 of the REDWOOD-HCM phase 2 clinical trial, which included 13 patients with symptomatic obstructive HCM and a resting or post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) of 50 mm Hg or greater whose background therapy included disopyramide.

Treatment with aficamten led to substantial reductions in the average resting LVOT-G, as well as the post-Valsalva LVOT-G (defined as resting gradient less than 30 mm Hg and post-Valsalva gradient less than 50 mm Hg), the company reported.

These “clinically relevant” decreases in pressure gradients were achieved with only modest decreases in average left ventricular ejection fraction (LVEF), the company said. 

In no patient did LVEF fall below the prespecified safety threshold of 50%.

New York Heart Association (NYHA) functional class was improved in most patients.

The safety and tolerability of aficamten in cohort 3 were consistent with previous experience in the REDWOOD-HCM trial, with no treatment interruptions and no serious treatment-related adverse events.

The pharmacokinetic data from cohort 3 are similar to those observed in REDWOOD-HCM cohorts 1 and 2, which included HCM patients taking background medications exclusive of disopyramide, as reported previously by this news organization.

“We are encouraged by the clinically relevant reductions in the LVOT gradient observed in these medically refractory patients and are pleased with the safety profile of aficamten when administered in combination with disopyramide,” Fady Malik, MD, PhD, Cytokinetics’ executive vice president of research and development, said in a news release.

“These results represent the first report of patients with obstructive HCM treated with a combination of a cardiac myosin inhibitor and disopyramide and support our plan to include this patient population in SEQUOIA-HCM, our phase 3 trial, which is important, given these patients have exhausted other available medical therapies,” Dr. Malik said.

The results from cohort 3 of the REDWOOD-HCM trial will be presented at the upcoming American College of Cardiology Annual Meeting in April.

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

The world’s most valuable mouse

You’ve heard of Mighty Mouse. Now say hello to the world’s newest mouse superhero, Crypto-Mouse! After being bitten by a radioactive cryptocurrency investor, Crypto-Mouse can tap directly into the power of the blockchain itself, allowing it to perform incredible, death-defying feats of strength!

We’re going to stop right there before Crypto-Mouse gains entry into the Marvel cinematic universe. Let’s rewind to the beginning, because that’s precisely where this crazy scheme is at. In late January, a new decentralized autonomous organization, BitMouseDAO, launched to enormous … -ly little fanfare, according to Vice. Two investors as of Jan. 31. But what they lack in money they make up for in sheer ambition.

Clker-Free-Vector-Images/Pixabay

BitMouseDAO’s $100 million dollar idea is to genetically engineer mice to carry bitcoin, the first cryptocurrency and one of the most valuable. This isn’t as crazy an idea as it sounds since DNA can be modified to store information, potentially even bitcoin information. Their plan is to create a private bitcoin wallet, which will be stored in the mouse DNA, and purchase online bitcoin to store in this wallet.

BitMouseDAO, being a “collection of artists,” plans to partner with a lab to translate its private key into a specific DNA sequence to be encoded into the mice during fertilization; or, if that doesn’t work, inject them with a harmless virus that carries the key.

Since these are artists, their ultimate plan is to use their bitcoin mice to make NFTs (scratch that off your cryptocurrency bingo card) and auction them off to people. Or, as Vice put it, BitMouseDAO essentially plans to send preserved dead mice to people. Artistic dead mice! Artistic dead mice worth millions! Maybe. Even BitMouseDAO admits bitcoin could be worthless by the time the project gets off the ground.

If this all sounds completely insane, that’s because it is. But it also sounds crazy enough to work. Now, if you’ll excuse us, we’re off to write a screenplay about a scrappy group of high-tech thieves who steal a group of genetically altered bitcoin mice to sell for millions, only to keep them as their adorable pets. Trust us Hollywood, it’ll make millions!
 

Alcoholic monkeys vs. the future of feces

Which is more important, the journey or the destination? Science is all about the destination, yes? Solving the problem, saving a life, expanding horizons. That’s science. Or is it? The scientific method is a process, so does that make it a journey?

Amandad/Pixabay

For us, today’s journey begins at the University of Iowa, where investigators are trying to reduce alcohol consumption. A worthy goal, and they seem to have made some progress by targeting a liver hormone called fibroblast growth factor 21 (FGF21). But we’re more interested in the process right now, so bring on the alcoholic monkeys. And no, that’s not a death metal/reggae fusion band. Should be, though.

“The vervet monkey population is [composed] of alcohol avoiders, moderate alcohol drinkers, and a group of heavy drinkers,” Matthew Potthoff, PhD, and associates wrote in Cell Metabolism. When this particular bunch of heavy-drinking vervets were given FGF21, they consumed 50% less alcohol than did vehicle-treated controls, so mission accomplished.

Maybe it could be a breakfast cereal. Who wouldn’t enjoy a bowl of alcoholic monkeys in the morning?

And after breakfast, you might be ready for a digitized bowel movement, courtesy of researchers at University of California, San Diego. They’re studying ulcerative colitis (UC) by examining the gut microbiome, and their “most useful biological sample is patient stool,” according to a written statement from the university.

“Once we had all the technology to digitize the stool, the question was, is this going to tell us what’s happening in these patients? The answer turned out to be yes,” co-senior author Rob Knight, PhD, said in the statement. “Digitizing fecal material is the future.” The road to UC treatment, in other words, is paved with digital stool.

About 40% of the UC patients had elevated protease levels, and their high-protease feces were then transplanted into germ-free mice, which subsequently developed colitis and were successfully treated with protease inhibitors. And that is our final destination.

As our revered founder and mentor, Josephine Lotmevich, used to say, an alcoholic monkey in the hand is worth a number 2 in the bush.
 

Raise a glass to delinquency

You wouldn’t think that a glass of water could lead to a life of crime, but a recent study suggests just that.

PxHere

Children exposed to lead in their drinking water during their early years had a 21% higher risk of delinquency after the age of 14 years and a 38% higher risk of having a record for a serious complaint, Jackie MacDonald Gibson and associates said in a statement on Eurekalert.

Data for the study came from Wake County, N.C., which includes rural areas, wealthy exurban developments, and predominantly Black communities. The investigators compared the blood lead levels for children tested between 1998 and 2011 with juvenile delinquency reports of the same children from the N.C. Department of Public Safety.

The main culprit, they found, was well water. Blood lead levels were 11% higher in the children whose water came from private wells, compared with children using community water. About 13% of U.S. households rely on private wells, which are not regulated under the Safe Drinking Water Act, for their water supply.

The researchers said there is an urgent need for better drinking-water solutions in communities that rely on well water, whether it be through subsidized home filtration or infrastructure redevelopment.

An earlier study had estimated that preventing just one child from entering the adult criminal justice system would save $1.3 to $1.5 million in 1997 dollars. That’s about $2.2 to $2.5 million dollars today!

If you do the math, it’s not hard to see what’s cheaper (and healthier) in the long run.
 

A ‘dirty’ scam

Another one? This is just getting sad. You’ve probably heard of muds and clays being good for the skin and maybe you’ve gone to a spa and sat in a mud bath, but would you believe it if someone told you that mud can cure all your ailments? No? Neither would we. Senatorial candidate Beto O’Rourke was definitely someone who brought this strange treatment to light, but it seems like this is something that has been going on for years, even before the pandemic.

Nandan/Pixahive

A company called Black Oxygen Organics (BOO) was selling “magic dirt” for $110 per 4-ounce package. It claimed the dirt was high in fulvic acid and humic acid, which are good for many things. They were, however, literally getting this mud from bogs with landfills nearby, Mel magazine reported.

That doesn’t sound appealing at all, but wait, there’s more. People were eating, drinking, bathing, and feeding their families this sludge in hopes that they would be cured of their ailments. A lot of people jumped aboard the magic dirt train when the pandemic arose, but it quickly became clear that this mud was not as helpful as BOO claimed it to be.

“We began to receive inquiries and calls on our website with people having problems and issues. Ultimately, we sent the products out for independent testing, and then when that came back and showed that there were toxic heavy metals [lead, arsenic, and cadmium among them] at an unsafe level, that’s when we knew we had to act,” Atlanta-based attorney Matt Wetherington, who filed a federal lawsuit against BOO, told Mel.

After a very complicated series of events involving an expose by NBC, product recalls, extortion claims, and grassroots activism, BOO was shut down by both the Canadian and U.S. governments.

As always, please listen only to health care professionals when you wish to use natural remedies for illnesses and ailments.

The world’s most valuable mouse

You’ve heard of Mighty Mouse. Now say hello to the world’s newest mouse superhero, Crypto-Mouse! After being bitten by a radioactive cryptocurrency investor, Crypto-Mouse can tap directly into the power of the blockchain itself, allowing it to perform incredible, death-defying feats of strength!

We’re going to stop right there before Crypto-Mouse gains entry into the Marvel cinematic universe. Let’s rewind to the beginning, because that’s precisely where this crazy scheme is at. In late January, a new decentralized autonomous organization, BitMouseDAO, launched to enormous … -ly little fanfare, according to Vice. Two investors as of Jan. 31. But what they lack in money they make up for in sheer ambition.

Clker-Free-Vector-Images/Pixabay

BitMouseDAO’s $100 million dollar idea is to genetically engineer mice to carry bitcoin, the first cryptocurrency and one of the most valuable. This isn’t as crazy an idea as it sounds since DNA can be modified to store information, potentially even bitcoin information. Their plan is to create a private bitcoin wallet, which will be stored in the mouse DNA, and purchase online bitcoin to store in this wallet.

BitMouseDAO, being a “collection of artists,” plans to partner with a lab to translate its private key into a specific DNA sequence to be encoded into the mice during fertilization; or, if that doesn’t work, inject them with a harmless virus that carries the key.

Since these are artists, their ultimate plan is to use their bitcoin mice to make NFTs (scratch that off your cryptocurrency bingo card) and auction them off to people. Or, as Vice put it, BitMouseDAO essentially plans to send preserved dead mice to people. Artistic dead mice! Artistic dead mice worth millions! Maybe. Even BitMouseDAO admits bitcoin could be worthless by the time the project gets off the ground.

If this all sounds completely insane, that’s because it is. But it also sounds crazy enough to work. Now, if you’ll excuse us, we’re off to write a screenplay about a scrappy group of high-tech thieves who steal a group of genetically altered bitcoin mice to sell for millions, only to keep them as their adorable pets. Trust us Hollywood, it’ll make millions!
 

Alcoholic monkeys vs. the future of feces

Which is more important, the journey or the destination? Science is all about the destination, yes? Solving the problem, saving a life, expanding horizons. That’s science. Or is it? The scientific method is a process, so does that make it a journey?

Amandad/Pixabay

For us, today’s journey begins at the University of Iowa, where investigators are trying to reduce alcohol consumption. A worthy goal, and they seem to have made some progress by targeting a liver hormone called fibroblast growth factor 21 (FGF21). But we’re more interested in the process right now, so bring on the alcoholic monkeys. And no, that’s not a death metal/reggae fusion band. Should be, though.

“The vervet monkey population is [composed] of alcohol avoiders, moderate alcohol drinkers, and a group of heavy drinkers,” Matthew Potthoff, PhD, and associates wrote in Cell Metabolism. When this particular bunch of heavy-drinking vervets were given FGF21, they consumed 50% less alcohol than did vehicle-treated controls, so mission accomplished.

Maybe it could be a breakfast cereal. Who wouldn’t enjoy a bowl of alcoholic monkeys in the morning?

And after breakfast, you might be ready for a digitized bowel movement, courtesy of researchers at University of California, San Diego. They’re studying ulcerative colitis (UC) by examining the gut microbiome, and their “most useful biological sample is patient stool,” according to a written statement from the university.

“Once we had all the technology to digitize the stool, the question was, is this going to tell us what’s happening in these patients? The answer turned out to be yes,” co-senior author Rob Knight, PhD, said in the statement. “Digitizing fecal material is the future.” The road to UC treatment, in other words, is paved with digital stool.

About 40% of the UC patients had elevated protease levels, and their high-protease feces were then transplanted into germ-free mice, which subsequently developed colitis and were successfully treated with protease inhibitors. And that is our final destination.

As our revered founder and mentor, Josephine Lotmevich, used to say, an alcoholic monkey in the hand is worth a number 2 in the bush.
 

Raise a glass to delinquency

You wouldn’t think that a glass of water could lead to a life of crime, but a recent study suggests just that.

PxHere

Children exposed to lead in their drinking water during their early years had a 21% higher risk of delinquency after the age of 14 years and a 38% higher risk of having a record for a serious complaint, Jackie MacDonald Gibson and associates said in a statement on Eurekalert.

Data for the study came from Wake County, N.C., which includes rural areas, wealthy exurban developments, and predominantly Black communities. The investigators compared the blood lead levels for children tested between 1998 and 2011 with juvenile delinquency reports of the same children from the N.C. Department of Public Safety.

The main culprit, they found, was well water. Blood lead levels were 11% higher in the children whose water came from private wells, compared with children using community water. About 13% of U.S. households rely on private wells, which are not regulated under the Safe Drinking Water Act, for their water supply.

The researchers said there is an urgent need for better drinking-water solutions in communities that rely on well water, whether it be through subsidized home filtration or infrastructure redevelopment.

An earlier study had estimated that preventing just one child from entering the adult criminal justice system would save $1.3 to $1.5 million in 1997 dollars. That’s about $2.2 to $2.5 million dollars today!

If you do the math, it’s not hard to see what’s cheaper (and healthier) in the long run.
 

A ‘dirty’ scam

Another one? This is just getting sad. You’ve probably heard of muds and clays being good for the skin and maybe you’ve gone to a spa and sat in a mud bath, but would you believe it if someone told you that mud can cure all your ailments? No? Neither would we. Senatorial candidate Beto O’Rourke was definitely someone who brought this strange treatment to light, but it seems like this is something that has been going on for years, even before the pandemic.

Nandan/Pixahive

A company called Black Oxygen Organics (BOO) was selling “magic dirt” for $110 per 4-ounce package. It claimed the dirt was high in fulvic acid and humic acid, which are good for many things. They were, however, literally getting this mud from bogs with landfills nearby, Mel magazine reported.

That doesn’t sound appealing at all, but wait, there’s more. People were eating, drinking, bathing, and feeding their families this sludge in hopes that they would be cured of their ailments. A lot of people jumped aboard the magic dirt train when the pandemic arose, but it quickly became clear that this mud was not as helpful as BOO claimed it to be.

“We began to receive inquiries and calls on our website with people having problems and issues. Ultimately, we sent the products out for independent testing, and then when that came back and showed that there were toxic heavy metals [lead, arsenic, and cadmium among them] at an unsafe level, that’s when we knew we had to act,” Atlanta-based attorney Matt Wetherington, who filed a federal lawsuit against BOO, told Mel.

After a very complicated series of events involving an expose by NBC, product recalls, extortion claims, and grassroots activism, BOO was shut down by both the Canadian and U.S. governments.

As always, please listen only to health care professionals when you wish to use natural remedies for illnesses and ailments.

The world’s most valuable mouse

You’ve heard of Mighty Mouse. Now say hello to the world’s newest mouse superhero, Crypto-Mouse! After being bitten by a radioactive cryptocurrency investor, Crypto-Mouse can tap directly into the power of the blockchain itself, allowing it to perform incredible, death-defying feats of strength!

We’re going to stop right there before Crypto-Mouse gains entry into the Marvel cinematic universe. Let’s rewind to the beginning, because that’s precisely where this crazy scheme is at. In late January, a new decentralized autonomous organization, BitMouseDAO, launched to enormous … -ly little fanfare, according to Vice. Two investors as of Jan. 31. But what they lack in money they make up for in sheer ambition.

Clker-Free-Vector-Images/Pixabay

BitMouseDAO’s $100 million dollar idea is to genetically engineer mice to carry bitcoin, the first cryptocurrency and one of the most valuable. This isn’t as crazy an idea as it sounds since DNA can be modified to store information, potentially even bitcoin information. Their plan is to create a private bitcoin wallet, which will be stored in the mouse DNA, and purchase online bitcoin to store in this wallet.

BitMouseDAO, being a “collection of artists,” plans to partner with a lab to translate its private key into a specific DNA sequence to be encoded into the mice during fertilization; or, if that doesn’t work, inject them with a harmless virus that carries the key.

Since these are artists, their ultimate plan is to use their bitcoin mice to make NFTs (scratch that off your cryptocurrency bingo card) and auction them off to people. Or, as Vice put it, BitMouseDAO essentially plans to send preserved dead mice to people. Artistic dead mice! Artistic dead mice worth millions! Maybe. Even BitMouseDAO admits bitcoin could be worthless by the time the project gets off the ground.

If this all sounds completely insane, that’s because it is. But it also sounds crazy enough to work. Now, if you’ll excuse us, we’re off to write a screenplay about a scrappy group of high-tech thieves who steal a group of genetically altered bitcoin mice to sell for millions, only to keep them as their adorable pets. Trust us Hollywood, it’ll make millions!
 

Alcoholic monkeys vs. the future of feces

Which is more important, the journey or the destination? Science is all about the destination, yes? Solving the problem, saving a life, expanding horizons. That’s science. Or is it? The scientific method is a process, so does that make it a journey?

Amandad/Pixabay

For us, today’s journey begins at the University of Iowa, where investigators are trying to reduce alcohol consumption. A worthy goal, and they seem to have made some progress by targeting a liver hormone called fibroblast growth factor 21 (FGF21). But we’re more interested in the process right now, so bring on the alcoholic monkeys. And no, that’s not a death metal/reggae fusion band. Should be, though.

“The vervet monkey population is [composed] of alcohol avoiders, moderate alcohol drinkers, and a group of heavy drinkers,” Matthew Potthoff, PhD, and associates wrote in Cell Metabolism. When this particular bunch of heavy-drinking vervets were given FGF21, they consumed 50% less alcohol than did vehicle-treated controls, so mission accomplished.

Maybe it could be a breakfast cereal. Who wouldn’t enjoy a bowl of alcoholic monkeys in the morning?

And after breakfast, you might be ready for a digitized bowel movement, courtesy of researchers at University of California, San Diego. They’re studying ulcerative colitis (UC) by examining the gut microbiome, and their “most useful biological sample is patient stool,” according to a written statement from the university.

“Once we had all the technology to digitize the stool, the question was, is this going to tell us what’s happening in these patients? The answer turned out to be yes,” co-senior author Rob Knight, PhD, said in the statement. “Digitizing fecal material is the future.” The road to UC treatment, in other words, is paved with digital stool.

About 40% of the UC patients had elevated protease levels, and their high-protease feces were then transplanted into germ-free mice, which subsequently developed colitis and were successfully treated with protease inhibitors. And that is our final destination.

As our revered founder and mentor, Josephine Lotmevich, used to say, an alcoholic monkey in the hand is worth a number 2 in the bush.
 

Raise a glass to delinquency

You wouldn’t think that a glass of water could lead to a life of crime, but a recent study suggests just that.

PxHere

Children exposed to lead in their drinking water during their early years had a 21% higher risk of delinquency after the age of 14 years and a 38% higher risk of having a record for a serious complaint, Jackie MacDonald Gibson and associates said in a statement on Eurekalert.

Data for the study came from Wake County, N.C., which includes rural areas, wealthy exurban developments, and predominantly Black communities. The investigators compared the blood lead levels for children tested between 1998 and 2011 with juvenile delinquency reports of the same children from the N.C. Department of Public Safety.

The main culprit, they found, was well water. Blood lead levels were 11% higher in the children whose water came from private wells, compared with children using community water. About 13% of U.S. households rely on private wells, which are not regulated under the Safe Drinking Water Act, for their water supply.

The researchers said there is an urgent need for better drinking-water solutions in communities that rely on well water, whether it be through subsidized home filtration or infrastructure redevelopment.

An earlier study had estimated that preventing just one child from entering the adult criminal justice system would save $1.3 to $1.5 million in 1997 dollars. That’s about $2.2 to $2.5 million dollars today!

If you do the math, it’s not hard to see what’s cheaper (and healthier) in the long run.
 

A ‘dirty’ scam

Another one? This is just getting sad. You’ve probably heard of muds and clays being good for the skin and maybe you’ve gone to a spa and sat in a mud bath, but would you believe it if someone told you that mud can cure all your ailments? No? Neither would we. Senatorial candidate Beto O’Rourke was definitely someone who brought this strange treatment to light, but it seems like this is something that has been going on for years, even before the pandemic.

Nandan/Pixahive

A company called Black Oxygen Organics (BOO) was selling “magic dirt” for $110 per 4-ounce package. It claimed the dirt was high in fulvic acid and humic acid, which are good for many things. They were, however, literally getting this mud from bogs with landfills nearby, Mel magazine reported.

That doesn’t sound appealing at all, but wait, there’s more. People were eating, drinking, bathing, and feeding their families this sludge in hopes that they would be cured of their ailments. A lot of people jumped aboard the magic dirt train when the pandemic arose, but it quickly became clear that this mud was not as helpful as BOO claimed it to be.

“We began to receive inquiries and calls on our website with people having problems and issues. Ultimately, we sent the products out for independent testing, and then when that came back and showed that there were toxic heavy metals [lead, arsenic, and cadmium among them] at an unsafe level, that’s when we knew we had to act,” Atlanta-based attorney Matt Wetherington, who filed a federal lawsuit against BOO, told Mel.

After a very complicated series of events involving an expose by NBC, product recalls, extortion claims, and grassroots activism, BOO was shut down by both the Canadian and U.S. governments.

As always, please listen only to health care professionals when you wish to use natural remedies for illnesses and ailments.

On the occasion of his 100th birthday, The Washington Post wrote of the trailblazing cardiologist and scientist Jeremiah Dr. Stamler, MD: “You may not know him, but he may have saved your life.”

Hyperbole, it was not.

Over a career spanning more than 70 years, Dr. Stamler transformed medicine and the public’s understanding of diet and lifestyle in cardiovascular health and helped introduce the concept of readily measured ‘risk factors’ such as cholesterol, hypertension, smoking, and diabetes.

Dr. Stamler, the founding chair and a professor emeritus of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago, died Wednesday at his home in Sag Harbor, New York, at age 102.

“It is no exaggeration to say that few people in history have had as great an impact on human health,” Donald Lloyd-Jones, MD, chair of the department of preventive medicine at Feinberg and president of the American Heart Association, said in a statement.

“Jerry was a giant intellect who founded the fields of cardiovascular epidemiology and preventive cardiology and led [the way] in defining new prevention concepts right up until his last days,” Dr. Lloyd-Jones added in a statement issued by the university.

Tom Frieden, MD, former director of the Centers for Disease Control and Prevention, tweeted, “Jerry and my father did research on sodium together in the early 1950s. He was a giant in the field of public health, and we’re still benefiting from his brilliance and dedication.”

Roger Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, tweeted, “R.I.P., Dr. Jeremiah Stamler, ‘the father of preventive cardiology,’ dies at 102 – a true legendary force for health.”

The son of Russian immigrants, Dr. Stamler was born in Brooklyn in 1919 and received a bachelor’s degree from Columbia University and a medical degree from State University of New York.

Discharged from the U.S. Army with the rank of captain, Dr. Stamler and his first wife, Rose, herself a distinguished cardiology researcher, moved to Chicago in 1947 and began researching nutrition and atherosclerosis under pioneering cardiology researcher Louis N. Katz, MD, ultimately showing that atherosclerosis could be introduced by changing the diet of chickens. She died in 1998.

Dr. Stamler also worked for Chicago’s Public Health Department in the 1950s, starting a rheumatic fever prevention program for children and the Chicago Coronary Prevention Evaluation Program, working with higher-risk middle-aged men.

Dr. Stamler’s international INTERSALT study established an independent relationship between blood pressure and increased sodium intake, as well as body mass index and heavy alcohol intake. First published in 1988, the research faced opposition from fellow scientists and the food industry alike.

In a 2006 interview, Dr. Stamler said he and fellow researchers began pressing the American Heart Association in the late 1950s to adopt a public policy of support to improve lifestyles, including smoking cessation and better nutrition. “It took some doing. The AHA was initially reluctant and was under pressure from industry.”

Their efforts were rewarded with the AHA’s first statement on smoking in 1959 and first statement on diet in 1960, whereas, Dr. Stamler noted, “the first World Health Organization statement did not come out until the 1980s.”

Philip Greenland, MD, professor of cardiology and former chair of preventive medicine at Northwestern, described Dr. Stamler as a “force for truth that never backed down when confronted by others who did not share his passion for truth and the best science.”

“I loved working with him since I always knew he would make our research better, clearer, more relevant, and more impactful,” he said in the AHA statement.

A lifelong activist and opponent of the Vietnam War, Dr. Stamler was subpoenaed in May 1965 by the House Un-American Activities Committee (HUAC) along with his nutritionist-assistant Yolanda Hall. Rather than pleading the Fifth Amendment against self-incrimination, Dr. Stamler and Ms. Hall refused to testify before the committee and were charged with contempt of Congress.

With the help of local attorneys, Dr. Stamler filed a civil suit against the HUAC, charging that its mandate was unconstitutional. After 8½ years of litigation that went all the way to the Supreme Court, the government agreed to drop its indictment against Dr. Stamler and he dropped his civil suit against the committee.

A year after the Stamler v. Willis case ended, the House voted to terminate the HUAC. In an essay detailing the high-profile case, Henry Blackburn quipped, “They simply did not know who they were taking on when they tagged ol’ Jerry Stamler.”

“Dr. Stamler’s exceptional science was paralleled by his remarkable humanity. He was a champion of our best American ideals, he was fearless when facing the status quo, and he was tireless in the pursuit of what was right and just. He remains a beacon for all that is noble in medicine,” said Clyde Yancy, MD, MSc, Northwestern’s chair of cardiology.

Over the course of his career, Dr. Stamler published more than 670 peer-reviewed papers, 22 books and monographs, and his work has been cited more than 56,000 times. A committed mentor, Dr. Stamler was the 2014 recipient of the AHA’s Eugene Braunwald Academic Mentorship Award.

A lifelong proponent of the Mediterranean diet, Dr. Stamler divided his time between New York, a home in Italy, and Chicago, with his wife Gloria Beckerman Stamler, whom he married in 2004 and who preceded him in death.

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

On the occasion of his 100th birthday, The Washington Post wrote of the trailblazing cardiologist and scientist Jeremiah Dr. Stamler, MD: “You may not know him, but he may have saved your life.”

Hyperbole, it was not.

Over a career spanning more than 70 years, Dr. Stamler transformed medicine and the public’s understanding of diet and lifestyle in cardiovascular health and helped introduce the concept of readily measured ‘risk factors’ such as cholesterol, hypertension, smoking, and diabetes.

Dr. Stamler, the founding chair and a professor emeritus of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago, died Wednesday at his home in Sag Harbor, New York, at age 102.

“It is no exaggeration to say that few people in history have had as great an impact on human health,” Donald Lloyd-Jones, MD, chair of the department of preventive medicine at Feinberg and president of the American Heart Association, said in a statement.

“Jerry was a giant intellect who founded the fields of cardiovascular epidemiology and preventive cardiology and led [the way] in defining new prevention concepts right up until his last days,” Dr. Lloyd-Jones added in a statement issued by the university.

Tom Frieden, MD, former director of the Centers for Disease Control and Prevention, tweeted, “Jerry and my father did research on sodium together in the early 1950s. He was a giant in the field of public health, and we’re still benefiting from his brilliance and dedication.”

Roger Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, tweeted, “R.I.P., Dr. Jeremiah Stamler, ‘the father of preventive cardiology,’ dies at 102 – a true legendary force for health.”

The son of Russian immigrants, Dr. Stamler was born in Brooklyn in 1919 and received a bachelor’s degree from Columbia University and a medical degree from State University of New York.

Discharged from the U.S. Army with the rank of captain, Dr. Stamler and his first wife, Rose, herself a distinguished cardiology researcher, moved to Chicago in 1947 and began researching nutrition and atherosclerosis under pioneering cardiology researcher Louis N. Katz, MD, ultimately showing that atherosclerosis could be introduced by changing the diet of chickens. She died in 1998.

Dr. Stamler also worked for Chicago’s Public Health Department in the 1950s, starting a rheumatic fever prevention program for children and the Chicago Coronary Prevention Evaluation Program, working with higher-risk middle-aged men.

Dr. Stamler’s international INTERSALT study established an independent relationship between blood pressure and increased sodium intake, as well as body mass index and heavy alcohol intake. First published in 1988, the research faced opposition from fellow scientists and the food industry alike.

In a 2006 interview, Dr. Stamler said he and fellow researchers began pressing the American Heart Association in the late 1950s to adopt a public policy of support to improve lifestyles, including smoking cessation and better nutrition. “It took some doing. The AHA was initially reluctant and was under pressure from industry.”

Their efforts were rewarded with the AHA’s first statement on smoking in 1959 and first statement on diet in 1960, whereas, Dr. Stamler noted, “the first World Health Organization statement did not come out until the 1980s.”

Philip Greenland, MD, professor of cardiology and former chair of preventive medicine at Northwestern, described Dr. Stamler as a “force for truth that never backed down when confronted by others who did not share his passion for truth and the best science.”

“I loved working with him since I always knew he would make our research better, clearer, more relevant, and more impactful,” he said in the AHA statement.

A lifelong activist and opponent of the Vietnam War, Dr. Stamler was subpoenaed in May 1965 by the House Un-American Activities Committee (HUAC) along with his nutritionist-assistant Yolanda Hall. Rather than pleading the Fifth Amendment against self-incrimination, Dr. Stamler and Ms. Hall refused to testify before the committee and were charged with contempt of Congress.

With the help of local attorneys, Dr. Stamler filed a civil suit against the HUAC, charging that its mandate was unconstitutional. After 8½ years of litigation that went all the way to the Supreme Court, the government agreed to drop its indictment against Dr. Stamler and he dropped his civil suit against the committee.

A year after the Stamler v. Willis case ended, the House voted to terminate the HUAC. In an essay detailing the high-profile case, Henry Blackburn quipped, “They simply did not know who they were taking on when they tagged ol’ Jerry Stamler.”

“Dr. Stamler’s exceptional science was paralleled by his remarkable humanity. He was a champion of our best American ideals, he was fearless when facing the status quo, and he was tireless in the pursuit of what was right and just. He remains a beacon for all that is noble in medicine,” said Clyde Yancy, MD, MSc, Northwestern’s chair of cardiology.

Over the course of his career, Dr. Stamler published more than 670 peer-reviewed papers, 22 books and monographs, and his work has been cited more than 56,000 times. A committed mentor, Dr. Stamler was the 2014 recipient of the AHA’s Eugene Braunwald Academic Mentorship Award.

A lifelong proponent of the Mediterranean diet, Dr. Stamler divided his time between New York, a home in Italy, and Chicago, with his wife Gloria Beckerman Stamler, whom he married in 2004 and who preceded him in death.

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

On the occasion of his 100th birthday, The Washington Post wrote of the trailblazing cardiologist and scientist Jeremiah Dr. Stamler, MD: “You may not know him, but he may have saved your life.”

Hyperbole, it was not.

Over a career spanning more than 70 years, Dr. Stamler transformed medicine and the public’s understanding of diet and lifestyle in cardiovascular health and helped introduce the concept of readily measured ‘risk factors’ such as cholesterol, hypertension, smoking, and diabetes.

Dr. Stamler, the founding chair and a professor emeritus of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago, died Wednesday at his home in Sag Harbor, New York, at age 102.

“It is no exaggeration to say that few people in history have had as great an impact on human health,” Donald Lloyd-Jones, MD, chair of the department of preventive medicine at Feinberg and president of the American Heart Association, said in a statement.

“Jerry was a giant intellect who founded the fields of cardiovascular epidemiology and preventive cardiology and led [the way] in defining new prevention concepts right up until his last days,” Dr. Lloyd-Jones added in a statement issued by the university.

Tom Frieden, MD, former director of the Centers for Disease Control and Prevention, tweeted, “Jerry and my father did research on sodium together in the early 1950s. He was a giant in the field of public health, and we’re still benefiting from his brilliance and dedication.”

Roger Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, tweeted, “R.I.P., Dr. Jeremiah Stamler, ‘the father of preventive cardiology,’ dies at 102 – a true legendary force for health.”

The son of Russian immigrants, Dr. Stamler was born in Brooklyn in 1919 and received a bachelor’s degree from Columbia University and a medical degree from State University of New York.

Discharged from the U.S. Army with the rank of captain, Dr. Stamler and his first wife, Rose, herself a distinguished cardiology researcher, moved to Chicago in 1947 and began researching nutrition and atherosclerosis under pioneering cardiology researcher Louis N. Katz, MD, ultimately showing that atherosclerosis could be introduced by changing the diet of chickens. She died in 1998.

Dr. Stamler also worked for Chicago’s Public Health Department in the 1950s, starting a rheumatic fever prevention program for children and the Chicago Coronary Prevention Evaluation Program, working with higher-risk middle-aged men.

Dr. Stamler’s international INTERSALT study established an independent relationship between blood pressure and increased sodium intake, as well as body mass index and heavy alcohol intake. First published in 1988, the research faced opposition from fellow scientists and the food industry alike.

In a 2006 interview, Dr. Stamler said he and fellow researchers began pressing the American Heart Association in the late 1950s to adopt a public policy of support to improve lifestyles, including smoking cessation and better nutrition. “It took some doing. The AHA was initially reluctant and was under pressure from industry.”

Their efforts were rewarded with the AHA’s first statement on smoking in 1959 and first statement on diet in 1960, whereas, Dr. Stamler noted, “the first World Health Organization statement did not come out until the 1980s.”

Philip Greenland, MD, professor of cardiology and former chair of preventive medicine at Northwestern, described Dr. Stamler as a “force for truth that never backed down when confronted by others who did not share his passion for truth and the best science.”

“I loved working with him since I always knew he would make our research better, clearer, more relevant, and more impactful,” he said in the AHA statement.

A lifelong activist and opponent of the Vietnam War, Dr. Stamler was subpoenaed in May 1965 by the House Un-American Activities Committee (HUAC) along with his nutritionist-assistant Yolanda Hall. Rather than pleading the Fifth Amendment against self-incrimination, Dr. Stamler and Ms. Hall refused to testify before the committee and were charged with contempt of Congress.

With the help of local attorneys, Dr. Stamler filed a civil suit against the HUAC, charging that its mandate was unconstitutional. After 8½ years of litigation that went all the way to the Supreme Court, the government agreed to drop its indictment against Dr. Stamler and he dropped his civil suit against the committee.

A year after the Stamler v. Willis case ended, the House voted to terminate the HUAC. In an essay detailing the high-profile case, Henry Blackburn quipped, “They simply did not know who they were taking on when they tagged ol’ Jerry Stamler.”

“Dr. Stamler’s exceptional science was paralleled by his remarkable humanity. He was a champion of our best American ideals, he was fearless when facing the status quo, and he was tireless in the pursuit of what was right and just. He remains a beacon for all that is noble in medicine,” said Clyde Yancy, MD, MSc, Northwestern’s chair of cardiology.

Over the course of his career, Dr. Stamler published more than 670 peer-reviewed papers, 22 books and monographs, and his work has been cited more than 56,000 times. A committed mentor, Dr. Stamler was the 2014 recipient of the AHA’s Eugene Braunwald Academic Mentorship Award.

A lifelong proponent of the Mediterranean diet, Dr. Stamler divided his time between New York, a home in Italy, and Chicago, with his wife Gloria Beckerman Stamler, whom he married in 2004 and who preceded him in death.

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

The Omicron-fueled surge appears to have peaked as new cases of COVID-19 in U.S. children dropped for the first time since late November 2021, dipping back below the 1 million mark for the week, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The case count for Jan. 21-27 was just over 808,000, down by almost 30% from the previous week’s 1.15 million. The total number of cases in children was up to 11.4 million as of Jan. 27, with children representing 18.6% of all cases reported since the pandemic started, the AAP and CHA said in their weekly COVID-19 report.

As children remain the largest reservoir of unvaccinated Americans, their share of the COVID case load continues to rise quickly. Just 2 weeks ago, children made up 17.8% of the cumulative number of cases, and at the end of December it was 17.4%, the AAP/CHA data show.

The latest data from the Centers for Disease Control and Prevention show that trends for admissions and emergency department visits reflect the decline in new cases. New admissions of children aged 0-17 years with diagnosed COVID-19 peaked at 1.25 per 100,000 population on Jan. 15 and were down to 0.95 per 100,000 on Jan. 29.

Daily ED visits for COVID-19, measured as a percentage of all ED visits, peaked at 13.9% on Jan. 14 for children aged 0-11 years and on Jan. 9 for both 12- to 15-year-olds (14.1%) and 16- to 17-year-olds (13.8%). By Jan. 28, the rates were down to 5.6% (0-11), 3.1% (12-15), and 3.3% (16-17), the CDC reported based on data from the National Syndromic Surveillance Program.

Trends involving more severe illness support observations that Omicron is milder than earlier variants. Children hospitalized with COVID-19 were less likely to be admitted to an intensive care unit over the last 2 months than during the Delta surge in the late summer and early fall or during the winter of 2020-2021, the CDC said based on data from the BD Insights Research Database, which includes 229,000 patients and 267 hospitals.

Those data show that the highest monthly rate occurred early on, in May of 2020, when 27.8% of children with COVID-19 ended up in the ICU. The rates for December 2021 and January 2022, by comparison, were 11.0% and 11.3%, respectively, the CDC said.

Vaccination lags in younger children

As reports surface about Pfizer-BioNTech filing an emergency use request to extend vaccine coverage to children aged 6 months to 5 years, it does appear that prevention efforts could use the proverbial shot in the arm.

As of Jan. 30, just 30.4% of children aged 5-11 have received at least one dose of the COVID-19 vaccine, and only 21.6% are fully vaccinated. At a comparable point in their timeline – just short of 3 months after approval – the respective numbers for children aged 12-15 were about 42% and 31%, CDC data show.

In the younger group, both initial doses and completions rose slightly in the first 2 weeks of January but then dropped in each of the last 2 weeks. There was a more significant surge in interest among the 12- to 17-year-olds in mid-January, but the last full week of the month brought declines of more than 50% in both measures, according to a separate AAP analysis.

The Omicron-fueled surge appears to have peaked as new cases of COVID-19 in U.S. children dropped for the first time since late November 2021, dipping back below the 1 million mark for the week, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The case count for Jan. 21-27 was just over 808,000, down by almost 30% from the previous week’s 1.15 million. The total number of cases in children was up to 11.4 million as of Jan. 27, with children representing 18.6% of all cases reported since the pandemic started, the AAP and CHA said in their weekly COVID-19 report.

As children remain the largest reservoir of unvaccinated Americans, their share of the COVID case load continues to rise quickly. Just 2 weeks ago, children made up 17.8% of the cumulative number of cases, and at the end of December it was 17.4%, the AAP/CHA data show.

The latest data from the Centers for Disease Control and Prevention show that trends for admissions and emergency department visits reflect the decline in new cases. New admissions of children aged 0-17 years with diagnosed COVID-19 peaked at 1.25 per 100,000 population on Jan. 15 and were down to 0.95 per 100,000 on Jan. 29.

Daily ED visits for COVID-19, measured as a percentage of all ED visits, peaked at 13.9% on Jan. 14 for children aged 0-11 years and on Jan. 9 for both 12- to 15-year-olds (14.1%) and 16- to 17-year-olds (13.8%). By Jan. 28, the rates were down to 5.6% (0-11), 3.1% (12-15), and 3.3% (16-17), the CDC reported based on data from the National Syndromic Surveillance Program.

Trends involving more severe illness support observations that Omicron is milder than earlier variants. Children hospitalized with COVID-19 were less likely to be admitted to an intensive care unit over the last 2 months than during the Delta surge in the late summer and early fall or during the winter of 2020-2021, the CDC said based on data from the BD Insights Research Database, which includes 229,000 patients and 267 hospitals.

Those data show that the highest monthly rate occurred early on, in May of 2020, when 27.8% of children with COVID-19 ended up in the ICU. The rates for December 2021 and January 2022, by comparison, were 11.0% and 11.3%, respectively, the CDC said.

Vaccination lags in younger children

As reports surface about Pfizer-BioNTech filing an emergency use request to extend vaccine coverage to children aged 6 months to 5 years, it does appear that prevention efforts could use the proverbial shot in the arm.

As of Jan. 30, just 30.4% of children aged 5-11 have received at least one dose of the COVID-19 vaccine, and only 21.6% are fully vaccinated. At a comparable point in their timeline – just short of 3 months after approval – the respective numbers for children aged 12-15 were about 42% and 31%, CDC data show.

In the younger group, both initial doses and completions rose slightly in the first 2 weeks of January but then dropped in each of the last 2 weeks. There was a more significant surge in interest among the 12- to 17-year-olds in mid-January, but the last full week of the month brought declines of more than 50% in both measures, according to a separate AAP analysis.

The Omicron-fueled surge appears to have peaked as new cases of COVID-19 in U.S. children dropped for the first time since late November 2021, dipping back below the 1 million mark for the week, according to the American Academy of Pediatrics and the Children’s Hospital Association.

The case count for Jan. 21-27 was just over 808,000, down by almost 30% from the previous week’s 1.15 million. The total number of cases in children was up to 11.4 million as of Jan. 27, with children representing 18.6% of all cases reported since the pandemic started, the AAP and CHA said in their weekly COVID-19 report.

As children remain the largest reservoir of unvaccinated Americans, their share of the COVID case load continues to rise quickly. Just 2 weeks ago, children made up 17.8% of the cumulative number of cases, and at the end of December it was 17.4%, the AAP/CHA data show.

The latest data from the Centers for Disease Control and Prevention show that trends for admissions and emergency department visits reflect the decline in new cases. New admissions of children aged 0-17 years with diagnosed COVID-19 peaked at 1.25 per 100,000 population on Jan. 15 and were down to 0.95 per 100,000 on Jan. 29.

Daily ED visits for COVID-19, measured as a percentage of all ED visits, peaked at 13.9% on Jan. 14 for children aged 0-11 years and on Jan. 9 for both 12- to 15-year-olds (14.1%) and 16- to 17-year-olds (13.8%). By Jan. 28, the rates were down to 5.6% (0-11), 3.1% (12-15), and 3.3% (16-17), the CDC reported based on data from the National Syndromic Surveillance Program.

Trends involving more severe illness support observations that Omicron is milder than earlier variants. Children hospitalized with COVID-19 were less likely to be admitted to an intensive care unit over the last 2 months than during the Delta surge in the late summer and early fall or during the winter of 2020-2021, the CDC said based on data from the BD Insights Research Database, which includes 229,000 patients and 267 hospitals.

Those data show that the highest monthly rate occurred early on, in May of 2020, when 27.8% of children with COVID-19 ended up in the ICU. The rates for December 2021 and January 2022, by comparison, were 11.0% and 11.3%, respectively, the CDC said.

Vaccination lags in younger children

As reports surface about Pfizer-BioNTech filing an emergency use request to extend vaccine coverage to children aged 6 months to 5 years, it does appear that prevention efforts could use the proverbial shot in the arm.

As of Jan. 30, just 30.4% of children aged 5-11 have received at least one dose of the COVID-19 vaccine, and only 21.6% are fully vaccinated. At a comparable point in their timeline – just short of 3 months after approval – the respective numbers for children aged 12-15 were about 42% and 31%, CDC data show.

In the younger group, both initial doses and completions rose slightly in the first 2 weeks of January but then dropped in each of the last 2 weeks. There was a more significant surge in interest among the 12- to 17-year-olds in mid-January, but the last full week of the month brought declines of more than 50% in both measures, according to a separate AAP analysis.