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‘Valid option’ for partial breast irradiation in breast cancer
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- According to numerous guidelines, partial breast irradiation after lumpectomy is a sound approach for early-stage breast cancer, but there is a lack of consensus about treatment schedules.
- The investigators suggest that 30 Gy in five daily fractions is a “valid option” for these patients in a field that lacks consensus.
Study design
- The team reviewed 381 women with early breast cancer treated with this approach (30 Gy in five daily fractions) at their center from 2013 to 2022.
- Half of patients had left-sided tumors, 94.5% had invasive ductal carcinomas, 96.6% had grade 1 or grade 2 disease, and tumors were luminal like in 99.2% of patients.
- Following lumpectomy, women underwent partial breast irradiation to the tumor bed plus 15 mm of isometric expansion beyond it.
- Follow-up was a median of 28 months.
Key results
- Seven patients (2%) had a local recurrence, of which two were in the treatment field.
- Three-year local control, disease-free survival, and overall survival were high (97.5%, 95.7%, and 96.9%, respectively).
- Nearly 90% of patients and 97% of physicians reported good or excellent cosmesis.
- Ten patients (2.9%) had grade 2 late toxicities, including edema, asthenia, and fibrosis; there were no grade 3 or higher adverse events.
- Five patients (1.5%) had late cardiac major events, four of whom were treated on the right breast; three patients (0.9%) had late pulmonary fibrosis.
- The safety and efficacy outcomes are in line with previous reports, including those that used different dosage and/or fractionation schedules.
Limitations
- The study was retrospective, with a relatively short follow-up.
- Quality of life was not assessed.
- There was no objective baseline measure of cosmesis against which to compare cosmetic results.
Disclosures
- There was no funding for the study, and the investigators didn’t have any conflicts of interest to report.
This is a summary of a preprint research study, “One-Week External Beam Partial Breast Irradiation: Survival and Toxicity Outcomes,” led by Riccardo Ray Colciago from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. The study has not been peer reviewed. The full text can be found at researchsquare.com.
A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- According to numerous guidelines, partial breast irradiation after lumpectomy is a sound approach for early-stage breast cancer, but there is a lack of consensus about treatment schedules.
- The investigators suggest that 30 Gy in five daily fractions is a “valid option” for these patients in a field that lacks consensus.
Study design
- The team reviewed 381 women with early breast cancer treated with this approach (30 Gy in five daily fractions) at their center from 2013 to 2022.
- Half of patients had left-sided tumors, 94.5% had invasive ductal carcinomas, 96.6% had grade 1 or grade 2 disease, and tumors were luminal like in 99.2% of patients.
- Following lumpectomy, women underwent partial breast irradiation to the tumor bed plus 15 mm of isometric expansion beyond it.
- Follow-up was a median of 28 months.
Key results
- Seven patients (2%) had a local recurrence, of which two were in the treatment field.
- Three-year local control, disease-free survival, and overall survival were high (97.5%, 95.7%, and 96.9%, respectively).
- Nearly 90% of patients and 97% of physicians reported good or excellent cosmesis.
- Ten patients (2.9%) had grade 2 late toxicities, including edema, asthenia, and fibrosis; there were no grade 3 or higher adverse events.
- Five patients (1.5%) had late cardiac major events, four of whom were treated on the right breast; three patients (0.9%) had late pulmonary fibrosis.
- The safety and efficacy outcomes are in line with previous reports, including those that used different dosage and/or fractionation schedules.
Limitations
- The study was retrospective, with a relatively short follow-up.
- Quality of life was not assessed.
- There was no objective baseline measure of cosmesis against which to compare cosmetic results.
Disclosures
- There was no funding for the study, and the investigators didn’t have any conflicts of interest to report.
This is a summary of a preprint research study, “One-Week External Beam Partial Breast Irradiation: Survival and Toxicity Outcomes,” led by Riccardo Ray Colciago from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. The study has not been peer reviewed. The full text can be found at researchsquare.com.
A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- According to numerous guidelines, partial breast irradiation after lumpectomy is a sound approach for early-stage breast cancer, but there is a lack of consensus about treatment schedules.
- The investigators suggest that 30 Gy in five daily fractions is a “valid option” for these patients in a field that lacks consensus.
Study design
- The team reviewed 381 women with early breast cancer treated with this approach (30 Gy in five daily fractions) at their center from 2013 to 2022.
- Half of patients had left-sided tumors, 94.5% had invasive ductal carcinomas, 96.6% had grade 1 or grade 2 disease, and tumors were luminal like in 99.2% of patients.
- Following lumpectomy, women underwent partial breast irradiation to the tumor bed plus 15 mm of isometric expansion beyond it.
- Follow-up was a median of 28 months.
Key results
- Seven patients (2%) had a local recurrence, of which two were in the treatment field.
- Three-year local control, disease-free survival, and overall survival were high (97.5%, 95.7%, and 96.9%, respectively).
- Nearly 90% of patients and 97% of physicians reported good or excellent cosmesis.
- Ten patients (2.9%) had grade 2 late toxicities, including edema, asthenia, and fibrosis; there were no grade 3 or higher adverse events.
- Five patients (1.5%) had late cardiac major events, four of whom were treated on the right breast; three patients (0.9%) had late pulmonary fibrosis.
- The safety and efficacy outcomes are in line with previous reports, including those that used different dosage and/or fractionation schedules.
Limitations
- The study was retrospective, with a relatively short follow-up.
- Quality of life was not assessed.
- There was no objective baseline measure of cosmesis against which to compare cosmetic results.
Disclosures
- There was no funding for the study, and the investigators didn’t have any conflicts of interest to report.
This is a summary of a preprint research study, “One-Week External Beam Partial Breast Irradiation: Survival and Toxicity Outcomes,” led by Riccardo Ray Colciago from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. The study has not been peer reviewed. The full text can be found at researchsquare.com.
A version of this article first appeared on Medscape.com.
Facial lipoatrophy with semaglutide-related weight loss
Ozempic and Wegovy are two prescription drugs that have transformed the management of type 2 diabetes and obesity. Both are a form of semaglutide; the Food and Drug Administration approved Ozempic for treating type 2 diabetes in 2017, followed by Wegovy in 2021 for weight loss in adults with obesity or those who are overweight and have least one weight-related health condition, such as hypertension or hypercholesterolemia. Ozempic is not approved for weight loss, but it has been prescribed off label for that purpose.
An effective treatment, participants with overweight or obesity in one study experienced almost a mean 15% drop in body weight with subcutaneous semaglutide administered once a week versus about 2% with placebo after 68 weeks.
In 2022, high demand and global supply constraints gave rise to shortages of both medications. The FDA reported a Wegovy shortage in March 2022, followed by an Ozempic shortage in August. Social media attention and increased off-label prescribing, with some patients purporting to have had significant improvements with weight loss and their quality of life, including having their clothing fit better and being able to bend over and tie their shoes, increased attention on these medications to the point that off-label prescribing of both drugs for weight loss resulted in some patients with type 2 diabetes unable to receive their medication on time. In late January 2023, NBC reported that Ozempic prescriptions had “tripled from 2021 to 2022,” based on data from the prescription drug discount company SingleCare.
Semaglutide is designed to mimic a hormone that signals to the brain when a person is full and promotes the release of insulin. In turn, the medications can result in lower blood glucose levels, appetite suppression, and reduced caloric intake. Injected once weekly, the medication, a glucagonlike peptide–1 receptor agonist, specifically, activates GLP-1 receptors in the brain, increasing insulin secretion, decreasing glucagon secretion, and delaying gastric emptying (acting as an incretin mimetic).
‘Ozempic face’
Common adverse events with semaglutide can include nausea, vomiting, diarrhea, abdominal pain, constipation, and injection-site reactions. Rare, but more severe adverse events may include thyroid C-cell tumor (in animal studies), medullary thyroid cancer risk, hypersensitivity reaction, anaphylaxis, acute renal injury, chronic renal failure exacerbation, pancreatitis, and cholelithiasis.
A less severe but noticeable side effect that has gained attention is facial wasting and aging, reportedly coined “Ozempic face” by a dermatologist interviewed for an article published in January in The New York Times.
As of Feb. 9, TikTok videos from individuals describing their personal experiences, health care professionals, and others with the tag #ozempicface had 4.8 million views.
Theories as to why noticeable facial changes occur with these medications include: accelerated loss of facial pads that already tend to diminish or shift with normal aging, as well as the inability of skin elasticity to keep up with the loss of volume (fat), resulting in more prominent hanging skin and the appearance of “jowls.” Wan and colleagues have described the fat pad distribution in the face and the facial aging that occurs as a result of the loss and shifting of these fat pads over time.
In the same way that we use facial fillers to help treat and correct volume/fat loss associated with photoaging, facial fillers may be used to help restore volume where it’s been lost after weight loss. The sagging skin or loss of elasticity often associated with Ozempic-related weight loss or with rapid or noticeable weight loss in general, may or may not also require other interventions that include treatment with tissue tightening devices – such as radiofrequency energy, high-focused ultrasound energy, threads, and/or surgery – such as a face lift. The potential high cost of both off-label prescribing of these medications (especially without use of prescription health insurance) as well as treatment to correct any facial wasting has also received attention in news media and social media discussions of this topic.
Dr. Wesley practices dermatology in Beverly Hills, Calif. Write to her at [email protected]. She has no relevant disclosures.
*Correction 1/28/23: An earlier version of this story misstated the approval date of Wegovy. It was in 2021.
Ozempic and Wegovy are two prescription drugs that have transformed the management of type 2 diabetes and obesity. Both are a form of semaglutide; the Food and Drug Administration approved Ozempic for treating type 2 diabetes in 2017, followed by Wegovy in 2021 for weight loss in adults with obesity or those who are overweight and have least one weight-related health condition, such as hypertension or hypercholesterolemia. Ozempic is not approved for weight loss, but it has been prescribed off label for that purpose.
An effective treatment, participants with overweight or obesity in one study experienced almost a mean 15% drop in body weight with subcutaneous semaglutide administered once a week versus about 2% with placebo after 68 weeks.
In 2022, high demand and global supply constraints gave rise to shortages of both medications. The FDA reported a Wegovy shortage in March 2022, followed by an Ozempic shortage in August. Social media attention and increased off-label prescribing, with some patients purporting to have had significant improvements with weight loss and their quality of life, including having their clothing fit better and being able to bend over and tie their shoes, increased attention on these medications to the point that off-label prescribing of both drugs for weight loss resulted in some patients with type 2 diabetes unable to receive their medication on time. In late January 2023, NBC reported that Ozempic prescriptions had “tripled from 2021 to 2022,” based on data from the prescription drug discount company SingleCare.
Semaglutide is designed to mimic a hormone that signals to the brain when a person is full and promotes the release of insulin. In turn, the medications can result in lower blood glucose levels, appetite suppression, and reduced caloric intake. Injected once weekly, the medication, a glucagonlike peptide–1 receptor agonist, specifically, activates GLP-1 receptors in the brain, increasing insulin secretion, decreasing glucagon secretion, and delaying gastric emptying (acting as an incretin mimetic).
‘Ozempic face’
Common adverse events with semaglutide can include nausea, vomiting, diarrhea, abdominal pain, constipation, and injection-site reactions. Rare, but more severe adverse events may include thyroid C-cell tumor (in animal studies), medullary thyroid cancer risk, hypersensitivity reaction, anaphylaxis, acute renal injury, chronic renal failure exacerbation, pancreatitis, and cholelithiasis.
A less severe but noticeable side effect that has gained attention is facial wasting and aging, reportedly coined “Ozempic face” by a dermatologist interviewed for an article published in January in The New York Times.
As of Feb. 9, TikTok videos from individuals describing their personal experiences, health care professionals, and others with the tag #ozempicface had 4.8 million views.
Theories as to why noticeable facial changes occur with these medications include: accelerated loss of facial pads that already tend to diminish or shift with normal aging, as well as the inability of skin elasticity to keep up with the loss of volume (fat), resulting in more prominent hanging skin and the appearance of “jowls.” Wan and colleagues have described the fat pad distribution in the face and the facial aging that occurs as a result of the loss and shifting of these fat pads over time.
In the same way that we use facial fillers to help treat and correct volume/fat loss associated with photoaging, facial fillers may be used to help restore volume where it’s been lost after weight loss. The sagging skin or loss of elasticity often associated with Ozempic-related weight loss or with rapid or noticeable weight loss in general, may or may not also require other interventions that include treatment with tissue tightening devices – such as radiofrequency energy, high-focused ultrasound energy, threads, and/or surgery – such as a face lift. The potential high cost of both off-label prescribing of these medications (especially without use of prescription health insurance) as well as treatment to correct any facial wasting has also received attention in news media and social media discussions of this topic.
Dr. Wesley practices dermatology in Beverly Hills, Calif. Write to her at [email protected]. She has no relevant disclosures.
*Correction 1/28/23: An earlier version of this story misstated the approval date of Wegovy. It was in 2021.
Ozempic and Wegovy are two prescription drugs that have transformed the management of type 2 diabetes and obesity. Both are a form of semaglutide; the Food and Drug Administration approved Ozempic for treating type 2 diabetes in 2017, followed by Wegovy in 2021 for weight loss in adults with obesity or those who are overweight and have least one weight-related health condition, such as hypertension or hypercholesterolemia. Ozempic is not approved for weight loss, but it has been prescribed off label for that purpose.
An effective treatment, participants with overweight or obesity in one study experienced almost a mean 15% drop in body weight with subcutaneous semaglutide administered once a week versus about 2% with placebo after 68 weeks.
In 2022, high demand and global supply constraints gave rise to shortages of both medications. The FDA reported a Wegovy shortage in March 2022, followed by an Ozempic shortage in August. Social media attention and increased off-label prescribing, with some patients purporting to have had significant improvements with weight loss and their quality of life, including having their clothing fit better and being able to bend over and tie their shoes, increased attention on these medications to the point that off-label prescribing of both drugs for weight loss resulted in some patients with type 2 diabetes unable to receive their medication on time. In late January 2023, NBC reported that Ozempic prescriptions had “tripled from 2021 to 2022,” based on data from the prescription drug discount company SingleCare.
Semaglutide is designed to mimic a hormone that signals to the brain when a person is full and promotes the release of insulin. In turn, the medications can result in lower blood glucose levels, appetite suppression, and reduced caloric intake. Injected once weekly, the medication, a glucagonlike peptide–1 receptor agonist, specifically, activates GLP-1 receptors in the brain, increasing insulin secretion, decreasing glucagon secretion, and delaying gastric emptying (acting as an incretin mimetic).
‘Ozempic face’
Common adverse events with semaglutide can include nausea, vomiting, diarrhea, abdominal pain, constipation, and injection-site reactions. Rare, but more severe adverse events may include thyroid C-cell tumor (in animal studies), medullary thyroid cancer risk, hypersensitivity reaction, anaphylaxis, acute renal injury, chronic renal failure exacerbation, pancreatitis, and cholelithiasis.
A less severe but noticeable side effect that has gained attention is facial wasting and aging, reportedly coined “Ozempic face” by a dermatologist interviewed for an article published in January in The New York Times.
As of Feb. 9, TikTok videos from individuals describing their personal experiences, health care professionals, and others with the tag #ozempicface had 4.8 million views.
Theories as to why noticeable facial changes occur with these medications include: accelerated loss of facial pads that already tend to diminish or shift with normal aging, as well as the inability of skin elasticity to keep up with the loss of volume (fat), resulting in more prominent hanging skin and the appearance of “jowls.” Wan and colleagues have described the fat pad distribution in the face and the facial aging that occurs as a result of the loss and shifting of these fat pads over time.
In the same way that we use facial fillers to help treat and correct volume/fat loss associated with photoaging, facial fillers may be used to help restore volume where it’s been lost after weight loss. The sagging skin or loss of elasticity often associated with Ozempic-related weight loss or with rapid or noticeable weight loss in general, may or may not also require other interventions that include treatment with tissue tightening devices – such as radiofrequency energy, high-focused ultrasound energy, threads, and/or surgery – such as a face lift. The potential high cost of both off-label prescribing of these medications (especially without use of prescription health insurance) as well as treatment to correct any facial wasting has also received attention in news media and social media discussions of this topic.
Dr. Wesley practices dermatology in Beverly Hills, Calif. Write to her at [email protected]. She has no relevant disclosures.
*Correction 1/28/23: An earlier version of this story misstated the approval date of Wegovy. It was in 2021.
Novel neuroprotective agent promising in stroke
preliminary results of a first-in-human study show.
The findings illustrate that it is possible to improve outcomes for stroke patients “not only with reperfusion therapy but with neuroprotectants,” study author Macarena Hernandez, PhD, associate professor, University Complutense, Madrid, told this news organization.
Dr. Hernandez said she hopes these positive results will spur investigation into other neuroprotective agents.
The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Best doses
The study investigated ApTOLL, which blocks the TOLL-like receptor 4 (TLR4) that induces inflammation after a stroke. Previous studies found that ApTOLL protected brain tissue in animal models of stroke.
The phase 1B part of the study found no safety issues and determined the best two doses to be used in phase 2A were 0.05 mg/kg and 0.2 mg/kg.
The analysis included 139 patients at 14 centers in Spain and France (mean age, about 70 years; 42% women) who had a large-vessel occlusion and were eligible for endovascular therapy.
“Our aim was to have a very homogeneous population” to try to replicate in humans what had worked in animals, another study author, Marc Ribó, MD, interventional neurologist, Hospital Vall d’Hebron, Barcelona, told this news organization.
Study participants had an Alberta Stroke Program Early CT Score (ASPECTS) of 5-10, and estimated infarct core volume on CT-perfusion was 5-70 mL. All were treated within 6 hours of stroke onset.
Researchers randomly assigned patients to receive the low dose of the drug, the high dose of the drug, or placebo. The drug was administered intravenously over a 30-minute period just prior to the groin puncture for the thrombectomy procedure.
“So, the drug had already started to work when they underwent the usual standard practice, the thrombectomy,” said Dr. Ribó.
Those who were eligible also received tissue plasminogen activator.
The primary endpoint was safety, including death, symptomatic intracranial hemorrhage (SICH), and recurrent stroke.
Lower mortality
At 90 days, there was a statistically significant lower mortality rate in the high-dose group, compared with the group that received placebo (4.76% vs. 18.18%).
The mortality rate was 26.19% in the low-dose group, but Dr. Ribó stressed that this dose was a quarter of the higher dose and so performed “much more like placebo.”
The higher dose also yielded a better SICH outcome (4.76% of patients vs. 7.27% for placebo and 7.14% for the lower dose). And it was superior in terms of brain edema (2.4% of the population vs. 7.3% for the placebo and 4.8% for the low-dose groups).
About 7.1% of the high-dose group, 3.7% of the placebo group, and 4.8% of the low-dose group had a recurrent transient ischemic attack or stroke.
A secondary efficacy endpoint was infarct volume on MRI at 72 hours. Here, for the higher-dose group, mean infarct volume was reduced, compared with the patients who received placebo (–29.31 cc; 90% confidence interval, –49.28 to –9.34).
This higher dose was also superior for the secondary outcome of National Institutes of Health Stroke Scale score at 72 hours and for the disability outcome on the modified Rankin Score (mRS).
Clear shift in disability
“There was a clear shift toward less disability across levels of the mRS score in the high-dose group at 90 days,” said Dr. Ribó.
He added that he and his colleagues are “very happy” with these results, as they reflect “a consistency” of outcomes.
“We observed that the infarct volumes were lower in the high-dose group, and that led to a significant lower NIH score, meaning less clinical neurological symptoms at 72 hours, and finally, this led to less disability at 90 days.”
These results are “very exciting,” Dr. Hernandez added. “This is the first neuroprotectant that has demonstrated this acute effect in reducing deaths, in reducing the infarct volume and improving functionality long-term in patients treated with the higher dose.”
Dr. Ribó noted the treatment would eventually be used in addition to reperfusion therapy. “It’s not competing with reperfusion treatment; it’s an additional layer” of treatment.
Although it would initially be offered only to patients eligible for thrombectomy, researchers will explore the drug’s effectiveness for other stroke patients, said Dr. Ribó. “We wanted to secure this indication, and from there, progressively expand to other profiles of stroke patients, and even to patients with intracranial hemorrhage.”
The study confirmed the safety of the drug. “There were no safety issues at all,” said Dr. Ribó. “We were initially concerned that an anti-inflammatory in these patients could lead to higher rates of infections, but this was absolutely not the case.”
The next step is to confirm the effects in a larger, multicenter study, which is planned to launch at the end of this year, said Dr. Hernandez.
‘Very robust results’
In a comment, Philip B. Gorelick, MD, professor of neurology, Northwestern University, Chicago, said that, while this was a small early-phase study, the results are “very robust.”
“The authors demonstrated proof of a neuroprotective effect; they showed at 90 days that the death rates were substantially reduced by about four times – 4% vs. 18% – and the size of the damaged tissue at about 72 hours was reduced by 40%,” said Dr. Gorelick, who did not participate in the study.
He also noted that the disability was “less pronounced” at 90 days in the 0.2 mg/kg group.
“So overall, these are very encouraging results,” said Dr. Gorelick. “We have had a lot of difficulty finding neuroprotectant drugs that work, and this drug, in combination with endovascular therapy, seems to be very promising.”
However, he stressed the drug “is not ready for prime-time practice.”
“The proof in the pudding will be in the large-scale main phase 3 trials,” he added.
The study was funded by aptaTargets. Dr. Hernandez is chief scientific officer at aptaTargets. Dr. Ribó is an adviser at AptaTargets; a consultant at Medtronic; has ownership interest in Anaconda and NoraHealth; is a consultant for Cerenovus and Philips; and has stock options at Methink. Dr. Gorelick has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
preliminary results of a first-in-human study show.
The findings illustrate that it is possible to improve outcomes for stroke patients “not only with reperfusion therapy but with neuroprotectants,” study author Macarena Hernandez, PhD, associate professor, University Complutense, Madrid, told this news organization.
Dr. Hernandez said she hopes these positive results will spur investigation into other neuroprotective agents.
The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Best doses
The study investigated ApTOLL, which blocks the TOLL-like receptor 4 (TLR4) that induces inflammation after a stroke. Previous studies found that ApTOLL protected brain tissue in animal models of stroke.
The phase 1B part of the study found no safety issues and determined the best two doses to be used in phase 2A were 0.05 mg/kg and 0.2 mg/kg.
The analysis included 139 patients at 14 centers in Spain and France (mean age, about 70 years; 42% women) who had a large-vessel occlusion and were eligible for endovascular therapy.
“Our aim was to have a very homogeneous population” to try to replicate in humans what had worked in animals, another study author, Marc Ribó, MD, interventional neurologist, Hospital Vall d’Hebron, Barcelona, told this news organization.
Study participants had an Alberta Stroke Program Early CT Score (ASPECTS) of 5-10, and estimated infarct core volume on CT-perfusion was 5-70 mL. All were treated within 6 hours of stroke onset.
Researchers randomly assigned patients to receive the low dose of the drug, the high dose of the drug, or placebo. The drug was administered intravenously over a 30-minute period just prior to the groin puncture for the thrombectomy procedure.
“So, the drug had already started to work when they underwent the usual standard practice, the thrombectomy,” said Dr. Ribó.
Those who were eligible also received tissue plasminogen activator.
The primary endpoint was safety, including death, symptomatic intracranial hemorrhage (SICH), and recurrent stroke.
Lower mortality
At 90 days, there was a statistically significant lower mortality rate in the high-dose group, compared with the group that received placebo (4.76% vs. 18.18%).
The mortality rate was 26.19% in the low-dose group, but Dr. Ribó stressed that this dose was a quarter of the higher dose and so performed “much more like placebo.”
The higher dose also yielded a better SICH outcome (4.76% of patients vs. 7.27% for placebo and 7.14% for the lower dose). And it was superior in terms of brain edema (2.4% of the population vs. 7.3% for the placebo and 4.8% for the low-dose groups).
About 7.1% of the high-dose group, 3.7% of the placebo group, and 4.8% of the low-dose group had a recurrent transient ischemic attack or stroke.
A secondary efficacy endpoint was infarct volume on MRI at 72 hours. Here, for the higher-dose group, mean infarct volume was reduced, compared with the patients who received placebo (–29.31 cc; 90% confidence interval, –49.28 to –9.34).
This higher dose was also superior for the secondary outcome of National Institutes of Health Stroke Scale score at 72 hours and for the disability outcome on the modified Rankin Score (mRS).
Clear shift in disability
“There was a clear shift toward less disability across levels of the mRS score in the high-dose group at 90 days,” said Dr. Ribó.
He added that he and his colleagues are “very happy” with these results, as they reflect “a consistency” of outcomes.
“We observed that the infarct volumes were lower in the high-dose group, and that led to a significant lower NIH score, meaning less clinical neurological symptoms at 72 hours, and finally, this led to less disability at 90 days.”
These results are “very exciting,” Dr. Hernandez added. “This is the first neuroprotectant that has demonstrated this acute effect in reducing deaths, in reducing the infarct volume and improving functionality long-term in patients treated with the higher dose.”
Dr. Ribó noted the treatment would eventually be used in addition to reperfusion therapy. “It’s not competing with reperfusion treatment; it’s an additional layer” of treatment.
Although it would initially be offered only to patients eligible for thrombectomy, researchers will explore the drug’s effectiveness for other stroke patients, said Dr. Ribó. “We wanted to secure this indication, and from there, progressively expand to other profiles of stroke patients, and even to patients with intracranial hemorrhage.”
The study confirmed the safety of the drug. “There were no safety issues at all,” said Dr. Ribó. “We were initially concerned that an anti-inflammatory in these patients could lead to higher rates of infections, but this was absolutely not the case.”
The next step is to confirm the effects in a larger, multicenter study, which is planned to launch at the end of this year, said Dr. Hernandez.
‘Very robust results’
In a comment, Philip B. Gorelick, MD, professor of neurology, Northwestern University, Chicago, said that, while this was a small early-phase study, the results are “very robust.”
“The authors demonstrated proof of a neuroprotective effect; they showed at 90 days that the death rates were substantially reduced by about four times – 4% vs. 18% – and the size of the damaged tissue at about 72 hours was reduced by 40%,” said Dr. Gorelick, who did not participate in the study.
He also noted that the disability was “less pronounced” at 90 days in the 0.2 mg/kg group.
“So overall, these are very encouraging results,” said Dr. Gorelick. “We have had a lot of difficulty finding neuroprotectant drugs that work, and this drug, in combination with endovascular therapy, seems to be very promising.”
However, he stressed the drug “is not ready for prime-time practice.”
“The proof in the pudding will be in the large-scale main phase 3 trials,” he added.
The study was funded by aptaTargets. Dr. Hernandez is chief scientific officer at aptaTargets. Dr. Ribó is an adviser at AptaTargets; a consultant at Medtronic; has ownership interest in Anaconda and NoraHealth; is a consultant for Cerenovus and Philips; and has stock options at Methink. Dr. Gorelick has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
preliminary results of a first-in-human study show.
The findings illustrate that it is possible to improve outcomes for stroke patients “not only with reperfusion therapy but with neuroprotectants,” study author Macarena Hernandez, PhD, associate professor, University Complutense, Madrid, told this news organization.
Dr. Hernandez said she hopes these positive results will spur investigation into other neuroprotective agents.
The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
Best doses
The study investigated ApTOLL, which blocks the TOLL-like receptor 4 (TLR4) that induces inflammation after a stroke. Previous studies found that ApTOLL protected brain tissue in animal models of stroke.
The phase 1B part of the study found no safety issues and determined the best two doses to be used in phase 2A were 0.05 mg/kg and 0.2 mg/kg.
The analysis included 139 patients at 14 centers in Spain and France (mean age, about 70 years; 42% women) who had a large-vessel occlusion and were eligible for endovascular therapy.
“Our aim was to have a very homogeneous population” to try to replicate in humans what had worked in animals, another study author, Marc Ribó, MD, interventional neurologist, Hospital Vall d’Hebron, Barcelona, told this news organization.
Study participants had an Alberta Stroke Program Early CT Score (ASPECTS) of 5-10, and estimated infarct core volume on CT-perfusion was 5-70 mL. All were treated within 6 hours of stroke onset.
Researchers randomly assigned patients to receive the low dose of the drug, the high dose of the drug, or placebo. The drug was administered intravenously over a 30-minute period just prior to the groin puncture for the thrombectomy procedure.
“So, the drug had already started to work when they underwent the usual standard practice, the thrombectomy,” said Dr. Ribó.
Those who were eligible also received tissue plasminogen activator.
The primary endpoint was safety, including death, symptomatic intracranial hemorrhage (SICH), and recurrent stroke.
Lower mortality
At 90 days, there was a statistically significant lower mortality rate in the high-dose group, compared with the group that received placebo (4.76% vs. 18.18%).
The mortality rate was 26.19% in the low-dose group, but Dr. Ribó stressed that this dose was a quarter of the higher dose and so performed “much more like placebo.”
The higher dose also yielded a better SICH outcome (4.76% of patients vs. 7.27% for placebo and 7.14% for the lower dose). And it was superior in terms of brain edema (2.4% of the population vs. 7.3% for the placebo and 4.8% for the low-dose groups).
About 7.1% of the high-dose group, 3.7% of the placebo group, and 4.8% of the low-dose group had a recurrent transient ischemic attack or stroke.
A secondary efficacy endpoint was infarct volume on MRI at 72 hours. Here, for the higher-dose group, mean infarct volume was reduced, compared with the patients who received placebo (–29.31 cc; 90% confidence interval, –49.28 to –9.34).
This higher dose was also superior for the secondary outcome of National Institutes of Health Stroke Scale score at 72 hours and for the disability outcome on the modified Rankin Score (mRS).
Clear shift in disability
“There was a clear shift toward less disability across levels of the mRS score in the high-dose group at 90 days,” said Dr. Ribó.
He added that he and his colleagues are “very happy” with these results, as they reflect “a consistency” of outcomes.
“We observed that the infarct volumes were lower in the high-dose group, and that led to a significant lower NIH score, meaning less clinical neurological symptoms at 72 hours, and finally, this led to less disability at 90 days.”
These results are “very exciting,” Dr. Hernandez added. “This is the first neuroprotectant that has demonstrated this acute effect in reducing deaths, in reducing the infarct volume and improving functionality long-term in patients treated with the higher dose.”
Dr. Ribó noted the treatment would eventually be used in addition to reperfusion therapy. “It’s not competing with reperfusion treatment; it’s an additional layer” of treatment.
Although it would initially be offered only to patients eligible for thrombectomy, researchers will explore the drug’s effectiveness for other stroke patients, said Dr. Ribó. “We wanted to secure this indication, and from there, progressively expand to other profiles of stroke patients, and even to patients with intracranial hemorrhage.”
The study confirmed the safety of the drug. “There were no safety issues at all,” said Dr. Ribó. “We were initially concerned that an anti-inflammatory in these patients could lead to higher rates of infections, but this was absolutely not the case.”
The next step is to confirm the effects in a larger, multicenter study, which is planned to launch at the end of this year, said Dr. Hernandez.
‘Very robust results’
In a comment, Philip B. Gorelick, MD, professor of neurology, Northwestern University, Chicago, said that, while this was a small early-phase study, the results are “very robust.”
“The authors demonstrated proof of a neuroprotective effect; they showed at 90 days that the death rates were substantially reduced by about four times – 4% vs. 18% – and the size of the damaged tissue at about 72 hours was reduced by 40%,” said Dr. Gorelick, who did not participate in the study.
He also noted that the disability was “less pronounced” at 90 days in the 0.2 mg/kg group.
“So overall, these are very encouraging results,” said Dr. Gorelick. “We have had a lot of difficulty finding neuroprotectant drugs that work, and this drug, in combination with endovascular therapy, seems to be very promising.”
However, he stressed the drug “is not ready for prime-time practice.”
“The proof in the pudding will be in the large-scale main phase 3 trials,” he added.
The study was funded by aptaTargets. Dr. Hernandez is chief scientific officer at aptaTargets. Dr. Ribó is an adviser at AptaTargets; a consultant at Medtronic; has ownership interest in Anaconda and NoraHealth; is a consultant for Cerenovus and Philips; and has stock options at Methink. Dr. Gorelick has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023
Radiotherapy for early breast cancer: Sharp cutoff at age 70
say researchers reporting new data showing a sharp cut-off at age 70.
“In our study, one of the most significant variables in determining whether breast cancer patients who are close their 70th birthday are recommended standard-of-care radiation or de-escalated treatment is whether they show up a few months before or a few months after that 70th birthday,” commented study author Wesley J. Talcott, MD, of the department of therapeutic radiology at the Yale School of Medicine, New Haven, Conn.
The results show a trend in which radiation therapy is 50% less likely to be prescribed for patients age 70 and older with early-stage breast cancer, even when controlling for population size, patient demographics, and disease specific variables.
This suggests that oncologists are weighing the variable of age too heavily when deciding on adjuvant treatments, the authors suggest.
“In certain circumstances, breast cancer oncology providers are treating age like a binary categorical variable when selecting patients for treatments or diagnostic procedures, rather than the continuous variable that it is,” Dr. Talcott commented.
The study was published online in the International Journal of Radiation Oncology: Biology, Physics.
Approached for comment, Casey Chollet-Lipscomb, MD, radiation oncologist with Tennessee Oncology, Nashville, who was not associated with the study, agreed with its main finding.
“The study helps emphasize the importance of individualized care,” she said. “Increasing age is the most common risk factor for breast cancer, but breast cancer is an incredibly diverse disease. While you can observe trends based on age, every patient is unique, and they can’t be lumped into one bucket and prescribed treatment based on a strict age cutoff.”
The retrospective study included two cohorts of women identified in the National Cancer Data Base (2004-2017) all of whom underwent lumpectomy for early-stage breast cancer. All patients had “strong indications” for adjuvant treatment.
Patients in cohort 1 (n = 160,990) included women with estrogen-receptor negative cancer, tumor size greater than 3 cm, who were determined to be “appropriate” for radiation therapy.
Patients in cohort 2 (n = 394,946) had hormone-receptor positive cancer, tumor size greater than 5 mm, and were considered to be “appropriate” candidates for endocrine therapy.
Multivariable analysis was performed to control for comorbidity burden (measured by the Charlson-Deyo Comorbidity Index), race and ethnicity, insurance status, academic versus non-academic treatment center, median annual income of a patient’s area of residence, distance from the site of treatment, and pathology variables including number of lymph nodes sampled, histologic grade, and genomic risk score.
In cohort 1, radiation was recommended for 90%-92% of patients between the ages of 50-69; this dropped to 81% for those aged 70.
After MVA, it was determined that age difference was an independent predictor for adjuvant radiation recommendation only at age 70 versus 69 (odds ratio, 0.47; 95% confidence interval 0.39-0.57, P < .001).
For cohort 2, year-over-year age difference predicted endocrine therapy recommendation only at the juncture between age 70 versus 69 (OR, 0.86, 95% CI 0.74-0.99, P = .001).
“Our results don’t say that we should be increasing the amount of treatment for patients over the age [of] 70 or decreasing that patient treatment for patients younger than age 70. What we believe is that we need to be assessing physiologic age of our patients when treating patients,” Dr. Talcott said.
“We would do this by looking at not just how many years a patient has been on this Earth but also what their current health status is, how many good quality-of-life years they might have after treatment or without it, and what the patient wants in terms of burden of treatment. This is a much more valuable way to approach the allocation of treatments than using age alone,” he added.
Both Dr. Talcott and Dr. Chollet-Lipscomb agreed that a limitation of the study was a lack of data on how physicians decided on a specific treatment in each individual case, but they agree that even without this information the results were “significant.”
Dr. Chollet-Lipscomb also highlighted the factors other than age she would use to determine the best adjuvant treatment for a patient with early stage breast cancer, including the individual features of the tumor, how aggressive it looks under the microscope, what the receptor status is, and a patient’s overall performance status and comorbidities.
Dr. Talcott and Dr. Chollet-Lipscomb report no relevant financial relationships. The authors had no acknowledgement of research support for this study.
A version of this article first appeared on Medscape.com.
say researchers reporting new data showing a sharp cut-off at age 70.
“In our study, one of the most significant variables in determining whether breast cancer patients who are close their 70th birthday are recommended standard-of-care radiation or de-escalated treatment is whether they show up a few months before or a few months after that 70th birthday,” commented study author Wesley J. Talcott, MD, of the department of therapeutic radiology at the Yale School of Medicine, New Haven, Conn.
The results show a trend in which radiation therapy is 50% less likely to be prescribed for patients age 70 and older with early-stage breast cancer, even when controlling for population size, patient demographics, and disease specific variables.
This suggests that oncologists are weighing the variable of age too heavily when deciding on adjuvant treatments, the authors suggest.
“In certain circumstances, breast cancer oncology providers are treating age like a binary categorical variable when selecting patients for treatments or diagnostic procedures, rather than the continuous variable that it is,” Dr. Talcott commented.
The study was published online in the International Journal of Radiation Oncology: Biology, Physics.
Approached for comment, Casey Chollet-Lipscomb, MD, radiation oncologist with Tennessee Oncology, Nashville, who was not associated with the study, agreed with its main finding.
“The study helps emphasize the importance of individualized care,” she said. “Increasing age is the most common risk factor for breast cancer, but breast cancer is an incredibly diverse disease. While you can observe trends based on age, every patient is unique, and they can’t be lumped into one bucket and prescribed treatment based on a strict age cutoff.”
The retrospective study included two cohorts of women identified in the National Cancer Data Base (2004-2017) all of whom underwent lumpectomy for early-stage breast cancer. All patients had “strong indications” for adjuvant treatment.
Patients in cohort 1 (n = 160,990) included women with estrogen-receptor negative cancer, tumor size greater than 3 cm, who were determined to be “appropriate” for radiation therapy.
Patients in cohort 2 (n = 394,946) had hormone-receptor positive cancer, tumor size greater than 5 mm, and were considered to be “appropriate” candidates for endocrine therapy.
Multivariable analysis was performed to control for comorbidity burden (measured by the Charlson-Deyo Comorbidity Index), race and ethnicity, insurance status, academic versus non-academic treatment center, median annual income of a patient’s area of residence, distance from the site of treatment, and pathology variables including number of lymph nodes sampled, histologic grade, and genomic risk score.
In cohort 1, radiation was recommended for 90%-92% of patients between the ages of 50-69; this dropped to 81% for those aged 70.
After MVA, it was determined that age difference was an independent predictor for adjuvant radiation recommendation only at age 70 versus 69 (odds ratio, 0.47; 95% confidence interval 0.39-0.57, P < .001).
For cohort 2, year-over-year age difference predicted endocrine therapy recommendation only at the juncture between age 70 versus 69 (OR, 0.86, 95% CI 0.74-0.99, P = .001).
“Our results don’t say that we should be increasing the amount of treatment for patients over the age [of] 70 or decreasing that patient treatment for patients younger than age 70. What we believe is that we need to be assessing physiologic age of our patients when treating patients,” Dr. Talcott said.
“We would do this by looking at not just how many years a patient has been on this Earth but also what their current health status is, how many good quality-of-life years they might have after treatment or without it, and what the patient wants in terms of burden of treatment. This is a much more valuable way to approach the allocation of treatments than using age alone,” he added.
Both Dr. Talcott and Dr. Chollet-Lipscomb agreed that a limitation of the study was a lack of data on how physicians decided on a specific treatment in each individual case, but they agree that even without this information the results were “significant.”
Dr. Chollet-Lipscomb also highlighted the factors other than age she would use to determine the best adjuvant treatment for a patient with early stage breast cancer, including the individual features of the tumor, how aggressive it looks under the microscope, what the receptor status is, and a patient’s overall performance status and comorbidities.
Dr. Talcott and Dr. Chollet-Lipscomb report no relevant financial relationships. The authors had no acknowledgement of research support for this study.
A version of this article first appeared on Medscape.com.
say researchers reporting new data showing a sharp cut-off at age 70.
“In our study, one of the most significant variables in determining whether breast cancer patients who are close their 70th birthday are recommended standard-of-care radiation or de-escalated treatment is whether they show up a few months before or a few months after that 70th birthday,” commented study author Wesley J. Talcott, MD, of the department of therapeutic radiology at the Yale School of Medicine, New Haven, Conn.
The results show a trend in which radiation therapy is 50% less likely to be prescribed for patients age 70 and older with early-stage breast cancer, even when controlling for population size, patient demographics, and disease specific variables.
This suggests that oncologists are weighing the variable of age too heavily when deciding on adjuvant treatments, the authors suggest.
“In certain circumstances, breast cancer oncology providers are treating age like a binary categorical variable when selecting patients for treatments or diagnostic procedures, rather than the continuous variable that it is,” Dr. Talcott commented.
The study was published online in the International Journal of Radiation Oncology: Biology, Physics.
Approached for comment, Casey Chollet-Lipscomb, MD, radiation oncologist with Tennessee Oncology, Nashville, who was not associated with the study, agreed with its main finding.
“The study helps emphasize the importance of individualized care,” she said. “Increasing age is the most common risk factor for breast cancer, but breast cancer is an incredibly diverse disease. While you can observe trends based on age, every patient is unique, and they can’t be lumped into one bucket and prescribed treatment based on a strict age cutoff.”
The retrospective study included two cohorts of women identified in the National Cancer Data Base (2004-2017) all of whom underwent lumpectomy for early-stage breast cancer. All patients had “strong indications” for adjuvant treatment.
Patients in cohort 1 (n = 160,990) included women with estrogen-receptor negative cancer, tumor size greater than 3 cm, who were determined to be “appropriate” for radiation therapy.
Patients in cohort 2 (n = 394,946) had hormone-receptor positive cancer, tumor size greater than 5 mm, and were considered to be “appropriate” candidates for endocrine therapy.
Multivariable analysis was performed to control for comorbidity burden (measured by the Charlson-Deyo Comorbidity Index), race and ethnicity, insurance status, academic versus non-academic treatment center, median annual income of a patient’s area of residence, distance from the site of treatment, and pathology variables including number of lymph nodes sampled, histologic grade, and genomic risk score.
In cohort 1, radiation was recommended for 90%-92% of patients between the ages of 50-69; this dropped to 81% for those aged 70.
After MVA, it was determined that age difference was an independent predictor for adjuvant radiation recommendation only at age 70 versus 69 (odds ratio, 0.47; 95% confidence interval 0.39-0.57, P < .001).
For cohort 2, year-over-year age difference predicted endocrine therapy recommendation only at the juncture between age 70 versus 69 (OR, 0.86, 95% CI 0.74-0.99, P = .001).
“Our results don’t say that we should be increasing the amount of treatment for patients over the age [of] 70 or decreasing that patient treatment for patients younger than age 70. What we believe is that we need to be assessing physiologic age of our patients when treating patients,” Dr. Talcott said.
“We would do this by looking at not just how many years a patient has been on this Earth but also what their current health status is, how many good quality-of-life years they might have after treatment or without it, and what the patient wants in terms of burden of treatment. This is a much more valuable way to approach the allocation of treatments than using age alone,” he added.
Both Dr. Talcott and Dr. Chollet-Lipscomb agreed that a limitation of the study was a lack of data on how physicians decided on a specific treatment in each individual case, but they agree that even without this information the results were “significant.”
Dr. Chollet-Lipscomb also highlighted the factors other than age she would use to determine the best adjuvant treatment for a patient with early stage breast cancer, including the individual features of the tumor, how aggressive it looks under the microscope, what the receptor status is, and a patient’s overall performance status and comorbidities.
Dr. Talcott and Dr. Chollet-Lipscomb report no relevant financial relationships. The authors had no acknowledgement of research support for this study.
A version of this article first appeared on Medscape.com.
FROM THE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY: BIOLOGY, PHYSICS
How a concussion led a former football player/WWE star to a pioneering neuroscience career
On Oct. 5, 2022, at 10:24 a.m., Chris Nowinski, PhD, cofounder of the Boston-based Concussion Legacy Foundation (CLF), was in his home office when the email came through.
“I pounded my desk, shouted YES! and went to find my wife so I could pick her up and give her a big hug,” he recalled. “It was the culmination of 15 years of research and hard work.”
Robert Cantu, MD, who has been studying head trauma for 50+ years and has published more than 500 papers about it, compares the announcement to the 1964 Surgeon General’s report that linked cigarette smoking with lung cancer and heart disease. With the NIH and the Centers of Disease Control and Prevention (CDC) now in agreement about the risks of participating in impact sports and activities, he said, “We’ve reached a tipping point that should finally prompt deniers such as the NHL, NCAA, FIFA, World Rugby, the International Olympic Committee, and other [sports organizations] to remove all unnecessary head trauma from their sports.”
“A lot of the credit for this must go to Chris,” added Dr. Cantu, medical director and director of clinical research at the Cantu Concussion Center at Emerson Hospital in Concord, Mass. “Clinicians like myself can reach only so many people by writing papers and giving speeches at medical conferences. For this to happen, the message needed to get out to parents, athletes, and society in general. And Chris was the vehicle for doing that.”
Dr. Nowinski didn’t set out to be the messenger. He played football at Harvard in the late 1990s, making second-team All-Ivy as a defensive tackle his senior year. In 2000, he enrolled in Killer Kowalski’s Wrestling Institute and eventually joined Vince McMahon’s World Wrestling Entertainment (WWE).
There he played the role of 295-pound villain “Chris Harvard,” an intellectual snob who dressed in crimson tights and insulted the crowd’s IQ. “Roses are red. Violets are blue. The reason I’m talking so slowly is because no one in [insert name of town he was appearing in] has passed grade 2!”
“I’d often apply my education during a match,” he wrote in his book, “Head Games: Football’s Concussion Crisis.“ In a match in Bridgeport, Conn., I assaulted [my opponent] with a human skeleton, ripped off the skull, got down on bended knee, and began reciting Hamlet. Those were good times.”
Those good times ended abruptly, however, during a match with Bubba Ray Dudley at the Hartford Civic Center in Connecticut in 2003. Even though pro wrestling matches are rehearsed, and the blows aren’t real, accidents happen. Mr. Dudley mistakenly kicked Dr. Nowinski in the jaw with enough force to put him on his back and make the whole ring shake.
“Holy shit, kid! You okay?” asked the referee. Before a foggy Dr. Nowinski could reply, 300-pound Mr. Dudley crashed down on him, hooked his leg, and the ref began counting, “One! Two! …” Dr. Nowinski instinctively kicked out but had forgotten the rest of the script. He managed to finish the match and stagger backstage.
His coherence and awareness gradually returned, but a “throbbing headache” persisted. A locker room doctor said he might have a concussion and recommended he wait to see how he felt before wrestling in Albany, N.Y., the next evening.
The following day the headache had subsided, but he still felt “a little strange.” Nonetheless, he told the doctor he was fine and strutted out to again battle Bubba Ray, this time in a match where he eventually got thrown through a ringside table and suffered the Dudley Death Drop. Afterward, “I crawled backstage and laid down. The headache was much, much worse.”
An event and a process
Dr. Nowinski continued to insist he was “fine” and wrestled a few more matches in the following days before finally acknowledging something was wrong. He’d had his bell rung numerous times in football, but this was different. Even more worrisome, none of the doctors he consulted could give him any definitive answers. He finally found his way to Emerson Hospital, where Dr. Cantu was the chief of neurosurgery.
“I remember that day vividly,” said Dr. Cantu. “Chris was this big, strapping, handsome guy – a hell of an athlete whose star was rising. He didn’t realize that he’d suffered a series of concussions and that trying to push through them was the worst thing he could be doing.”
Concussions and their effects were misunderstood by many athletes, coaches, and even physicians back then. It was assumed that the quarter inch of bone surrounding the adult brain provided adequate protection from common sports impacts and that any aftereffects were temporary. A common treatment was smelling salts and a pat on the back as the athlete returned to action.
However, the brain floats inside the skull in a bath of cerebral fluid. Any significant impact causes it to slosh violently from side to side, damaging tissue, synapses, and cells resulting in inflammation that can manifest as confusion and brain fog.
“A concussion is actually not defined by a physical injury,” explained Dr. Nowinski, “but by a loss of brain function that is induced by trauma. Concussion is not just an event, but also a process.” It’s almost as if the person has suffered a small seizure.
Fortunately, most concussion symptoms resolve within 2 weeks, but in some cases, especially if there’s been additional head trauma, they can persist, causing anxiety, depression, anger, and/or sleep disorders. Known as postconcussion syndrome (PCS), this is what Dr. Nowinski was unknowingly suffering from when he consulted Dr. Cantu.
In fact, one night it an Indianapolis hotel, weeks after his initial concussion, he awoke to find himself on the floor and the room in shambles. His girlfriend was yelling his name and shaking him. She told him he’d been having a nightmare and had suddenly started screaming and tearing up the room. “I didn’t remember any of it,” he said.
Dr. Cantu eventually advised Dr. Nowinski against ever returning to the ring or any activity with the risk for head injury. Research shows that sustaining a single significant concussion increases the risk of subsequent more-severe brain injuries.
“My diagnosis could have sent Chris off the deep end because he could no longer do what he wanted to do with this life,” said Dr. Cantu. “But instead, he used it as a tool to find meaning for his life.”
Dr. Nowinski decided to use his experience as a teaching opportunity, not just for other athletes but also for sports organizations and the medical community.
His book, which focused on the NFL’s “tobacco-industry-like refusal to acknowledge the depths of the problem,” was published in 2006. A year later, Dr. Nowinski partnered with Dr. Cantu to found the Sports Legacy Institute, which eventually became the Concussion Legacy Foundation (CLF).
Cold calling for brain donations
Robert Stern, PhD, is another highly respected authority in the study of neurodegenerative disease. In 2007, he was directing the clinical core of Boston University’s Alzheimer’s Disease Center. After giving a lecture to a group of financial planners and elder-law attorneys one morning, he got a request for a private meeting from a fellow named Chris Nowinski.
“I’d never heard of him, but I agreed,” recalled Dr. Stern, a professor of neurology, neurosurgery, anatomy, and neurobiology at Boston University. “A few days later, this larger-than-life guy walked into our conference room at the BU School of Medicine, exuding a great deal of passion, intellect, and determination. He told me his story and then started talking about the long-term consequences of concussions in sports.”
Dr. Stern had seen patients with dementia pugilistica, the old-school term for CTE. These were mostly boxers with cognitive and behavioral impairment. “But I had not heard about football players,” he said. “I hadn’t put the two together. And as I was listening to Chris, I realized if what he was saying was true then it was not only a potentially huge public health issue, but it was also a potentially huge scientific issue in the field of neurodegenerative disease.”
Dr. Nowinski introduced Dr. Stern to Dr. Cantu, and together with Ann McKee, MD, professor of neurology and pathology at BU, they cofounded the Center for the Study of Traumatic Encephalopathy (CSTE) in 2008. It was the first center of its kind devoted to the study of CTE in the world.
One of Dr. Nowinski’s first jobs at the CSTE was soliciting and procuring brain donations. Since CTE is generally a progressive condition that can take decades to manifest, autopsy was the only way to detect it.
The brains of two former Pittsburgh Steelers, Mike Webster and Terry Long, had been examined after their untimely deaths. After immunostaining, investigators found both former NFL players had “protein misfolds” characteristic of CTE.
This finding drew a lot of public and scientific attention, given that Mr. Long died by suicide and Mr. Webster was homeless when he died of a heart attack. But more scientific evidence was needed to prove a causal link between the head trauma and CTE.
Dr. Nowinski scoured obituaries looking for potential brains to study. When he found one, he would cold call the family and try to convince them to donate it to science. The first brain he secured for the center belonged to John Grimsley, a former NFL linebacker who in 2008 died at age 45 of an accidental gunshot wound. Often, Dr. Nowinski would even be the courier, traveling to pick up the brain after it had been harvested.
Over the next 10 years, Dr. Nowinski and his research team secured 500 brain donations. The research that resulted was staggering. In the beginning only 45 cases of CTE had been identified in the world, but in the first 111 NFL players who were autopsied, 110 had the disorder.
Of the first 53 college football players autopsied, 48 had CTE. Although Dr. Nowinski’s initial focus was football, evidence of CTE was soon detected among athletes in boxing, hockey, soccer, and rugby, as well as in combat veterans. However, the National Football League and other governing sports bodies initially denied any connection between sport-related head trauma and CTE.
Cumulative damage
In 2017, after 7 years of study, Dr. Nowinski earned a PhD in neurology. As the scientific evidence continued to accumulate, two shifts occurred that Dr. Stern said represent Dr. Nowinski’s greatest contributions. First, concussion is now widely recognized as an acute brain injury with symptoms that need to be immediately diagnosed and addressed.
“This is a completely different story from where things were just 10 years ago,” said Dr. Stern, “and Chris played a central role, if not the central role, in raising awareness about that.”
All 50 states and the District of Columbia now have laws regarding sports-related concussion. And there are brain banks in Australia, Canada, New Zealand, Brazil, and the United Kingdom studying CTE. More than 2,500 athletes in a variety of sports, including NASCAR’s Dale Earnhardt Jr. and NFL hall of famer Nick Buoniconti, have publicly pledged to donate their brains to science after their deaths.
Second, said Dr. Stern, we now know that although concussions can contribute to CTE, they are not the sole cause. It’s repetitive subconcussive trauma, without symptoms of concussion, that do the most damage.
“These happen during every practice and in every game,” said Dr. Stern. In fact, it’s estimated that pro football players suffer thousands of subconcussive incidents over the course of their careers. So, a player doesn’t have to see stars or lose consciousness to suffer brain damage; small impacts can accumulate over time.
Understanding this point is crucial for making youth sports safer. “Chris has played a critical role in raising awareness here, too,” said Dr. Stern. “Allowing our kids to get hit in the head over and over can put them at greater risk for later problems, plus it just doesn’t make common sense.”
“The biggest misconception surrounding head trauma in sports,” said Dr. Nowinski, “is the belief among players, coaches, and even the medical and scientific communities that if you get hit in the head and don’t have any symptoms then you’re okay and there hasn’t been any damage. That couldn’t be further from the truth. We now know that people are suffering serious brain injuries due to the accumulated effect of subconcussive impacts, and we need to get the word out about that.”
A major initiative from the Concussion Legacy Foundation called “Stop Hitting Kids in the Head” has the goal of convincing every sport to eliminate repetitive head impacts in players under age 14 – the time when the skull and brain are still developing and most vulnerable – by 2026. In fact, Dr. Nowinski wrote that “there could be a lot of kids who are misdiagnosed and medicated for various behavioral or emotional problems that may actually be head injury–related.”
Starting in 2009, the NFL adopted a series of rule changes designed to better protect its players against repeated head trauma. Among them is a ban on spearing or leading with the helmet, penalties for hitting defenseless players, and more stringent return-to-play guidelines, including concussion protocols.
The NFL has also put more emphasis on flag football options for youngsters and, for the first time, showcased this alternative in the 2023 Pro Bowl. But Dr. Nowinski is pressuring the league to go further. “While acknowledging that the game causes CTE, the NFL still underwrites recruiting 5-year-olds to play tackle football,” he said. “In my opinion, that’s unethical, and it needs to be addressed.”
WWE one of the most responsive organizations
Dr. Nowinski said WWE has been one of the most responsive sports organizations for protecting athletes. A doctor is now ringside at every match as is an observer who knows the script, thereby allowing for instant medical intervention if something goes wrong. “Since everyone is trying to look like they have a concussion all the time, it takes a deep understanding of the business to recognize a real one,” he said.
But this hasn’t been the case with other sports. “I am eternally disappointed in the response of the professional sports industry to the knowledge of CTE and long-term concussion symptoms,” said Dr. Nowinski.
“For example, FIFA [international soccer’s governing body] still doesn’t allow doctors to evaluate [potentially concussed] players on the sidelines and put them back in the game with a free substitution [if they’re deemed okay]. Not giving players proper medical care for a brain injury is unethical,” he said. BU’s Center for the Study of Traumatic Encephalopathy diagnosed the first CTE case in soccer in 2012, and in 2015 Dr. Nowinski successfully lobbied U.S. Soccer to ban heading the ball before age 11.
“Unfortunately, many governing bodies have circled the wagons in denying their sport causes CTE,” he continued. “FIFA, World Rugby, the NHL, even the NCAA and International Olympic Committee refuse to acknowledge it and, therefore, aren’t taking any steps to prevent it. They see it as a threat to their business model. Hopefully, now that the NIH and CDC are aligned about the risks of head impact in sports, this will begin to change.”
Meanwhile, research is continuing. Scientists are getting closer to being able to diagnose CTE in living humans, with ongoing studies using PET scans, blood markers, and spinal fluid markers. In 2019, researchers identified tau proteins specific to CTE that they believe are distinct from those of Alzheimer’s and other neurodegenerative diseases. Next step would be developing a drug to slow the development of CTE once detected.
Nonetheless, athletes at all levels in impact sports still don’t fully appreciate the risks of repeated head trauma and especially subconcussive blows. “I talk to former NFL and college players every week,” said Dr. Stern. “Some tell me, ‘I love the sport, it gave me so much, and I would do it again, but I’m not letting my grandchildren play.’ But others say, ‘As long as they know the risks, they can make their own decision.’ “
Dr. Nowinski has a daughter who is 4 and a son who’s 2. Both play soccer but, thanks to dad, heading isn’t allowed in their age groups. If they continue playing sports, Dr. Nowinski said he’ll make sure they understand the risks and how to protect themselves. This is a conversation all parents should have with their kids at every level to make sure they play safe, he added.
Those in the medical community can also volunteer their time to explain head trauma to athletes, coaches, and school administrators to be sure they understand its seriousness and are doing everything to protect players.
As you watch this year’s Super Bowl, Dr. Nowinski and his team would like you to keep something in mind. Those young men on the field for your entertainment are receiving mild brain trauma repeatedly throughout the game.
Even if it’s not a huge hit that gets replayed and makes everyone gasp, even if no one gets ushered into the little sideline tent for a concussion screening, even if no one loses consciousness, brain damage is still occurring. Watch the heads of the players during every play and think about what’s going on inside their skulls regardless of how big and strong those helmets look.
A version of this article first appeared on Medscape.com.
On Oct. 5, 2022, at 10:24 a.m., Chris Nowinski, PhD, cofounder of the Boston-based Concussion Legacy Foundation (CLF), was in his home office when the email came through.
“I pounded my desk, shouted YES! and went to find my wife so I could pick her up and give her a big hug,” he recalled. “It was the culmination of 15 years of research and hard work.”
Robert Cantu, MD, who has been studying head trauma for 50+ years and has published more than 500 papers about it, compares the announcement to the 1964 Surgeon General’s report that linked cigarette smoking with lung cancer and heart disease. With the NIH and the Centers of Disease Control and Prevention (CDC) now in agreement about the risks of participating in impact sports and activities, he said, “We’ve reached a tipping point that should finally prompt deniers such as the NHL, NCAA, FIFA, World Rugby, the International Olympic Committee, and other [sports organizations] to remove all unnecessary head trauma from their sports.”
“A lot of the credit for this must go to Chris,” added Dr. Cantu, medical director and director of clinical research at the Cantu Concussion Center at Emerson Hospital in Concord, Mass. “Clinicians like myself can reach only so many people by writing papers and giving speeches at medical conferences. For this to happen, the message needed to get out to parents, athletes, and society in general. And Chris was the vehicle for doing that.”
Dr. Nowinski didn’t set out to be the messenger. He played football at Harvard in the late 1990s, making second-team All-Ivy as a defensive tackle his senior year. In 2000, he enrolled in Killer Kowalski’s Wrestling Institute and eventually joined Vince McMahon’s World Wrestling Entertainment (WWE).
There he played the role of 295-pound villain “Chris Harvard,” an intellectual snob who dressed in crimson tights and insulted the crowd’s IQ. “Roses are red. Violets are blue. The reason I’m talking so slowly is because no one in [insert name of town he was appearing in] has passed grade 2!”
“I’d often apply my education during a match,” he wrote in his book, “Head Games: Football’s Concussion Crisis.“ In a match in Bridgeport, Conn., I assaulted [my opponent] with a human skeleton, ripped off the skull, got down on bended knee, and began reciting Hamlet. Those were good times.”
Those good times ended abruptly, however, during a match with Bubba Ray Dudley at the Hartford Civic Center in Connecticut in 2003. Even though pro wrestling matches are rehearsed, and the blows aren’t real, accidents happen. Mr. Dudley mistakenly kicked Dr. Nowinski in the jaw with enough force to put him on his back and make the whole ring shake.
“Holy shit, kid! You okay?” asked the referee. Before a foggy Dr. Nowinski could reply, 300-pound Mr. Dudley crashed down on him, hooked his leg, and the ref began counting, “One! Two! …” Dr. Nowinski instinctively kicked out but had forgotten the rest of the script. He managed to finish the match and stagger backstage.
His coherence and awareness gradually returned, but a “throbbing headache” persisted. A locker room doctor said he might have a concussion and recommended he wait to see how he felt before wrestling in Albany, N.Y., the next evening.
The following day the headache had subsided, but he still felt “a little strange.” Nonetheless, he told the doctor he was fine and strutted out to again battle Bubba Ray, this time in a match where he eventually got thrown through a ringside table and suffered the Dudley Death Drop. Afterward, “I crawled backstage and laid down. The headache was much, much worse.”
An event and a process
Dr. Nowinski continued to insist he was “fine” and wrestled a few more matches in the following days before finally acknowledging something was wrong. He’d had his bell rung numerous times in football, but this was different. Even more worrisome, none of the doctors he consulted could give him any definitive answers. He finally found his way to Emerson Hospital, where Dr. Cantu was the chief of neurosurgery.
“I remember that day vividly,” said Dr. Cantu. “Chris was this big, strapping, handsome guy – a hell of an athlete whose star was rising. He didn’t realize that he’d suffered a series of concussions and that trying to push through them was the worst thing he could be doing.”
Concussions and their effects were misunderstood by many athletes, coaches, and even physicians back then. It was assumed that the quarter inch of bone surrounding the adult brain provided adequate protection from common sports impacts and that any aftereffects were temporary. A common treatment was smelling salts and a pat on the back as the athlete returned to action.
However, the brain floats inside the skull in a bath of cerebral fluid. Any significant impact causes it to slosh violently from side to side, damaging tissue, synapses, and cells resulting in inflammation that can manifest as confusion and brain fog.
“A concussion is actually not defined by a physical injury,” explained Dr. Nowinski, “but by a loss of brain function that is induced by trauma. Concussion is not just an event, but also a process.” It’s almost as if the person has suffered a small seizure.
Fortunately, most concussion symptoms resolve within 2 weeks, but in some cases, especially if there’s been additional head trauma, they can persist, causing anxiety, depression, anger, and/or sleep disorders. Known as postconcussion syndrome (PCS), this is what Dr. Nowinski was unknowingly suffering from when he consulted Dr. Cantu.
In fact, one night it an Indianapolis hotel, weeks after his initial concussion, he awoke to find himself on the floor and the room in shambles. His girlfriend was yelling his name and shaking him. She told him he’d been having a nightmare and had suddenly started screaming and tearing up the room. “I didn’t remember any of it,” he said.
Dr. Cantu eventually advised Dr. Nowinski against ever returning to the ring or any activity with the risk for head injury. Research shows that sustaining a single significant concussion increases the risk of subsequent more-severe brain injuries.
“My diagnosis could have sent Chris off the deep end because he could no longer do what he wanted to do with this life,” said Dr. Cantu. “But instead, he used it as a tool to find meaning for his life.”
Dr. Nowinski decided to use his experience as a teaching opportunity, not just for other athletes but also for sports organizations and the medical community.
His book, which focused on the NFL’s “tobacco-industry-like refusal to acknowledge the depths of the problem,” was published in 2006. A year later, Dr. Nowinski partnered with Dr. Cantu to found the Sports Legacy Institute, which eventually became the Concussion Legacy Foundation (CLF).
Cold calling for brain donations
Robert Stern, PhD, is another highly respected authority in the study of neurodegenerative disease. In 2007, he was directing the clinical core of Boston University’s Alzheimer’s Disease Center. After giving a lecture to a group of financial planners and elder-law attorneys one morning, he got a request for a private meeting from a fellow named Chris Nowinski.
“I’d never heard of him, but I agreed,” recalled Dr. Stern, a professor of neurology, neurosurgery, anatomy, and neurobiology at Boston University. “A few days later, this larger-than-life guy walked into our conference room at the BU School of Medicine, exuding a great deal of passion, intellect, and determination. He told me his story and then started talking about the long-term consequences of concussions in sports.”
Dr. Stern had seen patients with dementia pugilistica, the old-school term for CTE. These were mostly boxers with cognitive and behavioral impairment. “But I had not heard about football players,” he said. “I hadn’t put the two together. And as I was listening to Chris, I realized if what he was saying was true then it was not only a potentially huge public health issue, but it was also a potentially huge scientific issue in the field of neurodegenerative disease.”
Dr. Nowinski introduced Dr. Stern to Dr. Cantu, and together with Ann McKee, MD, professor of neurology and pathology at BU, they cofounded the Center for the Study of Traumatic Encephalopathy (CSTE) in 2008. It was the first center of its kind devoted to the study of CTE in the world.
One of Dr. Nowinski’s first jobs at the CSTE was soliciting and procuring brain donations. Since CTE is generally a progressive condition that can take decades to manifest, autopsy was the only way to detect it.
The brains of two former Pittsburgh Steelers, Mike Webster and Terry Long, had been examined after their untimely deaths. After immunostaining, investigators found both former NFL players had “protein misfolds” characteristic of CTE.
This finding drew a lot of public and scientific attention, given that Mr. Long died by suicide and Mr. Webster was homeless when he died of a heart attack. But more scientific evidence was needed to prove a causal link between the head trauma and CTE.
Dr. Nowinski scoured obituaries looking for potential brains to study. When he found one, he would cold call the family and try to convince them to donate it to science. The first brain he secured for the center belonged to John Grimsley, a former NFL linebacker who in 2008 died at age 45 of an accidental gunshot wound. Often, Dr. Nowinski would even be the courier, traveling to pick up the brain after it had been harvested.
Over the next 10 years, Dr. Nowinski and his research team secured 500 brain donations. The research that resulted was staggering. In the beginning only 45 cases of CTE had been identified in the world, but in the first 111 NFL players who were autopsied, 110 had the disorder.
Of the first 53 college football players autopsied, 48 had CTE. Although Dr. Nowinski’s initial focus was football, evidence of CTE was soon detected among athletes in boxing, hockey, soccer, and rugby, as well as in combat veterans. However, the National Football League and other governing sports bodies initially denied any connection between sport-related head trauma and CTE.
Cumulative damage
In 2017, after 7 years of study, Dr. Nowinski earned a PhD in neurology. As the scientific evidence continued to accumulate, two shifts occurred that Dr. Stern said represent Dr. Nowinski’s greatest contributions. First, concussion is now widely recognized as an acute brain injury with symptoms that need to be immediately diagnosed and addressed.
“This is a completely different story from where things were just 10 years ago,” said Dr. Stern, “and Chris played a central role, if not the central role, in raising awareness about that.”
All 50 states and the District of Columbia now have laws regarding sports-related concussion. And there are brain banks in Australia, Canada, New Zealand, Brazil, and the United Kingdom studying CTE. More than 2,500 athletes in a variety of sports, including NASCAR’s Dale Earnhardt Jr. and NFL hall of famer Nick Buoniconti, have publicly pledged to donate their brains to science after their deaths.
Second, said Dr. Stern, we now know that although concussions can contribute to CTE, they are not the sole cause. It’s repetitive subconcussive trauma, without symptoms of concussion, that do the most damage.
“These happen during every practice and in every game,” said Dr. Stern. In fact, it’s estimated that pro football players suffer thousands of subconcussive incidents over the course of their careers. So, a player doesn’t have to see stars or lose consciousness to suffer brain damage; small impacts can accumulate over time.
Understanding this point is crucial for making youth sports safer. “Chris has played a critical role in raising awareness here, too,” said Dr. Stern. “Allowing our kids to get hit in the head over and over can put them at greater risk for later problems, plus it just doesn’t make common sense.”
“The biggest misconception surrounding head trauma in sports,” said Dr. Nowinski, “is the belief among players, coaches, and even the medical and scientific communities that if you get hit in the head and don’t have any symptoms then you’re okay and there hasn’t been any damage. That couldn’t be further from the truth. We now know that people are suffering serious brain injuries due to the accumulated effect of subconcussive impacts, and we need to get the word out about that.”
A major initiative from the Concussion Legacy Foundation called “Stop Hitting Kids in the Head” has the goal of convincing every sport to eliminate repetitive head impacts in players under age 14 – the time when the skull and brain are still developing and most vulnerable – by 2026. In fact, Dr. Nowinski wrote that “there could be a lot of kids who are misdiagnosed and medicated for various behavioral or emotional problems that may actually be head injury–related.”
Starting in 2009, the NFL adopted a series of rule changes designed to better protect its players against repeated head trauma. Among them is a ban on spearing or leading with the helmet, penalties for hitting defenseless players, and more stringent return-to-play guidelines, including concussion protocols.
The NFL has also put more emphasis on flag football options for youngsters and, for the first time, showcased this alternative in the 2023 Pro Bowl. But Dr. Nowinski is pressuring the league to go further. “While acknowledging that the game causes CTE, the NFL still underwrites recruiting 5-year-olds to play tackle football,” he said. “In my opinion, that’s unethical, and it needs to be addressed.”
WWE one of the most responsive organizations
Dr. Nowinski said WWE has been one of the most responsive sports organizations for protecting athletes. A doctor is now ringside at every match as is an observer who knows the script, thereby allowing for instant medical intervention if something goes wrong. “Since everyone is trying to look like they have a concussion all the time, it takes a deep understanding of the business to recognize a real one,” he said.
But this hasn’t been the case with other sports. “I am eternally disappointed in the response of the professional sports industry to the knowledge of CTE and long-term concussion symptoms,” said Dr. Nowinski.
“For example, FIFA [international soccer’s governing body] still doesn’t allow doctors to evaluate [potentially concussed] players on the sidelines and put them back in the game with a free substitution [if they’re deemed okay]. Not giving players proper medical care for a brain injury is unethical,” he said. BU’s Center for the Study of Traumatic Encephalopathy diagnosed the first CTE case in soccer in 2012, and in 2015 Dr. Nowinski successfully lobbied U.S. Soccer to ban heading the ball before age 11.
“Unfortunately, many governing bodies have circled the wagons in denying their sport causes CTE,” he continued. “FIFA, World Rugby, the NHL, even the NCAA and International Olympic Committee refuse to acknowledge it and, therefore, aren’t taking any steps to prevent it. They see it as a threat to their business model. Hopefully, now that the NIH and CDC are aligned about the risks of head impact in sports, this will begin to change.”
Meanwhile, research is continuing. Scientists are getting closer to being able to diagnose CTE in living humans, with ongoing studies using PET scans, blood markers, and spinal fluid markers. In 2019, researchers identified tau proteins specific to CTE that they believe are distinct from those of Alzheimer’s and other neurodegenerative diseases. Next step would be developing a drug to slow the development of CTE once detected.
Nonetheless, athletes at all levels in impact sports still don’t fully appreciate the risks of repeated head trauma and especially subconcussive blows. “I talk to former NFL and college players every week,” said Dr. Stern. “Some tell me, ‘I love the sport, it gave me so much, and I would do it again, but I’m not letting my grandchildren play.’ But others say, ‘As long as they know the risks, they can make their own decision.’ “
Dr. Nowinski has a daughter who is 4 and a son who’s 2. Both play soccer but, thanks to dad, heading isn’t allowed in their age groups. If they continue playing sports, Dr. Nowinski said he’ll make sure they understand the risks and how to protect themselves. This is a conversation all parents should have with their kids at every level to make sure they play safe, he added.
Those in the medical community can also volunteer their time to explain head trauma to athletes, coaches, and school administrators to be sure they understand its seriousness and are doing everything to protect players.
As you watch this year’s Super Bowl, Dr. Nowinski and his team would like you to keep something in mind. Those young men on the field for your entertainment are receiving mild brain trauma repeatedly throughout the game.
Even if it’s not a huge hit that gets replayed and makes everyone gasp, even if no one gets ushered into the little sideline tent for a concussion screening, even if no one loses consciousness, brain damage is still occurring. Watch the heads of the players during every play and think about what’s going on inside their skulls regardless of how big and strong those helmets look.
A version of this article first appeared on Medscape.com.
On Oct. 5, 2022, at 10:24 a.m., Chris Nowinski, PhD, cofounder of the Boston-based Concussion Legacy Foundation (CLF), was in his home office when the email came through.
“I pounded my desk, shouted YES! and went to find my wife so I could pick her up and give her a big hug,” he recalled. “It was the culmination of 15 years of research and hard work.”
Robert Cantu, MD, who has been studying head trauma for 50+ years and has published more than 500 papers about it, compares the announcement to the 1964 Surgeon General’s report that linked cigarette smoking with lung cancer and heart disease. With the NIH and the Centers of Disease Control and Prevention (CDC) now in agreement about the risks of participating in impact sports and activities, he said, “We’ve reached a tipping point that should finally prompt deniers such as the NHL, NCAA, FIFA, World Rugby, the International Olympic Committee, and other [sports organizations] to remove all unnecessary head trauma from their sports.”
“A lot of the credit for this must go to Chris,” added Dr. Cantu, medical director and director of clinical research at the Cantu Concussion Center at Emerson Hospital in Concord, Mass. “Clinicians like myself can reach only so many people by writing papers and giving speeches at medical conferences. For this to happen, the message needed to get out to parents, athletes, and society in general. And Chris was the vehicle for doing that.”
Dr. Nowinski didn’t set out to be the messenger. He played football at Harvard in the late 1990s, making second-team All-Ivy as a defensive tackle his senior year. In 2000, he enrolled in Killer Kowalski’s Wrestling Institute and eventually joined Vince McMahon’s World Wrestling Entertainment (WWE).
There he played the role of 295-pound villain “Chris Harvard,” an intellectual snob who dressed in crimson tights and insulted the crowd’s IQ. “Roses are red. Violets are blue. The reason I’m talking so slowly is because no one in [insert name of town he was appearing in] has passed grade 2!”
“I’d often apply my education during a match,” he wrote in his book, “Head Games: Football’s Concussion Crisis.“ In a match in Bridgeport, Conn., I assaulted [my opponent] with a human skeleton, ripped off the skull, got down on bended knee, and began reciting Hamlet. Those were good times.”
Those good times ended abruptly, however, during a match with Bubba Ray Dudley at the Hartford Civic Center in Connecticut in 2003. Even though pro wrestling matches are rehearsed, and the blows aren’t real, accidents happen. Mr. Dudley mistakenly kicked Dr. Nowinski in the jaw with enough force to put him on his back and make the whole ring shake.
“Holy shit, kid! You okay?” asked the referee. Before a foggy Dr. Nowinski could reply, 300-pound Mr. Dudley crashed down on him, hooked his leg, and the ref began counting, “One! Two! …” Dr. Nowinski instinctively kicked out but had forgotten the rest of the script. He managed to finish the match and stagger backstage.
His coherence and awareness gradually returned, but a “throbbing headache” persisted. A locker room doctor said he might have a concussion and recommended he wait to see how he felt before wrestling in Albany, N.Y., the next evening.
The following day the headache had subsided, but he still felt “a little strange.” Nonetheless, he told the doctor he was fine and strutted out to again battle Bubba Ray, this time in a match where he eventually got thrown through a ringside table and suffered the Dudley Death Drop. Afterward, “I crawled backstage and laid down. The headache was much, much worse.”
An event and a process
Dr. Nowinski continued to insist he was “fine” and wrestled a few more matches in the following days before finally acknowledging something was wrong. He’d had his bell rung numerous times in football, but this was different. Even more worrisome, none of the doctors he consulted could give him any definitive answers. He finally found his way to Emerson Hospital, where Dr. Cantu was the chief of neurosurgery.
“I remember that day vividly,” said Dr. Cantu. “Chris was this big, strapping, handsome guy – a hell of an athlete whose star was rising. He didn’t realize that he’d suffered a series of concussions and that trying to push through them was the worst thing he could be doing.”
Concussions and their effects were misunderstood by many athletes, coaches, and even physicians back then. It was assumed that the quarter inch of bone surrounding the adult brain provided adequate protection from common sports impacts and that any aftereffects were temporary. A common treatment was smelling salts and a pat on the back as the athlete returned to action.
However, the brain floats inside the skull in a bath of cerebral fluid. Any significant impact causes it to slosh violently from side to side, damaging tissue, synapses, and cells resulting in inflammation that can manifest as confusion and brain fog.
“A concussion is actually not defined by a physical injury,” explained Dr. Nowinski, “but by a loss of brain function that is induced by trauma. Concussion is not just an event, but also a process.” It’s almost as if the person has suffered a small seizure.
Fortunately, most concussion symptoms resolve within 2 weeks, but in some cases, especially if there’s been additional head trauma, they can persist, causing anxiety, depression, anger, and/or sleep disorders. Known as postconcussion syndrome (PCS), this is what Dr. Nowinski was unknowingly suffering from when he consulted Dr. Cantu.
In fact, one night it an Indianapolis hotel, weeks after his initial concussion, he awoke to find himself on the floor and the room in shambles. His girlfriend was yelling his name and shaking him. She told him he’d been having a nightmare and had suddenly started screaming and tearing up the room. “I didn’t remember any of it,” he said.
Dr. Cantu eventually advised Dr. Nowinski against ever returning to the ring or any activity with the risk for head injury. Research shows that sustaining a single significant concussion increases the risk of subsequent more-severe brain injuries.
“My diagnosis could have sent Chris off the deep end because he could no longer do what he wanted to do with this life,” said Dr. Cantu. “But instead, he used it as a tool to find meaning for his life.”
Dr. Nowinski decided to use his experience as a teaching opportunity, not just for other athletes but also for sports organizations and the medical community.
His book, which focused on the NFL’s “tobacco-industry-like refusal to acknowledge the depths of the problem,” was published in 2006. A year later, Dr. Nowinski partnered with Dr. Cantu to found the Sports Legacy Institute, which eventually became the Concussion Legacy Foundation (CLF).
Cold calling for brain donations
Robert Stern, PhD, is another highly respected authority in the study of neurodegenerative disease. In 2007, he was directing the clinical core of Boston University’s Alzheimer’s Disease Center. After giving a lecture to a group of financial planners and elder-law attorneys one morning, he got a request for a private meeting from a fellow named Chris Nowinski.
“I’d never heard of him, but I agreed,” recalled Dr. Stern, a professor of neurology, neurosurgery, anatomy, and neurobiology at Boston University. “A few days later, this larger-than-life guy walked into our conference room at the BU School of Medicine, exuding a great deal of passion, intellect, and determination. He told me his story and then started talking about the long-term consequences of concussions in sports.”
Dr. Stern had seen patients with dementia pugilistica, the old-school term for CTE. These were mostly boxers with cognitive and behavioral impairment. “But I had not heard about football players,” he said. “I hadn’t put the two together. And as I was listening to Chris, I realized if what he was saying was true then it was not only a potentially huge public health issue, but it was also a potentially huge scientific issue in the field of neurodegenerative disease.”
Dr. Nowinski introduced Dr. Stern to Dr. Cantu, and together with Ann McKee, MD, professor of neurology and pathology at BU, they cofounded the Center for the Study of Traumatic Encephalopathy (CSTE) in 2008. It was the first center of its kind devoted to the study of CTE in the world.
One of Dr. Nowinski’s first jobs at the CSTE was soliciting and procuring brain donations. Since CTE is generally a progressive condition that can take decades to manifest, autopsy was the only way to detect it.
The brains of two former Pittsburgh Steelers, Mike Webster and Terry Long, had been examined after their untimely deaths. After immunostaining, investigators found both former NFL players had “protein misfolds” characteristic of CTE.
This finding drew a lot of public and scientific attention, given that Mr. Long died by suicide and Mr. Webster was homeless when he died of a heart attack. But more scientific evidence was needed to prove a causal link between the head trauma and CTE.
Dr. Nowinski scoured obituaries looking for potential brains to study. When he found one, he would cold call the family and try to convince them to donate it to science. The first brain he secured for the center belonged to John Grimsley, a former NFL linebacker who in 2008 died at age 45 of an accidental gunshot wound. Often, Dr. Nowinski would even be the courier, traveling to pick up the brain after it had been harvested.
Over the next 10 years, Dr. Nowinski and his research team secured 500 brain donations. The research that resulted was staggering. In the beginning only 45 cases of CTE had been identified in the world, but in the first 111 NFL players who were autopsied, 110 had the disorder.
Of the first 53 college football players autopsied, 48 had CTE. Although Dr. Nowinski’s initial focus was football, evidence of CTE was soon detected among athletes in boxing, hockey, soccer, and rugby, as well as in combat veterans. However, the National Football League and other governing sports bodies initially denied any connection between sport-related head trauma and CTE.
Cumulative damage
In 2017, after 7 years of study, Dr. Nowinski earned a PhD in neurology. As the scientific evidence continued to accumulate, two shifts occurred that Dr. Stern said represent Dr. Nowinski’s greatest contributions. First, concussion is now widely recognized as an acute brain injury with symptoms that need to be immediately diagnosed and addressed.
“This is a completely different story from where things were just 10 years ago,” said Dr. Stern, “and Chris played a central role, if not the central role, in raising awareness about that.”
All 50 states and the District of Columbia now have laws regarding sports-related concussion. And there are brain banks in Australia, Canada, New Zealand, Brazil, and the United Kingdom studying CTE. More than 2,500 athletes in a variety of sports, including NASCAR’s Dale Earnhardt Jr. and NFL hall of famer Nick Buoniconti, have publicly pledged to donate their brains to science after their deaths.
Second, said Dr. Stern, we now know that although concussions can contribute to CTE, they are not the sole cause. It’s repetitive subconcussive trauma, without symptoms of concussion, that do the most damage.
“These happen during every practice and in every game,” said Dr. Stern. In fact, it’s estimated that pro football players suffer thousands of subconcussive incidents over the course of their careers. So, a player doesn’t have to see stars or lose consciousness to suffer brain damage; small impacts can accumulate over time.
Understanding this point is crucial for making youth sports safer. “Chris has played a critical role in raising awareness here, too,” said Dr. Stern. “Allowing our kids to get hit in the head over and over can put them at greater risk for later problems, plus it just doesn’t make common sense.”
“The biggest misconception surrounding head trauma in sports,” said Dr. Nowinski, “is the belief among players, coaches, and even the medical and scientific communities that if you get hit in the head and don’t have any symptoms then you’re okay and there hasn’t been any damage. That couldn’t be further from the truth. We now know that people are suffering serious brain injuries due to the accumulated effect of subconcussive impacts, and we need to get the word out about that.”
A major initiative from the Concussion Legacy Foundation called “Stop Hitting Kids in the Head” has the goal of convincing every sport to eliminate repetitive head impacts in players under age 14 – the time when the skull and brain are still developing and most vulnerable – by 2026. In fact, Dr. Nowinski wrote that “there could be a lot of kids who are misdiagnosed and medicated for various behavioral or emotional problems that may actually be head injury–related.”
Starting in 2009, the NFL adopted a series of rule changes designed to better protect its players against repeated head trauma. Among them is a ban on spearing or leading with the helmet, penalties for hitting defenseless players, and more stringent return-to-play guidelines, including concussion protocols.
The NFL has also put more emphasis on flag football options for youngsters and, for the first time, showcased this alternative in the 2023 Pro Bowl. But Dr. Nowinski is pressuring the league to go further. “While acknowledging that the game causes CTE, the NFL still underwrites recruiting 5-year-olds to play tackle football,” he said. “In my opinion, that’s unethical, and it needs to be addressed.”
WWE one of the most responsive organizations
Dr. Nowinski said WWE has been one of the most responsive sports organizations for protecting athletes. A doctor is now ringside at every match as is an observer who knows the script, thereby allowing for instant medical intervention if something goes wrong. “Since everyone is trying to look like they have a concussion all the time, it takes a deep understanding of the business to recognize a real one,” he said.
But this hasn’t been the case with other sports. “I am eternally disappointed in the response of the professional sports industry to the knowledge of CTE and long-term concussion symptoms,” said Dr. Nowinski.
“For example, FIFA [international soccer’s governing body] still doesn’t allow doctors to evaluate [potentially concussed] players on the sidelines and put them back in the game with a free substitution [if they’re deemed okay]. Not giving players proper medical care for a brain injury is unethical,” he said. BU’s Center for the Study of Traumatic Encephalopathy diagnosed the first CTE case in soccer in 2012, and in 2015 Dr. Nowinski successfully lobbied U.S. Soccer to ban heading the ball before age 11.
“Unfortunately, many governing bodies have circled the wagons in denying their sport causes CTE,” he continued. “FIFA, World Rugby, the NHL, even the NCAA and International Olympic Committee refuse to acknowledge it and, therefore, aren’t taking any steps to prevent it. They see it as a threat to their business model. Hopefully, now that the NIH and CDC are aligned about the risks of head impact in sports, this will begin to change.”
Meanwhile, research is continuing. Scientists are getting closer to being able to diagnose CTE in living humans, with ongoing studies using PET scans, blood markers, and spinal fluid markers. In 2019, researchers identified tau proteins specific to CTE that they believe are distinct from those of Alzheimer’s and other neurodegenerative diseases. Next step would be developing a drug to slow the development of CTE once detected.
Nonetheless, athletes at all levels in impact sports still don’t fully appreciate the risks of repeated head trauma and especially subconcussive blows. “I talk to former NFL and college players every week,” said Dr. Stern. “Some tell me, ‘I love the sport, it gave me so much, and I would do it again, but I’m not letting my grandchildren play.’ But others say, ‘As long as they know the risks, they can make their own decision.’ “
Dr. Nowinski has a daughter who is 4 and a son who’s 2. Both play soccer but, thanks to dad, heading isn’t allowed in their age groups. If they continue playing sports, Dr. Nowinski said he’ll make sure they understand the risks and how to protect themselves. This is a conversation all parents should have with their kids at every level to make sure they play safe, he added.
Those in the medical community can also volunteer their time to explain head trauma to athletes, coaches, and school administrators to be sure they understand its seriousness and are doing everything to protect players.
As you watch this year’s Super Bowl, Dr. Nowinski and his team would like you to keep something in mind. Those young men on the field for your entertainment are receiving mild brain trauma repeatedly throughout the game.
Even if it’s not a huge hit that gets replayed and makes everyone gasp, even if no one gets ushered into the little sideline tent for a concussion screening, even if no one loses consciousness, brain damage is still occurring. Watch the heads of the players during every play and think about what’s going on inside their skulls regardless of how big and strong those helmets look.
A version of this article first appeared on Medscape.com.
Must-read acute care medicine articles from 2022
When 2022 began, we started seeing some light at the end of the COVID-19 tunnel. Vaccines were widely available, and even with new variants of the virus still occasionally emerging, the rates of severe morbidity and mortality appeared to be decreasing.
Expectedly, journals appeared to start moving more toward mainstream topics and publications rather than what seemed like a major focus on COVID-19 publications. The resulting literature was fantastic.
Several of those topics were discussed in a prior Emergency Medicine Viewpoint from this news organization, and many more of the research advances of 2022 will be discussed in the near future. However, in this Viewpoint, I would like to present my annual review of my three “must-read” articles of the past year.
As in past years, I am choosing reviews of the literature rather than original research articles (which, all too often, become outdated or debunked within a few years). I choose these articles in the hopes that readers will not simply settle for my brief reviews of the key points but instead will feel compelled to download and read the entire articles. These publications address common conditions and quandaries we face in the daily practice of emergency medicine and are practice-changing.
Myocardial dysfunction after cardiac arrest: Tips and pitfalls
The management of post–cardiac arrest patients remains a hot topic in the resuscitation literature as we continue to understand that the immediate post-arrest period is critical to patient outcome.
Ortuno and colleagues reviewed the current literature on post-arrest care and wrote an outstanding summary of how to optimally care for these patients. More specifically, they focused on post-arrest patients who demonstrate continued shock, or “post–cardiac arrest myocardial dysfunction” (PCAMD).
They propose three mechanisms for the pathogenesis of PCAMD: ischemia reperfusion phenomenon, systemic inflammatory response, and increased catecholamine release
I will skip through the details of the pathophysiology that they describe in the article, but I certainly do recommend that everyone review their descriptions.
Management of these patients begins with a good hemodynamic assessment, which includes clinical markers of perfusion (blood pressure, capillary refill), ECG, and point-of-care ultrasound (POCUS). If the initial assessment reveals an obvious cause of the cardiac arrest (e.g., massive pulmonary embolism, myocardial infarction, pericardial tamponade), then the underlying cause should be treated expeditiously.
In the absence of an obvious treatable cause of the shock, the fluid status and cardiac function should be addressed with POCUS. If the patient is hypovolemic, intravenous fluids should be administered. If the fluid status is adequate, POCUS should be used to estimate the patient’s ventricular function. If the ventricle appears to be hyperdynamic with good contractility, shock should be treated with norepinephrine. On the other hand, if the ventricle is hypodynamic, dobutamine should be substituted for norepinephrine or, more often, added to norepinephrine.
The above represents a simplified summary of the critical points, but the authors do delve into further detail and also discuss some other options for therapies, including steroids, coronary revascularization, extracorporeal membrane oxygenation, and so on. The review is very thoughtful, thorough, and definitely worth a full read.
Top myths of diagnosis and management of infectious diseases in hospital medicine
Most, if not all of us in medicine, have heard the saying that 50% of what we learn in medical school (or residency) will turn out to be wrong. I certainly believe in this concept and consequently, like many of you, I enjoy reading about myths and misconceptions that we have been taught. With that in mind, I have to say that I love this article because it seems to have been written specifically to address what I was taught!
This author group, consisting mostly of clinical PharmDs who are experts in antibiotic use, provide us with an evidence-based discussion of myths and pitfalls in how antibiotics are often used in current clinical practice. The authors review their top 10 myths involving the use of antibiotics in treating infections in the hospital setting. A few of these relate more to the inpatient setting, but here are my favorite emergency department (ED)–related myths that they address:
- “Antibiotics do no harm.” The authors address the risk-benefit of antibiotics based on assumed vs. confirmed infections, including a brief discussion of adverse drug effects.
- “Antibiotic durations of 7, 14, or 21 days are typically necessary.” The authors address appropriate duration of antibiotic use and the fact that unnecessarily long durations of use can lead to resistance. They also provide reassurance that some infections can be treated with quite short durations of antibiotics.
- “If one drug is good, two (or more!) is better.” The use of multiple antibiotics, often with overlapping bacterial coverage, is rampant in medicine and further increases the risk for adverse drug effects and resistance.
- “Oral antibiotics are not as good as intravenous antibiotics for hospitalized patients.” This is definitely a myth that I learned. I recall being taught by many senior physicians that anyone sick enough for admission should be treated with intravenous antibiotics. As it turns out, absorption and effectiveness of most oral antibiotics is just as good as intravenous antibiotics, and the oral formulations are often safer.
- “A history of a penicillin allergy means the patient can never receive a beta-lactam antibiotic.” This is a myth that was debunked quite a few years ago, but it seems that many clinicians still need a reminder.
The authors included five more myths that are worth the read. This is an article that needs to be disseminated among all hospital clinicians.
Guidelines for low-risk, recurrent abdominal pain in the emergency department
The Society for Academic Emergency Medicine (SAEM) recently initiated a program focused on creating evidence-based approaches to challenging chief complaints and presentations in the emergency department (ED). In 2021, they published an approach to managing patients with recurrent, low-risk chest pain in the ED. This past year, they published their second guideline, focused on the management of patients with low-risk, recurrent abdominal pain in the ED.
Recurrent low-risk abdominal pain is a common and vexing presentation to EDs around the world, and there is little prior published guidance. Do all of these patients need repeat imaging? How do we manage their pain? Are there nonabdominal conditions that should be considered?
Broder and colleagues did a fantastic review of the current literature and, on behalf of SAEM, have provided a rational approach to optimal management of these patients. The four major questions they addressed, with brief summaries of their recommendations, are:
- Should adult ED patients with low-risk, recurrent and previously undifferentiated abdominal pain receive a repeat CT abdomen-pelvis (CTAP) after a negative CTAP within the past 12 months? This is a typical question that we all ponder when managing these patients. Unfortunately, the writing group found insufficient evidence to definitively identify populations in whom CTAP was recommended vs could be safely withheld. It is a bit disappointing that there is no definite answer to the question. On the other hand, it is reassuring to know that the world’s best evidence essentially says that it is perfectly appropriate to use your own good clinical judgment.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain with a negative CTAP receive additional imaging with abdominal ultrasound? In this case, the writing group found enough evidence, though low-level, to suggest against routine ultrasound in the absence of concern specifically for pelvic or hepatobiliary pathology. Like most tests, ultrasound is best used when there are specific concerns rather than being used in an undifferentiated fashion.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain receive screening for depression/anxiety? The writing group found enough evidence, though low-level again, to suggest that screening for depression and/or anxiety be performed during the ED evaluation. This could lead to successful therapy for the abdominal pain.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain receive nonopioid and/or nonpharmacologic analgesics? The writing group found little evidence to suggest for or against these analgesics, but they made a consensus recommendation suggesting an opioid-minimizing strategy for pain control.
Although the final recommendations of the writing group were not definitive or based on the strongest level of evidence, I find it helpful to have this guidance, nevertheless, on behalf of a major national organization. I also find it helpful to know that even with the best evidence available, optimal patient care will often boil down to physician experience and gestalt. I should also add that the overall article is chock-full of pearls and helpful information that will further inform the readers’ decisions, and so the full version is definitely worth the read.
In summary
There you have it – my three favorite practice-changing articles of 2022. Although I have tried to provide key points here, the full discussions of those key points in the published articles will provide a great deal more education than I can offer in this brief write-up, and so I strongly encourage everyone to read the full versions. Please be sure to include in the comments section your own pick for favorite or must-read articles from the past year.
Amal Mattu, MD, is a professor, vice chair of education, and codirector of the emergency cardiology fellowship in the department of emergency medicine at the University of Maryland, Baltimore. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
When 2022 began, we started seeing some light at the end of the COVID-19 tunnel. Vaccines were widely available, and even with new variants of the virus still occasionally emerging, the rates of severe morbidity and mortality appeared to be decreasing.
Expectedly, journals appeared to start moving more toward mainstream topics and publications rather than what seemed like a major focus on COVID-19 publications. The resulting literature was fantastic.
Several of those topics were discussed in a prior Emergency Medicine Viewpoint from this news organization, and many more of the research advances of 2022 will be discussed in the near future. However, in this Viewpoint, I would like to present my annual review of my three “must-read” articles of the past year.
As in past years, I am choosing reviews of the literature rather than original research articles (which, all too often, become outdated or debunked within a few years). I choose these articles in the hopes that readers will not simply settle for my brief reviews of the key points but instead will feel compelled to download and read the entire articles. These publications address common conditions and quandaries we face in the daily practice of emergency medicine and are practice-changing.
Myocardial dysfunction after cardiac arrest: Tips and pitfalls
The management of post–cardiac arrest patients remains a hot topic in the resuscitation literature as we continue to understand that the immediate post-arrest period is critical to patient outcome.
Ortuno and colleagues reviewed the current literature on post-arrest care and wrote an outstanding summary of how to optimally care for these patients. More specifically, they focused on post-arrest patients who demonstrate continued shock, or “post–cardiac arrest myocardial dysfunction” (PCAMD).
They propose three mechanisms for the pathogenesis of PCAMD: ischemia reperfusion phenomenon, systemic inflammatory response, and increased catecholamine release
I will skip through the details of the pathophysiology that they describe in the article, but I certainly do recommend that everyone review their descriptions.
Management of these patients begins with a good hemodynamic assessment, which includes clinical markers of perfusion (blood pressure, capillary refill), ECG, and point-of-care ultrasound (POCUS). If the initial assessment reveals an obvious cause of the cardiac arrest (e.g., massive pulmonary embolism, myocardial infarction, pericardial tamponade), then the underlying cause should be treated expeditiously.
In the absence of an obvious treatable cause of the shock, the fluid status and cardiac function should be addressed with POCUS. If the patient is hypovolemic, intravenous fluids should be administered. If the fluid status is adequate, POCUS should be used to estimate the patient’s ventricular function. If the ventricle appears to be hyperdynamic with good contractility, shock should be treated with norepinephrine. On the other hand, if the ventricle is hypodynamic, dobutamine should be substituted for norepinephrine or, more often, added to norepinephrine.
The above represents a simplified summary of the critical points, but the authors do delve into further detail and also discuss some other options for therapies, including steroids, coronary revascularization, extracorporeal membrane oxygenation, and so on. The review is very thoughtful, thorough, and definitely worth a full read.
Top myths of diagnosis and management of infectious diseases in hospital medicine
Most, if not all of us in medicine, have heard the saying that 50% of what we learn in medical school (or residency) will turn out to be wrong. I certainly believe in this concept and consequently, like many of you, I enjoy reading about myths and misconceptions that we have been taught. With that in mind, I have to say that I love this article because it seems to have been written specifically to address what I was taught!
This author group, consisting mostly of clinical PharmDs who are experts in antibiotic use, provide us with an evidence-based discussion of myths and pitfalls in how antibiotics are often used in current clinical practice. The authors review their top 10 myths involving the use of antibiotics in treating infections in the hospital setting. A few of these relate more to the inpatient setting, but here are my favorite emergency department (ED)–related myths that they address:
- “Antibiotics do no harm.” The authors address the risk-benefit of antibiotics based on assumed vs. confirmed infections, including a brief discussion of adverse drug effects.
- “Antibiotic durations of 7, 14, or 21 days are typically necessary.” The authors address appropriate duration of antibiotic use and the fact that unnecessarily long durations of use can lead to resistance. They also provide reassurance that some infections can be treated with quite short durations of antibiotics.
- “If one drug is good, two (or more!) is better.” The use of multiple antibiotics, often with overlapping bacterial coverage, is rampant in medicine and further increases the risk for adverse drug effects and resistance.
- “Oral antibiotics are not as good as intravenous antibiotics for hospitalized patients.” This is definitely a myth that I learned. I recall being taught by many senior physicians that anyone sick enough for admission should be treated with intravenous antibiotics. As it turns out, absorption and effectiveness of most oral antibiotics is just as good as intravenous antibiotics, and the oral formulations are often safer.
- “A history of a penicillin allergy means the patient can never receive a beta-lactam antibiotic.” This is a myth that was debunked quite a few years ago, but it seems that many clinicians still need a reminder.
The authors included five more myths that are worth the read. This is an article that needs to be disseminated among all hospital clinicians.
Guidelines for low-risk, recurrent abdominal pain in the emergency department
The Society for Academic Emergency Medicine (SAEM) recently initiated a program focused on creating evidence-based approaches to challenging chief complaints and presentations in the emergency department (ED). In 2021, they published an approach to managing patients with recurrent, low-risk chest pain in the ED. This past year, they published their second guideline, focused on the management of patients with low-risk, recurrent abdominal pain in the ED.
Recurrent low-risk abdominal pain is a common and vexing presentation to EDs around the world, and there is little prior published guidance. Do all of these patients need repeat imaging? How do we manage their pain? Are there nonabdominal conditions that should be considered?
Broder and colleagues did a fantastic review of the current literature and, on behalf of SAEM, have provided a rational approach to optimal management of these patients. The four major questions they addressed, with brief summaries of their recommendations, are:
- Should adult ED patients with low-risk, recurrent and previously undifferentiated abdominal pain receive a repeat CT abdomen-pelvis (CTAP) after a negative CTAP within the past 12 months? This is a typical question that we all ponder when managing these patients. Unfortunately, the writing group found insufficient evidence to definitively identify populations in whom CTAP was recommended vs could be safely withheld. It is a bit disappointing that there is no definite answer to the question. On the other hand, it is reassuring to know that the world’s best evidence essentially says that it is perfectly appropriate to use your own good clinical judgment.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain with a negative CTAP receive additional imaging with abdominal ultrasound? In this case, the writing group found enough evidence, though low-level, to suggest against routine ultrasound in the absence of concern specifically for pelvic or hepatobiliary pathology. Like most tests, ultrasound is best used when there are specific concerns rather than being used in an undifferentiated fashion.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain receive screening for depression/anxiety? The writing group found enough evidence, though low-level again, to suggest that screening for depression and/or anxiety be performed during the ED evaluation. This could lead to successful therapy for the abdominal pain.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain receive nonopioid and/or nonpharmacologic analgesics? The writing group found little evidence to suggest for or against these analgesics, but they made a consensus recommendation suggesting an opioid-minimizing strategy for pain control.
Although the final recommendations of the writing group were not definitive or based on the strongest level of evidence, I find it helpful to have this guidance, nevertheless, on behalf of a major national organization. I also find it helpful to know that even with the best evidence available, optimal patient care will often boil down to physician experience and gestalt. I should also add that the overall article is chock-full of pearls and helpful information that will further inform the readers’ decisions, and so the full version is definitely worth the read.
In summary
There you have it – my three favorite practice-changing articles of 2022. Although I have tried to provide key points here, the full discussions of those key points in the published articles will provide a great deal more education than I can offer in this brief write-up, and so I strongly encourage everyone to read the full versions. Please be sure to include in the comments section your own pick for favorite or must-read articles from the past year.
Amal Mattu, MD, is a professor, vice chair of education, and codirector of the emergency cardiology fellowship in the department of emergency medicine at the University of Maryland, Baltimore. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
When 2022 began, we started seeing some light at the end of the COVID-19 tunnel. Vaccines were widely available, and even with new variants of the virus still occasionally emerging, the rates of severe morbidity and mortality appeared to be decreasing.
Expectedly, journals appeared to start moving more toward mainstream topics and publications rather than what seemed like a major focus on COVID-19 publications. The resulting literature was fantastic.
Several of those topics were discussed in a prior Emergency Medicine Viewpoint from this news organization, and many more of the research advances of 2022 will be discussed in the near future. However, in this Viewpoint, I would like to present my annual review of my three “must-read” articles of the past year.
As in past years, I am choosing reviews of the literature rather than original research articles (which, all too often, become outdated or debunked within a few years). I choose these articles in the hopes that readers will not simply settle for my brief reviews of the key points but instead will feel compelled to download and read the entire articles. These publications address common conditions and quandaries we face in the daily practice of emergency medicine and are practice-changing.
Myocardial dysfunction after cardiac arrest: Tips and pitfalls
The management of post–cardiac arrest patients remains a hot topic in the resuscitation literature as we continue to understand that the immediate post-arrest period is critical to patient outcome.
Ortuno and colleagues reviewed the current literature on post-arrest care and wrote an outstanding summary of how to optimally care for these patients. More specifically, they focused on post-arrest patients who demonstrate continued shock, or “post–cardiac arrest myocardial dysfunction” (PCAMD).
They propose three mechanisms for the pathogenesis of PCAMD: ischemia reperfusion phenomenon, systemic inflammatory response, and increased catecholamine release
I will skip through the details of the pathophysiology that they describe in the article, but I certainly do recommend that everyone review their descriptions.
Management of these patients begins with a good hemodynamic assessment, which includes clinical markers of perfusion (blood pressure, capillary refill), ECG, and point-of-care ultrasound (POCUS). If the initial assessment reveals an obvious cause of the cardiac arrest (e.g., massive pulmonary embolism, myocardial infarction, pericardial tamponade), then the underlying cause should be treated expeditiously.
In the absence of an obvious treatable cause of the shock, the fluid status and cardiac function should be addressed with POCUS. If the patient is hypovolemic, intravenous fluids should be administered. If the fluid status is adequate, POCUS should be used to estimate the patient’s ventricular function. If the ventricle appears to be hyperdynamic with good contractility, shock should be treated with norepinephrine. On the other hand, if the ventricle is hypodynamic, dobutamine should be substituted for norepinephrine or, more often, added to norepinephrine.
The above represents a simplified summary of the critical points, but the authors do delve into further detail and also discuss some other options for therapies, including steroids, coronary revascularization, extracorporeal membrane oxygenation, and so on. The review is very thoughtful, thorough, and definitely worth a full read.
Top myths of diagnosis and management of infectious diseases in hospital medicine
Most, if not all of us in medicine, have heard the saying that 50% of what we learn in medical school (or residency) will turn out to be wrong. I certainly believe in this concept and consequently, like many of you, I enjoy reading about myths and misconceptions that we have been taught. With that in mind, I have to say that I love this article because it seems to have been written specifically to address what I was taught!
This author group, consisting mostly of clinical PharmDs who are experts in antibiotic use, provide us with an evidence-based discussion of myths and pitfalls in how antibiotics are often used in current clinical practice. The authors review their top 10 myths involving the use of antibiotics in treating infections in the hospital setting. A few of these relate more to the inpatient setting, but here are my favorite emergency department (ED)–related myths that they address:
- “Antibiotics do no harm.” The authors address the risk-benefit of antibiotics based on assumed vs. confirmed infections, including a brief discussion of adverse drug effects.
- “Antibiotic durations of 7, 14, or 21 days are typically necessary.” The authors address appropriate duration of antibiotic use and the fact that unnecessarily long durations of use can lead to resistance. They also provide reassurance that some infections can be treated with quite short durations of antibiotics.
- “If one drug is good, two (or more!) is better.” The use of multiple antibiotics, often with overlapping bacterial coverage, is rampant in medicine and further increases the risk for adverse drug effects and resistance.
- “Oral antibiotics are not as good as intravenous antibiotics for hospitalized patients.” This is definitely a myth that I learned. I recall being taught by many senior physicians that anyone sick enough for admission should be treated with intravenous antibiotics. As it turns out, absorption and effectiveness of most oral antibiotics is just as good as intravenous antibiotics, and the oral formulations are often safer.
- “A history of a penicillin allergy means the patient can never receive a beta-lactam antibiotic.” This is a myth that was debunked quite a few years ago, but it seems that many clinicians still need a reminder.
The authors included five more myths that are worth the read. This is an article that needs to be disseminated among all hospital clinicians.
Guidelines for low-risk, recurrent abdominal pain in the emergency department
The Society for Academic Emergency Medicine (SAEM) recently initiated a program focused on creating evidence-based approaches to challenging chief complaints and presentations in the emergency department (ED). In 2021, they published an approach to managing patients with recurrent, low-risk chest pain in the ED. This past year, they published their second guideline, focused on the management of patients with low-risk, recurrent abdominal pain in the ED.
Recurrent low-risk abdominal pain is a common and vexing presentation to EDs around the world, and there is little prior published guidance. Do all of these patients need repeat imaging? How do we manage their pain? Are there nonabdominal conditions that should be considered?
Broder and colleagues did a fantastic review of the current literature and, on behalf of SAEM, have provided a rational approach to optimal management of these patients. The four major questions they addressed, with brief summaries of their recommendations, are:
- Should adult ED patients with low-risk, recurrent and previously undifferentiated abdominal pain receive a repeat CT abdomen-pelvis (CTAP) after a negative CTAP within the past 12 months? This is a typical question that we all ponder when managing these patients. Unfortunately, the writing group found insufficient evidence to definitively identify populations in whom CTAP was recommended vs could be safely withheld. It is a bit disappointing that there is no definite answer to the question. On the other hand, it is reassuring to know that the world’s best evidence essentially says that it is perfectly appropriate to use your own good clinical judgment.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain with a negative CTAP receive additional imaging with abdominal ultrasound? In this case, the writing group found enough evidence, though low-level, to suggest against routine ultrasound in the absence of concern specifically for pelvic or hepatobiliary pathology. Like most tests, ultrasound is best used when there are specific concerns rather than being used in an undifferentiated fashion.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain receive screening for depression/anxiety? The writing group found enough evidence, though low-level again, to suggest that screening for depression and/or anxiety be performed during the ED evaluation. This could lead to successful therapy for the abdominal pain.
- Should adult ED patients with low-risk, recurrent, and previously undifferentiated abdominal pain receive nonopioid and/or nonpharmacologic analgesics? The writing group found little evidence to suggest for or against these analgesics, but they made a consensus recommendation suggesting an opioid-minimizing strategy for pain control.
Although the final recommendations of the writing group were not definitive or based on the strongest level of evidence, I find it helpful to have this guidance, nevertheless, on behalf of a major national organization. I also find it helpful to know that even with the best evidence available, optimal patient care will often boil down to physician experience and gestalt. I should also add that the overall article is chock-full of pearls and helpful information that will further inform the readers’ decisions, and so the full version is definitely worth the read.
In summary
There you have it – my three favorite practice-changing articles of 2022. Although I have tried to provide key points here, the full discussions of those key points in the published articles will provide a great deal more education than I can offer in this brief write-up, and so I strongly encourage everyone to read the full versions. Please be sure to include in the comments section your own pick for favorite or must-read articles from the past year.
Amal Mattu, MD, is a professor, vice chair of education, and codirector of the emergency cardiology fellowship in the department of emergency medicine at the University of Maryland, Baltimore. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Mental health system failing kids leaving ED
Only 56% of children enrolled in Medicaid received any outpatient follow-up within 30 days after a mental health emergency department discharge, according to results of a large study released in Pediatrics.
Fewer than one-third (31.2%) had an outpatient visit within a week after a mental health ED discharge.
Researchers conducted a retrospective study of 28,551 children ages 6-17 years old who had mental health discharges from EDs from January 2018 to June 2019.
The researchers, led by Jennifer A. Hoffmann, MD, MS, with the division of emergency medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University, Chicago, also analyzed the effect that having a timely follow-up had on whether the child was likely to return to the ED.
Follow-up within 30 days cuts risk of quick return to ED
They found that follow-up within 30 days was linked with a 26% decreased risk of return within 5 days of the initial ED discharge (hazard ratio, 0.74; 95% confidence interval, 0.63-0.91).
The researchers also found racial disparities in the data. The odds for getting follow-up outpatient care were lower for non-Hispanic Black children, for children with fee-for-service insurance, and for children with no previous mental health outpatient visits.
The numbers were particularly striking for Black children, who were 10% less likely to get outpatient follow-up than their White counterparts.
In addition, 27% of all children in this sample returned to the ED for mental health-related symptoms within 6 months, 20% spent more than 48 hours in the ED for their initial mental health visit, and children with 14 or more mental health outpatient visits had five times higher adjusted odds of follow-up within 7 days and 9.5 times higher adjusted odds of follow-up within 30 days, compared with children with no outpatient mental health visits in the previous year.
A ‘mental health system of care in crisis’
In an accompanying editorial, Hannah E. Karpman, MSW, PhD, with the department of pediatrics, University of Massachusetts, Worcester, and colleagues said those statistics help expose other signs of “a pediatric mental health system of care in crisis.”
If one in five children are spending more than 2 days in the ED for their initial mental health visit, they wrote, that signals the follow-up care they need is not readily available.
The 27% returning to the ED shows that, even if the children are getting outpatient services, that environment is failing them, they noted.
Additionally, 28% of children presented with more than four mental health diagnoses, “suggesting poor diagnostic specificity or perhaps inadequate diagnostic categories to characterize their needs.”
The authors called for interventions that link patients to outpatient care within 5 days of a mental health ED discharge.
The editorialists wrote: “We believe it is time for a “child mental health moonshot,” and call on the field and its funders to come together to launch the next wave of bold mental health research for the benefit of these children and their families who so desperately need our support.”
Things may even be worse in light of COVID
David Rettew, MD, a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland, said in an interview the numbers won’t surprise clinicians who support these children or the patients’ families.
He added that he wouldn’t be surprised if things are even worse now after this study’s data collection, “as COVID and other factors have driven more mental health professionals away from many of the people who need them the most.”
The study does present new evidence that quick access to care is particularly tough for young people who aren’t already established in care, he noted.
“As wait lists grow at outpatient clinics, we are seeing ever stronger need for centers willing and able to provide actual mental health assessment and treatment for people right ‘off the street,’” he said.
Dr. Rettew emphasized that, because mental health conditions rarely improve quickly, having a timely follow-up appointment is important, but won’t likely bring quick improvement.
He agreed with the editorialists’ argument and emphasized, “not only do we need to focus on more rapid care, but also more comprehensive and effective care.
“For an adolescent in crisis, achieving stability often involves more than a medication tweak and a supportive conversation,” Dr. Rettew said. “Rather, it can require an intensive multimodal approach that addresses things like family financial stressors, parental mental health and substance use concerns, school supports, and health promotion or lifestyle changes. What we desperately need are more teams that can quickly intervene on all these levels.”
Addressing problems before crisis is essential
Ideally, teams would address these issues before a crisis. That helps support the “moonshot” charge the editorialists suggest, which “would significantly disrupt the current way we value different components of our health care system,” Dr. Rettew said.
He highlighted a statistic that may get lost in the data: Nearly 40% of youth in enough danger to need an ED visit had no more than one health-related appointment of any kind in the previous year.
“To me, this speaks volumes about the need for earlier involvement before things escalate to the level of an emergency,” Dr. Rettew said.
The authors and editorialists declared no relevant financial relationships. Dr. Rettew is author of the book, “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.”
Only 56% of children enrolled in Medicaid received any outpatient follow-up within 30 days after a mental health emergency department discharge, according to results of a large study released in Pediatrics.
Fewer than one-third (31.2%) had an outpatient visit within a week after a mental health ED discharge.
Researchers conducted a retrospective study of 28,551 children ages 6-17 years old who had mental health discharges from EDs from January 2018 to June 2019.
The researchers, led by Jennifer A. Hoffmann, MD, MS, with the division of emergency medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University, Chicago, also analyzed the effect that having a timely follow-up had on whether the child was likely to return to the ED.
Follow-up within 30 days cuts risk of quick return to ED
They found that follow-up within 30 days was linked with a 26% decreased risk of return within 5 days of the initial ED discharge (hazard ratio, 0.74; 95% confidence interval, 0.63-0.91).
The researchers also found racial disparities in the data. The odds for getting follow-up outpatient care were lower for non-Hispanic Black children, for children with fee-for-service insurance, and for children with no previous mental health outpatient visits.
The numbers were particularly striking for Black children, who were 10% less likely to get outpatient follow-up than their White counterparts.
In addition, 27% of all children in this sample returned to the ED for mental health-related symptoms within 6 months, 20% spent more than 48 hours in the ED for their initial mental health visit, and children with 14 or more mental health outpatient visits had five times higher adjusted odds of follow-up within 7 days and 9.5 times higher adjusted odds of follow-up within 30 days, compared with children with no outpatient mental health visits in the previous year.
A ‘mental health system of care in crisis’
In an accompanying editorial, Hannah E. Karpman, MSW, PhD, with the department of pediatrics, University of Massachusetts, Worcester, and colleagues said those statistics help expose other signs of “a pediatric mental health system of care in crisis.”
If one in five children are spending more than 2 days in the ED for their initial mental health visit, they wrote, that signals the follow-up care they need is not readily available.
The 27% returning to the ED shows that, even if the children are getting outpatient services, that environment is failing them, they noted.
Additionally, 28% of children presented with more than four mental health diagnoses, “suggesting poor diagnostic specificity or perhaps inadequate diagnostic categories to characterize their needs.”
The authors called for interventions that link patients to outpatient care within 5 days of a mental health ED discharge.
The editorialists wrote: “We believe it is time for a “child mental health moonshot,” and call on the field and its funders to come together to launch the next wave of bold mental health research for the benefit of these children and their families who so desperately need our support.”
Things may even be worse in light of COVID
David Rettew, MD, a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland, said in an interview the numbers won’t surprise clinicians who support these children or the patients’ families.
He added that he wouldn’t be surprised if things are even worse now after this study’s data collection, “as COVID and other factors have driven more mental health professionals away from many of the people who need them the most.”
The study does present new evidence that quick access to care is particularly tough for young people who aren’t already established in care, he noted.
“As wait lists grow at outpatient clinics, we are seeing ever stronger need for centers willing and able to provide actual mental health assessment and treatment for people right ‘off the street,’” he said.
Dr. Rettew emphasized that, because mental health conditions rarely improve quickly, having a timely follow-up appointment is important, but won’t likely bring quick improvement.
He agreed with the editorialists’ argument and emphasized, “not only do we need to focus on more rapid care, but also more comprehensive and effective care.
“For an adolescent in crisis, achieving stability often involves more than a medication tweak and a supportive conversation,” Dr. Rettew said. “Rather, it can require an intensive multimodal approach that addresses things like family financial stressors, parental mental health and substance use concerns, school supports, and health promotion or lifestyle changes. What we desperately need are more teams that can quickly intervene on all these levels.”
Addressing problems before crisis is essential
Ideally, teams would address these issues before a crisis. That helps support the “moonshot” charge the editorialists suggest, which “would significantly disrupt the current way we value different components of our health care system,” Dr. Rettew said.
He highlighted a statistic that may get lost in the data: Nearly 40% of youth in enough danger to need an ED visit had no more than one health-related appointment of any kind in the previous year.
“To me, this speaks volumes about the need for earlier involvement before things escalate to the level of an emergency,” Dr. Rettew said.
The authors and editorialists declared no relevant financial relationships. Dr. Rettew is author of the book, “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.”
Only 56% of children enrolled in Medicaid received any outpatient follow-up within 30 days after a mental health emergency department discharge, according to results of a large study released in Pediatrics.
Fewer than one-third (31.2%) had an outpatient visit within a week after a mental health ED discharge.
Researchers conducted a retrospective study of 28,551 children ages 6-17 years old who had mental health discharges from EDs from January 2018 to June 2019.
The researchers, led by Jennifer A. Hoffmann, MD, MS, with the division of emergency medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University, Chicago, also analyzed the effect that having a timely follow-up had on whether the child was likely to return to the ED.
Follow-up within 30 days cuts risk of quick return to ED
They found that follow-up within 30 days was linked with a 26% decreased risk of return within 5 days of the initial ED discharge (hazard ratio, 0.74; 95% confidence interval, 0.63-0.91).
The researchers also found racial disparities in the data. The odds for getting follow-up outpatient care were lower for non-Hispanic Black children, for children with fee-for-service insurance, and for children with no previous mental health outpatient visits.
The numbers were particularly striking for Black children, who were 10% less likely to get outpatient follow-up than their White counterparts.
In addition, 27% of all children in this sample returned to the ED for mental health-related symptoms within 6 months, 20% spent more than 48 hours in the ED for their initial mental health visit, and children with 14 or more mental health outpatient visits had five times higher adjusted odds of follow-up within 7 days and 9.5 times higher adjusted odds of follow-up within 30 days, compared with children with no outpatient mental health visits in the previous year.
A ‘mental health system of care in crisis’
In an accompanying editorial, Hannah E. Karpman, MSW, PhD, with the department of pediatrics, University of Massachusetts, Worcester, and colleagues said those statistics help expose other signs of “a pediatric mental health system of care in crisis.”
If one in five children are spending more than 2 days in the ED for their initial mental health visit, they wrote, that signals the follow-up care they need is not readily available.
The 27% returning to the ED shows that, even if the children are getting outpatient services, that environment is failing them, they noted.
Additionally, 28% of children presented with more than four mental health diagnoses, “suggesting poor diagnostic specificity or perhaps inadequate diagnostic categories to characterize their needs.”
The authors called for interventions that link patients to outpatient care within 5 days of a mental health ED discharge.
The editorialists wrote: “We believe it is time for a “child mental health moonshot,” and call on the field and its funders to come together to launch the next wave of bold mental health research for the benefit of these children and their families who so desperately need our support.”
Things may even be worse in light of COVID
David Rettew, MD, a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland, said in an interview the numbers won’t surprise clinicians who support these children or the patients’ families.
He added that he wouldn’t be surprised if things are even worse now after this study’s data collection, “as COVID and other factors have driven more mental health professionals away from many of the people who need them the most.”
The study does present new evidence that quick access to care is particularly tough for young people who aren’t already established in care, he noted.
“As wait lists grow at outpatient clinics, we are seeing ever stronger need for centers willing and able to provide actual mental health assessment and treatment for people right ‘off the street,’” he said.
Dr. Rettew emphasized that, because mental health conditions rarely improve quickly, having a timely follow-up appointment is important, but won’t likely bring quick improvement.
He agreed with the editorialists’ argument and emphasized, “not only do we need to focus on more rapid care, but also more comprehensive and effective care.
“For an adolescent in crisis, achieving stability often involves more than a medication tweak and a supportive conversation,” Dr. Rettew said. “Rather, it can require an intensive multimodal approach that addresses things like family financial stressors, parental mental health and substance use concerns, school supports, and health promotion or lifestyle changes. What we desperately need are more teams that can quickly intervene on all these levels.”
Addressing problems before crisis is essential
Ideally, teams would address these issues before a crisis. That helps support the “moonshot” charge the editorialists suggest, which “would significantly disrupt the current way we value different components of our health care system,” Dr. Rettew said.
He highlighted a statistic that may get lost in the data: Nearly 40% of youth in enough danger to need an ED visit had no more than one health-related appointment of any kind in the previous year.
“To me, this speaks volumes about the need for earlier involvement before things escalate to the level of an emergency,” Dr. Rettew said.
The authors and editorialists declared no relevant financial relationships. Dr. Rettew is author of the book, “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.”
FROM PEDIATRICS
The X-waiver is dead
In 2016, when Erin Schanning lost her brother Ethan to an overdose, she wanted to know what could have been done to have helped him. Ethan, who had struggled with opioids since getting a prescription for the drugs after a dental procedure in middle school, had tried dozens of treatments. But at the age of 30, he was gone.
“After my brother died, I started researching and was surprised to learn that there were many evidence-based ways to treat substance use disorder that he hadn’t had access to, even though he had doggedly pursued treatment,” Ms. Schanning told me in an interview. One of those treatments, buprenorphine, is one of the most effective tools that health care providers have to treat opioid use disorder. A partial opioid agonist, it reduces cravings and prevents overdose, decreasing mortality more effectively than almost any medication for any disease. Yet most providers have never prescribed it.
That may be about to change. The special license to prescribe the medication, commonly known as the “X-waiver,” was officially eliminated as part of the passage of the Mainstreaming Addiction Treatment (MAT) Act. Immediately, following the passage of the Act, any provider with a DEA license became eligible to prescribe buprenorphine to treat opioid use disorder, and limits on the number of patients they could treat were eliminated.
Previously, buprenorphine, which has a better safety profile than almost any other prescription opioid because of its ceiling effect on respiratory depression,nonetheless required providers to obtain a special license to prescribe it, and – prior to an executive order from the Biden administration – 8 to 24 hours of training to do so. This led to a misconception that buprenorphine was dangerous, and created barriers for treatment during the worst overdose crisis in our country’s history. More than 110,00 overdose deaths occurred in 2021, representing a 468% increase in the last 2 decades.
Along with the MAT Act, the Medication Access and Training Expansion Act was passed in the same spending bill, requiring all prescribers who obtain a DEA license to do 8 hours of training on the treatment of substance use disorders. According to the Act, addiction specialty societies will have a role in creating trainings. Medical schools and residencies will also be able to fulfill this requirement with a “comprehensive” curriculum that covers all approved medications for the treatment of substance use disorders.
The DEA has not yet confirmed what training will be accepted, according to the Chief Medical Officer of the Substance Abuse and Mental Health Services Administration, Neeraj Gandotra, MD, who spoke to me in an interview. However, it is required to do so by April 5, 2023. Dr. Gandotra also emphasized that state and local laws, as well as insurance requirements, remain in place, and may place other constraints on prescribing. According to the Act, this new rule will be in effect by June 2023.
As an addiction medicine specialist and longtime buprenorphine prescriber, I am excited about these changes but wary of lingering resistance among health care providers. Will providers who have chosen not to get an X-waiver now look for another reason to not treat patients with substance use disorders?
Ms. Schanning remains hopeful. “I’m incredibly optimistic that health care providers are going to learn about buprenorphine and prescribe it to patients, and that patients are going to start asking about this medication,” she told me. “Seven in 10 providers say that they do feel an obligation to treat their patients with [opioid use disorder], but the federal government has made it very difficult to do so.”
Now with the X-waiver gone, providers and patients may be able to push for a long overdue shift in how we treat and conceptualize substance use disorders, she noted.
“Health care providers need to recognize substance use disorder as a medical condition that deserves treatment, and to speak about it like a medical condition,” Ms. Schanning said, by, for instance, moving away from using words such as “abuse” and “clean” and, instead, talking about treatable substance use disorders that can improve with evidence-based care, such as buprenorphine and methadone. “We also need to share stories of success and hope with people,” she added. “Once you’ve seen how someone can be transformed by treatment, it’s really difficult to say that substance use disorder is a character flaw, or their fault.”
A patient-centered approach
Over the past decade of practicing medicine, I have experienced this transformation personally. In residency, I believed that people had to be ready for help, to stop using, to change. I failed to recognize that many of those same people were asking me for help, and I wasn’t offering what they needed. The person who had to change was me.
As I moved toward a patient-centered approach, lowering barriers to starting and remaining in treatment, and collaborating with teams that could meet people wherever they might be, addictions became the most rewarding part of my practice.
I have never had more people thank me spontaneously and deeply for the care I provide. Plus, I have never seen a more profound change in the students I work with than when they witness someone with a substance use disorder offered treatment that works.
The X-waiver was not the only barrier to care, and the overdose crisis is not slowing down. But maybe with a new tool widely accessible, more of us will be ready to help.
Dr. Poorman is board certified in internal medicine and addiction medicine, assistant professor of medicine, University of Illinois at Chicago, and provides primary care and addiction services in Chicago. Her views do not necessarily reflect the views of her employer. She has reported no relevant disclosures, and she serves on the editorial advisory board of Internal Medicine News.
In 2016, when Erin Schanning lost her brother Ethan to an overdose, she wanted to know what could have been done to have helped him. Ethan, who had struggled with opioids since getting a prescription for the drugs after a dental procedure in middle school, had tried dozens of treatments. But at the age of 30, he was gone.
“After my brother died, I started researching and was surprised to learn that there were many evidence-based ways to treat substance use disorder that he hadn’t had access to, even though he had doggedly pursued treatment,” Ms. Schanning told me in an interview. One of those treatments, buprenorphine, is one of the most effective tools that health care providers have to treat opioid use disorder. A partial opioid agonist, it reduces cravings and prevents overdose, decreasing mortality more effectively than almost any medication for any disease. Yet most providers have never prescribed it.
That may be about to change. The special license to prescribe the medication, commonly known as the “X-waiver,” was officially eliminated as part of the passage of the Mainstreaming Addiction Treatment (MAT) Act. Immediately, following the passage of the Act, any provider with a DEA license became eligible to prescribe buprenorphine to treat opioid use disorder, and limits on the number of patients they could treat were eliminated.
Previously, buprenorphine, which has a better safety profile than almost any other prescription opioid because of its ceiling effect on respiratory depression,nonetheless required providers to obtain a special license to prescribe it, and – prior to an executive order from the Biden administration – 8 to 24 hours of training to do so. This led to a misconception that buprenorphine was dangerous, and created barriers for treatment during the worst overdose crisis in our country’s history. More than 110,00 overdose deaths occurred in 2021, representing a 468% increase in the last 2 decades.
Along with the MAT Act, the Medication Access and Training Expansion Act was passed in the same spending bill, requiring all prescribers who obtain a DEA license to do 8 hours of training on the treatment of substance use disorders. According to the Act, addiction specialty societies will have a role in creating trainings. Medical schools and residencies will also be able to fulfill this requirement with a “comprehensive” curriculum that covers all approved medications for the treatment of substance use disorders.
The DEA has not yet confirmed what training will be accepted, according to the Chief Medical Officer of the Substance Abuse and Mental Health Services Administration, Neeraj Gandotra, MD, who spoke to me in an interview. However, it is required to do so by April 5, 2023. Dr. Gandotra also emphasized that state and local laws, as well as insurance requirements, remain in place, and may place other constraints on prescribing. According to the Act, this new rule will be in effect by June 2023.
As an addiction medicine specialist and longtime buprenorphine prescriber, I am excited about these changes but wary of lingering resistance among health care providers. Will providers who have chosen not to get an X-waiver now look for another reason to not treat patients with substance use disorders?
Ms. Schanning remains hopeful. “I’m incredibly optimistic that health care providers are going to learn about buprenorphine and prescribe it to patients, and that patients are going to start asking about this medication,” she told me. “Seven in 10 providers say that they do feel an obligation to treat their patients with [opioid use disorder], but the federal government has made it very difficult to do so.”
Now with the X-waiver gone, providers and patients may be able to push for a long overdue shift in how we treat and conceptualize substance use disorders, she noted.
“Health care providers need to recognize substance use disorder as a medical condition that deserves treatment, and to speak about it like a medical condition,” Ms. Schanning said, by, for instance, moving away from using words such as “abuse” and “clean” and, instead, talking about treatable substance use disorders that can improve with evidence-based care, such as buprenorphine and methadone. “We also need to share stories of success and hope with people,” she added. “Once you’ve seen how someone can be transformed by treatment, it’s really difficult to say that substance use disorder is a character flaw, or their fault.”
A patient-centered approach
Over the past decade of practicing medicine, I have experienced this transformation personally. In residency, I believed that people had to be ready for help, to stop using, to change. I failed to recognize that many of those same people were asking me for help, and I wasn’t offering what they needed. The person who had to change was me.
As I moved toward a patient-centered approach, lowering barriers to starting and remaining in treatment, and collaborating with teams that could meet people wherever they might be, addictions became the most rewarding part of my practice.
I have never had more people thank me spontaneously and deeply for the care I provide. Plus, I have never seen a more profound change in the students I work with than when they witness someone with a substance use disorder offered treatment that works.
The X-waiver was not the only barrier to care, and the overdose crisis is not slowing down. But maybe with a new tool widely accessible, more of us will be ready to help.
Dr. Poorman is board certified in internal medicine and addiction medicine, assistant professor of medicine, University of Illinois at Chicago, and provides primary care and addiction services in Chicago. Her views do not necessarily reflect the views of her employer. She has reported no relevant disclosures, and she serves on the editorial advisory board of Internal Medicine News.
In 2016, when Erin Schanning lost her brother Ethan to an overdose, she wanted to know what could have been done to have helped him. Ethan, who had struggled with opioids since getting a prescription for the drugs after a dental procedure in middle school, had tried dozens of treatments. But at the age of 30, he was gone.
“After my brother died, I started researching and was surprised to learn that there were many evidence-based ways to treat substance use disorder that he hadn’t had access to, even though he had doggedly pursued treatment,” Ms. Schanning told me in an interview. One of those treatments, buprenorphine, is one of the most effective tools that health care providers have to treat opioid use disorder. A partial opioid agonist, it reduces cravings and prevents overdose, decreasing mortality more effectively than almost any medication for any disease. Yet most providers have never prescribed it.
That may be about to change. The special license to prescribe the medication, commonly known as the “X-waiver,” was officially eliminated as part of the passage of the Mainstreaming Addiction Treatment (MAT) Act. Immediately, following the passage of the Act, any provider with a DEA license became eligible to prescribe buprenorphine to treat opioid use disorder, and limits on the number of patients they could treat were eliminated.
Previously, buprenorphine, which has a better safety profile than almost any other prescription opioid because of its ceiling effect on respiratory depression,nonetheless required providers to obtain a special license to prescribe it, and – prior to an executive order from the Biden administration – 8 to 24 hours of training to do so. This led to a misconception that buprenorphine was dangerous, and created barriers for treatment during the worst overdose crisis in our country’s history. More than 110,00 overdose deaths occurred in 2021, representing a 468% increase in the last 2 decades.
Along with the MAT Act, the Medication Access and Training Expansion Act was passed in the same spending bill, requiring all prescribers who obtain a DEA license to do 8 hours of training on the treatment of substance use disorders. According to the Act, addiction specialty societies will have a role in creating trainings. Medical schools and residencies will also be able to fulfill this requirement with a “comprehensive” curriculum that covers all approved medications for the treatment of substance use disorders.
The DEA has not yet confirmed what training will be accepted, according to the Chief Medical Officer of the Substance Abuse and Mental Health Services Administration, Neeraj Gandotra, MD, who spoke to me in an interview. However, it is required to do so by April 5, 2023. Dr. Gandotra also emphasized that state and local laws, as well as insurance requirements, remain in place, and may place other constraints on prescribing. According to the Act, this new rule will be in effect by June 2023.
As an addiction medicine specialist and longtime buprenorphine prescriber, I am excited about these changes but wary of lingering resistance among health care providers. Will providers who have chosen not to get an X-waiver now look for another reason to not treat patients with substance use disorders?
Ms. Schanning remains hopeful. “I’m incredibly optimistic that health care providers are going to learn about buprenorphine and prescribe it to patients, and that patients are going to start asking about this medication,” she told me. “Seven in 10 providers say that they do feel an obligation to treat their patients with [opioid use disorder], but the federal government has made it very difficult to do so.”
Now with the X-waiver gone, providers and patients may be able to push for a long overdue shift in how we treat and conceptualize substance use disorders, she noted.
“Health care providers need to recognize substance use disorder as a medical condition that deserves treatment, and to speak about it like a medical condition,” Ms. Schanning said, by, for instance, moving away from using words such as “abuse” and “clean” and, instead, talking about treatable substance use disorders that can improve with evidence-based care, such as buprenorphine and methadone. “We also need to share stories of success and hope with people,” she added. “Once you’ve seen how someone can be transformed by treatment, it’s really difficult to say that substance use disorder is a character flaw, or their fault.”
A patient-centered approach
Over the past decade of practicing medicine, I have experienced this transformation personally. In residency, I believed that people had to be ready for help, to stop using, to change. I failed to recognize that many of those same people were asking me for help, and I wasn’t offering what they needed. The person who had to change was me.
As I moved toward a patient-centered approach, lowering barriers to starting and remaining in treatment, and collaborating with teams that could meet people wherever they might be, addictions became the most rewarding part of my practice.
I have never had more people thank me spontaneously and deeply for the care I provide. Plus, I have never seen a more profound change in the students I work with than when they witness someone with a substance use disorder offered treatment that works.
The X-waiver was not the only barrier to care, and the overdose crisis is not slowing down. But maybe with a new tool widely accessible, more of us will be ready to help.
Dr. Poorman is board certified in internal medicine and addiction medicine, assistant professor of medicine, University of Illinois at Chicago, and provides primary care and addiction services in Chicago. Her views do not necessarily reflect the views of her employer. She has reported no relevant disclosures, and she serves on the editorial advisory board of Internal Medicine News.
Scientists create ‘vagina on a chip’: What to know
For years, women’s health advocates have argued that far more research is needed on women’s bodies and health. The world’s first-ever “vagina on a chip,” recently developed at Harvard’s Wyss Institute for Biologically Inspired Engineering in Boston, could go a long way to making that happen.
“Women’s health has not received the attention it deserves,” says Don Ingber, MD, PhD, who led the team that created the vagina chip. The advance quickly drew media attention after it was reported in the journal Microbiome. But researchers hope for more than headlines. They see the chip as a way to facilitate vaginal health research and open the door to vital new treatments.
By now, you may have heard of “organs on chips”: tiny devices about the size of a flash drive that are designed to mimic the biological activity of human organs. These glass chips contain living human cells within grooves that allow the passage of fluid, to either maintain or disrupt the cells’ function. So far, Dr. Ingber and his team at the Wyss Institute have developed more than 15 organ chip models, including chips that mimic the lung, intestine, kidney, and bone marrow.
The idea to develop a vagina chip grew out of research, funded by the Gates Foundation, on a childhood disease called environmental enteric dysfunction, an intestinal disease most commonly found in low-resource nations that is the second leading cause of death in children under 5. That’s when Dr. Ingber discovered just how much the child’s microbiome influences this disease.
Stemming from that work, the Gates Foundation turned its attention to newborn health – in particular, the impact of bacterial vaginosis, an imbalance in the vagina’s bacterial makeup. Bacterial vaginosis occurs in one out of four women worldwide and has been linked to premature birth as well as HIV, HPV persistence, and cervical cancer.
The goal was to test “live biotherapeutic products,” or living microbes like probiotics, that might restore the vagina’s microbiome to health.
No other preclinical model exists to perform tests like that, says Dr. Ingber.
“The vagina chip is a way to help make some advances,” he says.
The Gates Foundation recognized that women’s reproductive health is a major issue, not only in low-income nations, but everywhere around the world. As the project evolved, Dr. Ingber began to hear from female colleagues about how neglected women’s reproductive health is in medical science.
“It is something I became sensitive to and realized this is just the starting point,” Dr. Ingber says.
Take bacterial vaginosis, for example. Since 1982, treatment has revolved around the same two antibiotics. That’s partly because there is no animal model to study. No other species has the same vaginal bacterial community as humans do.
That makes developing any new therapy “incredibly challenging,” explains Caroline Mitchell, MD, MPH, an ob.gyn. at Massachusetts General Hospital, Boston, and a member of the consortium.
It turns out, replicating the vagina in a lab dish is, to use the technical term, very hard.
“That’s where a vagina chip offers an opportunity,” Dr. Mitchell says. “It’s not super-high throughput, but it’s way more high throughput than a [human] clinical trial.”
As such, the vagina chip could help scientists find new treatments much faster.
Like Dr. Ingber, Dr. Mitchell also sees the chip as a way to bring more attention to the largely unmet needs in female reproductive medicine.
“Women’s reproductive health has been under-resourced, under-prioritized, and largely disregarded for decades,” she says. And the time may be ripe for change: Dr. Mitchell says she was encouraged by the National Institutes of Health’s Advancing NIH Research on the Health of Women conference, held in 2021 in response to a congressional request to address women’s health research efforts.
Beyond bacterial vaginosis, Dr. Mitchell imagines the chip could help scientists find new treatments for vaginal yeast infection (candidiasis), chlamydia, and endometriosis. As with bacterial vaginosis, medicines for vaginal yeast infections have not advanced in decades, Dr. Mitchell says. Efforts to develop a vaccine for chlamydia – which can cause permanent damage to a woman’s reproductive system – have dragged on for many years. And endometriosis, an often painful condition in which the tissue that makes up the uterine lining grows outside the uterus, remains under-researched despite affecting 10% of childbearing-age women.
While some mouse models are used in chlamydia research, it’s hard to say if they’ll translate to humans, given the vaginal and cervical bacterial differences.
“Our understanding of the basic physiology of the environment of the vagina and cervix is another area where we’re woefully ignorant,” Dr. Mitchell says.
To that end, Dr. Ingber’s team is developing more complex chips mimicking the vagina and the cervix. One of his team members wants to use the chips to study infertility. The researchers have already used the chips to see how bacterial vaginosis and mucous changes impact the way sperm migrates up the reproductive tract.
The lab is now linking vagina and cervix chips together to study viral infections of the cervix, like HPV, and all types of bacterial diseases of the vaginal tract. By applying cervical mucus to the vagina chip, they hope to learn more about how female reproductive tissues respond to infection and inflammation.
“I always say that organ chips are like synthetic biology at the cell tissue and organ level,” says Dr. Ingber. “You start simple and see if you [can] mimic a clinical situation.”
As they make the chips more complex – perhaps by adding blood vessel cells and female hormones – Dr. Ingber foresees being able to study the response to hormonal changes during the menstrual cycle.
“We can begin to explore the effects of cycling over time as well as other types of hormonal effects,” he says.
Dr. Ingber also envisions linking the vagina chip to other organ chips – he’s already succeeded in linking eight different organ types together. But for now, the team hopes the vagina chip will enhance our understanding of basic female reproductive biology and speed up the process of developing new treatments for women’s health.
A version of this article first appeared on WebMD.com.
For years, women’s health advocates have argued that far more research is needed on women’s bodies and health. The world’s first-ever “vagina on a chip,” recently developed at Harvard’s Wyss Institute for Biologically Inspired Engineering in Boston, could go a long way to making that happen.
“Women’s health has not received the attention it deserves,” says Don Ingber, MD, PhD, who led the team that created the vagina chip. The advance quickly drew media attention after it was reported in the journal Microbiome. But researchers hope for more than headlines. They see the chip as a way to facilitate vaginal health research and open the door to vital new treatments.
By now, you may have heard of “organs on chips”: tiny devices about the size of a flash drive that are designed to mimic the biological activity of human organs. These glass chips contain living human cells within grooves that allow the passage of fluid, to either maintain or disrupt the cells’ function. So far, Dr. Ingber and his team at the Wyss Institute have developed more than 15 organ chip models, including chips that mimic the lung, intestine, kidney, and bone marrow.
The idea to develop a vagina chip grew out of research, funded by the Gates Foundation, on a childhood disease called environmental enteric dysfunction, an intestinal disease most commonly found in low-resource nations that is the second leading cause of death in children under 5. That’s when Dr. Ingber discovered just how much the child’s microbiome influences this disease.
Stemming from that work, the Gates Foundation turned its attention to newborn health – in particular, the impact of bacterial vaginosis, an imbalance in the vagina’s bacterial makeup. Bacterial vaginosis occurs in one out of four women worldwide and has been linked to premature birth as well as HIV, HPV persistence, and cervical cancer.
The goal was to test “live biotherapeutic products,” or living microbes like probiotics, that might restore the vagina’s microbiome to health.
No other preclinical model exists to perform tests like that, says Dr. Ingber.
“The vagina chip is a way to help make some advances,” he says.
The Gates Foundation recognized that women’s reproductive health is a major issue, not only in low-income nations, but everywhere around the world. As the project evolved, Dr. Ingber began to hear from female colleagues about how neglected women’s reproductive health is in medical science.
“It is something I became sensitive to and realized this is just the starting point,” Dr. Ingber says.
Take bacterial vaginosis, for example. Since 1982, treatment has revolved around the same two antibiotics. That’s partly because there is no animal model to study. No other species has the same vaginal bacterial community as humans do.
That makes developing any new therapy “incredibly challenging,” explains Caroline Mitchell, MD, MPH, an ob.gyn. at Massachusetts General Hospital, Boston, and a member of the consortium.
It turns out, replicating the vagina in a lab dish is, to use the technical term, very hard.
“That’s where a vagina chip offers an opportunity,” Dr. Mitchell says. “It’s not super-high throughput, but it’s way more high throughput than a [human] clinical trial.”
As such, the vagina chip could help scientists find new treatments much faster.
Like Dr. Ingber, Dr. Mitchell also sees the chip as a way to bring more attention to the largely unmet needs in female reproductive medicine.
“Women’s reproductive health has been under-resourced, under-prioritized, and largely disregarded for decades,” she says. And the time may be ripe for change: Dr. Mitchell says she was encouraged by the National Institutes of Health’s Advancing NIH Research on the Health of Women conference, held in 2021 in response to a congressional request to address women’s health research efforts.
Beyond bacterial vaginosis, Dr. Mitchell imagines the chip could help scientists find new treatments for vaginal yeast infection (candidiasis), chlamydia, and endometriosis. As with bacterial vaginosis, medicines for vaginal yeast infections have not advanced in decades, Dr. Mitchell says. Efforts to develop a vaccine for chlamydia – which can cause permanent damage to a woman’s reproductive system – have dragged on for many years. And endometriosis, an often painful condition in which the tissue that makes up the uterine lining grows outside the uterus, remains under-researched despite affecting 10% of childbearing-age women.
While some mouse models are used in chlamydia research, it’s hard to say if they’ll translate to humans, given the vaginal and cervical bacterial differences.
“Our understanding of the basic physiology of the environment of the vagina and cervix is another area where we’re woefully ignorant,” Dr. Mitchell says.
To that end, Dr. Ingber’s team is developing more complex chips mimicking the vagina and the cervix. One of his team members wants to use the chips to study infertility. The researchers have already used the chips to see how bacterial vaginosis and mucous changes impact the way sperm migrates up the reproductive tract.
The lab is now linking vagina and cervix chips together to study viral infections of the cervix, like HPV, and all types of bacterial diseases of the vaginal tract. By applying cervical mucus to the vagina chip, they hope to learn more about how female reproductive tissues respond to infection and inflammation.
“I always say that organ chips are like synthetic biology at the cell tissue and organ level,” says Dr. Ingber. “You start simple and see if you [can] mimic a clinical situation.”
As they make the chips more complex – perhaps by adding blood vessel cells and female hormones – Dr. Ingber foresees being able to study the response to hormonal changes during the menstrual cycle.
“We can begin to explore the effects of cycling over time as well as other types of hormonal effects,” he says.
Dr. Ingber also envisions linking the vagina chip to other organ chips – he’s already succeeded in linking eight different organ types together. But for now, the team hopes the vagina chip will enhance our understanding of basic female reproductive biology and speed up the process of developing new treatments for women’s health.
A version of this article first appeared on WebMD.com.
For years, women’s health advocates have argued that far more research is needed on women’s bodies and health. The world’s first-ever “vagina on a chip,” recently developed at Harvard’s Wyss Institute for Biologically Inspired Engineering in Boston, could go a long way to making that happen.
“Women’s health has not received the attention it deserves,” says Don Ingber, MD, PhD, who led the team that created the vagina chip. The advance quickly drew media attention after it was reported in the journal Microbiome. But researchers hope for more than headlines. They see the chip as a way to facilitate vaginal health research and open the door to vital new treatments.
By now, you may have heard of “organs on chips”: tiny devices about the size of a flash drive that are designed to mimic the biological activity of human organs. These glass chips contain living human cells within grooves that allow the passage of fluid, to either maintain or disrupt the cells’ function. So far, Dr. Ingber and his team at the Wyss Institute have developed more than 15 organ chip models, including chips that mimic the lung, intestine, kidney, and bone marrow.
The idea to develop a vagina chip grew out of research, funded by the Gates Foundation, on a childhood disease called environmental enteric dysfunction, an intestinal disease most commonly found in low-resource nations that is the second leading cause of death in children under 5. That’s when Dr. Ingber discovered just how much the child’s microbiome influences this disease.
Stemming from that work, the Gates Foundation turned its attention to newborn health – in particular, the impact of bacterial vaginosis, an imbalance in the vagina’s bacterial makeup. Bacterial vaginosis occurs in one out of four women worldwide and has been linked to premature birth as well as HIV, HPV persistence, and cervical cancer.
The goal was to test “live biotherapeutic products,” or living microbes like probiotics, that might restore the vagina’s microbiome to health.
No other preclinical model exists to perform tests like that, says Dr. Ingber.
“The vagina chip is a way to help make some advances,” he says.
The Gates Foundation recognized that women’s reproductive health is a major issue, not only in low-income nations, but everywhere around the world. As the project evolved, Dr. Ingber began to hear from female colleagues about how neglected women’s reproductive health is in medical science.
“It is something I became sensitive to and realized this is just the starting point,” Dr. Ingber says.
Take bacterial vaginosis, for example. Since 1982, treatment has revolved around the same two antibiotics. That’s partly because there is no animal model to study. No other species has the same vaginal bacterial community as humans do.
That makes developing any new therapy “incredibly challenging,” explains Caroline Mitchell, MD, MPH, an ob.gyn. at Massachusetts General Hospital, Boston, and a member of the consortium.
It turns out, replicating the vagina in a lab dish is, to use the technical term, very hard.
“That’s where a vagina chip offers an opportunity,” Dr. Mitchell says. “It’s not super-high throughput, but it’s way more high throughput than a [human] clinical trial.”
As such, the vagina chip could help scientists find new treatments much faster.
Like Dr. Ingber, Dr. Mitchell also sees the chip as a way to bring more attention to the largely unmet needs in female reproductive medicine.
“Women’s reproductive health has been under-resourced, under-prioritized, and largely disregarded for decades,” she says. And the time may be ripe for change: Dr. Mitchell says she was encouraged by the National Institutes of Health’s Advancing NIH Research on the Health of Women conference, held in 2021 in response to a congressional request to address women’s health research efforts.
Beyond bacterial vaginosis, Dr. Mitchell imagines the chip could help scientists find new treatments for vaginal yeast infection (candidiasis), chlamydia, and endometriosis. As with bacterial vaginosis, medicines for vaginal yeast infections have not advanced in decades, Dr. Mitchell says. Efforts to develop a vaccine for chlamydia – which can cause permanent damage to a woman’s reproductive system – have dragged on for many years. And endometriosis, an often painful condition in which the tissue that makes up the uterine lining grows outside the uterus, remains under-researched despite affecting 10% of childbearing-age women.
While some mouse models are used in chlamydia research, it’s hard to say if they’ll translate to humans, given the vaginal and cervical bacterial differences.
“Our understanding of the basic physiology of the environment of the vagina and cervix is another area where we’re woefully ignorant,” Dr. Mitchell says.
To that end, Dr. Ingber’s team is developing more complex chips mimicking the vagina and the cervix. One of his team members wants to use the chips to study infertility. The researchers have already used the chips to see how bacterial vaginosis and mucous changes impact the way sperm migrates up the reproductive tract.
The lab is now linking vagina and cervix chips together to study viral infections of the cervix, like HPV, and all types of bacterial diseases of the vaginal tract. By applying cervical mucus to the vagina chip, they hope to learn more about how female reproductive tissues respond to infection and inflammation.
“I always say that organ chips are like synthetic biology at the cell tissue and organ level,” says Dr. Ingber. “You start simple and see if you [can] mimic a clinical situation.”
As they make the chips more complex – perhaps by adding blood vessel cells and female hormones – Dr. Ingber foresees being able to study the response to hormonal changes during the menstrual cycle.
“We can begin to explore the effects of cycling over time as well as other types of hormonal effects,” he says.
Dr. Ingber also envisions linking the vagina chip to other organ chips – he’s already succeeded in linking eight different organ types together. But for now, the team hopes the vagina chip will enhance our understanding of basic female reproductive biology and speed up the process of developing new treatments for women’s health.
A version of this article first appeared on WebMD.com.
FROM MICROBIOME
Unexpected link between light drinking and dementia risk
new research suggests.
Investigators assessed dementia risk using changes in alcohol consumption over a 2-year period in nearly 4 million people in South Korea. After about 7 years, dementia was 21% less likely in mild drinkers and 17% less likely in moderate drinkers. Heavy drinking was linked to an 8% increased risk.
Other studies of the relationship between alcohol and dementia have yielded mixed results, and this study does little to clear those murky waters. Nor do the results mean that drinking is recommended, the investigators note.
But the study does offer new information on how risk changes over time as people change their drinking habits, lead investigator Keun Hye Jeon, MD, assistant professor of family medicine at Cha Gumi Medical Center at Cha University, Gumi, South Korea, told this news organization.
“Although numerous studies have shown a relationship between alcohol consumption and dementia, there is a paucity of understanding as to how the incidence of dementia changes with changes in drinking habits,” Dr. Jeon said.
“By measuring alcohol consumption at two time points, we were able to study the relationship between reducing, ceasing, maintaining, and increasing alcohol consumption and incident dementia,” he added.
The findings were published online in JAMA Network Open.
Tracking drinking habits
Researchers analyzed data from nearly 4 million individuals aged 40 years and older in the Korean National Health Insurance Service who completed questionnaires and underwent physical exams in 2009 and 2011.
Study participants completed questionnaires on their drinking habits and were assigned to one of five groups according to change in alcohol consumption during the study period. These groups consisted of sustained nondrinkers; those who stopped drinking (quitters); those who reduced their consumption of alcohol but did not stop drinking (reducers); those who maintained the same level of consumption (sustainers); and those who increased their level of consumption (increasers).
A standard drink in the United States contains 14 g of alcohol. For this study, mild drinking was defined as less than 15 g/day, or one drink; moderate consumption as 15-29.9 g/day, or one to two drinks; and heavy drinking as 30 g/day or more, or three or more drinks.
At baseline, 54.8% of participants were nondrinkers, 26.7% were mild drinkers, 11.0% were moderate drinkers, and 7.5% were heavy drinkers.
From 2009 to 2011, 24.2% of mild drinkers, 8.4% of moderate drinkers, and 7.6% of heavy drinkers became quitters. In the same period, 13.9% of nondrinkers, 16.1% of mild drinkers, and 17.4% of moderate drinkers increased their drinking level.
After a mean follow-up of 6.3 years, 2.5% of participants were diagnosed with dementia, 2.0% with Alzheimer’s disease, and 0.3% with vascular dementia.
Unexpected finding
Compared with consistently not drinking, mild and moderate alcohol consumption was associated with a 21% (adjust hazard ratio, 0.79; 95% confidence interval, 0.77-0.81) and 17% (aHR, 0.83; 95% CI, 0.79-0.88) decreased risk for dementia, respectively.
Heavy drinking was linked to an 8% increased risk (aHR, 1.08; 95% CI, 1.03-1.12).
Similar associations were found between alcohol consumption and risk for Alzheimer’s disease and vascular dementia.
Reducing drinking habits from heavy to moderate led to a reduction in risk for dementia and Alzheimer’s, and increasing drinking levels led to an increase in risk for both conditions.
But when the researchers analyzed dementia risk for nondrinkers who began drinking at mild levels during the study period, they found something unexpected – the risk in this group decreased by 7% for dementia (aHR, 0.93; 95% CI, 0.90-0.96) and by 8% for Alzheimer’s (aHR, 0.92; 95% CI, 0.89-0.95), compared with sustained mild drinkers.
“Our study showed that initiation of mild alcohol consumption leads to a reduced risk of all-cause dementia and Alzheimer’s disease, which has never been reported in previous studies,” Dr. Jeon said.
However, Dr. Jeon was quick to point out that this doesn’t mean that people who don’t drink should start.
Previous studies have shown that heavy alcohol use can triple an individual’s dementia risk, while other studies have shown that no amount of alcohol consumption is good for the brain.
“None of the existing health guidelines recommend starting alcohol drinking,” Dr. Jeon said. “Our findings regarding an initiation of mild alcohol consumption cannot be directly translated into clinical recommendations,” but the findings do warrant additional study, he added.
Risks persist
Commenting on the findings, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association in Chicago, agrees.
“While this study is interesting, and this topic deserves further study, no one should drink alcohol as a method of reducing risk of Alzheimer’s disease or other dementia based on this study,” said Dr. Griffin, who was not part of the study.
The exact tipping point in alcohol consumption that can lead to problems with cognition or increased dementia risk is unknown, Dr. Griffin said. Nor do researchers understand why mild drinking may have a protective effect.
“We do know, however, that excessive alcohol consumption has negative effects on heart health and general health, which can lead to problems with brain function,” he said. “Clinicians should have discussions with their patients around their alcohol consumption patterns and the risks associated with drinking in excess, including potential damage to their cognition.”
Funding for the study was not disclosed. Dr. Jeon and Dr. Griffin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
Investigators assessed dementia risk using changes in alcohol consumption over a 2-year period in nearly 4 million people in South Korea. After about 7 years, dementia was 21% less likely in mild drinkers and 17% less likely in moderate drinkers. Heavy drinking was linked to an 8% increased risk.
Other studies of the relationship between alcohol and dementia have yielded mixed results, and this study does little to clear those murky waters. Nor do the results mean that drinking is recommended, the investigators note.
But the study does offer new information on how risk changes over time as people change their drinking habits, lead investigator Keun Hye Jeon, MD, assistant professor of family medicine at Cha Gumi Medical Center at Cha University, Gumi, South Korea, told this news organization.
“Although numerous studies have shown a relationship between alcohol consumption and dementia, there is a paucity of understanding as to how the incidence of dementia changes with changes in drinking habits,” Dr. Jeon said.
“By measuring alcohol consumption at two time points, we were able to study the relationship between reducing, ceasing, maintaining, and increasing alcohol consumption and incident dementia,” he added.
The findings were published online in JAMA Network Open.
Tracking drinking habits
Researchers analyzed data from nearly 4 million individuals aged 40 years and older in the Korean National Health Insurance Service who completed questionnaires and underwent physical exams in 2009 and 2011.
Study participants completed questionnaires on their drinking habits and were assigned to one of five groups according to change in alcohol consumption during the study period. These groups consisted of sustained nondrinkers; those who stopped drinking (quitters); those who reduced their consumption of alcohol but did not stop drinking (reducers); those who maintained the same level of consumption (sustainers); and those who increased their level of consumption (increasers).
A standard drink in the United States contains 14 g of alcohol. For this study, mild drinking was defined as less than 15 g/day, or one drink; moderate consumption as 15-29.9 g/day, or one to two drinks; and heavy drinking as 30 g/day or more, or three or more drinks.
At baseline, 54.8% of participants were nondrinkers, 26.7% were mild drinkers, 11.0% were moderate drinkers, and 7.5% were heavy drinkers.
From 2009 to 2011, 24.2% of mild drinkers, 8.4% of moderate drinkers, and 7.6% of heavy drinkers became quitters. In the same period, 13.9% of nondrinkers, 16.1% of mild drinkers, and 17.4% of moderate drinkers increased their drinking level.
After a mean follow-up of 6.3 years, 2.5% of participants were diagnosed with dementia, 2.0% with Alzheimer’s disease, and 0.3% with vascular dementia.
Unexpected finding
Compared with consistently not drinking, mild and moderate alcohol consumption was associated with a 21% (adjust hazard ratio, 0.79; 95% confidence interval, 0.77-0.81) and 17% (aHR, 0.83; 95% CI, 0.79-0.88) decreased risk for dementia, respectively.
Heavy drinking was linked to an 8% increased risk (aHR, 1.08; 95% CI, 1.03-1.12).
Similar associations were found between alcohol consumption and risk for Alzheimer’s disease and vascular dementia.
Reducing drinking habits from heavy to moderate led to a reduction in risk for dementia and Alzheimer’s, and increasing drinking levels led to an increase in risk for both conditions.
But when the researchers analyzed dementia risk for nondrinkers who began drinking at mild levels during the study period, they found something unexpected – the risk in this group decreased by 7% for dementia (aHR, 0.93; 95% CI, 0.90-0.96) and by 8% for Alzheimer’s (aHR, 0.92; 95% CI, 0.89-0.95), compared with sustained mild drinkers.
“Our study showed that initiation of mild alcohol consumption leads to a reduced risk of all-cause dementia and Alzheimer’s disease, which has never been reported in previous studies,” Dr. Jeon said.
However, Dr. Jeon was quick to point out that this doesn’t mean that people who don’t drink should start.
Previous studies have shown that heavy alcohol use can triple an individual’s dementia risk, while other studies have shown that no amount of alcohol consumption is good for the brain.
“None of the existing health guidelines recommend starting alcohol drinking,” Dr. Jeon said. “Our findings regarding an initiation of mild alcohol consumption cannot be directly translated into clinical recommendations,” but the findings do warrant additional study, he added.
Risks persist
Commenting on the findings, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association in Chicago, agrees.
“While this study is interesting, and this topic deserves further study, no one should drink alcohol as a method of reducing risk of Alzheimer’s disease or other dementia based on this study,” said Dr. Griffin, who was not part of the study.
The exact tipping point in alcohol consumption that can lead to problems with cognition or increased dementia risk is unknown, Dr. Griffin said. Nor do researchers understand why mild drinking may have a protective effect.
“We do know, however, that excessive alcohol consumption has negative effects on heart health and general health, which can lead to problems with brain function,” he said. “Clinicians should have discussions with their patients around their alcohol consumption patterns and the risks associated with drinking in excess, including potential damage to their cognition.”
Funding for the study was not disclosed. Dr. Jeon and Dr. Griffin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
Investigators assessed dementia risk using changes in alcohol consumption over a 2-year period in nearly 4 million people in South Korea. After about 7 years, dementia was 21% less likely in mild drinkers and 17% less likely in moderate drinkers. Heavy drinking was linked to an 8% increased risk.
Other studies of the relationship between alcohol and dementia have yielded mixed results, and this study does little to clear those murky waters. Nor do the results mean that drinking is recommended, the investigators note.
But the study does offer new information on how risk changes over time as people change their drinking habits, lead investigator Keun Hye Jeon, MD, assistant professor of family medicine at Cha Gumi Medical Center at Cha University, Gumi, South Korea, told this news organization.
“Although numerous studies have shown a relationship between alcohol consumption and dementia, there is a paucity of understanding as to how the incidence of dementia changes with changes in drinking habits,” Dr. Jeon said.
“By measuring alcohol consumption at two time points, we were able to study the relationship between reducing, ceasing, maintaining, and increasing alcohol consumption and incident dementia,” he added.
The findings were published online in JAMA Network Open.
Tracking drinking habits
Researchers analyzed data from nearly 4 million individuals aged 40 years and older in the Korean National Health Insurance Service who completed questionnaires and underwent physical exams in 2009 and 2011.
Study participants completed questionnaires on their drinking habits and were assigned to one of five groups according to change in alcohol consumption during the study period. These groups consisted of sustained nondrinkers; those who stopped drinking (quitters); those who reduced their consumption of alcohol but did not stop drinking (reducers); those who maintained the same level of consumption (sustainers); and those who increased their level of consumption (increasers).
A standard drink in the United States contains 14 g of alcohol. For this study, mild drinking was defined as less than 15 g/day, or one drink; moderate consumption as 15-29.9 g/day, or one to two drinks; and heavy drinking as 30 g/day or more, or three or more drinks.
At baseline, 54.8% of participants were nondrinkers, 26.7% were mild drinkers, 11.0% were moderate drinkers, and 7.5% were heavy drinkers.
From 2009 to 2011, 24.2% of mild drinkers, 8.4% of moderate drinkers, and 7.6% of heavy drinkers became quitters. In the same period, 13.9% of nondrinkers, 16.1% of mild drinkers, and 17.4% of moderate drinkers increased their drinking level.
After a mean follow-up of 6.3 years, 2.5% of participants were diagnosed with dementia, 2.0% with Alzheimer’s disease, and 0.3% with vascular dementia.
Unexpected finding
Compared with consistently not drinking, mild and moderate alcohol consumption was associated with a 21% (adjust hazard ratio, 0.79; 95% confidence interval, 0.77-0.81) and 17% (aHR, 0.83; 95% CI, 0.79-0.88) decreased risk for dementia, respectively.
Heavy drinking was linked to an 8% increased risk (aHR, 1.08; 95% CI, 1.03-1.12).
Similar associations were found between alcohol consumption and risk for Alzheimer’s disease and vascular dementia.
Reducing drinking habits from heavy to moderate led to a reduction in risk for dementia and Alzheimer’s, and increasing drinking levels led to an increase in risk for both conditions.
But when the researchers analyzed dementia risk for nondrinkers who began drinking at mild levels during the study period, they found something unexpected – the risk in this group decreased by 7% for dementia (aHR, 0.93; 95% CI, 0.90-0.96) and by 8% for Alzheimer’s (aHR, 0.92; 95% CI, 0.89-0.95), compared with sustained mild drinkers.
“Our study showed that initiation of mild alcohol consumption leads to a reduced risk of all-cause dementia and Alzheimer’s disease, which has never been reported in previous studies,” Dr. Jeon said.
However, Dr. Jeon was quick to point out that this doesn’t mean that people who don’t drink should start.
Previous studies have shown that heavy alcohol use can triple an individual’s dementia risk, while other studies have shown that no amount of alcohol consumption is good for the brain.
“None of the existing health guidelines recommend starting alcohol drinking,” Dr. Jeon said. “Our findings regarding an initiation of mild alcohol consumption cannot be directly translated into clinical recommendations,” but the findings do warrant additional study, he added.
Risks persist
Commenting on the findings, Percy Griffin, PhD, director of scientific engagement for the Alzheimer’s Association in Chicago, agrees.
“While this study is interesting, and this topic deserves further study, no one should drink alcohol as a method of reducing risk of Alzheimer’s disease or other dementia based on this study,” said Dr. Griffin, who was not part of the study.
The exact tipping point in alcohol consumption that can lead to problems with cognition or increased dementia risk is unknown, Dr. Griffin said. Nor do researchers understand why mild drinking may have a protective effect.
“We do know, however, that excessive alcohol consumption has negative effects on heart health and general health, which can lead to problems with brain function,” he said. “Clinicians should have discussions with their patients around their alcohol consumption patterns and the risks associated with drinking in excess, including potential damage to their cognition.”
Funding for the study was not disclosed. Dr. Jeon and Dr. Griffin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN