Conference Coverage

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Dermatologists and other clinicians should advise their patients with skin of color to practice sensible sun protection, including wearing protective clothing, staying in the shade when outdoors, and applying a tinted sunscreen with an SPF of 30 or greater to exposed areas, according to Henry W. Lim, MD.

In addition, “with rigorous photoprotection, vitamin D supplementation should be advised to patients,” Dr. Lim, a former chair of the department of dermatology at Henry Ford Health System, Detroit, said during the Society for Pediatric Dermatology pre-AAD meeting. “One multivitamin a day should be sufficient for most patients. This is especially relevant because we do know that skin of color patients tend to have lower vitamin D levels to start with.”

Photoprotection for people of color helps minimize the development of photodermatoses, postinflammatory hyperpigmentation, polymorphous light eruption, and chronic actinic dermatitis, he said. In a retrospective chart review of 1,080 people conducted at four academic medical centers in the United States, Dr. Lim and colleagues found a higher proportion of polymorphous light eruption and chronic actinic dermatitis in Black individuals, and a higher proportion of photoallergic contact dermatitis, phototoxic drug eruptions, phytophotodermatitis, porphyria, and solar urticaria in White individuals.

“Another pediatric photodermatosis, actinic prurigo, tends to occur most often in Mestizo individuals, patients of American Indian heritage,” he added. “This is a significant issue, especially in Latin America.”

In a systematic review of 20 studies in the medical literature, researchers assessed the quality of life and psychological impact of photodermatoses in affected patients. Studies included in the review drew from 2,487 adults and 119 children. Among adults, the self-administered Dermatology Life Quality Index (DLQI) revealed that photodermatoses adversely affected employment, education, and leisure activities in adults. Among children, the condition adversely affected outdoor activities and exacerbated symptoms in those with erythropoietic protoporphyria (EPP).

As for skin cancer risk, the association between UV light exposure and the development of melanoma is not as strong in people with skin of color, compared with light-skinned individuals. In a recent systematic review of 13 studies on the topic, 11 showed no association, one showed a small positive relationship in Black males and 1 showed a weak association in Hispanic males.

“The conclusion from this review is that UV protection for melanoma prevention in people of color is not supported by most studies,” said Dr. Lim, who was not affiliated with the review. “The authors also noted, however, that the evidence is of moderate to low quality. Larger studies should be done.”

The association between UV exposure and the development to squamous cell cancer in skin of color is also not strong. “However, we do know that sun exposure is associated with the development of basal cell carcinoma in this population,” he said.

Sunscreen ingredient studies

Dr. Lim also highlighted findings from two studies related to the effect of sunscreen application on plasma concentration of sunscreen active ingredients, both in adults. In the most recent analysis, scientists at the Food and Drug Administration and colleagues conducted a randomized clinical trial in 48 individuals with skin types II-IV.

Participants applied sunscreen at 2 mg/cm² to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals. Over the course of 21 days, the researchers collected 34 blood samples from each participant, and evaluated six active ingredients in four sunscreen products: avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate.

For all active ingredients, levels of greater than 0.5 ng/mL were detected after a single application on day 1. Levels of greater than 0.5 ng/mL were detected up to day 7, and up to day 21 for oxybenzone. All were detected in skin on days 7 and 14 via tape stripping. The authors called for further studies to determine the clinical significance of these findings and emphasized that the results “do not indicate that individuals should refrain from the use of sunscreen.”

The FDA is asking for additional studies on the safety of these 12 filters, noted Dr. Lim, who is a past president of the American Academy of Dermatology. On Feb. 26, 2019, the FDA issued a proposed rule regarding sunscreen drug products for over-the-counter human use. It proposes that the 16 UV filters be classified into one of 3 categories. Category I would include zinc oxide and titanium dioxide, which are generally recognized as safe and effective (GRASE). Category II would include PABA and trolamine salicylate, which are not used in the United States and are not GRASE. Category III would include 12 filters that lack insufficient safety data to make a determination regarding GRASE.

The final FDA rule was scheduled to be released in September of 2020, but a result of the Coronavirus Aid, Relief, and Economic Security (CARES) Act, the FDA “will be moving from a laborious rulemaking process to an administrative order process, which means it should not take as long to implement a monograph,” Dr. Lim said. “The FDA has decided that there will not be a final rule regarding sunscreen drug products,” but is required to issue a proposed administrative order by Sept. 27, 2021, he said.

When the final administrative order has been issued, manufacturers would have at least 1 year to comply with sunscreen products offered in the United States. “The approximate timeline is probably going to be 2023,” he said.

Dr. Lim disclosed that he is an investigator for Incyte, L’Oreal, Pfizer, and the Patient-centered Outcomes Research Institute, and a consultant for Pierre Fabre, ISDIN, Ferndale, La Roche–Posay, and Beiersdorf. He has been a speaker at general educational sessions sponsored by La Roche–Posay and Cantabria Labs.

dbrunk@mdedge.com

Dermatologists and other clinicians should advise their patients with skin of color to practice sensible sun protection, including wearing protective clothing, staying in the shade when outdoors, and applying a tinted sunscreen with an SPF of 30 or greater to exposed areas, according to Henry W. Lim, MD.

In addition, “with rigorous photoprotection, vitamin D supplementation should be advised to patients,” Dr. Lim, a former chair of the department of dermatology at Henry Ford Health System, Detroit, said during the Society for Pediatric Dermatology pre-AAD meeting. “One multivitamin a day should be sufficient for most patients. This is especially relevant because we do know that skin of color patients tend to have lower vitamin D levels to start with.”

Photoprotection for people of color helps minimize the development of photodermatoses, postinflammatory hyperpigmentation, polymorphous light eruption, and chronic actinic dermatitis, he said. In a retrospective chart review of 1,080 people conducted at four academic medical centers in the United States, Dr. Lim and colleagues found a higher proportion of polymorphous light eruption and chronic actinic dermatitis in Black individuals, and a higher proportion of photoallergic contact dermatitis, phototoxic drug eruptions, phytophotodermatitis, porphyria, and solar urticaria in White individuals.

“Another pediatric photodermatosis, actinic prurigo, tends to occur most often in Mestizo individuals, patients of American Indian heritage,” he added. “This is a significant issue, especially in Latin America.”

In a systematic review of 20 studies in the medical literature, researchers assessed the quality of life and psychological impact of photodermatoses in affected patients. Studies included in the review drew from 2,487 adults and 119 children. Among adults, the self-administered Dermatology Life Quality Index (DLQI) revealed that photodermatoses adversely affected employment, education, and leisure activities in adults. Among children, the condition adversely affected outdoor activities and exacerbated symptoms in those with erythropoietic protoporphyria (EPP).

As for skin cancer risk, the association between UV light exposure and the development of melanoma is not as strong in people with skin of color, compared with light-skinned individuals. In a recent systematic review of 13 studies on the topic, 11 showed no association, one showed a small positive relationship in Black males and 1 showed a weak association in Hispanic males.

“The conclusion from this review is that UV protection for melanoma prevention in people of color is not supported by most studies,” said Dr. Lim, who was not affiliated with the review. “The authors also noted, however, that the evidence is of moderate to low quality. Larger studies should be done.”

The association between UV exposure and the development to squamous cell cancer in skin of color is also not strong. “However, we do know that sun exposure is associated with the development of basal cell carcinoma in this population,” he said.

Sunscreen ingredient studies

Dr. Lim also highlighted findings from two studies related to the effect of sunscreen application on plasma concentration of sunscreen active ingredients, both in adults. In the most recent analysis, scientists at the Food and Drug Administration and colleagues conducted a randomized clinical trial in 48 individuals with skin types II-IV.

Participants applied sunscreen at 2 mg/cm² to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals. Over the course of 21 days, the researchers collected 34 blood samples from each participant, and evaluated six active ingredients in four sunscreen products: avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate.

For all active ingredients, levels of greater than 0.5 ng/mL were detected after a single application on day 1. Levels of greater than 0.5 ng/mL were detected up to day 7, and up to day 21 for oxybenzone. All were detected in skin on days 7 and 14 via tape stripping. The authors called for further studies to determine the clinical significance of these findings and emphasized that the results “do not indicate that individuals should refrain from the use of sunscreen.”

The FDA is asking for additional studies on the safety of these 12 filters, noted Dr. Lim, who is a past president of the American Academy of Dermatology. On Feb. 26, 2019, the FDA issued a proposed rule regarding sunscreen drug products for over-the-counter human use. It proposes that the 16 UV filters be classified into one of 3 categories. Category I would include zinc oxide and titanium dioxide, which are generally recognized as safe and effective (GRASE). Category II would include PABA and trolamine salicylate, which are not used in the United States and are not GRASE. Category III would include 12 filters that lack insufficient safety data to make a determination regarding GRASE.

The final FDA rule was scheduled to be released in September of 2020, but a result of the Coronavirus Aid, Relief, and Economic Security (CARES) Act, the FDA “will be moving from a laborious rulemaking process to an administrative order process, which means it should not take as long to implement a monograph,” Dr. Lim said. “The FDA has decided that there will not be a final rule regarding sunscreen drug products,” but is required to issue a proposed administrative order by Sept. 27, 2021, he said.

When the final administrative order has been issued, manufacturers would have at least 1 year to comply with sunscreen products offered in the United States. “The approximate timeline is probably going to be 2023,” he said.

Dr. Lim disclosed that he is an investigator for Incyte, L’Oreal, Pfizer, and the Patient-centered Outcomes Research Institute, and a consultant for Pierre Fabre, ISDIN, Ferndale, La Roche–Posay, and Beiersdorf. He has been a speaker at general educational sessions sponsored by La Roche–Posay and Cantabria Labs.

dbrunk@mdedge.com

Dermatologists and other clinicians should advise their patients with skin of color to practice sensible sun protection, including wearing protective clothing, staying in the shade when outdoors, and applying a tinted sunscreen with an SPF of 30 or greater to exposed areas, according to Henry W. Lim, MD.

In addition, “with rigorous photoprotection, vitamin D supplementation should be advised to patients,” Dr. Lim, a former chair of the department of dermatology at Henry Ford Health System, Detroit, said during the Society for Pediatric Dermatology pre-AAD meeting. “One multivitamin a day should be sufficient for most patients. This is especially relevant because we do know that skin of color patients tend to have lower vitamin D levels to start with.”

Photoprotection for people of color helps minimize the development of photodermatoses, postinflammatory hyperpigmentation, polymorphous light eruption, and chronic actinic dermatitis, he said. In a retrospective chart review of 1,080 people conducted at four academic medical centers in the United States, Dr. Lim and colleagues found a higher proportion of polymorphous light eruption and chronic actinic dermatitis in Black individuals, and a higher proportion of photoallergic contact dermatitis, phototoxic drug eruptions, phytophotodermatitis, porphyria, and solar urticaria in White individuals.

“Another pediatric photodermatosis, actinic prurigo, tends to occur most often in Mestizo individuals, patients of American Indian heritage,” he added. “This is a significant issue, especially in Latin America.”

In a systematic review of 20 studies in the medical literature, researchers assessed the quality of life and psychological impact of photodermatoses in affected patients. Studies included in the review drew from 2,487 adults and 119 children. Among adults, the self-administered Dermatology Life Quality Index (DLQI) revealed that photodermatoses adversely affected employment, education, and leisure activities in adults. Among children, the condition adversely affected outdoor activities and exacerbated symptoms in those with erythropoietic protoporphyria (EPP).

As for skin cancer risk, the association between UV light exposure and the development of melanoma is not as strong in people with skin of color, compared with light-skinned individuals. In a recent systematic review of 13 studies on the topic, 11 showed no association, one showed a small positive relationship in Black males and 1 showed a weak association in Hispanic males.

“The conclusion from this review is that UV protection for melanoma prevention in people of color is not supported by most studies,” said Dr. Lim, who was not affiliated with the review. “The authors also noted, however, that the evidence is of moderate to low quality. Larger studies should be done.”

The association between UV exposure and the development to squamous cell cancer in skin of color is also not strong. “However, we do know that sun exposure is associated with the development of basal cell carcinoma in this population,” he said.

Sunscreen ingredient studies

Dr. Lim also highlighted findings from two studies related to the effect of sunscreen application on plasma concentration of sunscreen active ingredients, both in adults. In the most recent analysis, scientists at the Food and Drug Administration and colleagues conducted a randomized clinical trial in 48 individuals with skin types II-IV.

Participants applied sunscreen at 2 mg/cm² to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals. Over the course of 21 days, the researchers collected 34 blood samples from each participant, and evaluated six active ingredients in four sunscreen products: avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate.

For all active ingredients, levels of greater than 0.5 ng/mL were detected after a single application on day 1. Levels of greater than 0.5 ng/mL were detected up to day 7, and up to day 21 for oxybenzone. All were detected in skin on days 7 and 14 via tape stripping. The authors called for further studies to determine the clinical significance of these findings and emphasized that the results “do not indicate that individuals should refrain from the use of sunscreen.”

The FDA is asking for additional studies on the safety of these 12 filters, noted Dr. Lim, who is a past president of the American Academy of Dermatology. On Feb. 26, 2019, the FDA issued a proposed rule regarding sunscreen drug products for over-the-counter human use. It proposes that the 16 UV filters be classified into one of 3 categories. Category I would include zinc oxide and titanium dioxide, which are generally recognized as safe and effective (GRASE). Category II would include PABA and trolamine salicylate, which are not used in the United States and are not GRASE. Category III would include 12 filters that lack insufficient safety data to make a determination regarding GRASE.

The final FDA rule was scheduled to be released in September of 2020, but a result of the Coronavirus Aid, Relief, and Economic Security (CARES) Act, the FDA “will be moving from a laborious rulemaking process to an administrative order process, which means it should not take as long to implement a monograph,” Dr. Lim said. “The FDA has decided that there will not be a final rule regarding sunscreen drug products,” but is required to issue a proposed administrative order by Sept. 27, 2021, he said.

When the final administrative order has been issued, manufacturers would have at least 1 year to comply with sunscreen products offered in the United States. “The approximate timeline is probably going to be 2023,” he said.

Dr. Lim disclosed that he is an investigator for Incyte, L’Oreal, Pfizer, and the Patient-centered Outcomes Research Institute, and a consultant for Pierre Fabre, ISDIN, Ferndale, La Roche–Posay, and Beiersdorf. He has been a speaker at general educational sessions sponsored by La Roche–Posay and Cantabria Labs.

dbrunk@mdedge.com

Is innervation of cartilage the driving force behind development of osteoarthritis and subsequent pain, or is the degeneration of joints in osteoarthritis affecting nerves and creating pain?

This was the question underpinning a fascinating debate at the OARSI 2021 World Congress, featuring two giants of the OA research community: Anne-Marie Malfait, MD, PhD, professor of medicine in the division of rheumatology at Rush Medical College, Chicago, and Stefan Lohmander, MD, PhD, professor emeritus of orthopedics at Lund (Sweden) University in Sweden.

At stake in the discussion is a greater understanding of the physiological processes that underpin both the development of OA in joints and the experience of pain in patients with OA.

Dr. Lohmander started by pointing out that, while pain is the primary symptoms of OA, it does not always overlap with the physiological processes of the disease, as measured by techniques such as MRI, x-ray, biomarkers, and gait analysis.

“This lack of complete overlap is often a problem when doing our clinical trials,” Dr. Lohmander told the conference, sponsored by Osteoarthritis Research Society International. “When talking about osteoarthritis, we also need to remind ourselves every so often that we are speaking of either the symptoms or the disease and maybe not always the both of them.”

While a healthy joint has pain receptors everywhere but the cartilage, studies have found that the osteoarthritic joint brings blood vessels, sensory nerves, and cells expressing nerve growth factor from the subchondral bone into even noncalcified articular cartilage, he said.

These nociceptor neurons are mechanosensitive, so mechanical injury to the joint triggers inflammation, and the inflammatory proteins themselves act on the nociceptors to generate pain signals in the brain, “so clearly, it is the joint that signals the brain,” Dr. Lohmander said.

However, Dr. Malfait pointed out that there is a body of evidence from animal studies showing that the absence of sensory nerves in joints – either from disease or removal – is associated with the onset or worsening of OA.

“Healthy nerves are really important to ensure healthy joints,” Dr. Malfait said. She said age-related loss of sensory nerves always preceded age-related OA, and was also associated with age-related loss of proprioception and vibratory perception.

Interestingly, animal studies suggest that removing intra-articular nociceptors can actually have a protective effect on the osteoarthritic joint, Dr. Malfait said. Studies in humans who have experienced neurologic lesions also suggests improvement in conditions such as rheumatoid arthritis.

She raised the idea of neurogenic inflammation: that peripheral neurons are releasing vasoactive mediators that contribute to inflammation in tissues. “These nerves and nerve products are talking to all the different cells in the joints,” she said.

Defending his argument that joint pathology is the cause of pain, not the pain causing the joint pathology, Dr. Lohmander gave the example of studies that looked at radiographic abnormalities between two knees of the same patient who also had discordant pain measures for each knee. This research “showed strong association between radiographic osteoarthritis and knee pain, supporting the argument that structural abnormalities cause knee pain,” he said.

Martin van der Esch, PhD, of the Amsterdam University of Applied Sciences, said the debate was one of the highlights of the conference because it addressed such an important and longstanding question in OA.

“Is osteoarthritis leading to a generalized pain, so involvement of the nervous system, but the source – the causality – is in the joint?” he said in an interview. “Or is it the other way around, so that means is there first a problem inside the nervous system – including also the vascular system – and which is presented in the joint?”

It is more than an academic discussion because the conclusions of that could mean different treatment approaches are needed for different groups of patients, and raises the different ways of thinking about OA, he said.

None of the sources for this story declared having any relevant conflicts of interest.

Is innervation of cartilage the driving force behind development of osteoarthritis and subsequent pain, or is the degeneration of joints in osteoarthritis affecting nerves and creating pain?

This was the question underpinning a fascinating debate at the OARSI 2021 World Congress, featuring two giants of the OA research community: Anne-Marie Malfait, MD, PhD, professor of medicine in the division of rheumatology at Rush Medical College, Chicago, and Stefan Lohmander, MD, PhD, professor emeritus of orthopedics at Lund (Sweden) University in Sweden.

At stake in the discussion is a greater understanding of the physiological processes that underpin both the development of OA in joints and the experience of pain in patients with OA.

Dr. Lohmander started by pointing out that, while pain is the primary symptoms of OA, it does not always overlap with the physiological processes of the disease, as measured by techniques such as MRI, x-ray, biomarkers, and gait analysis.

“This lack of complete overlap is often a problem when doing our clinical trials,” Dr. Lohmander told the conference, sponsored by Osteoarthritis Research Society International. “When talking about osteoarthritis, we also need to remind ourselves every so often that we are speaking of either the symptoms or the disease and maybe not always the both of them.”

While a healthy joint has pain receptors everywhere but the cartilage, studies have found that the osteoarthritic joint brings blood vessels, sensory nerves, and cells expressing nerve growth factor from the subchondral bone into even noncalcified articular cartilage, he said.

These nociceptor neurons are mechanosensitive, so mechanical injury to the joint triggers inflammation, and the inflammatory proteins themselves act on the nociceptors to generate pain signals in the brain, “so clearly, it is the joint that signals the brain,” Dr. Lohmander said.

However, Dr. Malfait pointed out that there is a body of evidence from animal studies showing that the absence of sensory nerves in joints – either from disease or removal – is associated with the onset or worsening of OA.

“Healthy nerves are really important to ensure healthy joints,” Dr. Malfait said. She said age-related loss of sensory nerves always preceded age-related OA, and was also associated with age-related loss of proprioception and vibratory perception.

Interestingly, animal studies suggest that removing intra-articular nociceptors can actually have a protective effect on the osteoarthritic joint, Dr. Malfait said. Studies in humans who have experienced neurologic lesions also suggests improvement in conditions such as rheumatoid arthritis.

She raised the idea of neurogenic inflammation: that peripheral neurons are releasing vasoactive mediators that contribute to inflammation in tissues. “These nerves and nerve products are talking to all the different cells in the joints,” she said.

Defending his argument that joint pathology is the cause of pain, not the pain causing the joint pathology, Dr. Lohmander gave the example of studies that looked at radiographic abnormalities between two knees of the same patient who also had discordant pain measures for each knee. This research “showed strong association between radiographic osteoarthritis and knee pain, supporting the argument that structural abnormalities cause knee pain,” he said.

Martin van der Esch, PhD, of the Amsterdam University of Applied Sciences, said the debate was one of the highlights of the conference because it addressed such an important and longstanding question in OA.

“Is osteoarthritis leading to a generalized pain, so involvement of the nervous system, but the source – the causality – is in the joint?” he said in an interview. “Or is it the other way around, so that means is there first a problem inside the nervous system – including also the vascular system – and which is presented in the joint?”

It is more than an academic discussion because the conclusions of that could mean different treatment approaches are needed for different groups of patients, and raises the different ways of thinking about OA, he said.

None of the sources for this story declared having any relevant conflicts of interest.

Is innervation of cartilage the driving force behind development of osteoarthritis and subsequent pain, or is the degeneration of joints in osteoarthritis affecting nerves and creating pain?

This was the question underpinning a fascinating debate at the OARSI 2021 World Congress, featuring two giants of the OA research community: Anne-Marie Malfait, MD, PhD, professor of medicine in the division of rheumatology at Rush Medical College, Chicago, and Stefan Lohmander, MD, PhD, professor emeritus of orthopedics at Lund (Sweden) University in Sweden.

At stake in the discussion is a greater understanding of the physiological processes that underpin both the development of OA in joints and the experience of pain in patients with OA.

Dr. Lohmander started by pointing out that, while pain is the primary symptoms of OA, it does not always overlap with the physiological processes of the disease, as measured by techniques such as MRI, x-ray, biomarkers, and gait analysis.

“This lack of complete overlap is often a problem when doing our clinical trials,” Dr. Lohmander told the conference, sponsored by Osteoarthritis Research Society International. “When talking about osteoarthritis, we also need to remind ourselves every so often that we are speaking of either the symptoms or the disease and maybe not always the both of them.”

While a healthy joint has pain receptors everywhere but the cartilage, studies have found that the osteoarthritic joint brings blood vessels, sensory nerves, and cells expressing nerve growth factor from the subchondral bone into even noncalcified articular cartilage, he said.

These nociceptor neurons are mechanosensitive, so mechanical injury to the joint triggers inflammation, and the inflammatory proteins themselves act on the nociceptors to generate pain signals in the brain, “so clearly, it is the joint that signals the brain,” Dr. Lohmander said.

However, Dr. Malfait pointed out that there is a body of evidence from animal studies showing that the absence of sensory nerves in joints – either from disease or removal – is associated with the onset or worsening of OA.

“Healthy nerves are really important to ensure healthy joints,” Dr. Malfait said. She said age-related loss of sensory nerves always preceded age-related OA, and was also associated with age-related loss of proprioception and vibratory perception.

Interestingly, animal studies suggest that removing intra-articular nociceptors can actually have a protective effect on the osteoarthritic joint, Dr. Malfait said. Studies in humans who have experienced neurologic lesions also suggests improvement in conditions such as rheumatoid arthritis.

She raised the idea of neurogenic inflammation: that peripheral neurons are releasing vasoactive mediators that contribute to inflammation in tissues. “These nerves and nerve products are talking to all the different cells in the joints,” she said.

Defending his argument that joint pathology is the cause of pain, not the pain causing the joint pathology, Dr. Lohmander gave the example of studies that looked at radiographic abnormalities between two knees of the same patient who also had discordant pain measures for each knee. This research “showed strong association between radiographic osteoarthritis and knee pain, supporting the argument that structural abnormalities cause knee pain,” he said.

Martin van der Esch, PhD, of the Amsterdam University of Applied Sciences, said the debate was one of the highlights of the conference because it addressed such an important and longstanding question in OA.

“Is osteoarthritis leading to a generalized pain, so involvement of the nervous system, but the source – the causality – is in the joint?” he said in an interview. “Or is it the other way around, so that means is there first a problem inside the nervous system – including also the vascular system – and which is presented in the joint?”

It is more than an academic discussion because the conclusions of that could mean different treatment approaches are needed for different groups of patients, and raises the different ways of thinking about OA, he said.

None of the sources for this story declared having any relevant conflicts of interest.

The American College of Cardiology pulled off an impressive all-virtual meeting in March 2020, less than 3 weeks after canceling its in-person event and just 2 weeks after COVID-19 was declared a national emergency.

Optimistic plans for the annual scientific sessions of the American College of Cardiology (ACC 2021) to be a March hybrid affair in Atlanta pivoted not once, but twice, as the pandemic evolved, with the date pushed back 2 full months, to May 15-17, and the format revised to fully virtual.

“While this meeting is being delivered virtually, I think you’ll see there have been benefits in the time to plan and also the lessons that ACC has learned in virtual education over the past year. This has come together to really create a robust educational and scientific agenda,” ACC 2021 chair Pamela B. Morris, MD, said in a press conference focused on the upcoming meeting.

Over the 3 days, there will be more than 200 education sessions, 10 guideline-specific sessions, and 11 learning pathways that include core areas, but also special topics, such as COVID-19 and the emerging cardio-obstetrics subspecialty.

The meeting will be delivered through a new virtual education program built to optimize real-time interaction between faculty members and attendees, she said. A dedicated portal on the platform will allow attendees to interact virtually, for example, with presenters of the nearly 3,000 ePosters and 420 moderated posters.

For those suffering from Zoom fatigue, the increasingly popular Heart2Heart stage talks have also been converted to podcasts, which cover topics like gender equity in cardiology, the evolving role of advanced practice professionals, and “one of my favorites: art as a tool for healing,” said Dr. Morris, from the Medical University of South Carolina, Charleston. “Those sessions are really not to be missed.”

Reconnecting is an underlying theme of the meeting but the great divider will not be ignored. COVID-19 will be the focus of two 90-minute Intensive Sessions on Saturday, May 15, the first kicking off at 10:30 a.m. ET, with the Bishop Keynote lecture on bringing health equity to the frontline of cardiovascular care, followed by lessons learned during the pandemic, how to conduct clinical trials, and vaccine development.

The second session, set for 12:15 p.m., continues the “silver linings” theme, with case presentations on advances in telehealth, myocardial involvement, and thrombosis in COVID. For those wanting more, 18 abstracts are on tap in a 2-hour Spotlight on Special Topics session beginning at 2:30 p.m.

Asked about the pandemic’s effect on bringing science to fruition this past year, Dr. Morris said there’s no question it’s slowed some of the progress the cardiology community had made but, like clinical practice, “we’ve also surmounted many of those obstacles.”

“I think research has rebounded,” she said. “Just in terms of the number of abstracts and the quality of abstracts that were submitted this year, I don’t think there’s any question that we are right on par with previous years.”

Indeed, 5,258 abstracts from 76 countries were submitted, with more than 3,400 chosen for oral and poster presentation, including 25 late-breaking clinical trials to be presented in five sessions.

The late-breaking presentations and discussions will be prerecorded but speakers and panelists have been invited to be present during the streaming to answer live any questions that may arise in the chat box, ACC 2021 vice chair Douglas Drachman, MD, Massachusetts General Hospital, Boston, said in an interview.
 

Late-breaking clinical trials

The Joint ACC/JACC Late-Breaking Clinical Trials I (Saturday, May 15, 9:00 a.m.–-10:00 a.m.) kicks off with PARADISE-MI, the first head-to-head comparison of an angiotensin receptor neprilysin inhibitor (ARNI) and an ACE inhibitor in patients with reduced ejection fractions (EFs) after MI but no history of heart failure (HF), studying 200 mg sacubitril/valsartan (Entresto) versus 5 mg of ramipril, both twice daily, in 5,669 patients.

Sacubitril/valsartan was initially approved for HF with reduced EF and added a new indication to treat some HF patients with preserved EF. Novartis, however, recently told investors that although numerical trends consistently favored the ARNI over the ACE inhibitor ramipril, the phase 3 study failed to meet the primary endpoint for efficacy superiority of reducing the risk for cardiovascular (CV) death and HF events after an acute MI.

Second up is ADAPTABLE, which looks to close a surprising evidence gap over whether 81 mg or 325 mg daily is the optimal dose of the ubiquitously prescribed aspirin for secondary prevention in high-risk patients with established atherosclerotic CV disease.

The open-label, randomized study will look at efficacy and major bleeding over roughly 4 years in 15,000 patients within PCORnet, the National Patient-centered Clinical Research Network, a partnership of clinical research, health plan research, and patient-powered networks created to streamline patient-reported outcomes research.

“This study will not only give important clinical information for us, practically speaking, whether we should prescribe lower- or higher-dose aspirin, but it may also serve as a template for future pragmatic clinical trial design in the real world,” Dr. Drachman said during the press conference.

Up next is the 4,812-patient Canadian LAAOS III, the largest trial to examine the efficacy of left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation (AFib) already undergoing cardiac surgery. The primary outcome is the first occurrence of stroke or systemic arterial embolism over an average follow-up of 4 years.

Percutaneous closure of the left atrial appendage (LAA) has been shown to reduce stroke in AFib patients at high-risk of bleeding on systemic anticoagulation. But these devices can be expensive and studies haven’t included patients who also have valvular heart disease, a group that actually comprises more than half of patients undergoing cardiac surgery who also have AFib, he noted.

At the same time, surgical LAA closure studies have been small and have had very mixed results. “There isn’t a large-scale rigorous assessment out there for these patients undergoing surgery, so I think this is going to be fascinating to see,” Dr. Drachman said.

The session closes with ATLANTIS, which looks to shed some light on the role of anticoagulation therapy in patients after transcatheter aortic valve replacement (TAVR or TAVI). POPular TAVI, presented at ACC 2020, showed aspirin alone was the preferred antithrombotic therapy over aspirin plus clopidogrel (Plavix) in patients not on oral anticoagulants, but the optimal anticoagulation regimen remains unsettled.

The French open-label, 1,510-patient ATLANTIS trial examined whether the novel oral anticoagulant apixaban (Eliquis) is superior in preventing CV events after TAVR, compared with antiplatelet therapy in patients without an indication for anticoagulation and compared with vitamin K antagonists in those receiving anticoagulants.

An ATLANTIS 4D CT substudy of valve thrombosis is also slated for Saturday’s Featured Clinical Research 1 session at 12:15 p.m. to 1:45 p.m..
 

Sunday LBCTs

Dr. Drachman highlighted a series of other late-breaking studies, including the global DARE-19 trial testing the diabetes and HF drug dapagliflozin (Farxiga) given with local standard-of-care therapy for 30 days in hospitalized COVID-19 patients with CV, metabolic, or renal risk factors.

Although sodium-glucose cotransporter-2 inhibitors have been white-hot of late, top-line results reported last month show dapagliflozin failed to achieve statistical significance for the primary endpoints of reducing organ dysfunction and all-cause mortality and for improving recovery. Details will be presented in the Joint ACC/JAMA Late-Breaking Clinical Trials II (Sunday, May 16, 8:00 a.m.-9:30 a.m.).

Two trials, FLOWER-MI and RADIANCE-HTN TRIO, were singled out in the Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials III (Sunday, May 16, 10:45 a.m.-12:00 p.m.). FLOWER-MI examines whether fractional flow reserve (FFR) is better than angiography to guide complete multivessel revascularization in ST-elevation MI patients with at least 50% stenosis in at least one nonculprit lesion requiring percutaneous coronary intervention (PCI). Recent studies have shown the superiority of FFR-guided PCI for nonculprit lesions, compared with culprit lesion treatment-only, but this is the first time FFR- and angiography-guided PCI have been compared in STEMI patients.

RADIANCE-HTN TRIO already tipped its hand, with top-line results reported in late 2020 showing that the trial met its primary efficacy endpoint of greater reduction in daytime blood pressure over 2 months with the Paradise endovascular ultrasound renal denervation system, compared with a sham procedure, in 136 patients with resistant hypertension, importantly, after being given a single pill containing a calcium channel blocker, angiotensin II receptor blocker, and diuretic.

Renal denervation for hypertension has been making something of a comeback, with the 2018 RADIANCE-HTN SOLO reporting better ambulatory blood pressure control with the Paradise system than with a sham procedure in the absence of antihypertensive agents. The device has been granted breakthrough device designation from the Food and Drug Administration for the treatment of hypertensive patients who are unable to sufficiently respond to or are intolerant of antihypertensive therapy.
 

Monday LBCTs

In the Late-Breaking Clinical Trials IV session (Monday, May 17, 8 a.m.–9:30 a.m.), Drachman called out a secondary analysis from GALATIC-HF looking at the impact of EF on the therapeutic effect of omecamtiv mecarbil. In last year’s primary analysis, the selective cardiac myosin activator produced a modest but significant reduction in HF events or CV death in 8,232 patients with HF and an EF of 35% or less.

Rounding out the list is the Canadian CAPITAL CHILL study of moderate versus mild therapeutic hypothermia in out-of-hospital cardiac arrest, to be presented in the final Late-Breaking Clinical Trials V session (Monday, May 17, 10:45 a.m.–12:00 p.m.).

The double-blind trial sought to determine whether neurologic outcomes at 6 months are improved by targeting a core temperature of 31 ˚C versus 34 ˚C after the return of spontaneous circulation in comatose survivors of out-of-hospital cardiac arrest.

“For me, I think this could really change practice and has personal relevance from experience with cardiac arrest survivors that I’ve known and care for very deeply,” Dr. Drachman said in an interview. “I think that there’s a lot of opportunity here as well.”

Asked what other trials have the potential to change practice, Dr. Drachman said FLOWER-MI holds particular interest because it looks at how to manage patients with STEMI with multiple lesions at the point of care.

“We’ve gained a lot of clarity from several other prior clinical trials, but this will help to answer the question in a slightly different way of saying: can you eyeball it, can you look at the angiogram and say whether or not that other, nonculprit lesion ought to be treated in the same hospitalization or should you really be using a pressure wire,” he said. “For me as an interventionalist, this is really important because when you finish up doing an intervention on a patient it might be the middle of the night and the patient may be more or less stable, but you’ve already exposed them to the risk of a procedure, should you then move on and do another aspect of the procedure to interrogate with a pressure wire a remaining narrowing? I think that’s very important; that’ll help me make decisions on a day-to-day basis.”

Dr. Drachman also cited RADIANCE-HTN TRIO because it employs an endovascular technique to control blood pressure in patients with hypertension, specifically those resistant to multiple drugs.

During the press conference, Dr. Morris, a preventive cardiologist, put her money on the ADAPTABLE study of aspirin dosing, reiterating that the unique trial design could inform future research, and on Sunday’s 8:45 a.m. late-breaking post hoc analysis from the STRENGTH trial that looks to pick up where the controversy over omega-3 fatty acid preparations left off at last year’s American Heart Association meeting.

A lack of benefit on CV event rates reported with Epanova, a high-dose combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid, led to a contentious debate over how to reconcile STRENGTH with the findings from REDUCE-IT, which showed a 25% relative risk reduction in major CV events with the EPA product icosapent ethyl (Vascepa).

STRENGTH investigator Steven Nissen, MD, Cleveland Clinic, and REDUCE-IT investigator and session panelist Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, will share the virtual stage at ACC 2021, but Dr. Morris said the “good news” is both researchers know one another very well and “will really be focusing on no political issues, just the omega-3 fatty levels in the bloodstream and what does that mean in either trial.

“This is not designed to be a debate, point counterpoint,” she added.

For that, as all cardiologists and journalists know, there will be the wild and woolly #CardioTwitter sphere.

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

The American College of Cardiology pulled off an impressive all-virtual meeting in March 2020, less than 3 weeks after canceling its in-person event and just 2 weeks after COVID-19 was declared a national emergency.

Optimistic plans for the annual scientific sessions of the American College of Cardiology (ACC 2021) to be a March hybrid affair in Atlanta pivoted not once, but twice, as the pandemic evolved, with the date pushed back 2 full months, to May 15-17, and the format revised to fully virtual.

“While this meeting is being delivered virtually, I think you’ll see there have been benefits in the time to plan and also the lessons that ACC has learned in virtual education over the past year. This has come together to really create a robust educational and scientific agenda,” ACC 2021 chair Pamela B. Morris, MD, said in a press conference focused on the upcoming meeting.

Over the 3 days, there will be more than 200 education sessions, 10 guideline-specific sessions, and 11 learning pathways that include core areas, but also special topics, such as COVID-19 and the emerging cardio-obstetrics subspecialty.

The meeting will be delivered through a new virtual education program built to optimize real-time interaction between faculty members and attendees, she said. A dedicated portal on the platform will allow attendees to interact virtually, for example, with presenters of the nearly 3,000 ePosters and 420 moderated posters.

For those suffering from Zoom fatigue, the increasingly popular Heart2Heart stage talks have also been converted to podcasts, which cover topics like gender equity in cardiology, the evolving role of advanced practice professionals, and “one of my favorites: art as a tool for healing,” said Dr. Morris, from the Medical University of South Carolina, Charleston. “Those sessions are really not to be missed.”

Reconnecting is an underlying theme of the meeting but the great divider will not be ignored. COVID-19 will be the focus of two 90-minute Intensive Sessions on Saturday, May 15, the first kicking off at 10:30 a.m. ET, with the Bishop Keynote lecture on bringing health equity to the frontline of cardiovascular care, followed by lessons learned during the pandemic, how to conduct clinical trials, and vaccine development.

The second session, set for 12:15 p.m., continues the “silver linings” theme, with case presentations on advances in telehealth, myocardial involvement, and thrombosis in COVID. For those wanting more, 18 abstracts are on tap in a 2-hour Spotlight on Special Topics session beginning at 2:30 p.m.

Asked about the pandemic’s effect on bringing science to fruition this past year, Dr. Morris said there’s no question it’s slowed some of the progress the cardiology community had made but, like clinical practice, “we’ve also surmounted many of those obstacles.”

“I think research has rebounded,” she said. “Just in terms of the number of abstracts and the quality of abstracts that were submitted this year, I don’t think there’s any question that we are right on par with previous years.”

Indeed, 5,258 abstracts from 76 countries were submitted, with more than 3,400 chosen for oral and poster presentation, including 25 late-breaking clinical trials to be presented in five sessions.

The late-breaking presentations and discussions will be prerecorded but speakers and panelists have been invited to be present during the streaming to answer live any questions that may arise in the chat box, ACC 2021 vice chair Douglas Drachman, MD, Massachusetts General Hospital, Boston, said in an interview.
 

Late-breaking clinical trials

The Joint ACC/JACC Late-Breaking Clinical Trials I (Saturday, May 15, 9:00 a.m.–-10:00 a.m.) kicks off with PARADISE-MI, the first head-to-head comparison of an angiotensin receptor neprilysin inhibitor (ARNI) and an ACE inhibitor in patients with reduced ejection fractions (EFs) after MI but no history of heart failure (HF), studying 200 mg sacubitril/valsartan (Entresto) versus 5 mg of ramipril, both twice daily, in 5,669 patients.

Sacubitril/valsartan was initially approved for HF with reduced EF and added a new indication to treat some HF patients with preserved EF. Novartis, however, recently told investors that although numerical trends consistently favored the ARNI over the ACE inhibitor ramipril, the phase 3 study failed to meet the primary endpoint for efficacy superiority of reducing the risk for cardiovascular (CV) death and HF events after an acute MI.

Second up is ADAPTABLE, which looks to close a surprising evidence gap over whether 81 mg or 325 mg daily is the optimal dose of the ubiquitously prescribed aspirin for secondary prevention in high-risk patients with established atherosclerotic CV disease.

The open-label, randomized study will look at efficacy and major bleeding over roughly 4 years in 15,000 patients within PCORnet, the National Patient-centered Clinical Research Network, a partnership of clinical research, health plan research, and patient-powered networks created to streamline patient-reported outcomes research.

“This study will not only give important clinical information for us, practically speaking, whether we should prescribe lower- or higher-dose aspirin, but it may also serve as a template for future pragmatic clinical trial design in the real world,” Dr. Drachman said during the press conference.

Up next is the 4,812-patient Canadian LAAOS III, the largest trial to examine the efficacy of left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation (AFib) already undergoing cardiac surgery. The primary outcome is the first occurrence of stroke or systemic arterial embolism over an average follow-up of 4 years.

Percutaneous closure of the left atrial appendage (LAA) has been shown to reduce stroke in AFib patients at high-risk of bleeding on systemic anticoagulation. But these devices can be expensive and studies haven’t included patients who also have valvular heart disease, a group that actually comprises more than half of patients undergoing cardiac surgery who also have AFib, he noted.

At the same time, surgical LAA closure studies have been small and have had very mixed results. “There isn’t a large-scale rigorous assessment out there for these patients undergoing surgery, so I think this is going to be fascinating to see,” Dr. Drachman said.

The session closes with ATLANTIS, which looks to shed some light on the role of anticoagulation therapy in patients after transcatheter aortic valve replacement (TAVR or TAVI). POPular TAVI, presented at ACC 2020, showed aspirin alone was the preferred antithrombotic therapy over aspirin plus clopidogrel (Plavix) in patients not on oral anticoagulants, but the optimal anticoagulation regimen remains unsettled.

The French open-label, 1,510-patient ATLANTIS trial examined whether the novel oral anticoagulant apixaban (Eliquis) is superior in preventing CV events after TAVR, compared with antiplatelet therapy in patients without an indication for anticoagulation and compared with vitamin K antagonists in those receiving anticoagulants.

An ATLANTIS 4D CT substudy of valve thrombosis is also slated for Saturday’s Featured Clinical Research 1 session at 12:15 p.m. to 1:45 p.m..
 

Sunday LBCTs

Dr. Drachman highlighted a series of other late-breaking studies, including the global DARE-19 trial testing the diabetes and HF drug dapagliflozin (Farxiga) given with local standard-of-care therapy for 30 days in hospitalized COVID-19 patients with CV, metabolic, or renal risk factors.

Although sodium-glucose cotransporter-2 inhibitors have been white-hot of late, top-line results reported last month show dapagliflozin failed to achieve statistical significance for the primary endpoints of reducing organ dysfunction and all-cause mortality and for improving recovery. Details will be presented in the Joint ACC/JAMA Late-Breaking Clinical Trials II (Sunday, May 16, 8:00 a.m.-9:30 a.m.).

Two trials, FLOWER-MI and RADIANCE-HTN TRIO, were singled out in the Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials III (Sunday, May 16, 10:45 a.m.-12:00 p.m.). FLOWER-MI examines whether fractional flow reserve (FFR) is better than angiography to guide complete multivessel revascularization in ST-elevation MI patients with at least 50% stenosis in at least one nonculprit lesion requiring percutaneous coronary intervention (PCI). Recent studies have shown the superiority of FFR-guided PCI for nonculprit lesions, compared with culprit lesion treatment-only, but this is the first time FFR- and angiography-guided PCI have been compared in STEMI patients.

RADIANCE-HTN TRIO already tipped its hand, with top-line results reported in late 2020 showing that the trial met its primary efficacy endpoint of greater reduction in daytime blood pressure over 2 months with the Paradise endovascular ultrasound renal denervation system, compared with a sham procedure, in 136 patients with resistant hypertension, importantly, after being given a single pill containing a calcium channel blocker, angiotensin II receptor blocker, and diuretic.

Renal denervation for hypertension has been making something of a comeback, with the 2018 RADIANCE-HTN SOLO reporting better ambulatory blood pressure control with the Paradise system than with a sham procedure in the absence of antihypertensive agents. The device has been granted breakthrough device designation from the Food and Drug Administration for the treatment of hypertensive patients who are unable to sufficiently respond to or are intolerant of antihypertensive therapy.
 

Monday LBCTs

In the Late-Breaking Clinical Trials IV session (Monday, May 17, 8 a.m.–9:30 a.m.), Drachman called out a secondary analysis from GALATIC-HF looking at the impact of EF on the therapeutic effect of omecamtiv mecarbil. In last year’s primary analysis, the selective cardiac myosin activator produced a modest but significant reduction in HF events or CV death in 8,232 patients with HF and an EF of 35% or less.

Rounding out the list is the Canadian CAPITAL CHILL study of moderate versus mild therapeutic hypothermia in out-of-hospital cardiac arrest, to be presented in the final Late-Breaking Clinical Trials V session (Monday, May 17, 10:45 a.m.–12:00 p.m.).

The double-blind trial sought to determine whether neurologic outcomes at 6 months are improved by targeting a core temperature of 31 ˚C versus 34 ˚C after the return of spontaneous circulation in comatose survivors of out-of-hospital cardiac arrest.

“For me, I think this could really change practice and has personal relevance from experience with cardiac arrest survivors that I’ve known and care for very deeply,” Dr. Drachman said in an interview. “I think that there’s a lot of opportunity here as well.”

Asked what other trials have the potential to change practice, Dr. Drachman said FLOWER-MI holds particular interest because it looks at how to manage patients with STEMI with multiple lesions at the point of care.

“We’ve gained a lot of clarity from several other prior clinical trials, but this will help to answer the question in a slightly different way of saying: can you eyeball it, can you look at the angiogram and say whether or not that other, nonculprit lesion ought to be treated in the same hospitalization or should you really be using a pressure wire,” he said. “For me as an interventionalist, this is really important because when you finish up doing an intervention on a patient it might be the middle of the night and the patient may be more or less stable, but you’ve already exposed them to the risk of a procedure, should you then move on and do another aspect of the procedure to interrogate with a pressure wire a remaining narrowing? I think that’s very important; that’ll help me make decisions on a day-to-day basis.”

Dr. Drachman also cited RADIANCE-HTN TRIO because it employs an endovascular technique to control blood pressure in patients with hypertension, specifically those resistant to multiple drugs.

During the press conference, Dr. Morris, a preventive cardiologist, put her money on the ADAPTABLE study of aspirin dosing, reiterating that the unique trial design could inform future research, and on Sunday’s 8:45 a.m. late-breaking post hoc analysis from the STRENGTH trial that looks to pick up where the controversy over omega-3 fatty acid preparations left off at last year’s American Heart Association meeting.

A lack of benefit on CV event rates reported with Epanova, a high-dose combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid, led to a contentious debate over how to reconcile STRENGTH with the findings from REDUCE-IT, which showed a 25% relative risk reduction in major CV events with the EPA product icosapent ethyl (Vascepa).

STRENGTH investigator Steven Nissen, MD, Cleveland Clinic, and REDUCE-IT investigator and session panelist Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, will share the virtual stage at ACC 2021, but Dr. Morris said the “good news” is both researchers know one another very well and “will really be focusing on no political issues, just the omega-3 fatty levels in the bloodstream and what does that mean in either trial.

“This is not designed to be a debate, point counterpoint,” she added.

For that, as all cardiologists and journalists know, there will be the wild and woolly #CardioTwitter sphere.

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

The American College of Cardiology pulled off an impressive all-virtual meeting in March 2020, less than 3 weeks after canceling its in-person event and just 2 weeks after COVID-19 was declared a national emergency.

Optimistic plans for the annual scientific sessions of the American College of Cardiology (ACC 2021) to be a March hybrid affair in Atlanta pivoted not once, but twice, as the pandemic evolved, with the date pushed back 2 full months, to May 15-17, and the format revised to fully virtual.

“While this meeting is being delivered virtually, I think you’ll see there have been benefits in the time to plan and also the lessons that ACC has learned in virtual education over the past year. This has come together to really create a robust educational and scientific agenda,” ACC 2021 chair Pamela B. Morris, MD, said in a press conference focused on the upcoming meeting.

Over the 3 days, there will be more than 200 education sessions, 10 guideline-specific sessions, and 11 learning pathways that include core areas, but also special topics, such as COVID-19 and the emerging cardio-obstetrics subspecialty.

The meeting will be delivered through a new virtual education program built to optimize real-time interaction between faculty members and attendees, she said. A dedicated portal on the platform will allow attendees to interact virtually, for example, with presenters of the nearly 3,000 ePosters and 420 moderated posters.

For those suffering from Zoom fatigue, the increasingly popular Heart2Heart stage talks have also been converted to podcasts, which cover topics like gender equity in cardiology, the evolving role of advanced practice professionals, and “one of my favorites: art as a tool for healing,” said Dr. Morris, from the Medical University of South Carolina, Charleston. “Those sessions are really not to be missed.”

Reconnecting is an underlying theme of the meeting but the great divider will not be ignored. COVID-19 will be the focus of two 90-minute Intensive Sessions on Saturday, May 15, the first kicking off at 10:30 a.m. ET, with the Bishop Keynote lecture on bringing health equity to the frontline of cardiovascular care, followed by lessons learned during the pandemic, how to conduct clinical trials, and vaccine development.

The second session, set for 12:15 p.m., continues the “silver linings” theme, with case presentations on advances in telehealth, myocardial involvement, and thrombosis in COVID. For those wanting more, 18 abstracts are on tap in a 2-hour Spotlight on Special Topics session beginning at 2:30 p.m.

Asked about the pandemic’s effect on bringing science to fruition this past year, Dr. Morris said there’s no question it’s slowed some of the progress the cardiology community had made but, like clinical practice, “we’ve also surmounted many of those obstacles.”

“I think research has rebounded,” she said. “Just in terms of the number of abstracts and the quality of abstracts that were submitted this year, I don’t think there’s any question that we are right on par with previous years.”

Indeed, 5,258 abstracts from 76 countries were submitted, with more than 3,400 chosen for oral and poster presentation, including 25 late-breaking clinical trials to be presented in five sessions.

The late-breaking presentations and discussions will be prerecorded but speakers and panelists have been invited to be present during the streaming to answer live any questions that may arise in the chat box, ACC 2021 vice chair Douglas Drachman, MD, Massachusetts General Hospital, Boston, said in an interview.
 

Late-breaking clinical trials

The Joint ACC/JACC Late-Breaking Clinical Trials I (Saturday, May 15, 9:00 a.m.–-10:00 a.m.) kicks off with PARADISE-MI, the first head-to-head comparison of an angiotensin receptor neprilysin inhibitor (ARNI) and an ACE inhibitor in patients with reduced ejection fractions (EFs) after MI but no history of heart failure (HF), studying 200 mg sacubitril/valsartan (Entresto) versus 5 mg of ramipril, both twice daily, in 5,669 patients.

Sacubitril/valsartan was initially approved for HF with reduced EF and added a new indication to treat some HF patients with preserved EF. Novartis, however, recently told investors that although numerical trends consistently favored the ARNI over the ACE inhibitor ramipril, the phase 3 study failed to meet the primary endpoint for efficacy superiority of reducing the risk for cardiovascular (CV) death and HF events after an acute MI.

Second up is ADAPTABLE, which looks to close a surprising evidence gap over whether 81 mg or 325 mg daily is the optimal dose of the ubiquitously prescribed aspirin for secondary prevention in high-risk patients with established atherosclerotic CV disease.

The open-label, randomized study will look at efficacy and major bleeding over roughly 4 years in 15,000 patients within PCORnet, the National Patient-centered Clinical Research Network, a partnership of clinical research, health plan research, and patient-powered networks created to streamline patient-reported outcomes research.

“This study will not only give important clinical information for us, practically speaking, whether we should prescribe lower- or higher-dose aspirin, but it may also serve as a template for future pragmatic clinical trial design in the real world,” Dr. Drachman said during the press conference.

Up next is the 4,812-patient Canadian LAAOS III, the largest trial to examine the efficacy of left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation (AFib) already undergoing cardiac surgery. The primary outcome is the first occurrence of stroke or systemic arterial embolism over an average follow-up of 4 years.

Percutaneous closure of the left atrial appendage (LAA) has been shown to reduce stroke in AFib patients at high-risk of bleeding on systemic anticoagulation. But these devices can be expensive and studies haven’t included patients who also have valvular heart disease, a group that actually comprises more than half of patients undergoing cardiac surgery who also have AFib, he noted.

At the same time, surgical LAA closure studies have been small and have had very mixed results. “There isn’t a large-scale rigorous assessment out there for these patients undergoing surgery, so I think this is going to be fascinating to see,” Dr. Drachman said.

The session closes with ATLANTIS, which looks to shed some light on the role of anticoagulation therapy in patients after transcatheter aortic valve replacement (TAVR or TAVI). POPular TAVI, presented at ACC 2020, showed aspirin alone was the preferred antithrombotic therapy over aspirin plus clopidogrel (Plavix) in patients not on oral anticoagulants, but the optimal anticoagulation regimen remains unsettled.

The French open-label, 1,510-patient ATLANTIS trial examined whether the novel oral anticoagulant apixaban (Eliquis) is superior in preventing CV events after TAVR, compared with antiplatelet therapy in patients without an indication for anticoagulation and compared with vitamin K antagonists in those receiving anticoagulants.

An ATLANTIS 4D CT substudy of valve thrombosis is also slated for Saturday’s Featured Clinical Research 1 session at 12:15 p.m. to 1:45 p.m..
 

Sunday LBCTs

Dr. Drachman highlighted a series of other late-breaking studies, including the global DARE-19 trial testing the diabetes and HF drug dapagliflozin (Farxiga) given with local standard-of-care therapy for 30 days in hospitalized COVID-19 patients with CV, metabolic, or renal risk factors.

Although sodium-glucose cotransporter-2 inhibitors have been white-hot of late, top-line results reported last month show dapagliflozin failed to achieve statistical significance for the primary endpoints of reducing organ dysfunction and all-cause mortality and for improving recovery. Details will be presented in the Joint ACC/JAMA Late-Breaking Clinical Trials II (Sunday, May 16, 8:00 a.m.-9:30 a.m.).

Two trials, FLOWER-MI and RADIANCE-HTN TRIO, were singled out in the Joint ACC/New England Journal of Medicine Late-Breaking Clinical Trials III (Sunday, May 16, 10:45 a.m.-12:00 p.m.). FLOWER-MI examines whether fractional flow reserve (FFR) is better than angiography to guide complete multivessel revascularization in ST-elevation MI patients with at least 50% stenosis in at least one nonculprit lesion requiring percutaneous coronary intervention (PCI). Recent studies have shown the superiority of FFR-guided PCI for nonculprit lesions, compared with culprit lesion treatment-only, but this is the first time FFR- and angiography-guided PCI have been compared in STEMI patients.

RADIANCE-HTN TRIO already tipped its hand, with top-line results reported in late 2020 showing that the trial met its primary efficacy endpoint of greater reduction in daytime blood pressure over 2 months with the Paradise endovascular ultrasound renal denervation system, compared with a sham procedure, in 136 patients with resistant hypertension, importantly, after being given a single pill containing a calcium channel blocker, angiotensin II receptor blocker, and diuretic.

Renal denervation for hypertension has been making something of a comeback, with the 2018 RADIANCE-HTN SOLO reporting better ambulatory blood pressure control with the Paradise system than with a sham procedure in the absence of antihypertensive agents. The device has been granted breakthrough device designation from the Food and Drug Administration for the treatment of hypertensive patients who are unable to sufficiently respond to or are intolerant of antihypertensive therapy.
 

Monday LBCTs

In the Late-Breaking Clinical Trials IV session (Monday, May 17, 8 a.m.–9:30 a.m.), Drachman called out a secondary analysis from GALATIC-HF looking at the impact of EF on the therapeutic effect of omecamtiv mecarbil. In last year’s primary analysis, the selective cardiac myosin activator produced a modest but significant reduction in HF events or CV death in 8,232 patients with HF and an EF of 35% or less.

Rounding out the list is the Canadian CAPITAL CHILL study of moderate versus mild therapeutic hypothermia in out-of-hospital cardiac arrest, to be presented in the final Late-Breaking Clinical Trials V session (Monday, May 17, 10:45 a.m.–12:00 p.m.).

The double-blind trial sought to determine whether neurologic outcomes at 6 months are improved by targeting a core temperature of 31 ˚C versus 34 ˚C after the return of spontaneous circulation in comatose survivors of out-of-hospital cardiac arrest.

“For me, I think this could really change practice and has personal relevance from experience with cardiac arrest survivors that I’ve known and care for very deeply,” Dr. Drachman said in an interview. “I think that there’s a lot of opportunity here as well.”

Asked what other trials have the potential to change practice, Dr. Drachman said FLOWER-MI holds particular interest because it looks at how to manage patients with STEMI with multiple lesions at the point of care.

“We’ve gained a lot of clarity from several other prior clinical trials, but this will help to answer the question in a slightly different way of saying: can you eyeball it, can you look at the angiogram and say whether or not that other, nonculprit lesion ought to be treated in the same hospitalization or should you really be using a pressure wire,” he said. “For me as an interventionalist, this is really important because when you finish up doing an intervention on a patient it might be the middle of the night and the patient may be more or less stable, but you’ve already exposed them to the risk of a procedure, should you then move on and do another aspect of the procedure to interrogate with a pressure wire a remaining narrowing? I think that’s very important; that’ll help me make decisions on a day-to-day basis.”

Dr. Drachman also cited RADIANCE-HTN TRIO because it employs an endovascular technique to control blood pressure in patients with hypertension, specifically those resistant to multiple drugs.

During the press conference, Dr. Morris, a preventive cardiologist, put her money on the ADAPTABLE study of aspirin dosing, reiterating that the unique trial design could inform future research, and on Sunday’s 8:45 a.m. late-breaking post hoc analysis from the STRENGTH trial that looks to pick up where the controversy over omega-3 fatty acid preparations left off at last year’s American Heart Association meeting.

A lack of benefit on CV event rates reported with Epanova, a high-dose combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid, led to a contentious debate over how to reconcile STRENGTH with the findings from REDUCE-IT, which showed a 25% relative risk reduction in major CV events with the EPA product icosapent ethyl (Vascepa).

STRENGTH investigator Steven Nissen, MD, Cleveland Clinic, and REDUCE-IT investigator and session panelist Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, will share the virtual stage at ACC 2021, but Dr. Morris said the “good news” is both researchers know one another very well and “will really be focusing on no political issues, just the omega-3 fatty levels in the bloodstream and what does that mean in either trial.

“This is not designed to be a debate, point counterpoint,” she added.

For that, as all cardiologists and journalists know, there will be the wild and woolly #CardioTwitter sphere.

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

Emerging data suggest that molecular classification of vascular anomalies can improve prognostication and treatment for babies born with these malformations, according to Beth Drolet, MD.

“We now know that 75%-80% of vascular malformations have gene mutations that make the cells either live longer, grow faster, or make them bigger in size,” Dr. Drolet, professor and chair of dermatology at the University of Wisconsin–Madison, said during the Society for Pediatric Dermatology pre-AAD meeting. “The basic binary premise of the current ISSVA [International Society for the Study of Vascular Anomalies] classification dividing vascular anomalies into tumors and malformations is wrong; the biology is not that straightforward. It may be helpful to differentiate between an infantile hemangioma and a capillary malformation during infancy as the hemangioma will grow in the next month, but we now know that patients with capillary malformations also have significant overgrowth of their tissue. We’ve all seen that; it just takes years, not months for us to notice it.”

The change in thinking about the root causes of vascular anomalies, she noted, stems from scientific advances in the understanding of embryonic mosaicism, DNA variation that happens after the zygote is formed, but before birth. “We know that each cell in a zygote will undergo 40 cell divisions before a baby is born,” she said. “Those cell divisions are not as neat as we thought they were. That cell and DNA duplication is actually quite messy, so there are mutations that happen purely because of embryonic cell division.”

Everyone is born with 120 somatic mutations per cell, she continued, “so we have multiple genomes in one human. Not all of those mutations are going to cause disease. Not all of those are going to be functional. About 10% of those mutations will actually be in a coding region of the gene and have the potential to change the function of the protein. If it changes the function of the protein so that the cell can’t survive, that cell dies off, but it gives the cell an advantage. It grows a little bit faster, let’s say. That cell survives, divides, producing a line of cells that can cause disease.”

In 2011, Dr. Drolet and colleagues from the Hemangioma Investigator Group and the Pediatric Dermatology Research Alliance (PeDRA) launched a multisite collaborative group to investigate the role of mosaic genetics in patients with vascular anomalies and discrepancy of growth. To date, 365 patients are enrolled, and the researchers have sequenced 97 of 165 affected tissue samples collected. “What’s nice about the registry is that we enrolled a wide spectrum of diseases: very mild diseases that might be treated by dermatologists to complex, syndromic diseases that might end up in an interdisciplinary vascular anomalies clinic,” she said.

For gene sequencing, the researchers drew from solid tumor biology and used next-generation sequencing with semi-target hybrid capture, “so we’re only looking at a subset of genes,” she said. “Right now, the chip we’re using has 180 cancer-related genes. It sequences the entire exome of the gene with a high depth of coverage, usually over 1,000 X. We use a specific pipeline that can detect very low allele frequency mutation: down to 1%, and robust criteria to determine variant pathogenicity.”

In 75% of tissue samples so far, the researchers have found a gene mutation in one of 13 genes: AKT1, AKT3, BRAF, GNA11, GNAQ, KRAS, MAP2K1, NRAS, PIK3CA, PIK3R1, PTPN11, RASA1, and TEK. According to Dr. Drolet, the common thread in these 13 genes is that they are implicated in cancer and have direct control over the cell cycle. “They’re intracellular proteins that control the cell cycle,” she explained. “These are proteins that are in the cell but interact with transmembrane proteins that receive extracellular messengers of cell growth”.

Understanding and recognizing genetic conditions is complicated, she said, because it involves determining which gene is altered, where in the DNA the gene is altered, how the gene variation will influence the function of the protein, and what tissue expresses that gene. “Then you get your phenotype,” Dr. Drolet said. “If you add mosaicism onto that, you have several additional variables. You need to know: When in embryogenesis did the mutation occur? What region of the body is affected? What cell lineage is affected? That predicts what phenotype you’re going to have.”

While molecular classification efforts continue to be refined, Dr. Drolet incorporates genotyping at every opportunity, like when she counsels parents of a baby born with a vascular stain on its face. “What can we tell them about what else might be wrong? What can we tell them about how this will change over time? What can we tell them about how we can treat it? I think genotyping absolutely helps to clarify that for me,” she said. “I can’t use that alone, but it gives me another piece of evidence to help do a better job in predicting when I need to screen, what I need to screen for, and what might happen in the future. If you combine your genotype with your clinical exam, I really do believe we can start to offer some prognostication for our families, to say, ‘this is the degree of overgrowth we may see over time; these are the complications I predict that you might have.’ ”

Even the vascular stain can give you a clue. “If it’s light and lacey, you probably don’t have a lot of cell cycle activation,” Dr. Drolet said. “If it’s dark and there’s blebs and you’ve got some bleeding at a young age, you’ve got a highly activated mutation, and there’s everything in between.”

Dr. Drolet disclosed that she is a consultant for Venthera and Novartis and is a board member for the Isthmus Project. She also holds intellectual property rights in and is a patent holder for Peds Derm Development Group. Dr. Drolet has also received funding from the Spirit Foundation, Kayleigh’s Crew Endowment, the SPD, PeDRA, and the National Institutes of Health.

dbrunk@mdedge.com

Emerging data suggest that molecular classification of vascular anomalies can improve prognostication and treatment for babies born with these malformations, according to Beth Drolet, MD.

“We now know that 75%-80% of vascular malformations have gene mutations that make the cells either live longer, grow faster, or make them bigger in size,” Dr. Drolet, professor and chair of dermatology at the University of Wisconsin–Madison, said during the Society for Pediatric Dermatology pre-AAD meeting. “The basic binary premise of the current ISSVA [International Society for the Study of Vascular Anomalies] classification dividing vascular anomalies into tumors and malformations is wrong; the biology is not that straightforward. It may be helpful to differentiate between an infantile hemangioma and a capillary malformation during infancy as the hemangioma will grow in the next month, but we now know that patients with capillary malformations also have significant overgrowth of their tissue. We’ve all seen that; it just takes years, not months for us to notice it.”

The change in thinking about the root causes of vascular anomalies, she noted, stems from scientific advances in the understanding of embryonic mosaicism, DNA variation that happens after the zygote is formed, but before birth. “We know that each cell in a zygote will undergo 40 cell divisions before a baby is born,” she said. “Those cell divisions are not as neat as we thought they were. That cell and DNA duplication is actually quite messy, so there are mutations that happen purely because of embryonic cell division.”

Everyone is born with 120 somatic mutations per cell, she continued, “so we have multiple genomes in one human. Not all of those mutations are going to cause disease. Not all of those are going to be functional. About 10% of those mutations will actually be in a coding region of the gene and have the potential to change the function of the protein. If it changes the function of the protein so that the cell can’t survive, that cell dies off, but it gives the cell an advantage. It grows a little bit faster, let’s say. That cell survives, divides, producing a line of cells that can cause disease.”

In 2011, Dr. Drolet and colleagues from the Hemangioma Investigator Group and the Pediatric Dermatology Research Alliance (PeDRA) launched a multisite collaborative group to investigate the role of mosaic genetics in patients with vascular anomalies and discrepancy of growth. To date, 365 patients are enrolled, and the researchers have sequenced 97 of 165 affected tissue samples collected. “What’s nice about the registry is that we enrolled a wide spectrum of diseases: very mild diseases that might be treated by dermatologists to complex, syndromic diseases that might end up in an interdisciplinary vascular anomalies clinic,” she said.

For gene sequencing, the researchers drew from solid tumor biology and used next-generation sequencing with semi-target hybrid capture, “so we’re only looking at a subset of genes,” she said. “Right now, the chip we’re using has 180 cancer-related genes. It sequences the entire exome of the gene with a high depth of coverage, usually over 1,000 X. We use a specific pipeline that can detect very low allele frequency mutation: down to 1%, and robust criteria to determine variant pathogenicity.”

In 75% of tissue samples so far, the researchers have found a gene mutation in one of 13 genes: AKT1, AKT3, BRAF, GNA11, GNAQ, KRAS, MAP2K1, NRAS, PIK3CA, PIK3R1, PTPN11, RASA1, and TEK. According to Dr. Drolet, the common thread in these 13 genes is that they are implicated in cancer and have direct control over the cell cycle. “They’re intracellular proteins that control the cell cycle,” she explained. “These are proteins that are in the cell but interact with transmembrane proteins that receive extracellular messengers of cell growth”.

Understanding and recognizing genetic conditions is complicated, she said, because it involves determining which gene is altered, where in the DNA the gene is altered, how the gene variation will influence the function of the protein, and what tissue expresses that gene. “Then you get your phenotype,” Dr. Drolet said. “If you add mosaicism onto that, you have several additional variables. You need to know: When in embryogenesis did the mutation occur? What region of the body is affected? What cell lineage is affected? That predicts what phenotype you’re going to have.”

While molecular classification efforts continue to be refined, Dr. Drolet incorporates genotyping at every opportunity, like when she counsels parents of a baby born with a vascular stain on its face. “What can we tell them about what else might be wrong? What can we tell them about how this will change over time? What can we tell them about how we can treat it? I think genotyping absolutely helps to clarify that for me,” she said. “I can’t use that alone, but it gives me another piece of evidence to help do a better job in predicting when I need to screen, what I need to screen for, and what might happen in the future. If you combine your genotype with your clinical exam, I really do believe we can start to offer some prognostication for our families, to say, ‘this is the degree of overgrowth we may see over time; these are the complications I predict that you might have.’ ”

Even the vascular stain can give you a clue. “If it’s light and lacey, you probably don’t have a lot of cell cycle activation,” Dr. Drolet said. “If it’s dark and there’s blebs and you’ve got some bleeding at a young age, you’ve got a highly activated mutation, and there’s everything in between.”

Dr. Drolet disclosed that she is a consultant for Venthera and Novartis and is a board member for the Isthmus Project. She also holds intellectual property rights in and is a patent holder for Peds Derm Development Group. Dr. Drolet has also received funding from the Spirit Foundation, Kayleigh’s Crew Endowment, the SPD, PeDRA, and the National Institutes of Health.

dbrunk@mdedge.com

Emerging data suggest that molecular classification of vascular anomalies can improve prognostication and treatment for babies born with these malformations, according to Beth Drolet, MD.

“We now know that 75%-80% of vascular malformations have gene mutations that make the cells either live longer, grow faster, or make them bigger in size,” Dr. Drolet, professor and chair of dermatology at the University of Wisconsin–Madison, said during the Society for Pediatric Dermatology pre-AAD meeting. “The basic binary premise of the current ISSVA [International Society for the Study of Vascular Anomalies] classification dividing vascular anomalies into tumors and malformations is wrong; the biology is not that straightforward. It may be helpful to differentiate between an infantile hemangioma and a capillary malformation during infancy as the hemangioma will grow in the next month, but we now know that patients with capillary malformations also have significant overgrowth of their tissue. We’ve all seen that; it just takes years, not months for us to notice it.”

The change in thinking about the root causes of vascular anomalies, she noted, stems from scientific advances in the understanding of embryonic mosaicism, DNA variation that happens after the zygote is formed, but before birth. “We know that each cell in a zygote will undergo 40 cell divisions before a baby is born,” she said. “Those cell divisions are not as neat as we thought they were. That cell and DNA duplication is actually quite messy, so there are mutations that happen purely because of embryonic cell division.”

Everyone is born with 120 somatic mutations per cell, she continued, “so we have multiple genomes in one human. Not all of those mutations are going to cause disease. Not all of those are going to be functional. About 10% of those mutations will actually be in a coding region of the gene and have the potential to change the function of the protein. If it changes the function of the protein so that the cell can’t survive, that cell dies off, but it gives the cell an advantage. It grows a little bit faster, let’s say. That cell survives, divides, producing a line of cells that can cause disease.”

In 2011, Dr. Drolet and colleagues from the Hemangioma Investigator Group and the Pediatric Dermatology Research Alliance (PeDRA) launched a multisite collaborative group to investigate the role of mosaic genetics in patients with vascular anomalies and discrepancy of growth. To date, 365 patients are enrolled, and the researchers have sequenced 97 of 165 affected tissue samples collected. “What’s nice about the registry is that we enrolled a wide spectrum of diseases: very mild diseases that might be treated by dermatologists to complex, syndromic diseases that might end up in an interdisciplinary vascular anomalies clinic,” she said.

For gene sequencing, the researchers drew from solid tumor biology and used next-generation sequencing with semi-target hybrid capture, “so we’re only looking at a subset of genes,” she said. “Right now, the chip we’re using has 180 cancer-related genes. It sequences the entire exome of the gene with a high depth of coverage, usually over 1,000 X. We use a specific pipeline that can detect very low allele frequency mutation: down to 1%, and robust criteria to determine variant pathogenicity.”

In 75% of tissue samples so far, the researchers have found a gene mutation in one of 13 genes: AKT1, AKT3, BRAF, GNA11, GNAQ, KRAS, MAP2K1, NRAS, PIK3CA, PIK3R1, PTPN11, RASA1, and TEK. According to Dr. Drolet, the common thread in these 13 genes is that they are implicated in cancer and have direct control over the cell cycle. “They’re intracellular proteins that control the cell cycle,” she explained. “These are proteins that are in the cell but interact with transmembrane proteins that receive extracellular messengers of cell growth”.

Understanding and recognizing genetic conditions is complicated, she said, because it involves determining which gene is altered, where in the DNA the gene is altered, how the gene variation will influence the function of the protein, and what tissue expresses that gene. “Then you get your phenotype,” Dr. Drolet said. “If you add mosaicism onto that, you have several additional variables. You need to know: When in embryogenesis did the mutation occur? What region of the body is affected? What cell lineage is affected? That predicts what phenotype you’re going to have.”

While molecular classification efforts continue to be refined, Dr. Drolet incorporates genotyping at every opportunity, like when she counsels parents of a baby born with a vascular stain on its face. “What can we tell them about what else might be wrong? What can we tell them about how this will change over time? What can we tell them about how we can treat it? I think genotyping absolutely helps to clarify that for me,” she said. “I can’t use that alone, but it gives me another piece of evidence to help do a better job in predicting when I need to screen, what I need to screen for, and what might happen in the future. If you combine your genotype with your clinical exam, I really do believe we can start to offer some prognostication for our families, to say, ‘this is the degree of overgrowth we may see over time; these are the complications I predict that you might have.’ ”

Even the vascular stain can give you a clue. “If it’s light and lacey, you probably don’t have a lot of cell cycle activation,” Dr. Drolet said. “If it’s dark and there’s blebs and you’ve got some bleeding at a young age, you’ve got a highly activated mutation, and there’s everything in between.”

Dr. Drolet disclosed that she is a consultant for Venthera and Novartis and is a board member for the Isthmus Project. She also holds intellectual property rights in and is a patent holder for Peds Derm Development Group. Dr. Drolet has also received funding from the Spirit Foundation, Kayleigh’s Crew Endowment, the SPD, PeDRA, and the National Institutes of Health.

dbrunk@mdedge.com

Wearing stable, supportive footwear reduces knee pain to a significantly greater extent than what’s felt with flat, flexible shoes in patients with severe knee osteoarthritis, according to results of a randomized, controlled trial presented at the OARSI 2021 World Congress.

Stockbyte/Thinkstock

Clinical guidelines for knee OA emphasize the importance of patients self-managing their condition with exercise, weight control, and appropriate footwear. However, there is limited evidence on which footwear is best, and some guidelines advocate stable supportive shoes based solely on expert opinion, Kade Paterson, PhD, of the University of Melbourne told the conference, sponsored by Osteoarthritis Research Society International.

“Recent research suggests that another type of shoe style – termed flat, flexible shoes – may be more beneficial,” Dr. Paterson said, citing a randomized, controlled trial that found greater improvement in pain and function with flat flexible shoes, compared with neutral tennis shoes. “Flat, flexible shoes are generally lighter, and have thinner, more flexible soles.”

In this study, which was published earlier this year in Annals of Internal Medicine, 164 individuals with knee OA who had experienced knee pain on most days of the past month were randomized to wear either stable, supportive shoes or flat, flexible shoes for at least 6 hours a day for 6 months. Six of each shoe type – three male styles and three female styles – were offered, having been chosen based on a survey in which participants were asked about a selection of commercially available shoes they were most likely to wear.

Researchers found participants who wore the stable, supportive shoes had significantly greater reductions in knee pain on walking during the previous week, representing a mean difference of 1.1 units on an 11-point numerical rating scale. More patients in the stable, supportive shoe arm of the study achieved minimal clinically important difference in pain than did those in the flat, flexible shoe group.

Stable, supportive shoes were also associated with greater improvements in knee-related quality of life scores and greater improvements in overall pain. However, there was no significant difference between the two groups in function. Patients wearing flat, flexible shoes reported significantly more adverse events – mainly onset of or increases in knee pain.

Dr. Paterson said the results were surprising, given previous research suggesting a benefit from lighter flat, flexible shoes. “Some previous research showed that those shoes reduced knee joint forces that were associated with pain and reduced it more than stable, supportive shoes, and based on the biomechanical research, we thought would be flat, flexible shoes,” he said in an interview.

Another observation to come from the study was the poor quality of most patients’ everyday shoes. Dr. Paterson said that most of the participants’ usual shoes were very old, and many were also wearing inappropriate footwear for knee OA, including shoes with heels or slippers.

“We would strongly recommend that clinicians ask patients to even bring in their most commonly worn shoes and then recommend new shoes, and based on our data, certainly stable supportive shoes,” he said.

Commenting on the findings, Jos Runhaar, PhD, of Erasmus University Medical Center in Rotterdam, the Netherlands, said this study provided high-quality evidence for this specific intervention in this specific group of patients, namely those with more severe, end-stage OA who had long-lasting changes in their foot posture and gait.

“Based on this, I would say that restoring the original posture of the foot – because that’s how the stable, supportive shoes are probably designed – is more beneficial than actually supporting the natural gait that people are already adapted to at that stage,” Dr. Runhaar said in an interview.

Dr. Paterson noted that the findings of the study were not generalizable to people with mild knee OA, and also that the study did not compare either shoe type with participants’ usual shoes.

The study and three authors were supported by the Australian National Health and Medical Research Council. No conflicts of interest were declared.

Wearing stable, supportive footwear reduces knee pain to a significantly greater extent than what’s felt with flat, flexible shoes in patients with severe knee osteoarthritis, according to results of a randomized, controlled trial presented at the OARSI 2021 World Congress.

Stockbyte/Thinkstock

Clinical guidelines for knee OA emphasize the importance of patients self-managing their condition with exercise, weight control, and appropriate footwear. However, there is limited evidence on which footwear is best, and some guidelines advocate stable supportive shoes based solely on expert opinion, Kade Paterson, PhD, of the University of Melbourne told the conference, sponsored by Osteoarthritis Research Society International.

“Recent research suggests that another type of shoe style – termed flat, flexible shoes – may be more beneficial,” Dr. Paterson said, citing a randomized, controlled trial that found greater improvement in pain and function with flat flexible shoes, compared with neutral tennis shoes. “Flat, flexible shoes are generally lighter, and have thinner, more flexible soles.”

In this study, which was published earlier this year in Annals of Internal Medicine, 164 individuals with knee OA who had experienced knee pain on most days of the past month were randomized to wear either stable, supportive shoes or flat, flexible shoes for at least 6 hours a day for 6 months. Six of each shoe type – three male styles and three female styles – were offered, having been chosen based on a survey in which participants were asked about a selection of commercially available shoes they were most likely to wear.

Researchers found participants who wore the stable, supportive shoes had significantly greater reductions in knee pain on walking during the previous week, representing a mean difference of 1.1 units on an 11-point numerical rating scale. More patients in the stable, supportive shoe arm of the study achieved minimal clinically important difference in pain than did those in the flat, flexible shoe group.

Stable, supportive shoes were also associated with greater improvements in knee-related quality of life scores and greater improvements in overall pain. However, there was no significant difference between the two groups in function. Patients wearing flat, flexible shoes reported significantly more adverse events – mainly onset of or increases in knee pain.

Dr. Paterson said the results were surprising, given previous research suggesting a benefit from lighter flat, flexible shoes. “Some previous research showed that those shoes reduced knee joint forces that were associated with pain and reduced it more than stable, supportive shoes, and based on the biomechanical research, we thought would be flat, flexible shoes,” he said in an interview.

Another observation to come from the study was the poor quality of most patients’ everyday shoes. Dr. Paterson said that most of the participants’ usual shoes were very old, and many were also wearing inappropriate footwear for knee OA, including shoes with heels or slippers.

“We would strongly recommend that clinicians ask patients to even bring in their most commonly worn shoes and then recommend new shoes, and based on our data, certainly stable supportive shoes,” he said.

Commenting on the findings, Jos Runhaar, PhD, of Erasmus University Medical Center in Rotterdam, the Netherlands, said this study provided high-quality evidence for this specific intervention in this specific group of patients, namely those with more severe, end-stage OA who had long-lasting changes in their foot posture and gait.

“Based on this, I would say that restoring the original posture of the foot – because that’s how the stable, supportive shoes are probably designed – is more beneficial than actually supporting the natural gait that people are already adapted to at that stage,” Dr. Runhaar said in an interview.

Dr. Paterson noted that the findings of the study were not generalizable to people with mild knee OA, and also that the study did not compare either shoe type with participants’ usual shoes.

The study and three authors were supported by the Australian National Health and Medical Research Council. No conflicts of interest were declared.

Wearing stable, supportive footwear reduces knee pain to a significantly greater extent than what’s felt with flat, flexible shoes in patients with severe knee osteoarthritis, according to results of a randomized, controlled trial presented at the OARSI 2021 World Congress.

Stockbyte/Thinkstock

Clinical guidelines for knee OA emphasize the importance of patients self-managing their condition with exercise, weight control, and appropriate footwear. However, there is limited evidence on which footwear is best, and some guidelines advocate stable supportive shoes based solely on expert opinion, Kade Paterson, PhD, of the University of Melbourne told the conference, sponsored by Osteoarthritis Research Society International.

“Recent research suggests that another type of shoe style – termed flat, flexible shoes – may be more beneficial,” Dr. Paterson said, citing a randomized, controlled trial that found greater improvement in pain and function with flat flexible shoes, compared with neutral tennis shoes. “Flat, flexible shoes are generally lighter, and have thinner, more flexible soles.”

In this study, which was published earlier this year in Annals of Internal Medicine, 164 individuals with knee OA who had experienced knee pain on most days of the past month were randomized to wear either stable, supportive shoes or flat, flexible shoes for at least 6 hours a day for 6 months. Six of each shoe type – three male styles and three female styles – were offered, having been chosen based on a survey in which participants were asked about a selection of commercially available shoes they were most likely to wear.

Researchers found participants who wore the stable, supportive shoes had significantly greater reductions in knee pain on walking during the previous week, representing a mean difference of 1.1 units on an 11-point numerical rating scale. More patients in the stable, supportive shoe arm of the study achieved minimal clinically important difference in pain than did those in the flat, flexible shoe group.

Stable, supportive shoes were also associated with greater improvements in knee-related quality of life scores and greater improvements in overall pain. However, there was no significant difference between the two groups in function. Patients wearing flat, flexible shoes reported significantly more adverse events – mainly onset of or increases in knee pain.

Dr. Paterson said the results were surprising, given previous research suggesting a benefit from lighter flat, flexible shoes. “Some previous research showed that those shoes reduced knee joint forces that were associated with pain and reduced it more than stable, supportive shoes, and based on the biomechanical research, we thought would be flat, flexible shoes,” he said in an interview.

Another observation to come from the study was the poor quality of most patients’ everyday shoes. Dr. Paterson said that most of the participants’ usual shoes were very old, and many were also wearing inappropriate footwear for knee OA, including shoes with heels or slippers.

“We would strongly recommend that clinicians ask patients to even bring in their most commonly worn shoes and then recommend new shoes, and based on our data, certainly stable supportive shoes,” he said.

Commenting on the findings, Jos Runhaar, PhD, of Erasmus University Medical Center in Rotterdam, the Netherlands, said this study provided high-quality evidence for this specific intervention in this specific group of patients, namely those with more severe, end-stage OA who had long-lasting changes in their foot posture and gait.

“Based on this, I would say that restoring the original posture of the foot – because that’s how the stable, supportive shoes are probably designed – is more beneficial than actually supporting the natural gait that people are already adapted to at that stage,” Dr. Runhaar said in an interview.

Dr. Paterson noted that the findings of the study were not generalizable to people with mild knee OA, and also that the study did not compare either shoe type with participants’ usual shoes.

The study and three authors were supported by the Australian National Health and Medical Research Council. No conflicts of interest were declared.

Most patients will not make a full recovery from attention-deficit/hyperactivity disorder in adulthood. This late-breaking finding headlined the World Congress on ADHD – Virtual Event. Held under the specter of SARS-CoV-2, the virtual program delved into the latest research on ADHD pathophysiology, imaging, genetics, and issues on medical and psychiatric comorbidities.

However, one of the conference’s highlights was a piece of unpublished work on remission patterns by Margaret Sibley, PhD, associate professor of psychiatry and behavioral sciences at the University of Washington, Seattle.

Anywhere from 65% to 67% of young adults have desistant ADHD – meaning that they no longer meet criteria. Only up to 23% experience full remission, said Dr. Sibley during a special late-breaking session. All research on remission and most on persistence consider just one endpoint – nothing is known about longitudinal fluctuations in remission status over time.

Her research sought to answer a key question: Do people fully recover from ADHD?

Using data from the Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) Study, Dr. Sibley prospectively followed over 550 children aged 7-9.9 years with DSM-IV combined-type ADHD over 14 years, until 16 years after baseline, using interviews, questionnaires, and rating scales to track symptoms, impairment, and treatment history.

The researchers also came up with a “winning” definition for full remission, which included three or fewer symptoms of inattention and hyperactive impulsivity from all available reporters, negligible ADHD-related impairment based on preestablished impairment rating thresholds, and discontinuation of medication and behavioral treatments for at least a month prior to assessment.

In the longitudinal results, Dr. Sibley and colleagues reported that the majority (63.8%) demonstrated fluctuations between full or partial remission and ADHD recurrence. Only 9.1% sustained full remission over the course of the study. From these findings, ADHD appears to be a fluctuating disorder. While it continues into adulthood for most people, there may also be periods of remission or “good functioning.”

Most desistance from ADHD represents partial, not full remission, said Dr. Sibley. The results also show that recovery by young adulthood is very rare – most patients with remitted ADHD have recurrences.

These are important findings, said Luis Augusto Rohde, MD, PhD, who co-organized the congress’ scientific program committee with Manfred Gerlach, PhD. It shows that a patient’s ADHD may sometimes be more definitive and at other times, no clear phenotype expression emerges.

COVID’s influence

COVID-19 greatly influenced this year’s program’s agenda, said Dr. Rohde. “There’s a lot of evidence that ADHD patients are at greater risk for COVID-19, which is not a surprise,” said Dr. Rohde, professor of child and adolescent psychiatry at the Federal University of Rio Grande do Sul’s department of psychiatry in Porto Alegre, Brazil.

ADHD is a combination of genetic liability and the demands of the environment. “In times like we are living in right now, if you have increasing demands and stress from the environment, you trigger symptoms in those even with lower genetic liability,” he said. ADHD’s pathophysiology involves attention and executive deficit disorder, which means these patients may not follow strategies to avoid infection.

This shows why COVID was so important to the discussion of program topics, he said.

Two experts addressed this subject head on in a point-counterpoint debate, “Residual effects of the 2019 pandemic will mirror the 1918 pandemic: Will we have lots of new ADHD cases?” James Swanson, PhD, professor of pediatrics at the University of California, Irvine, projected that biological coeffects of COVID-19 will lead to ADHD symptoms, generating potentially 5 million new ADHD cases.

David Coghill, MBChB, MD, a professor of child adolescent mental health at the University of Melbourne, countered that not enough data are available yet to back this hypothesis. “Researchers are asking this question, but clinically we don’t know enough.”

While the COVID virus might not directly lead to more cases of ADHD, this could potentially happen indirectly through environmental agents of the pandemic, offered Dr. Rohde. “We’ve clearly seen in our appointments with families and children that they can’t face the amount of schooling and working from home,” he said.

 

Novel treatments

The conference also addressed new treatments and nonpharmacologic interventions in the pipeline for ADHD. “We had a chance to discuss the possibilities about new medications that address the problems in the current market and to show the potential usefulness of nonpharma interventions such as neuromodulations in ADHD,” said Dr. Rohde. Speakers discussed strategies ranging from family-based mindfulness interventions to oligoantigenic diets in children with ADHD.

Other researchers are looking at novel digital tools to help patients manage and treat ADHD. Adherence is a major problem in chronic disorders like hypertension, diabetes, epilepsy, and ADHD, said Dr. Rohde. “Due to ADHD symptomatology including inattention, novelty-seeking, executive deficits, and difficulties in persistence, it is an even bigger problem in this disorder.”

Speakers at the “ADHD in the digital age – From pitfalls to challenges” session discussed video game strategies to reduce ADHD impairment, and a texting app to improve adherence. Dr. Rohde talked about the FOCUS app, which fosters collaboration between patients, families, and caregivers to efficiently track ADHD symptoms and help customize treatments.

Studies suggest these tools can significantly improve adherence. They’re also well accepted by patients, said Dr. Rohde. While the expectations are high, digital interventions are not a substitute for medication. “More data is needed to include them as part of the clinical interventions for ADHD.”

Dr. Sibley received book royalties from Guilford Press. Dr. Rohde has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Bial, Medice, Novartis/Sandoz, Pfizer, and Shire/Takeda in the last 3 years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by Dr. Rohde have received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Novartis/Sandoz and Shire/Takeda. Dr. Rohde has received authorship royalties from Oxford Press and ArtMed and travel grants from Shire to take part in the 2018 APA annual meeting. Dr. Swanson has two patents: (PIXA4), which uses a “time-of-flight” camera to measure growth of infants, and a provisional patent on the mechanism of tolerance to stimulant medication (PATSMTA). He has received travel support from Medice and has done legal review for NLS. Dr. Coghill worked for several pharmaceutical companies but had no disclosures relevant to the session debate on the pandemic.

Most patients will not make a full recovery from attention-deficit/hyperactivity disorder in adulthood. This late-breaking finding headlined the World Congress on ADHD – Virtual Event. Held under the specter of SARS-CoV-2, the virtual program delved into the latest research on ADHD pathophysiology, imaging, genetics, and issues on medical and psychiatric comorbidities.

However, one of the conference’s highlights was a piece of unpublished work on remission patterns by Margaret Sibley, PhD, associate professor of psychiatry and behavioral sciences at the University of Washington, Seattle.

Anywhere from 65% to 67% of young adults have desistant ADHD – meaning that they no longer meet criteria. Only up to 23% experience full remission, said Dr. Sibley during a special late-breaking session. All research on remission and most on persistence consider just one endpoint – nothing is known about longitudinal fluctuations in remission status over time.

Her research sought to answer a key question: Do people fully recover from ADHD?

Using data from the Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) Study, Dr. Sibley prospectively followed over 550 children aged 7-9.9 years with DSM-IV combined-type ADHD over 14 years, until 16 years after baseline, using interviews, questionnaires, and rating scales to track symptoms, impairment, and treatment history.

The researchers also came up with a “winning” definition for full remission, which included three or fewer symptoms of inattention and hyperactive impulsivity from all available reporters, negligible ADHD-related impairment based on preestablished impairment rating thresholds, and discontinuation of medication and behavioral treatments for at least a month prior to assessment.

In the longitudinal results, Dr. Sibley and colleagues reported that the majority (63.8%) demonstrated fluctuations between full or partial remission and ADHD recurrence. Only 9.1% sustained full remission over the course of the study. From these findings, ADHD appears to be a fluctuating disorder. While it continues into adulthood for most people, there may also be periods of remission or “good functioning.”

Most desistance from ADHD represents partial, not full remission, said Dr. Sibley. The results also show that recovery by young adulthood is very rare – most patients with remitted ADHD have recurrences.

These are important findings, said Luis Augusto Rohde, MD, PhD, who co-organized the congress’ scientific program committee with Manfred Gerlach, PhD. It shows that a patient’s ADHD may sometimes be more definitive and at other times, no clear phenotype expression emerges.

COVID’s influence

COVID-19 greatly influenced this year’s program’s agenda, said Dr. Rohde. “There’s a lot of evidence that ADHD patients are at greater risk for COVID-19, which is not a surprise,” said Dr. Rohde, professor of child and adolescent psychiatry at the Federal University of Rio Grande do Sul’s department of psychiatry in Porto Alegre, Brazil.

ADHD is a combination of genetic liability and the demands of the environment. “In times like we are living in right now, if you have increasing demands and stress from the environment, you trigger symptoms in those even with lower genetic liability,” he said. ADHD’s pathophysiology involves attention and executive deficit disorder, which means these patients may not follow strategies to avoid infection.

This shows why COVID was so important to the discussion of program topics, he said.

Two experts addressed this subject head on in a point-counterpoint debate, “Residual effects of the 2019 pandemic will mirror the 1918 pandemic: Will we have lots of new ADHD cases?” James Swanson, PhD, professor of pediatrics at the University of California, Irvine, projected that biological coeffects of COVID-19 will lead to ADHD symptoms, generating potentially 5 million new ADHD cases.

David Coghill, MBChB, MD, a professor of child adolescent mental health at the University of Melbourne, countered that not enough data are available yet to back this hypothesis. “Researchers are asking this question, but clinically we don’t know enough.”

While the COVID virus might not directly lead to more cases of ADHD, this could potentially happen indirectly through environmental agents of the pandemic, offered Dr. Rohde. “We’ve clearly seen in our appointments with families and children that they can’t face the amount of schooling and working from home,” he said.

 

Novel treatments

The conference also addressed new treatments and nonpharmacologic interventions in the pipeline for ADHD. “We had a chance to discuss the possibilities about new medications that address the problems in the current market and to show the potential usefulness of nonpharma interventions such as neuromodulations in ADHD,” said Dr. Rohde. Speakers discussed strategies ranging from family-based mindfulness interventions to oligoantigenic diets in children with ADHD.

Other researchers are looking at novel digital tools to help patients manage and treat ADHD. Adherence is a major problem in chronic disorders like hypertension, diabetes, epilepsy, and ADHD, said Dr. Rohde. “Due to ADHD symptomatology including inattention, novelty-seeking, executive deficits, and difficulties in persistence, it is an even bigger problem in this disorder.”

Speakers at the “ADHD in the digital age – From pitfalls to challenges” session discussed video game strategies to reduce ADHD impairment, and a texting app to improve adherence. Dr. Rohde talked about the FOCUS app, which fosters collaboration between patients, families, and caregivers to efficiently track ADHD symptoms and help customize treatments.

Studies suggest these tools can significantly improve adherence. They’re also well accepted by patients, said Dr. Rohde. While the expectations are high, digital interventions are not a substitute for medication. “More data is needed to include them as part of the clinical interventions for ADHD.”

Dr. Sibley received book royalties from Guilford Press. Dr. Rohde has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Bial, Medice, Novartis/Sandoz, Pfizer, and Shire/Takeda in the last 3 years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by Dr. Rohde have received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Novartis/Sandoz and Shire/Takeda. Dr. Rohde has received authorship royalties from Oxford Press and ArtMed and travel grants from Shire to take part in the 2018 APA annual meeting. Dr. Swanson has two patents: (PIXA4), which uses a “time-of-flight” camera to measure growth of infants, and a provisional patent on the mechanism of tolerance to stimulant medication (PATSMTA). He has received travel support from Medice and has done legal review for NLS. Dr. Coghill worked for several pharmaceutical companies but had no disclosures relevant to the session debate on the pandemic.

Most patients will not make a full recovery from attention-deficit/hyperactivity disorder in adulthood. This late-breaking finding headlined the World Congress on ADHD – Virtual Event. Held under the specter of SARS-CoV-2, the virtual program delved into the latest research on ADHD pathophysiology, imaging, genetics, and issues on medical and psychiatric comorbidities.

However, one of the conference’s highlights was a piece of unpublished work on remission patterns by Margaret Sibley, PhD, associate professor of psychiatry and behavioral sciences at the University of Washington, Seattle.

Anywhere from 65% to 67% of young adults have desistant ADHD – meaning that they no longer meet criteria. Only up to 23% experience full remission, said Dr. Sibley during a special late-breaking session. All research on remission and most on persistence consider just one endpoint – nothing is known about longitudinal fluctuations in remission status over time.

Her research sought to answer a key question: Do people fully recover from ADHD?

Using data from the Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) Study, Dr. Sibley prospectively followed over 550 children aged 7-9.9 years with DSM-IV combined-type ADHD over 14 years, until 16 years after baseline, using interviews, questionnaires, and rating scales to track symptoms, impairment, and treatment history.

The researchers also came up with a “winning” definition for full remission, which included three or fewer symptoms of inattention and hyperactive impulsivity from all available reporters, negligible ADHD-related impairment based on preestablished impairment rating thresholds, and discontinuation of medication and behavioral treatments for at least a month prior to assessment.

In the longitudinal results, Dr. Sibley and colleagues reported that the majority (63.8%) demonstrated fluctuations between full or partial remission and ADHD recurrence. Only 9.1% sustained full remission over the course of the study. From these findings, ADHD appears to be a fluctuating disorder. While it continues into adulthood for most people, there may also be periods of remission or “good functioning.”

Most desistance from ADHD represents partial, not full remission, said Dr. Sibley. The results also show that recovery by young adulthood is very rare – most patients with remitted ADHD have recurrences.

These are important findings, said Luis Augusto Rohde, MD, PhD, who co-organized the congress’ scientific program committee with Manfred Gerlach, PhD. It shows that a patient’s ADHD may sometimes be more definitive and at other times, no clear phenotype expression emerges.

COVID’s influence

COVID-19 greatly influenced this year’s program’s agenda, said Dr. Rohde. “There’s a lot of evidence that ADHD patients are at greater risk for COVID-19, which is not a surprise,” said Dr. Rohde, professor of child and adolescent psychiatry at the Federal University of Rio Grande do Sul’s department of psychiatry in Porto Alegre, Brazil.

ADHD is a combination of genetic liability and the demands of the environment. “In times like we are living in right now, if you have increasing demands and stress from the environment, you trigger symptoms in those even with lower genetic liability,” he said. ADHD’s pathophysiology involves attention and executive deficit disorder, which means these patients may not follow strategies to avoid infection.

This shows why COVID was so important to the discussion of program topics, he said.

Two experts addressed this subject head on in a point-counterpoint debate, “Residual effects of the 2019 pandemic will mirror the 1918 pandemic: Will we have lots of new ADHD cases?” James Swanson, PhD, professor of pediatrics at the University of California, Irvine, projected that biological coeffects of COVID-19 will lead to ADHD symptoms, generating potentially 5 million new ADHD cases.

David Coghill, MBChB, MD, a professor of child adolescent mental health at the University of Melbourne, countered that not enough data are available yet to back this hypothesis. “Researchers are asking this question, but clinically we don’t know enough.”

While the COVID virus might not directly lead to more cases of ADHD, this could potentially happen indirectly through environmental agents of the pandemic, offered Dr. Rohde. “We’ve clearly seen in our appointments with families and children that they can’t face the amount of schooling and working from home,” he said.

 

Novel treatments

The conference also addressed new treatments and nonpharmacologic interventions in the pipeline for ADHD. “We had a chance to discuss the possibilities about new medications that address the problems in the current market and to show the potential usefulness of nonpharma interventions such as neuromodulations in ADHD,” said Dr. Rohde. Speakers discussed strategies ranging from family-based mindfulness interventions to oligoantigenic diets in children with ADHD.

Other researchers are looking at novel digital tools to help patients manage and treat ADHD. Adherence is a major problem in chronic disorders like hypertension, diabetes, epilepsy, and ADHD, said Dr. Rohde. “Due to ADHD symptomatology including inattention, novelty-seeking, executive deficits, and difficulties in persistence, it is an even bigger problem in this disorder.”

Speakers at the “ADHD in the digital age – From pitfalls to challenges” session discussed video game strategies to reduce ADHD impairment, and a texting app to improve adherence. Dr. Rohde talked about the FOCUS app, which fosters collaboration between patients, families, and caregivers to efficiently track ADHD symptoms and help customize treatments.

Studies suggest these tools can significantly improve adherence. They’re also well accepted by patients, said Dr. Rohde. While the expectations are high, digital interventions are not a substitute for medication. “More data is needed to include them as part of the clinical interventions for ADHD.”

Dr. Sibley received book royalties from Guilford Press. Dr. Rohde has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Bial, Medice, Novartis/Sandoz, Pfizer, and Shire/Takeda in the last 3 years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by Dr. Rohde have received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Novartis/Sandoz and Shire/Takeda. Dr. Rohde has received authorship royalties from Oxford Press and ArtMed and travel grants from Shire to take part in the 2018 APA annual meeting. Dr. Swanson has two patents: (PIXA4), which uses a “time-of-flight” camera to measure growth of infants, and a provisional patent on the mechanism of tolerance to stimulant medication (PATSMTA). He has received travel support from Medice and has done legal review for NLS. Dr. Coghill worked for several pharmaceutical companies but had no disclosures relevant to the session debate on the pandemic.

Attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) often coexist in children and adults, but the range of cognitive abilities can vary widely in these patients. Researchers from around the world are leveraging symptom, cognitive assessment, and neurobiological measures to gain insights on how individuals with ADHD/ASD approach and solve problems.

Several experts discussed the progress of their research during the session, “Overlap and differences of ADHD and autism – new findings of functional imaging and cognition studies” at the World Congress on ADHD – Virtual Event.

“The overlap of these two disorders is a critical issue for our field,” said Sarah Karalunas, PhD, assistant professor of clinical psychology at Purdue University, West Lafayette, Ind., who moderated the session. Clinicians are often asked to make differential diagnoses between these two disorders. Only recently has the DSM-5 allowed their codiagnosis. “There’s increasing recognition that there may be shared cognitive and physiological features that reflect their shared risk and account for the high levels of symptom overlap,” said Dr. Karalunas.
 

Shared cognitive markers

Under the DSM’s change, “it’s now recognized that an estimated 20%-60% of children with ASD have comorbidities with ADHD, and around 20%-40% of children with ADHD have ASD symptoms,” said Beth Johnson, PhD, a research fellow with the Turner Institute for Brain and Mental Health at Monash University, Melbourne.

The shared overlap on genetic traits and comorbidities such as intellectual disability, anxiety, depression, and oppositional defiant disorder, make it difficult for clinicians to predict clinical outcomes, noted Dr. Johnson.

“We’re now understanding that they’re likely to be multiple autisms and ADHDs, that these symptoms exist on a spectrum of severity or ability,” she said. Dr. Johnson discussed a data-driven subtyping approach based on neurocognitive and symptom profiles in children with ADHD. The aim was to better understand how symptoms are managed across ADHD, ASD and comorbid ASD-ADHD.

As part of this research, her team recruited 295 controls and 117 children with ADHD who underwent clinical phenotyping and also completed working memory tasks, stop signal, and sustained attention tasks.

The researchers divided the children into four stable clusters based on the ADHD rating scale and autism questionnaire data: high ASD/ADHD traits, high ADHD/low ASD, low ADHD/moderate ASD, and low ADHD/ASD. Approximately half of the children with ADHD showed moderate to high ASD symptoms. Looking at neurocognition across the tasks, unsurprisingly, performance was lowest among the high-ASD/ADHD children, with performance on the stop signal being the most pronounced. “Notably, performance on the working memory task worsened with increasing ADHD symptoms,” she reported.
 

Drift model identifies information processing

Dr. Karalunas has also compared subgroups of ADHD and ASD children. “Our analysis examined whether cognitive impairments in ASD reflect a shared risk mechanism or co-occurring ADHD symptoms and why we see an overlap in these types of impairments,” she said.

Her study included 509 children with ADHD, 97 with ASD, and 301 controls (typical development). All three groups underwent a full cognitive assessment battery that measured attention arousal, basic processing speed, and working memory. Those tasks were collapsed into a series of variables as well as a set of tasks measuring response inhibition, switching, interference control, reward discounting, and measure of reaction time variability.

Four cognitive profiles emerged: a typically developing group, an ADHD group, an ASD group with low levels of ADHD symptoms and an ASD group with high levels of ADHD symptoms.

The ADHD group did worse on many of the tasks than the control group, and the ASD group with low ADHD levels also did poorly relative to the typically developing sample. This shows that autism – even in absence of co-occurring ADHD – demonstrates more cognitive impairment than typically developing kids. The ADHD group with high levels of autism did the most poorly across all of the tasks.

The findings also revealed a symptom severity pattern: the group with fewer symptoms did the best and the group with the most symptoms did the worst. “Overall, this reflects severity of impairment,” said Dr. Karalunas.

To identify measures more specific to either ADHD or autism, Dr. Karalunas and colleagues did a follow-up analysis to characterize cognitive performance. To accomplish this, they applied a drift-diffusion model to the same four cognitive profiles. The model assessed three parameters: drift rate, which relates to the speed or efficiency of information processing, boundary separation or speed accuracy trade-offs (impulsivity), and nondecision time such as motor preparation.

Using the same four cognitive profiles, they found that the ADHD group had slower drift rate relative to the control, although the two groups did not differ on boundary separation, which meant there were no differences on waiting to need to respond. The ADHD group had faster nondecision times. “This is a classic pattern, shown in the literature,” said Dr. Karalunas.
 

In other results, an interesting pattern began to evolve

Both ASD groups, for example, had much wider boundary separations, which meant they were waiting to be sure before they responded than the ADHD or typically developing groups. In contrast, the two ADHD groups had much faster non-decision times, whereas the two non-ADHD groups had similar nondecisions times.

Unlike the previous analysis, which saw a symptom severity pattern develop, “we’re getting two parameters that seem to track much more specifically to specific symptom domains,” observed Dr. Karalunas.

The results suggest there’s a substantial overlap in cognitive impairments in ADHD/ASD. “But we have pretty strong evidence at this point that these similarities are not accounted for by symptom overlap, especially for things like response and inhibition, working memory and processing speed. These seem to be independently related to ADHD and autism, regardless of the level of comorbid ADHD symptoms in the autism group,” said Dr. Karalunas.

The hope is to expand on these types of analyses to address the interaction of cognition-emotion and social cognition, and empirically define groups based on cognitive performance, she said.
 

Neurocognitive studies

Researchers have also been studying neural networks to assess ASD and ADHD. Roselyne Chauvin, PhD, a postdoctoral associate at Washington University, St. Louis, discussed the concept of “a task generic connectome,” in which researchers look for a common network between targeted task paradigms to get closer to a common alteration across impairments.

In her research, Dr. Chauvin and colleagues looked at connectivity modulations across three tasks: working memory, reward processing tasks, and stop signal tasks, comparing ADHD patients to siblings and controls. The ADHD group showed reduced sensitivity or a smaller number of connections modulated in the tasks compared with the other groups. Researchers wondered where those missed connections were located.

Dividing the cohorts into task generic and task specific groups, Dr. Chauvin and colleagues found that the ADHD group lacked common processing skills. They were also able to identify reproducible missing circuits in the ADHD participants. Among the cohorts, there was a higher modulation of task-specific edges in the ADHD group.

The ADHD patients seemed to be using more task-tailored alternative strategies that were more challenging and suboptimal.

She also previewed her ongoing work with the EU-AIMS Longitudinal European Autism Project (LEAP) database to study ASD-ADHD comorbidity. In this project, she and her colleagues looked at several tasks: probing emotion processing, inhibitory control, theory of mind, and reward anticipation. Comparing ASD groups with or without ADHD comorbidity or a shared connection, she and her team were able to devise a functional profile predictive of ADHD severity. As an example, “for the connection only used by the ASD with ADHD comorbidity, the more they were using those connections of higher amplitude in the modulation, inside this subset of connection, the higher they would have ADHD severity,” said Dr. Chauvin.

Neural correlates of different behavioral and cognitive profiles haven’t been widely studied, according to Charlotte Tye, PhD, who’s based at the Institute of Psychiatry, Psychology & Neuroscience, King’s College, London. Electroencephalography is a useful technique for understanding the neural correlates of cognitive impairments and teasing apart different models of co-occurrence in ASD and ADHD. 

Dr. Tye and colleagues tested this approach in a cohort of boys aged 8-13 years diagnosed with ASD and/or ADHD, measuring EEG while the children did various continuous performance tasks to assess changes in brain activity. Examining P3 amplitude (event-related potential components) they found that children with ADHD or ADHD+ASD showed an attenuated amplitude of the P3, compared with typically developing children and those with ASD.

“This suggests children with an ADHD diagnosis exhibited reduced inhibitory control,” said Dr. Tye. In contrast, children with ASD showed reduced conflict monitoring as indexed by altered N2 amplitude across task conditions.

These, and other studies conducted by Dr. Tye and colleagues indicate that children with ADHD show reduced neural responses during attentional processing, whereas autistic children show typical neural responses, supporting specific profiles.

“Autistic children with a diagnosis of ADHD appear to show the unique patterns of neural responses of autism and ADHD, supporting an additive co-occurrence rather than a distinct condition. This contributes to identification of transdiagnostic subgroups within neurodevelopmental conditions for targeting of personalized intervention, and suggests that children with co-occurring autism and ADHD require support for both conditions,” said Dr. Tye.

An important takeaway from all of these findings is “we can’t look just at how someone does overall on a single test,” said Dr. Karalunas in an interview. “There is a tremendous amount of variability between people who have the same diagnosis, and our research really needs to account for this.”

Attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) often coexist in children and adults, but the range of cognitive abilities can vary widely in these patients. Researchers from around the world are leveraging symptom, cognitive assessment, and neurobiological measures to gain insights on how individuals with ADHD/ASD approach and solve problems.

Several experts discussed the progress of their research during the session, “Overlap and differences of ADHD and autism – new findings of functional imaging and cognition studies” at the World Congress on ADHD – Virtual Event.

“The overlap of these two disorders is a critical issue for our field,” said Sarah Karalunas, PhD, assistant professor of clinical psychology at Purdue University, West Lafayette, Ind., who moderated the session. Clinicians are often asked to make differential diagnoses between these two disorders. Only recently has the DSM-5 allowed their codiagnosis. “There’s increasing recognition that there may be shared cognitive and physiological features that reflect their shared risk and account for the high levels of symptom overlap,” said Dr. Karalunas.
 

Shared cognitive markers

Under the DSM’s change, “it’s now recognized that an estimated 20%-60% of children with ASD have comorbidities with ADHD, and around 20%-40% of children with ADHD have ASD symptoms,” said Beth Johnson, PhD, a research fellow with the Turner Institute for Brain and Mental Health at Monash University, Melbourne.

The shared overlap on genetic traits and comorbidities such as intellectual disability, anxiety, depression, and oppositional defiant disorder, make it difficult for clinicians to predict clinical outcomes, noted Dr. Johnson.

“We’re now understanding that they’re likely to be multiple autisms and ADHDs, that these symptoms exist on a spectrum of severity or ability,” she said. Dr. Johnson discussed a data-driven subtyping approach based on neurocognitive and symptom profiles in children with ADHD. The aim was to better understand how symptoms are managed across ADHD, ASD and comorbid ASD-ADHD.

As part of this research, her team recruited 295 controls and 117 children with ADHD who underwent clinical phenotyping and also completed working memory tasks, stop signal, and sustained attention tasks.

The researchers divided the children into four stable clusters based on the ADHD rating scale and autism questionnaire data: high ASD/ADHD traits, high ADHD/low ASD, low ADHD/moderate ASD, and low ADHD/ASD. Approximately half of the children with ADHD showed moderate to high ASD symptoms. Looking at neurocognition across the tasks, unsurprisingly, performance was lowest among the high-ASD/ADHD children, with performance on the stop signal being the most pronounced. “Notably, performance on the working memory task worsened with increasing ADHD symptoms,” she reported.
 

Drift model identifies information processing

Dr. Karalunas has also compared subgroups of ADHD and ASD children. “Our analysis examined whether cognitive impairments in ASD reflect a shared risk mechanism or co-occurring ADHD symptoms and why we see an overlap in these types of impairments,” she said.

Her study included 509 children with ADHD, 97 with ASD, and 301 controls (typical development). All three groups underwent a full cognitive assessment battery that measured attention arousal, basic processing speed, and working memory. Those tasks were collapsed into a series of variables as well as a set of tasks measuring response inhibition, switching, interference control, reward discounting, and measure of reaction time variability.

Four cognitive profiles emerged: a typically developing group, an ADHD group, an ASD group with low levels of ADHD symptoms and an ASD group with high levels of ADHD symptoms.

The ADHD group did worse on many of the tasks than the control group, and the ASD group with low ADHD levels also did poorly relative to the typically developing sample. This shows that autism – even in absence of co-occurring ADHD – demonstrates more cognitive impairment than typically developing kids. The ADHD group with high levels of autism did the most poorly across all of the tasks.

The findings also revealed a symptom severity pattern: the group with fewer symptoms did the best and the group with the most symptoms did the worst. “Overall, this reflects severity of impairment,” said Dr. Karalunas.

To identify measures more specific to either ADHD or autism, Dr. Karalunas and colleagues did a follow-up analysis to characterize cognitive performance. To accomplish this, they applied a drift-diffusion model to the same four cognitive profiles. The model assessed three parameters: drift rate, which relates to the speed or efficiency of information processing, boundary separation or speed accuracy trade-offs (impulsivity), and nondecision time such as motor preparation.

Using the same four cognitive profiles, they found that the ADHD group had slower drift rate relative to the control, although the two groups did not differ on boundary separation, which meant there were no differences on waiting to need to respond. The ADHD group had faster nondecision times. “This is a classic pattern, shown in the literature,” said Dr. Karalunas.
 

In other results, an interesting pattern began to evolve

Both ASD groups, for example, had much wider boundary separations, which meant they were waiting to be sure before they responded than the ADHD or typically developing groups. In contrast, the two ADHD groups had much faster non-decision times, whereas the two non-ADHD groups had similar nondecisions times.

Unlike the previous analysis, which saw a symptom severity pattern develop, “we’re getting two parameters that seem to track much more specifically to specific symptom domains,” observed Dr. Karalunas.

The results suggest there’s a substantial overlap in cognitive impairments in ADHD/ASD. “But we have pretty strong evidence at this point that these similarities are not accounted for by symptom overlap, especially for things like response and inhibition, working memory and processing speed. These seem to be independently related to ADHD and autism, regardless of the level of comorbid ADHD symptoms in the autism group,” said Dr. Karalunas.

The hope is to expand on these types of analyses to address the interaction of cognition-emotion and social cognition, and empirically define groups based on cognitive performance, she said.
 

Neurocognitive studies

Researchers have also been studying neural networks to assess ASD and ADHD. Roselyne Chauvin, PhD, a postdoctoral associate at Washington University, St. Louis, discussed the concept of “a task generic connectome,” in which researchers look for a common network between targeted task paradigms to get closer to a common alteration across impairments.

In her research, Dr. Chauvin and colleagues looked at connectivity modulations across three tasks: working memory, reward processing tasks, and stop signal tasks, comparing ADHD patients to siblings and controls. The ADHD group showed reduced sensitivity or a smaller number of connections modulated in the tasks compared with the other groups. Researchers wondered where those missed connections were located.

Dividing the cohorts into task generic and task specific groups, Dr. Chauvin and colleagues found that the ADHD group lacked common processing skills. They were also able to identify reproducible missing circuits in the ADHD participants. Among the cohorts, there was a higher modulation of task-specific edges in the ADHD group.

The ADHD patients seemed to be using more task-tailored alternative strategies that were more challenging and suboptimal.

She also previewed her ongoing work with the EU-AIMS Longitudinal European Autism Project (LEAP) database to study ASD-ADHD comorbidity. In this project, she and her colleagues looked at several tasks: probing emotion processing, inhibitory control, theory of mind, and reward anticipation. Comparing ASD groups with or without ADHD comorbidity or a shared connection, she and her team were able to devise a functional profile predictive of ADHD severity. As an example, “for the connection only used by the ASD with ADHD comorbidity, the more they were using those connections of higher amplitude in the modulation, inside this subset of connection, the higher they would have ADHD severity,” said Dr. Chauvin.

Neural correlates of different behavioral and cognitive profiles haven’t been widely studied, according to Charlotte Tye, PhD, who’s based at the Institute of Psychiatry, Psychology & Neuroscience, King’s College, London. Electroencephalography is a useful technique for understanding the neural correlates of cognitive impairments and teasing apart different models of co-occurrence in ASD and ADHD. 

Dr. Tye and colleagues tested this approach in a cohort of boys aged 8-13 years diagnosed with ASD and/or ADHD, measuring EEG while the children did various continuous performance tasks to assess changes in brain activity. Examining P3 amplitude (event-related potential components) they found that children with ADHD or ADHD+ASD showed an attenuated amplitude of the P3, compared with typically developing children and those with ASD.

“This suggests children with an ADHD diagnosis exhibited reduced inhibitory control,” said Dr. Tye. In contrast, children with ASD showed reduced conflict monitoring as indexed by altered N2 amplitude across task conditions.

These, and other studies conducted by Dr. Tye and colleagues indicate that children with ADHD show reduced neural responses during attentional processing, whereas autistic children show typical neural responses, supporting specific profiles.

“Autistic children with a diagnosis of ADHD appear to show the unique patterns of neural responses of autism and ADHD, supporting an additive co-occurrence rather than a distinct condition. This contributes to identification of transdiagnostic subgroups within neurodevelopmental conditions for targeting of personalized intervention, and suggests that children with co-occurring autism and ADHD require support for both conditions,” said Dr. Tye.

An important takeaway from all of these findings is “we can’t look just at how someone does overall on a single test,” said Dr. Karalunas in an interview. “There is a tremendous amount of variability between people who have the same diagnosis, and our research really needs to account for this.”

Attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) often coexist in children and adults, but the range of cognitive abilities can vary widely in these patients. Researchers from around the world are leveraging symptom, cognitive assessment, and neurobiological measures to gain insights on how individuals with ADHD/ASD approach and solve problems.

Several experts discussed the progress of their research during the session, “Overlap and differences of ADHD and autism – new findings of functional imaging and cognition studies” at the World Congress on ADHD – Virtual Event.

“The overlap of these two disorders is a critical issue for our field,” said Sarah Karalunas, PhD, assistant professor of clinical psychology at Purdue University, West Lafayette, Ind., who moderated the session. Clinicians are often asked to make differential diagnoses between these two disorders. Only recently has the DSM-5 allowed their codiagnosis. “There’s increasing recognition that there may be shared cognitive and physiological features that reflect their shared risk and account for the high levels of symptom overlap,” said Dr. Karalunas.
 

Shared cognitive markers

Under the DSM’s change, “it’s now recognized that an estimated 20%-60% of children with ASD have comorbidities with ADHD, and around 20%-40% of children with ADHD have ASD symptoms,” said Beth Johnson, PhD, a research fellow with the Turner Institute for Brain and Mental Health at Monash University, Melbourne.

The shared overlap on genetic traits and comorbidities such as intellectual disability, anxiety, depression, and oppositional defiant disorder, make it difficult for clinicians to predict clinical outcomes, noted Dr. Johnson.

“We’re now understanding that they’re likely to be multiple autisms and ADHDs, that these symptoms exist on a spectrum of severity or ability,” she said. Dr. Johnson discussed a data-driven subtyping approach based on neurocognitive and symptom profiles in children with ADHD. The aim was to better understand how symptoms are managed across ADHD, ASD and comorbid ASD-ADHD.

As part of this research, her team recruited 295 controls and 117 children with ADHD who underwent clinical phenotyping and also completed working memory tasks, stop signal, and sustained attention tasks.

The researchers divided the children into four stable clusters based on the ADHD rating scale and autism questionnaire data: high ASD/ADHD traits, high ADHD/low ASD, low ADHD/moderate ASD, and low ADHD/ASD. Approximately half of the children with ADHD showed moderate to high ASD symptoms. Looking at neurocognition across the tasks, unsurprisingly, performance was lowest among the high-ASD/ADHD children, with performance on the stop signal being the most pronounced. “Notably, performance on the working memory task worsened with increasing ADHD symptoms,” she reported.
 

Drift model identifies information processing

Dr. Karalunas has also compared subgroups of ADHD and ASD children. “Our analysis examined whether cognitive impairments in ASD reflect a shared risk mechanism or co-occurring ADHD symptoms and why we see an overlap in these types of impairments,” she said.

Her study included 509 children with ADHD, 97 with ASD, and 301 controls (typical development). All three groups underwent a full cognitive assessment battery that measured attention arousal, basic processing speed, and working memory. Those tasks were collapsed into a series of variables as well as a set of tasks measuring response inhibition, switching, interference control, reward discounting, and measure of reaction time variability.

Four cognitive profiles emerged: a typically developing group, an ADHD group, an ASD group with low levels of ADHD symptoms and an ASD group with high levels of ADHD symptoms.

The ADHD group did worse on many of the tasks than the control group, and the ASD group with low ADHD levels also did poorly relative to the typically developing sample. This shows that autism – even in absence of co-occurring ADHD – demonstrates more cognitive impairment than typically developing kids. The ADHD group with high levels of autism did the most poorly across all of the tasks.

The findings also revealed a symptom severity pattern: the group with fewer symptoms did the best and the group with the most symptoms did the worst. “Overall, this reflects severity of impairment,” said Dr. Karalunas.

To identify measures more specific to either ADHD or autism, Dr. Karalunas and colleagues did a follow-up analysis to characterize cognitive performance. To accomplish this, they applied a drift-diffusion model to the same four cognitive profiles. The model assessed three parameters: drift rate, which relates to the speed or efficiency of information processing, boundary separation or speed accuracy trade-offs (impulsivity), and nondecision time such as motor preparation.

Using the same four cognitive profiles, they found that the ADHD group had slower drift rate relative to the control, although the two groups did not differ on boundary separation, which meant there were no differences on waiting to need to respond. The ADHD group had faster nondecision times. “This is a classic pattern, shown in the literature,” said Dr. Karalunas.
 

In other results, an interesting pattern began to evolve

Both ASD groups, for example, had much wider boundary separations, which meant they were waiting to be sure before they responded than the ADHD or typically developing groups. In contrast, the two ADHD groups had much faster non-decision times, whereas the two non-ADHD groups had similar nondecisions times.

Unlike the previous analysis, which saw a symptom severity pattern develop, “we’re getting two parameters that seem to track much more specifically to specific symptom domains,” observed Dr. Karalunas.

The results suggest there’s a substantial overlap in cognitive impairments in ADHD/ASD. “But we have pretty strong evidence at this point that these similarities are not accounted for by symptom overlap, especially for things like response and inhibition, working memory and processing speed. These seem to be independently related to ADHD and autism, regardless of the level of comorbid ADHD symptoms in the autism group,” said Dr. Karalunas.

The hope is to expand on these types of analyses to address the interaction of cognition-emotion and social cognition, and empirically define groups based on cognitive performance, she said.
 

Neurocognitive studies

Researchers have also been studying neural networks to assess ASD and ADHD. Roselyne Chauvin, PhD, a postdoctoral associate at Washington University, St. Louis, discussed the concept of “a task generic connectome,” in which researchers look for a common network between targeted task paradigms to get closer to a common alteration across impairments.

In her research, Dr. Chauvin and colleagues looked at connectivity modulations across three tasks: working memory, reward processing tasks, and stop signal tasks, comparing ADHD patients to siblings and controls. The ADHD group showed reduced sensitivity or a smaller number of connections modulated in the tasks compared with the other groups. Researchers wondered where those missed connections were located.

Dividing the cohorts into task generic and task specific groups, Dr. Chauvin and colleagues found that the ADHD group lacked common processing skills. They were also able to identify reproducible missing circuits in the ADHD participants. Among the cohorts, there was a higher modulation of task-specific edges in the ADHD group.

The ADHD patients seemed to be using more task-tailored alternative strategies that were more challenging and suboptimal.

She also previewed her ongoing work with the EU-AIMS Longitudinal European Autism Project (LEAP) database to study ASD-ADHD comorbidity. In this project, she and her colleagues looked at several tasks: probing emotion processing, inhibitory control, theory of mind, and reward anticipation. Comparing ASD groups with or without ADHD comorbidity or a shared connection, she and her team were able to devise a functional profile predictive of ADHD severity. As an example, “for the connection only used by the ASD with ADHD comorbidity, the more they were using those connections of higher amplitude in the modulation, inside this subset of connection, the higher they would have ADHD severity,” said Dr. Chauvin.

Neural correlates of different behavioral and cognitive profiles haven’t been widely studied, according to Charlotte Tye, PhD, who’s based at the Institute of Psychiatry, Psychology & Neuroscience, King’s College, London. Electroencephalography is a useful technique for understanding the neural correlates of cognitive impairments and teasing apart different models of co-occurrence in ASD and ADHD. 

Dr. Tye and colleagues tested this approach in a cohort of boys aged 8-13 years diagnosed with ASD and/or ADHD, measuring EEG while the children did various continuous performance tasks to assess changes in brain activity. Examining P3 amplitude (event-related potential components) they found that children with ADHD or ADHD+ASD showed an attenuated amplitude of the P3, compared with typically developing children and those with ASD.

“This suggests children with an ADHD diagnosis exhibited reduced inhibitory control,” said Dr. Tye. In contrast, children with ASD showed reduced conflict monitoring as indexed by altered N2 amplitude across task conditions.

These, and other studies conducted by Dr. Tye and colleagues indicate that children with ADHD show reduced neural responses during attentional processing, whereas autistic children show typical neural responses, supporting specific profiles.

“Autistic children with a diagnosis of ADHD appear to show the unique patterns of neural responses of autism and ADHD, supporting an additive co-occurrence rather than a distinct condition. This contributes to identification of transdiagnostic subgroups within neurodevelopmental conditions for targeting of personalized intervention, and suggests that children with co-occurring autism and ADHD require support for both conditions,” said Dr. Tye.

An important takeaway from all of these findings is “we can’t look just at how someone does overall on a single test,” said Dr. Karalunas in an interview. “There is a tremendous amount of variability between people who have the same diagnosis, and our research really needs to account for this.”

While it’s possible that residual effects of SARS-CoV-2 could lead to an eruption of attention-deficit/hyperactivity disorder (ADHD) cases, a debate at the World Congress on ADHD – Virtual Event underscored the fact that this is still a hypothesis. The bottom line is there needs to be more data, said Luis Augusto Rohde, MD, PhD, cochair of the congress’ scientific program committee and moderator of the session, “Residual effects of the 2019 pandemic will mirror the 1918 pandemic: Will we have lots of new ADHD cases?”

Considering the current pattern of the pandemic, there is not enough evidence for this to be a concern, Dr. Rohde said in an interview.

James Swanson, PhD, professor of pediatrics at the University of California, Irvine, opined that biological co-effects of COVID-19 are likely to have selective effects in children that may produce symptoms representative of ADHD. Using the 1918 Spanish flu pandemic as a historical reference, he estimated that COVID-19 would produce 5 million individuals with new-onset symptoms related to ADHD. “If these cases meet DSM-5 or ICD-11 criteria, there will be lots of new ADHD cases,” he predicted.

David Coghill, MD, a professor of child adolescent mental health at the University of Melbourne, observed that the sums Dr. Swanson presented “are based on maxing out the potential rather than looking at the sums more realistically.”
 

Could the 1918 pandemic offer clues?

In a commentary, Dr. Swanson and Nora D. Volkow, MD, wrote about “lessons learned” from the 1918 pandemic, and how residual sequelae in that era led to a condition labeled hyperkinetic syndrome in children. “It may be worthwhile to consider the hypothesis that the COVID-19 pandemic may result in a novel etiologic subtype of ADHD that clinicians may recognize in patients in the future,” wrote the commentators. 

In survivors of the 1918 pandemic, brain inflammation or encephalitis sometimes emerged as residual sequelae, said Dr. Swanson. In some adult cases, these symptoms were diagnosed as “encephalitis lethargica” (EL) and were associated with Parkinson’s disease. In 1930, based on patients evaluated after 1918, researchers Franz Kramer and Hans Pollnow at Charité Hospital in Berlin described the behavioral manifestation of EL in children as hyperkinetic syndrome, a condition that was characterized by symptoms similar to the properties of ADHD: lack of concentration, insufficient goal orientation, and increased distractibility. “They even reported on autopsy cases that described brain regions that we now know are associated with ADHD from decades of brain imaging studies,” said Dr. Swanson.

COVID-19 rarely results in severe respiratory problems in children but the absolute number requiring hospitalization has accumulated and is now relatively large, said Dr. Swanson. One study of 1,695 severe COVID-19 cases in children and adolescents used MRI and detected neural effects in specific brain regions such as basal ganglia and frontal lobes that previous research had associated with ADHD. Approximately 22% of these rare but severe cases had documented neurologic involvement, and studies of affected children with mild or none of the initial respiratory symptoms of COVID-19 also detected similar selective effects in these brain regions.

A recent survey of medical records of 80 million people that identified 240,000 COVID cases (mostly adults) revealed that a third had neurological and psychiatric sequelae. Dr. Swanson also mentioned an article he wrote more than a decade ago on environmental as well as genetic factors that resulted in etiologic subtypes of ADHD, which provided a model for the impact of COVID-19 on specific brain regions that are associated with ADHD.

So far, the COVID-19 pandemic has produced 150 million cases worldwide and there are about 100 million survivors, setting an estimate of a maximum number of cases with residual sequelae. “I think that severe COVID-19 will probably be related to severe residual sequelae, and that mild or asymptomatic COVID-19 may be associated with less severe residual sequelae, which may resemble ADHD” said Dr. Swanson. If one-third of the cases manifest in some neurologic or psychiatric systems, this means 27 million would have residual sequelae. If 20% have impaired concentration or brain fog, this could result in about 5 million ADHD cases, he said. 
 

Estimates aren’t evidence

The Swanson/Volkow commentary contains a lot of references to “might, could, and may,” said Dr. Coghill. While it’s true that COVID-19 could produce a novel etiologic subtype of ADHD, “the point here is at the moment, all of this is based on hypotheses,” he said.

The Spanish flu did produce mental health consequences – survivors reported depression, sleep disturbances, mental distraction, dizziness, and difficulties coping at work. In the United States, flu death rates from 1918 to 1920 were directly attributed to suicide rates. Unfortunately, these impacts weren’t widely researched, said Dr. Coghill.

It also seems clear that the 1918 Spanish flu outbreak was associated with significant neurological consequences, said Dr. Coghill. By 1919 and 1920, physicians and researchers in the United Kingdom were reporting increases in a variety of symptoms among some patients recovering from flu, such as neuropathy, neurasthenia, meningitis, degenerative changes in nerve cells, and a decline in visual acuity.

The EL cases Dr. Swanson mentioned did coincide with and reach epidemic proportions alongside the Spanish flu. “But still, a causal relationship is far from proven,” said Dr. Coghill.

Sol Levy, MD, described a “disease of criminals” following the 1918 pandemic, in which patients exhibited a high degree of general hyperkinesis, a difficulty in maintaining quiet attitudes, abruptness and clumsiness, and “explosive motor release of all voluntarily inhibited activities.”

However, these impairments suggest a much broader presentation typically seen in ADHD, noted Dr. Coghill.

Neurological complications occur more commonly than initially thought in severe COVID-19, with estimates ranging from 36% to 84%. But in a systematic review of neuropsychiatric complications of severe coronavirus infection, researchers found few psychiatric sequelae of these infections. While they did mention impaired concentration and difficulties with emotional ability, it’s very important to remember that these conditions “are cardinal symptoms of a wide range of psychiatric disorders,” said Dr. Coghill.

Overall, more neurological and neuropsychiatric symptoms largely confine to those with severe COVID-19, meaning they’re much less likely to occur in children and young adults, he said.

If there are severe effects of COVID-19, Dr. Swanson countered that “they might have more ADHD than the complex residual effects [Dr. Coghill] described. I hope that he’s right, but I do think there will be biological co-effects of COVID-19 that will produce symptoms that are more ADHD than other neurological disorders.”
 

Epigenetic effects

Researchers are now seeing transgenerational and intergenerational effects of potential infection. “So I certainly back high-quality studies looking at the effects of maternal and paternal infection on offspring,” said Dr. Coghill. Establishing clinical cohort studies to follow up on this population would be essential in understanding the risks of SARS-CoV-2. “That might be one way we’ll see an increase in ADHD,” said Dr. Coghill.

The reality is COVID-19 hasn’t been around for that long, and current knowledge about it is limited, he said. Rapid publications, cross-sectional or retrospective data, and poor methodological quality and rigor make generalizability difficult. In addition, limited testing and detection probably underestimate prevalence of neurological and neuropsychiatric complications.

“If history teaches us anything, it is that we should always be measured in how we glean lessons from the past. So let’s not get ahead of ourselves,” he cautioned.

An informal, post-discussion survey of session participants revealed that a slight majority – 55%-60% – expected residual effects of COVID-19 to lead to more ADHD, compared to 40%-45% who didn’t think this would happen.

Dr. Swanson has two patents: (PIXA4), which uses a “time-of-flight” camera to measure growth on infants, and a provisional patent on the mechanism of tolerance to stimulant medication (PATSMTA). Dr. Coghill worked for several pharmaceutical companies but had no disclosures relevant to this debate.

While it’s possible that residual effects of SARS-CoV-2 could lead to an eruption of attention-deficit/hyperactivity disorder (ADHD) cases, a debate at the World Congress on ADHD – Virtual Event underscored the fact that this is still a hypothesis. The bottom line is there needs to be more data, said Luis Augusto Rohde, MD, PhD, cochair of the congress’ scientific program committee and moderator of the session, “Residual effects of the 2019 pandemic will mirror the 1918 pandemic: Will we have lots of new ADHD cases?”

Considering the current pattern of the pandemic, there is not enough evidence for this to be a concern, Dr. Rohde said in an interview.

James Swanson, PhD, professor of pediatrics at the University of California, Irvine, opined that biological co-effects of COVID-19 are likely to have selective effects in children that may produce symptoms representative of ADHD. Using the 1918 Spanish flu pandemic as a historical reference, he estimated that COVID-19 would produce 5 million individuals with new-onset symptoms related to ADHD. “If these cases meet DSM-5 or ICD-11 criteria, there will be lots of new ADHD cases,” he predicted.

David Coghill, MD, a professor of child adolescent mental health at the University of Melbourne, observed that the sums Dr. Swanson presented “are based on maxing out the potential rather than looking at the sums more realistically.”
 

Could the 1918 pandemic offer clues?

In a commentary, Dr. Swanson and Nora D. Volkow, MD, wrote about “lessons learned” from the 1918 pandemic, and how residual sequelae in that era led to a condition labeled hyperkinetic syndrome in children. “It may be worthwhile to consider the hypothesis that the COVID-19 pandemic may result in a novel etiologic subtype of ADHD that clinicians may recognize in patients in the future,” wrote the commentators. 

In survivors of the 1918 pandemic, brain inflammation or encephalitis sometimes emerged as residual sequelae, said Dr. Swanson. In some adult cases, these symptoms were diagnosed as “encephalitis lethargica” (EL) and were associated with Parkinson’s disease. In 1930, based on patients evaluated after 1918, researchers Franz Kramer and Hans Pollnow at Charité Hospital in Berlin described the behavioral manifestation of EL in children as hyperkinetic syndrome, a condition that was characterized by symptoms similar to the properties of ADHD: lack of concentration, insufficient goal orientation, and increased distractibility. “They even reported on autopsy cases that described brain regions that we now know are associated with ADHD from decades of brain imaging studies,” said Dr. Swanson.

COVID-19 rarely results in severe respiratory problems in children but the absolute number requiring hospitalization has accumulated and is now relatively large, said Dr. Swanson. One study of 1,695 severe COVID-19 cases in children and adolescents used MRI and detected neural effects in specific brain regions such as basal ganglia and frontal lobes that previous research had associated with ADHD. Approximately 22% of these rare but severe cases had documented neurologic involvement, and studies of affected children with mild or none of the initial respiratory symptoms of COVID-19 also detected similar selective effects in these brain regions.

A recent survey of medical records of 80 million people that identified 240,000 COVID cases (mostly adults) revealed that a third had neurological and psychiatric sequelae. Dr. Swanson also mentioned an article he wrote more than a decade ago on environmental as well as genetic factors that resulted in etiologic subtypes of ADHD, which provided a model for the impact of COVID-19 on specific brain regions that are associated with ADHD.

So far, the COVID-19 pandemic has produced 150 million cases worldwide and there are about 100 million survivors, setting an estimate of a maximum number of cases with residual sequelae. “I think that severe COVID-19 will probably be related to severe residual sequelae, and that mild or asymptomatic COVID-19 may be associated with less severe residual sequelae, which may resemble ADHD” said Dr. Swanson. If one-third of the cases manifest in some neurologic or psychiatric systems, this means 27 million would have residual sequelae. If 20% have impaired concentration or brain fog, this could result in about 5 million ADHD cases, he said. 
 

Estimates aren’t evidence

The Swanson/Volkow commentary contains a lot of references to “might, could, and may,” said Dr. Coghill. While it’s true that COVID-19 could produce a novel etiologic subtype of ADHD, “the point here is at the moment, all of this is based on hypotheses,” he said.

The Spanish flu did produce mental health consequences – survivors reported depression, sleep disturbances, mental distraction, dizziness, and difficulties coping at work. In the United States, flu death rates from 1918 to 1920 were directly attributed to suicide rates. Unfortunately, these impacts weren’t widely researched, said Dr. Coghill.

It also seems clear that the 1918 Spanish flu outbreak was associated with significant neurological consequences, said Dr. Coghill. By 1919 and 1920, physicians and researchers in the United Kingdom were reporting increases in a variety of symptoms among some patients recovering from flu, such as neuropathy, neurasthenia, meningitis, degenerative changes in nerve cells, and a decline in visual acuity.

The EL cases Dr. Swanson mentioned did coincide with and reach epidemic proportions alongside the Spanish flu. “But still, a causal relationship is far from proven,” said Dr. Coghill.

Sol Levy, MD, described a “disease of criminals” following the 1918 pandemic, in which patients exhibited a high degree of general hyperkinesis, a difficulty in maintaining quiet attitudes, abruptness and clumsiness, and “explosive motor release of all voluntarily inhibited activities.”

However, these impairments suggest a much broader presentation typically seen in ADHD, noted Dr. Coghill.

Neurological complications occur more commonly than initially thought in severe COVID-19, with estimates ranging from 36% to 84%. But in a systematic review of neuropsychiatric complications of severe coronavirus infection, researchers found few psychiatric sequelae of these infections. While they did mention impaired concentration and difficulties with emotional ability, it’s very important to remember that these conditions “are cardinal symptoms of a wide range of psychiatric disorders,” said Dr. Coghill.

Overall, more neurological and neuropsychiatric symptoms largely confine to those with severe COVID-19, meaning they’re much less likely to occur in children and young adults, he said.

If there are severe effects of COVID-19, Dr. Swanson countered that “they might have more ADHD than the complex residual effects [Dr. Coghill] described. I hope that he’s right, but I do think there will be biological co-effects of COVID-19 that will produce symptoms that are more ADHD than other neurological disorders.”
 

Epigenetic effects

Researchers are now seeing transgenerational and intergenerational effects of potential infection. “So I certainly back high-quality studies looking at the effects of maternal and paternal infection on offspring,” said Dr. Coghill. Establishing clinical cohort studies to follow up on this population would be essential in understanding the risks of SARS-CoV-2. “That might be one way we’ll see an increase in ADHD,” said Dr. Coghill.

The reality is COVID-19 hasn’t been around for that long, and current knowledge about it is limited, he said. Rapid publications, cross-sectional or retrospective data, and poor methodological quality and rigor make generalizability difficult. In addition, limited testing and detection probably underestimate prevalence of neurological and neuropsychiatric complications.

“If history teaches us anything, it is that we should always be measured in how we glean lessons from the past. So let’s not get ahead of ourselves,” he cautioned.

An informal, post-discussion survey of session participants revealed that a slight majority – 55%-60% – expected residual effects of COVID-19 to lead to more ADHD, compared to 40%-45% who didn’t think this would happen.

Dr. Swanson has two patents: (PIXA4), which uses a “time-of-flight” camera to measure growth on infants, and a provisional patent on the mechanism of tolerance to stimulant medication (PATSMTA). Dr. Coghill worked for several pharmaceutical companies but had no disclosures relevant to this debate.

While it’s possible that residual effects of SARS-CoV-2 could lead to an eruption of attention-deficit/hyperactivity disorder (ADHD) cases, a debate at the World Congress on ADHD – Virtual Event underscored the fact that this is still a hypothesis. The bottom line is there needs to be more data, said Luis Augusto Rohde, MD, PhD, cochair of the congress’ scientific program committee and moderator of the session, “Residual effects of the 2019 pandemic will mirror the 1918 pandemic: Will we have lots of new ADHD cases?”

Considering the current pattern of the pandemic, there is not enough evidence for this to be a concern, Dr. Rohde said in an interview.

James Swanson, PhD, professor of pediatrics at the University of California, Irvine, opined that biological co-effects of COVID-19 are likely to have selective effects in children that may produce symptoms representative of ADHD. Using the 1918 Spanish flu pandemic as a historical reference, he estimated that COVID-19 would produce 5 million individuals with new-onset symptoms related to ADHD. “If these cases meet DSM-5 or ICD-11 criteria, there will be lots of new ADHD cases,” he predicted.

David Coghill, MD, a professor of child adolescent mental health at the University of Melbourne, observed that the sums Dr. Swanson presented “are based on maxing out the potential rather than looking at the sums more realistically.”
 

Could the 1918 pandemic offer clues?

In a commentary, Dr. Swanson and Nora D. Volkow, MD, wrote about “lessons learned” from the 1918 pandemic, and how residual sequelae in that era led to a condition labeled hyperkinetic syndrome in children. “It may be worthwhile to consider the hypothesis that the COVID-19 pandemic may result in a novel etiologic subtype of ADHD that clinicians may recognize in patients in the future,” wrote the commentators. 

In survivors of the 1918 pandemic, brain inflammation or encephalitis sometimes emerged as residual sequelae, said Dr. Swanson. In some adult cases, these symptoms were diagnosed as “encephalitis lethargica” (EL) and were associated with Parkinson’s disease. In 1930, based on patients evaluated after 1918, researchers Franz Kramer and Hans Pollnow at Charité Hospital in Berlin described the behavioral manifestation of EL in children as hyperkinetic syndrome, a condition that was characterized by symptoms similar to the properties of ADHD: lack of concentration, insufficient goal orientation, and increased distractibility. “They even reported on autopsy cases that described brain regions that we now know are associated with ADHD from decades of brain imaging studies,” said Dr. Swanson.

COVID-19 rarely results in severe respiratory problems in children but the absolute number requiring hospitalization has accumulated and is now relatively large, said Dr. Swanson. One study of 1,695 severe COVID-19 cases in children and adolescents used MRI and detected neural effects in specific brain regions such as basal ganglia and frontal lobes that previous research had associated with ADHD. Approximately 22% of these rare but severe cases had documented neurologic involvement, and studies of affected children with mild or none of the initial respiratory symptoms of COVID-19 also detected similar selective effects in these brain regions.

A recent survey of medical records of 80 million people that identified 240,000 COVID cases (mostly adults) revealed that a third had neurological and psychiatric sequelae. Dr. Swanson also mentioned an article he wrote more than a decade ago on environmental as well as genetic factors that resulted in etiologic subtypes of ADHD, which provided a model for the impact of COVID-19 on specific brain regions that are associated with ADHD.

So far, the COVID-19 pandemic has produced 150 million cases worldwide and there are about 100 million survivors, setting an estimate of a maximum number of cases with residual sequelae. “I think that severe COVID-19 will probably be related to severe residual sequelae, and that mild or asymptomatic COVID-19 may be associated with less severe residual sequelae, which may resemble ADHD” said Dr. Swanson. If one-third of the cases manifest in some neurologic or psychiatric systems, this means 27 million would have residual sequelae. If 20% have impaired concentration or brain fog, this could result in about 5 million ADHD cases, he said. 
 

Estimates aren’t evidence

The Swanson/Volkow commentary contains a lot of references to “might, could, and may,” said Dr. Coghill. While it’s true that COVID-19 could produce a novel etiologic subtype of ADHD, “the point here is at the moment, all of this is based on hypotheses,” he said.

The Spanish flu did produce mental health consequences – survivors reported depression, sleep disturbances, mental distraction, dizziness, and difficulties coping at work. In the United States, flu death rates from 1918 to 1920 were directly attributed to suicide rates. Unfortunately, these impacts weren’t widely researched, said Dr. Coghill.

It also seems clear that the 1918 Spanish flu outbreak was associated with significant neurological consequences, said Dr. Coghill. By 1919 and 1920, physicians and researchers in the United Kingdom were reporting increases in a variety of symptoms among some patients recovering from flu, such as neuropathy, neurasthenia, meningitis, degenerative changes in nerve cells, and a decline in visual acuity.

The EL cases Dr. Swanson mentioned did coincide with and reach epidemic proportions alongside the Spanish flu. “But still, a causal relationship is far from proven,” said Dr. Coghill.

Sol Levy, MD, described a “disease of criminals” following the 1918 pandemic, in which patients exhibited a high degree of general hyperkinesis, a difficulty in maintaining quiet attitudes, abruptness and clumsiness, and “explosive motor release of all voluntarily inhibited activities.”

However, these impairments suggest a much broader presentation typically seen in ADHD, noted Dr. Coghill.

Neurological complications occur more commonly than initially thought in severe COVID-19, with estimates ranging from 36% to 84%. But in a systematic review of neuropsychiatric complications of severe coronavirus infection, researchers found few psychiatric sequelae of these infections. While they did mention impaired concentration and difficulties with emotional ability, it’s very important to remember that these conditions “are cardinal symptoms of a wide range of psychiatric disorders,” said Dr. Coghill.

Overall, more neurological and neuropsychiatric symptoms largely confine to those with severe COVID-19, meaning they’re much less likely to occur in children and young adults, he said.

If there are severe effects of COVID-19, Dr. Swanson countered that “they might have more ADHD than the complex residual effects [Dr. Coghill] described. I hope that he’s right, but I do think there will be biological co-effects of COVID-19 that will produce symptoms that are more ADHD than other neurological disorders.”
 

Epigenetic effects

Researchers are now seeing transgenerational and intergenerational effects of potential infection. “So I certainly back high-quality studies looking at the effects of maternal and paternal infection on offspring,” said Dr. Coghill. Establishing clinical cohort studies to follow up on this population would be essential in understanding the risks of SARS-CoV-2. “That might be one way we’ll see an increase in ADHD,” said Dr. Coghill.

The reality is COVID-19 hasn’t been around for that long, and current knowledge about it is limited, he said. Rapid publications, cross-sectional or retrospective data, and poor methodological quality and rigor make generalizability difficult. In addition, limited testing and detection probably underestimate prevalence of neurological and neuropsychiatric complications.

“If history teaches us anything, it is that we should always be measured in how we glean lessons from the past. So let’s not get ahead of ourselves,” he cautioned.

An informal, post-discussion survey of session participants revealed that a slight majority – 55%-60% – expected residual effects of COVID-19 to lead to more ADHD, compared to 40%-45% who didn’t think this would happen.

Dr. Swanson has two patents: (PIXA4), which uses a “time-of-flight” camera to measure growth on infants, and a provisional patent on the mechanism of tolerance to stimulant medication (PATSMTA). Dr. Coghill worked for several pharmaceutical companies but had no disclosures relevant to this debate.

William of Ockham would have been proud because, at this year’s American Gastroenterological Association’s Shark Tank pitch competition, one product clearly demonstrated Ockham’s razor – that sometimes the simplest solution is best – and came away as the winner at the 2021 AGA Tech Summit sponsored by the AGA Center for GI Innovation and Technology.

Courtesy Dr. Toufic Kachaamy

Out of five innovative products, ranging from an educational app to a high-tech anorectal sensor, all aimed at improving outcomes in patients with gastrointestinal disorders, the winner was ... drumroll please ...

A needle.

That’s it. A needle. But not like any other needle.


 

Winner: Toufic Kachaamy, MD, FASGE, AGAF – An EUS-guided access needle

This EUS-guided access needle, invented by Dr. Kachaamy, enterprise clinical leader at Cancer Treatment Centers of America, Phoenix, is a simple device that overcomes a longstanding challenge presented by endoscopic retrograde cholangiopancreatography (ERCP): biliary access.

Many “ERCPs are considered difficult, and sometimes fail, depending on the center and the endoscopist,” Dr. Kachaamy said during a virtual presentation. “Most failures are due to failed initial access to the bile duct.”

Indeed, one study cited a failure rate in ductal cannulation of 5%-15% even among experienced hands.

Failure can have several consequences, Dr. Kachaamy noted, including increased complications, higher cost, delayed care, longer hospitalization, and greater likelihood of patient transfer.

He went on to explain why biliary access can be so challenging and how this EUS-guided access needle helps address these issues.

“[The] two main limitations [during endoscopic ultrasound–guided biliary access] are directing the wire into the narrowed areas and the wire shearing as we are manipulating the wire to get it to where we want it,” Dr. Kachaamy said. “[This EUS-guided access needle] is a 19-22 gauge, rotatable needle with a smooth, side exit for the wire to allow wire manipulation and direction without shearing.”

Dr. Kachaamy highlighted the simple design, which will keep the production cost below $300 per unit, and suggested that failed ERCPs are just the first potential indication of many. Future uses may include gallbladder access, peri-GI collection, gastrojejunostomy, and others.

In an interview, Dr. Kachaamy reacted to the win, which follows 2 years of collaborative development with Cancer Treatment Centers of America.

“For people who are innovators, there’s nothing that feels more rewarding than their ideas being recognized as adding something to the field and potentially helping people and patients,” Dr. Kachaamy said. “So [this is] very, very, very exciting. Very rewarding. Pride would probably be the best way I’d describe it.”

Dr. Kachaamy anticipates that this EUS-guided access needle will be commercially available within 1-2 years, pending regulatory approval. In the meantime, he and his colleagues are seeking a strategic partner.


 

A shark speaks

V. Raman Muthusamy, MD, AGAF, immediate past chair of the AGA Center for GI Innovation and Technology and director of endoscopy at UCLA Health System, moderated the Shark Tank session, calling it “the highlight” of the AGA Tech Summit.

Dr. Muthusamy and four other “sharks,” including a gastroenterologist, venture capitalist, regulatory device reviewer, and entrepreneur, scored the pitches using three equally weighted categories: the quality of the pitch, the level of innovation and impact on the field, and the quality of the business plan and overall feasibility.

“We saw a full spectrum [of innovations],” Dr. Muthusamy said. “I think it was an enjoyable session.”

Behind closed doors, the sharks narrowed the field to two top contenders. Ultimately, however, there could be only one winner: Dr. Kachaamy. Their decision aligned with a “Fan Favorite” audience poll.

“A lot of [Dr. Kachaamy’s win] had to do with the potential applications and commonality of the problem,” Dr. Muthusamy said in an interview. He highlighted how the EUS-guided access needle allows for an immediate response to ERCP failure without the need for a second procedure.

Dr. Muthusamy also noted that several product designs previously failed to achieve what the EUS-guided access needle has the potential to do.

“I think the feeling was that this seemed to be a way that may address some of the limitations and challenges that we’ve had with earlier [attempts at solving this problem],” Dr. Muthusamy said.

For innovators who didn’t make the cut this year, or those with products still in development, Dr. Muthusamy suggested applying next year.

“We encourage our colleagues and members of the AGA to continue to apply to this program,” Dr. Muthusamy said.
 

Other fish in the sea

Four other innovators entered the AGA Shark Tank this year. Here are snippets of their pitches:

Hans Gregersen, MD, PhD, MPH – Fecobionics
“Fecobionics is a simulated electronic stool with the consistency and shape of normal stool,” Dr. Gregersen said.

The balloon device, which contains multiple sensors, provides “real-time, quantitative, and mechanistic insights by simulating defecation.”

“It ... is inserted into the rectum,” Dr. Gregersen said. “It measures multiple pressures; it has gyroscopes that measure orientation; we can compute the bending of the device; and we can calculate the shape of the device.”

According to Dr. Gregersen, Fecobionics has “diagnostic potential for patients with fecal incontinence and for subtyping patients with constipation.” He highlighted fewer false-positives than current technology, alongside greater efficiency and lower cost.

Dr. Gregersen is a research professor at California Medical Innovations Institute, San Diego.

Mary J. Pattison, RN – Trans-Abdominal Gastric Surgical System (TAGSS)
TAGSS is a trans-abdominal gastric access device that “represents a novel and exciting means to address multiple gastrointestinal conditions that are without a standardized approach,” Ms. Pattison said. “Placed as simply as a [percutaneous endoscopic gastrostomy tube], TAGSS offers disruptive technology to address [gastroesophageal reflux disease], fundoplication, achalasia, gastroparesis, gastric tumors, and even obesity in a safe, efficient, and cost effective manner. TAGSS offers the first true hybrid approach for endoscopic/laparoscopic collaboration.”

Ms. Pattison is a nurse clinician and endoscopy assistant at WestGlen GI Consultants, Weston, Mo.

Pankaj Rajvanshi, MD, FAASLD – Healthswim App
“At this time, most patient education is provided by Dr. Google,” Dr. Rajvanshi said, “and we want to change that. We have built a platform which allows you, the physician, to create custom, curated, credible content that can be delivered seamlessly to your patients on an ongoing basis.”

Through the Healthswim app, patients subscribe to their providers, allowing access physician-approved content. Subscribers also receive provider updates through their social media feeds.

Dr. Rajvanshi is a gastroenterologist at Swedish Medical Center, Seattle.

Ali S. Karakurum, MD, FACP, FACG – A Device for Removal of Esophageal Food Impactions
“I would like to propose a device which consists of a clear overtube, a collapsible plastic cylindrical basket secured to the distal end of the overtube ... and a snare wire attached to the distal end of the basket which is controlled by the snare handle externally,” Dr. Karakurum said. “The device is ... gradually advanced over the scope for the basket to encompass the food bolus under direct visualization. Once the food bolus is within the basket, the wire loop at the end of the basket is closed via the external handle, securing the food bolus in the basket for safe removal.”

Dr. Karakurum is a gastroenterologist at Advanced Gastroenterology & Endoscopy, Port Jefferson, N.Y.

This article was updated 5/14/21.

William of Ockham would have been proud because, at this year’s American Gastroenterological Association’s Shark Tank pitch competition, one product clearly demonstrated Ockham’s razor – that sometimes the simplest solution is best – and came away as the winner at the 2021 AGA Tech Summit sponsored by the AGA Center for GI Innovation and Technology.

Courtesy Dr. Toufic Kachaamy

Out of five innovative products, ranging from an educational app to a high-tech anorectal sensor, all aimed at improving outcomes in patients with gastrointestinal disorders, the winner was ... drumroll please ...

A needle.

That’s it. A needle. But not like any other needle.


 

Winner: Toufic Kachaamy, MD, FASGE, AGAF – An EUS-guided access needle

This EUS-guided access needle, invented by Dr. Kachaamy, enterprise clinical leader at Cancer Treatment Centers of America, Phoenix, is a simple device that overcomes a longstanding challenge presented by endoscopic retrograde cholangiopancreatography (ERCP): biliary access.

Many “ERCPs are considered difficult, and sometimes fail, depending on the center and the endoscopist,” Dr. Kachaamy said during a virtual presentation. “Most failures are due to failed initial access to the bile duct.”

Indeed, one study cited a failure rate in ductal cannulation of 5%-15% even among experienced hands.

Failure can have several consequences, Dr. Kachaamy noted, including increased complications, higher cost, delayed care, longer hospitalization, and greater likelihood of patient transfer.

He went on to explain why biliary access can be so challenging and how this EUS-guided access needle helps address these issues.

“[The] two main limitations [during endoscopic ultrasound–guided biliary access] are directing the wire into the narrowed areas and the wire shearing as we are manipulating the wire to get it to where we want it,” Dr. Kachaamy said. “[This EUS-guided access needle] is a 19-22 gauge, rotatable needle with a smooth, side exit for the wire to allow wire manipulation and direction without shearing.”

Dr. Kachaamy highlighted the simple design, which will keep the production cost below $300 per unit, and suggested that failed ERCPs are just the first potential indication of many. Future uses may include gallbladder access, peri-GI collection, gastrojejunostomy, and others.

In an interview, Dr. Kachaamy reacted to the win, which follows 2 years of collaborative development with Cancer Treatment Centers of America.

“For people who are innovators, there’s nothing that feels more rewarding than their ideas being recognized as adding something to the field and potentially helping people and patients,” Dr. Kachaamy said. “So [this is] very, very, very exciting. Very rewarding. Pride would probably be the best way I’d describe it.”

Dr. Kachaamy anticipates that this EUS-guided access needle will be commercially available within 1-2 years, pending regulatory approval. In the meantime, he and his colleagues are seeking a strategic partner.


 

A shark speaks

V. Raman Muthusamy, MD, AGAF, immediate past chair of the AGA Center for GI Innovation and Technology and director of endoscopy at UCLA Health System, moderated the Shark Tank session, calling it “the highlight” of the AGA Tech Summit.

Dr. Muthusamy and four other “sharks,” including a gastroenterologist, venture capitalist, regulatory device reviewer, and entrepreneur, scored the pitches using three equally weighted categories: the quality of the pitch, the level of innovation and impact on the field, and the quality of the business plan and overall feasibility.

“We saw a full spectrum [of innovations],” Dr. Muthusamy said. “I think it was an enjoyable session.”

Behind closed doors, the sharks narrowed the field to two top contenders. Ultimately, however, there could be only one winner: Dr. Kachaamy. Their decision aligned with a “Fan Favorite” audience poll.

“A lot of [Dr. Kachaamy’s win] had to do with the potential applications and commonality of the problem,” Dr. Muthusamy said in an interview. He highlighted how the EUS-guided access needle allows for an immediate response to ERCP failure without the need for a second procedure.

Dr. Muthusamy also noted that several product designs previously failed to achieve what the EUS-guided access needle has the potential to do.

“I think the feeling was that this seemed to be a way that may address some of the limitations and challenges that we’ve had with earlier [attempts at solving this problem],” Dr. Muthusamy said.

For innovators who didn’t make the cut this year, or those with products still in development, Dr. Muthusamy suggested applying next year.

“We encourage our colleagues and members of the AGA to continue to apply to this program,” Dr. Muthusamy said.
 

Other fish in the sea

Four other innovators entered the AGA Shark Tank this year. Here are snippets of their pitches:

Hans Gregersen, MD, PhD, MPH – Fecobionics
“Fecobionics is a simulated electronic stool with the consistency and shape of normal stool,” Dr. Gregersen said.

The balloon device, which contains multiple sensors, provides “real-time, quantitative, and mechanistic insights by simulating defecation.”

“It ... is inserted into the rectum,” Dr. Gregersen said. “It measures multiple pressures; it has gyroscopes that measure orientation; we can compute the bending of the device; and we can calculate the shape of the device.”

According to Dr. Gregersen, Fecobionics has “diagnostic potential for patients with fecal incontinence and for subtyping patients with constipation.” He highlighted fewer false-positives than current technology, alongside greater efficiency and lower cost.

Dr. Gregersen is a research professor at California Medical Innovations Institute, San Diego.

Mary J. Pattison, RN – Trans-Abdominal Gastric Surgical System (TAGSS)
TAGSS is a trans-abdominal gastric access device that “represents a novel and exciting means to address multiple gastrointestinal conditions that are without a standardized approach,” Ms. Pattison said. “Placed as simply as a [percutaneous endoscopic gastrostomy tube], TAGSS offers disruptive technology to address [gastroesophageal reflux disease], fundoplication, achalasia, gastroparesis, gastric tumors, and even obesity in a safe, efficient, and cost effective manner. TAGSS offers the first true hybrid approach for endoscopic/laparoscopic collaboration.”

Ms. Pattison is a nurse clinician and endoscopy assistant at WestGlen GI Consultants, Weston, Mo.

Pankaj Rajvanshi, MD, FAASLD – Healthswim App
“At this time, most patient education is provided by Dr. Google,” Dr. Rajvanshi said, “and we want to change that. We have built a platform which allows you, the physician, to create custom, curated, credible content that can be delivered seamlessly to your patients on an ongoing basis.”

Through the Healthswim app, patients subscribe to their providers, allowing access physician-approved content. Subscribers also receive provider updates through their social media feeds.

Dr. Rajvanshi is a gastroenterologist at Swedish Medical Center, Seattle.

Ali S. Karakurum, MD, FACP, FACG – A Device for Removal of Esophageal Food Impactions
“I would like to propose a device which consists of a clear overtube, a collapsible plastic cylindrical basket secured to the distal end of the overtube ... and a snare wire attached to the distal end of the basket which is controlled by the snare handle externally,” Dr. Karakurum said. “The device is ... gradually advanced over the scope for the basket to encompass the food bolus under direct visualization. Once the food bolus is within the basket, the wire loop at the end of the basket is closed via the external handle, securing the food bolus in the basket for safe removal.”

Dr. Karakurum is a gastroenterologist at Advanced Gastroenterology & Endoscopy, Port Jefferson, N.Y.

This article was updated 5/14/21.

William of Ockham would have been proud because, at this year’s American Gastroenterological Association’s Shark Tank pitch competition, one product clearly demonstrated Ockham’s razor – that sometimes the simplest solution is best – and came away as the winner at the 2021 AGA Tech Summit sponsored by the AGA Center for GI Innovation and Technology.

Courtesy Dr. Toufic Kachaamy

Out of five innovative products, ranging from an educational app to a high-tech anorectal sensor, all aimed at improving outcomes in patients with gastrointestinal disorders, the winner was ... drumroll please ...

A needle.

That’s it. A needle. But not like any other needle.


 

Winner: Toufic Kachaamy, MD, FASGE, AGAF – An EUS-guided access needle

This EUS-guided access needle, invented by Dr. Kachaamy, enterprise clinical leader at Cancer Treatment Centers of America, Phoenix, is a simple device that overcomes a longstanding challenge presented by endoscopic retrograde cholangiopancreatography (ERCP): biliary access.

Many “ERCPs are considered difficult, and sometimes fail, depending on the center and the endoscopist,” Dr. Kachaamy said during a virtual presentation. “Most failures are due to failed initial access to the bile duct.”

Indeed, one study cited a failure rate in ductal cannulation of 5%-15% even among experienced hands.

Failure can have several consequences, Dr. Kachaamy noted, including increased complications, higher cost, delayed care, longer hospitalization, and greater likelihood of patient transfer.

He went on to explain why biliary access can be so challenging and how this EUS-guided access needle helps address these issues.

“[The] two main limitations [during endoscopic ultrasound–guided biliary access] are directing the wire into the narrowed areas and the wire shearing as we are manipulating the wire to get it to where we want it,” Dr. Kachaamy said. “[This EUS-guided access needle] is a 19-22 gauge, rotatable needle with a smooth, side exit for the wire to allow wire manipulation and direction without shearing.”

Dr. Kachaamy highlighted the simple design, which will keep the production cost below $300 per unit, and suggested that failed ERCPs are just the first potential indication of many. Future uses may include gallbladder access, peri-GI collection, gastrojejunostomy, and others.

In an interview, Dr. Kachaamy reacted to the win, which follows 2 years of collaborative development with Cancer Treatment Centers of America.

“For people who are innovators, there’s nothing that feels more rewarding than their ideas being recognized as adding something to the field and potentially helping people and patients,” Dr. Kachaamy said. “So [this is] very, very, very exciting. Very rewarding. Pride would probably be the best way I’d describe it.”

Dr. Kachaamy anticipates that this EUS-guided access needle will be commercially available within 1-2 years, pending regulatory approval. In the meantime, he and his colleagues are seeking a strategic partner.


 

A shark speaks

V. Raman Muthusamy, MD, AGAF, immediate past chair of the AGA Center for GI Innovation and Technology and director of endoscopy at UCLA Health System, moderated the Shark Tank session, calling it “the highlight” of the AGA Tech Summit.

Dr. Muthusamy and four other “sharks,” including a gastroenterologist, venture capitalist, regulatory device reviewer, and entrepreneur, scored the pitches using three equally weighted categories: the quality of the pitch, the level of innovation and impact on the field, and the quality of the business plan and overall feasibility.

“We saw a full spectrum [of innovations],” Dr. Muthusamy said. “I think it was an enjoyable session.”

Behind closed doors, the sharks narrowed the field to two top contenders. Ultimately, however, there could be only one winner: Dr. Kachaamy. Their decision aligned with a “Fan Favorite” audience poll.

“A lot of [Dr. Kachaamy’s win] had to do with the potential applications and commonality of the problem,” Dr. Muthusamy said in an interview. He highlighted how the EUS-guided access needle allows for an immediate response to ERCP failure without the need for a second procedure.

Dr. Muthusamy also noted that several product designs previously failed to achieve what the EUS-guided access needle has the potential to do.

“I think the feeling was that this seemed to be a way that may address some of the limitations and challenges that we’ve had with earlier [attempts at solving this problem],” Dr. Muthusamy said.

For innovators who didn’t make the cut this year, or those with products still in development, Dr. Muthusamy suggested applying next year.

“We encourage our colleagues and members of the AGA to continue to apply to this program,” Dr. Muthusamy said.
 

Other fish in the sea

Four other innovators entered the AGA Shark Tank this year. Here are snippets of their pitches:

Hans Gregersen, MD, PhD, MPH – Fecobionics
“Fecobionics is a simulated electronic stool with the consistency and shape of normal stool,” Dr. Gregersen said.

The balloon device, which contains multiple sensors, provides “real-time, quantitative, and mechanistic insights by simulating defecation.”

“It ... is inserted into the rectum,” Dr. Gregersen said. “It measures multiple pressures; it has gyroscopes that measure orientation; we can compute the bending of the device; and we can calculate the shape of the device.”

According to Dr. Gregersen, Fecobionics has “diagnostic potential for patients with fecal incontinence and for subtyping patients with constipation.” He highlighted fewer false-positives than current technology, alongside greater efficiency and lower cost.

Dr. Gregersen is a research professor at California Medical Innovations Institute, San Diego.

Mary J. Pattison, RN – Trans-Abdominal Gastric Surgical System (TAGSS)
TAGSS is a trans-abdominal gastric access device that “represents a novel and exciting means to address multiple gastrointestinal conditions that are without a standardized approach,” Ms. Pattison said. “Placed as simply as a [percutaneous endoscopic gastrostomy tube], TAGSS offers disruptive technology to address [gastroesophageal reflux disease], fundoplication, achalasia, gastroparesis, gastric tumors, and even obesity in a safe, efficient, and cost effective manner. TAGSS offers the first true hybrid approach for endoscopic/laparoscopic collaboration.”

Ms. Pattison is a nurse clinician and endoscopy assistant at WestGlen GI Consultants, Weston, Mo.

Pankaj Rajvanshi, MD, FAASLD – Healthswim App
“At this time, most patient education is provided by Dr. Google,” Dr. Rajvanshi said, “and we want to change that. We have built a platform which allows you, the physician, to create custom, curated, credible content that can be delivered seamlessly to your patients on an ongoing basis.”

Through the Healthswim app, patients subscribe to their providers, allowing access physician-approved content. Subscribers also receive provider updates through their social media feeds.

Dr. Rajvanshi is a gastroenterologist at Swedish Medical Center, Seattle.

Ali S. Karakurum, MD, FACP, FACG – A Device for Removal of Esophageal Food Impactions
“I would like to propose a device which consists of a clear overtube, a collapsible plastic cylindrical basket secured to the distal end of the overtube ... and a snare wire attached to the distal end of the basket which is controlled by the snare handle externally,” Dr. Karakurum said. “The device is ... gradually advanced over the scope for the basket to encompass the food bolus under direct visualization. Once the food bolus is within the basket, the wire loop at the end of the basket is closed via the external handle, securing the food bolus in the basket for safe removal.”

Dr. Karakurum is a gastroenterologist at Advanced Gastroenterology & Endoscopy, Port Jefferson, N.Y.

This article was updated 5/14/21.