Exposure to per- and polyfluoroalkyl substances (PFAS) - a class of widely used synthetic chemicals dubbed “forever chemicals” - can lead to liver damage and may be a culprit in rising rates of nonalcoholic fatty liver disease (NAFLD), say the authors of a comprehensive evidence review.

They found “consistent” evidence for PFAS hepatotoxicity from rodent studies. In addition, exposure to PFAS was found to be associated with markers of liver function in observational studies in people.

The review, published online in Environmental Health Perspectives, may be the first systematic analysis of PFAS exposure and liver damage.

Possible contributor to growing NAFLD epidemic

In their analysis, the authors included 85 rodent studies and 24 epidemiologic studies, primarily involving people from the United States and largely focusing on four “legacy” PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS).

Meta-analyses of human studies found that higher levels of alanine aminotransferase were significantly associated with exposure to three of the older chemicals – PFOA, PFOS, and PFNA.

The “positive” and “convincing” associations between exposure to these synthetic chemicals and higher ALT levels suggest that exposure may contribute to the growing NAFLD epidemic, the researchers write.

Exposure to one of the chemicals, PFOA, was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in people.

In rodents, exposure to these synthetic chemicals consistently resulted in higher ALT levels and steatosis.

“The mechanism is not well understood yet, but there are a few proposed theories,” first author Elizabeth Costello, MPH, PhD student, department of population and public health sciences, University of Southern California, Los Angeles, told this news organization.

“PFAS are similar to fatty acids in chemical structure, so it’s possible that they activate some of the same receptors or otherwise interfere with fat metabolism. This might lead to inflammation or fat accumulation in the liver,” Ms. Costello explained.

People widely exposed

PFAS are ubiquitous in the environment. They have been detected in the blood of most people and have been linked to a variety of health concerns. Possible sources of PFAS exposure run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

“We are exposed to PFAS in so many ways – through water, food, and products we use. It can be very difficult for individuals to control their own exposure,” Ms. Costello commented.

“At this point, it’s important to look for ways to remove PFAS from the environment and phase them out of our products and carefully consider the safety of any replacement chemicals,” she said.

Although most of the research to date has been limited to the four older PFAS (PFOA, PFOS, PFNA, and PFHxS), there are thousands of different PFAS chemicals.

“We don’t know very much about the effects of exposure to multiple PFAS at the same time or how newer replacement PFAS might affect liver disease or other health conditions,” Ms. Costello said.

Reached for comment, Lisa B. VanWagner, MD, with Northwestern University, Chicago, said this analysis is “very interesting,” but she is also “left wondering how we could do anything since it seems from my reading that these chemicals are ubiquitous and used regularly in the environment.”

Dr. VanWagner, who was not involved in the study, said the major limitation is the small number of human studies and the high heterogeneity between studies, “meaning it is hard to come to a firm conclusion about whether what has been observed in the animal studies does truly apply to humans.

“Overall, this study provides important proof of concept for future work to look more specifically at PFAS exposure, and more specific markers of fatty liver disease and liver damage, like liver biopsy, are needed in humans,” Dr. VanWagner said.

“If data accumulate showing that these chemicals do in fact contribute to fatty liver and worsening inflammation or liver damage as a result of exposure, then public health interventions to remove or reduce use of these chemicals could have wide-ranging public health effects,” Dr. VanWagner added.

Further research needed

The authors of an invited perspective published with the study say it underscores the “urgent need for further research and for immediate and reasonable public health action.”

“This work firmly puts PFAS exposure on the list of persistent pollutants, such as polychlorinated biphenyls, that cause hepatotoxicity and whose mechanism is linked to steatosis,” write Alan Ducatman, MD. MSc, with West Virginia University School of Public Health, Morgantown, and Suzanne Fenton, PhD, MS, with the National Institute of Environmental Health Sciences, Research Triangle Park, N.C.

They say other important questions raised by this review include whether individuals who are overweight or obese and those with diabetes are more susceptible to PFAS hepatoxicity, which “replacement” or emerging PFAS can cause liver damage, and whether high doses cause different kinds of liver toxicity than low doses.

“GenX, a current replacement [chemical] for PFOA, has shown significant hepatotoxicity in several recent experimental studies, suggesting it may not be a safe replacement,” they point out.

“A significant challenge will be deciding which of the multiple metabolic pathways altered by PFAS are most important and predictive for induction of liver damage and for progression of liver disease, so that emerging PFAS may be screened for hepatotoxicity prior to entering the market,” Dr. Ducatman and Dr. Fenton conclude.

Support for this research was provided by the National Institute of Environmental Health Science, part of the National Institutes of Health, and the U.S. Department of Agriculture National Institute of Food and Agriculture. Dr. Costello, Dr. VanWagner, Dr. Ducatman, and Dr. Fenton report no relevant financial relationships.

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

Exposure to per- and polyfluoroalkyl substances (PFAS) - a class of widely used synthetic chemicals dubbed “forever chemicals” - can lead to liver damage and may be a culprit in rising rates of nonalcoholic fatty liver disease (NAFLD), say the authors of a comprehensive evidence review.

They found “consistent” evidence for PFAS hepatotoxicity from rodent studies. In addition, exposure to PFAS was found to be associated with markers of liver function in observational studies in people.

The review, published online in Environmental Health Perspectives, may be the first systematic analysis of PFAS exposure and liver damage.

Possible contributor to growing NAFLD epidemic

In their analysis, the authors included 85 rodent studies and 24 epidemiologic studies, primarily involving people from the United States and largely focusing on four “legacy” PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS).

Meta-analyses of human studies found that higher levels of alanine aminotransferase were significantly associated with exposure to three of the older chemicals – PFOA, PFOS, and PFNA.

The “positive” and “convincing” associations between exposure to these synthetic chemicals and higher ALT levels suggest that exposure may contribute to the growing NAFLD epidemic, the researchers write.

Exposure to one of the chemicals, PFOA, was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in people.

In rodents, exposure to these synthetic chemicals consistently resulted in higher ALT levels and steatosis.

“The mechanism is not well understood yet, but there are a few proposed theories,” first author Elizabeth Costello, MPH, PhD student, department of population and public health sciences, University of Southern California, Los Angeles, told this news organization.

“PFAS are similar to fatty acids in chemical structure, so it’s possible that they activate some of the same receptors or otherwise interfere with fat metabolism. This might lead to inflammation or fat accumulation in the liver,” Ms. Costello explained.

People widely exposed

PFAS are ubiquitous in the environment. They have been detected in the blood of most people and have been linked to a variety of health concerns. Possible sources of PFAS exposure run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

“We are exposed to PFAS in so many ways – through water, food, and products we use. It can be very difficult for individuals to control their own exposure,” Ms. Costello commented.

“At this point, it’s important to look for ways to remove PFAS from the environment and phase them out of our products and carefully consider the safety of any replacement chemicals,” she said.

Although most of the research to date has been limited to the four older PFAS (PFOA, PFOS, PFNA, and PFHxS), there are thousands of different PFAS chemicals.

“We don’t know very much about the effects of exposure to multiple PFAS at the same time or how newer replacement PFAS might affect liver disease or other health conditions,” Ms. Costello said.

Reached for comment, Lisa B. VanWagner, MD, with Northwestern University, Chicago, said this analysis is “very interesting,” but she is also “left wondering how we could do anything since it seems from my reading that these chemicals are ubiquitous and used regularly in the environment.”

Dr. VanWagner, who was not involved in the study, said the major limitation is the small number of human studies and the high heterogeneity between studies, “meaning it is hard to come to a firm conclusion about whether what has been observed in the animal studies does truly apply to humans.

“Overall, this study provides important proof of concept for future work to look more specifically at PFAS exposure, and more specific markers of fatty liver disease and liver damage, like liver biopsy, are needed in humans,” Dr. VanWagner said.

“If data accumulate showing that these chemicals do in fact contribute to fatty liver and worsening inflammation or liver damage as a result of exposure, then public health interventions to remove or reduce use of these chemicals could have wide-ranging public health effects,” Dr. VanWagner added.

Further research needed

The authors of an invited perspective published with the study say it underscores the “urgent need for further research and for immediate and reasonable public health action.”

“This work firmly puts PFAS exposure on the list of persistent pollutants, such as polychlorinated biphenyls, that cause hepatotoxicity and whose mechanism is linked to steatosis,” write Alan Ducatman, MD. MSc, with West Virginia University School of Public Health, Morgantown, and Suzanne Fenton, PhD, MS, with the National Institute of Environmental Health Sciences, Research Triangle Park, N.C.

They say other important questions raised by this review include whether individuals who are overweight or obese and those with diabetes are more susceptible to PFAS hepatoxicity, which “replacement” or emerging PFAS can cause liver damage, and whether high doses cause different kinds of liver toxicity than low doses.

“GenX, a current replacement [chemical] for PFOA, has shown significant hepatotoxicity in several recent experimental studies, suggesting it may not be a safe replacement,” they point out.

“A significant challenge will be deciding which of the multiple metabolic pathways altered by PFAS are most important and predictive for induction of liver damage and for progression of liver disease, so that emerging PFAS may be screened for hepatotoxicity prior to entering the market,” Dr. Ducatman and Dr. Fenton conclude.

Support for this research was provided by the National Institute of Environmental Health Science, part of the National Institutes of Health, and the U.S. Department of Agriculture National Institute of Food and Agriculture. Dr. Costello, Dr. VanWagner, Dr. Ducatman, and Dr. Fenton report no relevant financial relationships.

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

Exposure to per- and polyfluoroalkyl substances (PFAS) - a class of widely used synthetic chemicals dubbed “forever chemicals” - can lead to liver damage and may be a culprit in rising rates of nonalcoholic fatty liver disease (NAFLD), say the authors of a comprehensive evidence review.

They found “consistent” evidence for PFAS hepatotoxicity from rodent studies. In addition, exposure to PFAS was found to be associated with markers of liver function in observational studies in people.

The review, published online in Environmental Health Perspectives, may be the first systematic analysis of PFAS exposure and liver damage.

Possible contributor to growing NAFLD epidemic

In their analysis, the authors included 85 rodent studies and 24 epidemiologic studies, primarily involving people from the United States and largely focusing on four “legacy” PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS).

Meta-analyses of human studies found that higher levels of alanine aminotransferase were significantly associated with exposure to three of the older chemicals – PFOA, PFOS, and PFNA.

The “positive” and “convincing” associations between exposure to these synthetic chemicals and higher ALT levels suggest that exposure may contribute to the growing NAFLD epidemic, the researchers write.

Exposure to one of the chemicals, PFOA, was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in people.

In rodents, exposure to these synthetic chemicals consistently resulted in higher ALT levels and steatosis.

“The mechanism is not well understood yet, but there are a few proposed theories,” first author Elizabeth Costello, MPH, PhD student, department of population and public health sciences, University of Southern California, Los Angeles, told this news organization.

“PFAS are similar to fatty acids in chemical structure, so it’s possible that they activate some of the same receptors or otherwise interfere with fat metabolism. This might lead to inflammation or fat accumulation in the liver,” Ms. Costello explained.

People widely exposed

PFAS are ubiquitous in the environment. They have been detected in the blood of most people and have been linked to a variety of health concerns. Possible sources of PFAS exposure run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

“We are exposed to PFAS in so many ways – through water, food, and products we use. It can be very difficult for individuals to control their own exposure,” Ms. Costello commented.

“At this point, it’s important to look for ways to remove PFAS from the environment and phase them out of our products and carefully consider the safety of any replacement chemicals,” she said.

Although most of the research to date has been limited to the four older PFAS (PFOA, PFOS, PFNA, and PFHxS), there are thousands of different PFAS chemicals.

“We don’t know very much about the effects of exposure to multiple PFAS at the same time or how newer replacement PFAS might affect liver disease or other health conditions,” Ms. Costello said.

Reached for comment, Lisa B. VanWagner, MD, with Northwestern University, Chicago, said this analysis is “very interesting,” but she is also “left wondering how we could do anything since it seems from my reading that these chemicals are ubiquitous and used regularly in the environment.”

Dr. VanWagner, who was not involved in the study, said the major limitation is the small number of human studies and the high heterogeneity between studies, “meaning it is hard to come to a firm conclusion about whether what has been observed in the animal studies does truly apply to humans.

“Overall, this study provides important proof of concept for future work to look more specifically at PFAS exposure, and more specific markers of fatty liver disease and liver damage, like liver biopsy, are needed in humans,” Dr. VanWagner said.

“If data accumulate showing that these chemicals do in fact contribute to fatty liver and worsening inflammation or liver damage as a result of exposure, then public health interventions to remove or reduce use of these chemicals could have wide-ranging public health effects,” Dr. VanWagner added.

Further research needed

The authors of an invited perspective published with the study say it underscores the “urgent need for further research and for immediate and reasonable public health action.”

“This work firmly puts PFAS exposure on the list of persistent pollutants, such as polychlorinated biphenyls, that cause hepatotoxicity and whose mechanism is linked to steatosis,” write Alan Ducatman, MD. MSc, with West Virginia University School of Public Health, Morgantown, and Suzanne Fenton, PhD, MS, with the National Institute of Environmental Health Sciences, Research Triangle Park, N.C.

They say other important questions raised by this review include whether individuals who are overweight or obese and those with diabetes are more susceptible to PFAS hepatoxicity, which “replacement” or emerging PFAS can cause liver damage, and whether high doses cause different kinds of liver toxicity than low doses.

“GenX, a current replacement [chemical] for PFOA, has shown significant hepatotoxicity in several recent experimental studies, suggesting it may not be a safe replacement,” they point out.

“A significant challenge will be deciding which of the multiple metabolic pathways altered by PFAS are most important and predictive for induction of liver damage and for progression of liver disease, so that emerging PFAS may be screened for hepatotoxicity prior to entering the market,” Dr. Ducatman and Dr. Fenton conclude.

Support for this research was provided by the National Institute of Environmental Health Science, part of the National Institutes of Health, and the U.S. Department of Agriculture National Institute of Food and Agriculture. Dr. Costello, Dr. VanWagner, Dr. Ducatman, and Dr. Fenton report no relevant financial relationships.

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

A new deep learning system can classify hepatocellular nodular lesions (HNLs) via whole-slide images, improving risk stratification of patients and diagnostic rate of hepatocellular carcinoma (HCC), according to investigators.

While the model requires further validation, it could eventually be used to optimize accuracy and efficiency of histologic diagnoses, potentially decreasing reliance on pathologists, particularly in areas with limited access to subspecialists.

In an article published in Gastroenterology, Na Cheng, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues wrote that the “diagnostic process [for HNLs] is laborious, time-consuming, and subject to the experience of the pathologists, often with significant interobserver and intraobserver variability. ... Therefore, [an] automated analysis system is highly demanded in the pathology field, which could considerably ease the workload, speed up the diagnosis, and facilitate the in-time treatment.”

To this end, Dr. Cheng and colleagues developed the hepatocellular-nodular artificial intelligence model (HnAIM) that can scan whole-image slides to identify seven types of tissue: well-differentiated HCC, high-grade dysplastic nodules, low-grade dysplastic nodules, hepatocellular adenoma, focal nodular hyperplasia, and background tissue.

Developing and testing HnAIM was a multistep process that began with three subspecialist pathologists, who independently reviewed and classified liver slides from surgical resection. Unanimous agreement was achieved in 649 slides from 462 patients. These slides were then scanned to create whole-slide images, which were divided into sets for training (70%), validation (15%), and internal testing (15%). Accuracy, measured by area under the curve (AUC), was over 99.9% for the internal testing set. The accuracy of HnAIM was independently, externally validated.

First, HnAIM evaluated liver biopsy slides from 30 patients at one center. Results were compared with diagnoses made by nine pathologists classified as either senior, intermediate, or junior. While HnAIM correctly diagnosed 100% of the cases, senior pathologists correctly diagnosed 94.4% of the cases, followed in accuracy by intermediate (86.7%) and junior (73.3%) pathologists.

The researchers noted that the “rate of agreement with subspecialists was higher for HnAIM than for all 9 pathologists at distinguishing 7 liver tissues, with important diagnostic implications for fragmentary or scarce biopsy specimens.”

Next, HnAIM evaluated 234 samples from three hospitals. Accuracy was slightly lower, with an AUC of 93.5%. The researchers highlighted how HnAIM consistently differentiated precancerous lesions and well-defined HCC from benign lesions and background tissues.

A final experiment showed how HnAIM reacted to the most challenging cases. The investigators selected 12 cases without definitive diagnoses and found that, similar to the findings of three subspecialist pathologists, HnAIM did not reach a single diagnostic conclusion.

The researchers reported that “This may be due to a number of potential reasons, such as inherent uncertainty in the 2-dimensional interpretation of a 3-dimensional specimen, the limited number of tissue samples, and cognitive factors such as anchoring.”

However, HnAIM contributed to the diagnostic process by generating multiple diagnostic possibilities with weighted likelihood. After reviewing these results, the expert pathologists reached consensus in 5 out of 12 cases. Moreover, two out of three expert pathologists agreed on all 12 cases, improving agreement rate from 25% to 100%.

The researchers concluded that the model holds the promise to facilitate human HNL diagnoses and improve efficiency and quality. It can also reduce the workload of pathologists, especially where subspecialists are unavailable.

The study was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Natural Science Foundation of Guangdong Province, and others. The investigators reported no conflicts of interest.

A new deep learning system can classify hepatocellular nodular lesions (HNLs) via whole-slide images, improving risk stratification of patients and diagnostic rate of hepatocellular carcinoma (HCC), according to investigators.

While the model requires further validation, it could eventually be used to optimize accuracy and efficiency of histologic diagnoses, potentially decreasing reliance on pathologists, particularly in areas with limited access to subspecialists.

In an article published in Gastroenterology, Na Cheng, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues wrote that the “diagnostic process [for HNLs] is laborious, time-consuming, and subject to the experience of the pathologists, often with significant interobserver and intraobserver variability. ... Therefore, [an] automated analysis system is highly demanded in the pathology field, which could considerably ease the workload, speed up the diagnosis, and facilitate the in-time treatment.”

To this end, Dr. Cheng and colleagues developed the hepatocellular-nodular artificial intelligence model (HnAIM) that can scan whole-image slides to identify seven types of tissue: well-differentiated HCC, high-grade dysplastic nodules, low-grade dysplastic nodules, hepatocellular adenoma, focal nodular hyperplasia, and background tissue.

Developing and testing HnAIM was a multistep process that began with three subspecialist pathologists, who independently reviewed and classified liver slides from surgical resection. Unanimous agreement was achieved in 649 slides from 462 patients. These slides were then scanned to create whole-slide images, which were divided into sets for training (70%), validation (15%), and internal testing (15%). Accuracy, measured by area under the curve (AUC), was over 99.9% for the internal testing set. The accuracy of HnAIM was independently, externally validated.

First, HnAIM evaluated liver biopsy slides from 30 patients at one center. Results were compared with diagnoses made by nine pathologists classified as either senior, intermediate, or junior. While HnAIM correctly diagnosed 100% of the cases, senior pathologists correctly diagnosed 94.4% of the cases, followed in accuracy by intermediate (86.7%) and junior (73.3%) pathologists.

The researchers noted that the “rate of agreement with subspecialists was higher for HnAIM than for all 9 pathologists at distinguishing 7 liver tissues, with important diagnostic implications for fragmentary or scarce biopsy specimens.”

Next, HnAIM evaluated 234 samples from three hospitals. Accuracy was slightly lower, with an AUC of 93.5%. The researchers highlighted how HnAIM consistently differentiated precancerous lesions and well-defined HCC from benign lesions and background tissues.

A final experiment showed how HnAIM reacted to the most challenging cases. The investigators selected 12 cases without definitive diagnoses and found that, similar to the findings of three subspecialist pathologists, HnAIM did not reach a single diagnostic conclusion.

The researchers reported that “This may be due to a number of potential reasons, such as inherent uncertainty in the 2-dimensional interpretation of a 3-dimensional specimen, the limited number of tissue samples, and cognitive factors such as anchoring.”

However, HnAIM contributed to the diagnostic process by generating multiple diagnostic possibilities with weighted likelihood. After reviewing these results, the expert pathologists reached consensus in 5 out of 12 cases. Moreover, two out of three expert pathologists agreed on all 12 cases, improving agreement rate from 25% to 100%.

The researchers concluded that the model holds the promise to facilitate human HNL diagnoses and improve efficiency and quality. It can also reduce the workload of pathologists, especially where subspecialists are unavailable.

The study was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Natural Science Foundation of Guangdong Province, and others. The investigators reported no conflicts of interest.

A new deep learning system can classify hepatocellular nodular lesions (HNLs) via whole-slide images, improving risk stratification of patients and diagnostic rate of hepatocellular carcinoma (HCC), according to investigators.

While the model requires further validation, it could eventually be used to optimize accuracy and efficiency of histologic diagnoses, potentially decreasing reliance on pathologists, particularly in areas with limited access to subspecialists.

In an article published in Gastroenterology, Na Cheng, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues wrote that the “diagnostic process [for HNLs] is laborious, time-consuming, and subject to the experience of the pathologists, often with significant interobserver and intraobserver variability. ... Therefore, [an] automated analysis system is highly demanded in the pathology field, which could considerably ease the workload, speed up the diagnosis, and facilitate the in-time treatment.”

To this end, Dr. Cheng and colleagues developed the hepatocellular-nodular artificial intelligence model (HnAIM) that can scan whole-image slides to identify seven types of tissue: well-differentiated HCC, high-grade dysplastic nodules, low-grade dysplastic nodules, hepatocellular adenoma, focal nodular hyperplasia, and background tissue.

Developing and testing HnAIM was a multistep process that began with three subspecialist pathologists, who independently reviewed and classified liver slides from surgical resection. Unanimous agreement was achieved in 649 slides from 462 patients. These slides were then scanned to create whole-slide images, which were divided into sets for training (70%), validation (15%), and internal testing (15%). Accuracy, measured by area under the curve (AUC), was over 99.9% for the internal testing set. The accuracy of HnAIM was independently, externally validated.

First, HnAIM evaluated liver biopsy slides from 30 patients at one center. Results were compared with diagnoses made by nine pathologists classified as either senior, intermediate, or junior. While HnAIM correctly diagnosed 100% of the cases, senior pathologists correctly diagnosed 94.4% of the cases, followed in accuracy by intermediate (86.7%) and junior (73.3%) pathologists.

The researchers noted that the “rate of agreement with subspecialists was higher for HnAIM than for all 9 pathologists at distinguishing 7 liver tissues, with important diagnostic implications for fragmentary or scarce biopsy specimens.”

Next, HnAIM evaluated 234 samples from three hospitals. Accuracy was slightly lower, with an AUC of 93.5%. The researchers highlighted how HnAIM consistently differentiated precancerous lesions and well-defined HCC from benign lesions and background tissues.

A final experiment showed how HnAIM reacted to the most challenging cases. The investigators selected 12 cases without definitive diagnoses and found that, similar to the findings of three subspecialist pathologists, HnAIM did not reach a single diagnostic conclusion.

The researchers reported that “This may be due to a number of potential reasons, such as inherent uncertainty in the 2-dimensional interpretation of a 3-dimensional specimen, the limited number of tissue samples, and cognitive factors such as anchoring.”

However, HnAIM contributed to the diagnostic process by generating multiple diagnostic possibilities with weighted likelihood. After reviewing these results, the expert pathologists reached consensus in 5 out of 12 cases. Moreover, two out of three expert pathologists agreed on all 12 cases, improving agreement rate from 25% to 100%.

The researchers concluded that the model holds the promise to facilitate human HNL diagnoses and improve efficiency and quality. It can also reduce the workload of pathologists, especially where subspecialists are unavailable.

The study was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Natural Science Foundation of Guangdong Province, and others. The investigators reported no conflicts of interest.

Hypertensive disorders in pregnancy affect nearly 16% of women who give birth in U.S. hospitals and appear to be increasing, according to an April 29 report from the Centers for Disease Control and Prevention.

Older patients and Black women are substantially more likely to experience hypertension in pregnancy, the analysis found.

“Addressing hypertensive disorders in pregnancy is a key strategy in reducing inequities in pregnancy-related mortality,” study coauthor Wanda Barfield, MD, MPH, director of CDC’s Division of Reproductive Health, said in a statement.
 

Age, obesity, diabetes

The overall prevalence of hypertensive disorders in pregnancy increased from 13.3% in 2017 to 15.9% in 2019, the researchers reported in the CDC’s Morbidity and Mortality Weekly Report.

The uptick in hypertension coincides with trends toward older maternal age and higher rates of obesity and diabetes, which may explain the increase, they said.

For the study, Dr. Barfield and her colleagues analyzed nationally representative data from the National Inpatient Sample. They identified patients with a diagnosis of chronic hypertension, pregnancy-associated hypertension, or unspecified maternal hypertension during their hospitalization.

Among women aged 45-55 years, the prevalence of hypertension was 31%. Among those aged 35-44 years, it was 18%.

Hypertension diagnoses were more common in women who were Black (20.9%) or American Indian or Alaska Native (16.4%), than in other groups.

Of patients who died during delivery hospitalization, 31.6% had a hypertensive disorder.

The study shows a marked increase in hypertensive disorders over a relatively short time, according to Jane van Dis, MD, of the department of obstetrics and gynecology at the University of Rochester (N.Y.), who was not involved in the research. The phenomenon is consistent with her own experience, she said.

“When I am admitting patients, I’m oftentimes surprised when someone does not have a hypertensive disorder because I feel like the majority of patients these days do,” Dr. van Dis told this news organization.

Dr. Van Dis speculated that factors related to the environment, including air pollution and endocrine disrupters, could contribute to elevated rates of hypertensive disorders.

Natalie Bello, MD, MPH, director of hypertension research at Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, said rates of hypertension today could be even higher than in the study.

The CDC report relied on pre-COVID data, and the pandemic “increased disparities in health outcomes,” Dr. Bello said in an interview. “I’m worried that in actuality these numbers are an underestimation of the current state of hypertension in pregnancy.”

Dr. Bello, who has studied the need for better training in cardio-obstetrics, applauded Vice President Kamala Harris’ efforts to improve maternal health.

“The racial and geographic disparities that we continue to see in the field are disheartening but should be a call to action to redouble our work to improve maternal outcomes,” Dr. Bello told this news organization. “The good news is that a lot of morbidity related to hypertension can be avoided with timely diagnosis and treatment of blood pressure. However, we need to act to provide all pregnant persons with optimal care.”

Janet Wright, MD, director of CDC’s Division for Heart Disease and Stroke Prevention, said blood pressure home monitoring is a “great example” of a strategy clinicians can use to identify and manage patients with hypertension.

But one approach – self-monitoring blood pressure from home during pregnancy – did not significantly improve the health of pregnant women, according to new results from randomized trials in the United Kingdom.

Trial results published in JAMA show that blood pressure home-monitoring coupled to telemonitoring, as compared with usual care, did not significantly improve blood pressure control among patients with chronic or gestational hypertension.

A second trial published in JAMA that included patients at risk for preeclampsia found that self-monitoring with telemonitoring did not lead to significantly earlier diagnoses of hypertension.

“Individuals at risk for a hypertensive disorder of pregnancy, or with gestational or chronic hypertension, cannot be treated with a single approach,” Malavika Prabhu, MD, with Weill Cornell Medicine, New York, and coauthors write in an editorial accompanying the JAMA studies. Although the data suggest that self-monitoring of blood pressure is practical and tolerated, “More research is needed to determine optimal, high-value, equitable approaches to averting adverse perinatal outcomes associated with hypertensive disorders of pregnancy,” they write.

The CDC study authors and Dr. van Dis have disclosed no relevant financial relationships. Dr. Bello is funded by the National Institutes of Health to study blood pressure monitoring in pregnancy. The JAMA editorial authors disclosed university, government, and corporate grants and work with publishing companies.

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

Hypertensive disorders in pregnancy affect nearly 16% of women who give birth in U.S. hospitals and appear to be increasing, according to an April 29 report from the Centers for Disease Control and Prevention.

Older patients and Black women are substantially more likely to experience hypertension in pregnancy, the analysis found.

“Addressing hypertensive disorders in pregnancy is a key strategy in reducing inequities in pregnancy-related mortality,” study coauthor Wanda Barfield, MD, MPH, director of CDC’s Division of Reproductive Health, said in a statement.
 

Age, obesity, diabetes

The overall prevalence of hypertensive disorders in pregnancy increased from 13.3% in 2017 to 15.9% in 2019, the researchers reported in the CDC’s Morbidity and Mortality Weekly Report.

The uptick in hypertension coincides with trends toward older maternal age and higher rates of obesity and diabetes, which may explain the increase, they said.

For the study, Dr. Barfield and her colleagues analyzed nationally representative data from the National Inpatient Sample. They identified patients with a diagnosis of chronic hypertension, pregnancy-associated hypertension, or unspecified maternal hypertension during their hospitalization.

Among women aged 45-55 years, the prevalence of hypertension was 31%. Among those aged 35-44 years, it was 18%.

Hypertension diagnoses were more common in women who were Black (20.9%) or American Indian or Alaska Native (16.4%), than in other groups.

Of patients who died during delivery hospitalization, 31.6% had a hypertensive disorder.

The study shows a marked increase in hypertensive disorders over a relatively short time, according to Jane van Dis, MD, of the department of obstetrics and gynecology at the University of Rochester (N.Y.), who was not involved in the research. The phenomenon is consistent with her own experience, she said.

“When I am admitting patients, I’m oftentimes surprised when someone does not have a hypertensive disorder because I feel like the majority of patients these days do,” Dr. van Dis told this news organization.

Dr. Van Dis speculated that factors related to the environment, including air pollution and endocrine disrupters, could contribute to elevated rates of hypertensive disorders.

Natalie Bello, MD, MPH, director of hypertension research at Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, said rates of hypertension today could be even higher than in the study.

The CDC report relied on pre-COVID data, and the pandemic “increased disparities in health outcomes,” Dr. Bello said in an interview. “I’m worried that in actuality these numbers are an underestimation of the current state of hypertension in pregnancy.”

Dr. Bello, who has studied the need for better training in cardio-obstetrics, applauded Vice President Kamala Harris’ efforts to improve maternal health.

“The racial and geographic disparities that we continue to see in the field are disheartening but should be a call to action to redouble our work to improve maternal outcomes,” Dr. Bello told this news organization. “The good news is that a lot of morbidity related to hypertension can be avoided with timely diagnosis and treatment of blood pressure. However, we need to act to provide all pregnant persons with optimal care.”

Janet Wright, MD, director of CDC’s Division for Heart Disease and Stroke Prevention, said blood pressure home monitoring is a “great example” of a strategy clinicians can use to identify and manage patients with hypertension.

But one approach – self-monitoring blood pressure from home during pregnancy – did not significantly improve the health of pregnant women, according to new results from randomized trials in the United Kingdom.

Trial results published in JAMA show that blood pressure home-monitoring coupled to telemonitoring, as compared with usual care, did not significantly improve blood pressure control among patients with chronic or gestational hypertension.

A second trial published in JAMA that included patients at risk for preeclampsia found that self-monitoring with telemonitoring did not lead to significantly earlier diagnoses of hypertension.

“Individuals at risk for a hypertensive disorder of pregnancy, or with gestational or chronic hypertension, cannot be treated with a single approach,” Malavika Prabhu, MD, with Weill Cornell Medicine, New York, and coauthors write in an editorial accompanying the JAMA studies. Although the data suggest that self-monitoring of blood pressure is practical and tolerated, “More research is needed to determine optimal, high-value, equitable approaches to averting adverse perinatal outcomes associated with hypertensive disorders of pregnancy,” they write.

The CDC study authors and Dr. van Dis have disclosed no relevant financial relationships. Dr. Bello is funded by the National Institutes of Health to study blood pressure monitoring in pregnancy. The JAMA editorial authors disclosed university, government, and corporate grants and work with publishing companies.

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

Hypertensive disorders in pregnancy affect nearly 16% of women who give birth in U.S. hospitals and appear to be increasing, according to an April 29 report from the Centers for Disease Control and Prevention.

Older patients and Black women are substantially more likely to experience hypertension in pregnancy, the analysis found.

“Addressing hypertensive disorders in pregnancy is a key strategy in reducing inequities in pregnancy-related mortality,” study coauthor Wanda Barfield, MD, MPH, director of CDC’s Division of Reproductive Health, said in a statement.
 

Age, obesity, diabetes

The overall prevalence of hypertensive disorders in pregnancy increased from 13.3% in 2017 to 15.9% in 2019, the researchers reported in the CDC’s Morbidity and Mortality Weekly Report.

The uptick in hypertension coincides with trends toward older maternal age and higher rates of obesity and diabetes, which may explain the increase, they said.

For the study, Dr. Barfield and her colleagues analyzed nationally representative data from the National Inpatient Sample. They identified patients with a diagnosis of chronic hypertension, pregnancy-associated hypertension, or unspecified maternal hypertension during their hospitalization.

Among women aged 45-55 years, the prevalence of hypertension was 31%. Among those aged 35-44 years, it was 18%.

Hypertension diagnoses were more common in women who were Black (20.9%) or American Indian or Alaska Native (16.4%), than in other groups.

Of patients who died during delivery hospitalization, 31.6% had a hypertensive disorder.

The study shows a marked increase in hypertensive disorders over a relatively short time, according to Jane van Dis, MD, of the department of obstetrics and gynecology at the University of Rochester (N.Y.), who was not involved in the research. The phenomenon is consistent with her own experience, she said.

“When I am admitting patients, I’m oftentimes surprised when someone does not have a hypertensive disorder because I feel like the majority of patients these days do,” Dr. van Dis told this news organization.

Dr. Van Dis speculated that factors related to the environment, including air pollution and endocrine disrupters, could contribute to elevated rates of hypertensive disorders.

Natalie Bello, MD, MPH, director of hypertension research at Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, said rates of hypertension today could be even higher than in the study.

The CDC report relied on pre-COVID data, and the pandemic “increased disparities in health outcomes,” Dr. Bello said in an interview. “I’m worried that in actuality these numbers are an underestimation of the current state of hypertension in pregnancy.”

Dr. Bello, who has studied the need for better training in cardio-obstetrics, applauded Vice President Kamala Harris’ efforts to improve maternal health.

“The racial and geographic disparities that we continue to see in the field are disheartening but should be a call to action to redouble our work to improve maternal outcomes,” Dr. Bello told this news organization. “The good news is that a lot of morbidity related to hypertension can be avoided with timely diagnosis and treatment of blood pressure. However, we need to act to provide all pregnant persons with optimal care.”

Janet Wright, MD, director of CDC’s Division for Heart Disease and Stroke Prevention, said blood pressure home monitoring is a “great example” of a strategy clinicians can use to identify and manage patients with hypertension.

But one approach – self-monitoring blood pressure from home during pregnancy – did not significantly improve the health of pregnant women, according to new results from randomized trials in the United Kingdom.

Trial results published in JAMA show that blood pressure home-monitoring coupled to telemonitoring, as compared with usual care, did not significantly improve blood pressure control among patients with chronic or gestational hypertension.

A second trial published in JAMA that included patients at risk for preeclampsia found that self-monitoring with telemonitoring did not lead to significantly earlier diagnoses of hypertension.

“Individuals at risk for a hypertensive disorder of pregnancy, or with gestational or chronic hypertension, cannot be treated with a single approach,” Malavika Prabhu, MD, with Weill Cornell Medicine, New York, and coauthors write in an editorial accompanying the JAMA studies. Although the data suggest that self-monitoring of blood pressure is practical and tolerated, “More research is needed to determine optimal, high-value, equitable approaches to averting adverse perinatal outcomes associated with hypertensive disorders of pregnancy,” they write.

The CDC study authors and Dr. van Dis have disclosed no relevant financial relationships. Dr. Bello is funded by the National Institutes of Health to study blood pressure monitoring in pregnancy. The JAMA editorial authors disclosed university, government, and corporate grants and work with publishing companies.

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

Consistently sleeping 7 hours per night was associated with optimal cognitive function and mental health for middle-aged adults, a new study found.

Sleep disturbances are common in older age, and previous studies have shown associations between too much or too little sleep and increased risk of cognitive decline, but the ideal amount of sleep for preserving mental health has not been well described, according to the authors of the new paper.

In the study published in Nature Aging, the team of researchers from China and the United Kingdom reviewed data from the UK Biobank, a national database of individuals in the United Kingdom that includes cognitive assessments, mental health questionnaires, and brain imaging data, as well as genetic information.

Sleep is important for physical and psychological health, and also serves a neuroprotective function by clearing waste products from the brain, lead author Yuzhu Li of Fudan University, Shanghai, China, and colleagues wrote.

The study population included 498,277 participants, aged 38-73 years, who completed touchscreen questionnaires about sleep duration between 2006 and 2010. The average age at baseline was 56.5 years, 54% were female, and the mean sleep duration was 7.15 hours.

The researchers also reviewed brain imaging data and genetic data from 39,692 participants in 2014 to examine the relationships between sleep duration and brain structure and between sleep duration and genetic risk. In addition, 156,884 participants completed an online follow-up mental health questionnaire in 2016-2017 to assess the longitudinal impact of sleep on mental health.

Both excessive and insufficient sleep was associated with impaired cognitive performance, evidenced by the U-shaped curve found by the researchers in their data analysis, which used quadratic associations.

Specific cognitive functions including pair matching, trail making, prospective memory, and reaction time were significantly impaired with too much or too little sleep, the researchers said. “This demonstrated the positive association of both insufficient and excessive sleep duration with inferior performance on cognitive tasks.”

When the researchers analyzed the association between sleep duration and mental health, sleep duration also showed a U-shaped association with symptoms of anxiety, depression, mental distress, mania, and self-harm, while well-being showed an inverted U-shape. All associations between sleep duration and mental health were statistically significant after controlling for confounding variables (P < .001).

On further analysis (using two-line tests), the researchers determined that consistent sleep duration of approximately 7 hours per night was optimal for cognitive performance and for good mental health.

The researchers also used neuroimaging data to examine the relationship between sleep duration and brain structure. Overall, greater changes were seen in the regions of the brain involved in cognitive processing and memory.

“The most significant cortical volumes nonlinearly associated with sleep duration included the precentral cortex, the superior frontal gyrus, the lateral orbitofrontal cortex, the pars orbitalis, the frontal pole, and the middle temporal cortex,” the researchers wrote (P < .05 for all).

The association between sleep duration and cognitive function diminished among individuals older than 65 years, compared with those aged approximately 40 years, which suggests that optimal sleep duration may be more beneficial in middle age, the researchers noted. However, no similar impact of age was seen for mental health. For brain structure, the nonlinear relationship between sleep duration and cortical volumes was greatest in those aged 44-59 years, and gradually flattened with older age.
 

Research supports sleep discussions with patients

“Primary care physicians can use this study in their discussions with middle-aged and older patients to recommend optimal sleep duration and measures to achieve this sleep target,” Noel Deep, MD, a general internist in group practice in Antigo, Wisc., who was not involved in the study, said in an interview.

“This study is important because it demonstrated that both inadequate and excessive sleep patterns were associated with cognitive and mental health changes,” said Dr. Deep. “It supported previous observations of cognitive decline and mental health disorders being linked to disturbed sleep. But this study was unique because it provides data supporting an optimal sleep duration of 7 hours and the ill effects of both insufficient and excessive sleep duration.

“The usual thought process has been to assume that older individuals may not require as much sleep as the younger individuals, but this study supports an optimal time duration of sleep of 7 hours that benefits the older individuals. It was also interesting to note the mental health effects caused by the inadequate and excessive sleep durations,” he added.

As for additional research, “I would like to look into the quality of the sleep, in addition to the duration of sleep,” said Dr. Deep. For example, whether the excessive sleep was caused by poor quality sleep or fragmented sleep leading to the structural and subsequent cognitive decline.
 

Study limitations

“The current study relied on self-reporting of the sleep duration and was not observed and recorded data,” Dr. Deep noted. “It would also be beneficial to not only rely on healthy volunteers reporting the sleep duration, but also obtain sleep data from individuals with known brain disorders.”

The study findings were limited by several other factors, including the use of total sleep duration only, without other measures of sleep hygiene, the researchers noted. More research is needed to investigate the mechanisms driving the association between too much and not enough sleep and poor mental health and cognitive function.

The study was supported by the National Key R&D Program of China, the Shanghai Municipal Science and Technology Major Project, the Shanghai Center for Brain Science and Brain-Inspired Technology, the 111 Project, the National Natural Sciences Foundation of China and the Shanghai Rising Star Program.

The researchers had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News.
 

Consistently sleeping 7 hours per night was associated with optimal cognitive function and mental health for middle-aged adults, a new study found.

Sleep disturbances are common in older age, and previous studies have shown associations between too much or too little sleep and increased risk of cognitive decline, but the ideal amount of sleep for preserving mental health has not been well described, according to the authors of the new paper.

In the study published in Nature Aging, the team of researchers from China and the United Kingdom reviewed data from the UK Biobank, a national database of individuals in the United Kingdom that includes cognitive assessments, mental health questionnaires, and brain imaging data, as well as genetic information.

Sleep is important for physical and psychological health, and also serves a neuroprotective function by clearing waste products from the brain, lead author Yuzhu Li of Fudan University, Shanghai, China, and colleagues wrote.

The study population included 498,277 participants, aged 38-73 years, who completed touchscreen questionnaires about sleep duration between 2006 and 2010. The average age at baseline was 56.5 years, 54% were female, and the mean sleep duration was 7.15 hours.

The researchers also reviewed brain imaging data and genetic data from 39,692 participants in 2014 to examine the relationships between sleep duration and brain structure and between sleep duration and genetic risk. In addition, 156,884 participants completed an online follow-up mental health questionnaire in 2016-2017 to assess the longitudinal impact of sleep on mental health.

Both excessive and insufficient sleep was associated with impaired cognitive performance, evidenced by the U-shaped curve found by the researchers in their data analysis, which used quadratic associations.

Specific cognitive functions including pair matching, trail making, prospective memory, and reaction time were significantly impaired with too much or too little sleep, the researchers said. “This demonstrated the positive association of both insufficient and excessive sleep duration with inferior performance on cognitive tasks.”

When the researchers analyzed the association between sleep duration and mental health, sleep duration also showed a U-shaped association with symptoms of anxiety, depression, mental distress, mania, and self-harm, while well-being showed an inverted U-shape. All associations between sleep duration and mental health were statistically significant after controlling for confounding variables (P < .001).

On further analysis (using two-line tests), the researchers determined that consistent sleep duration of approximately 7 hours per night was optimal for cognitive performance and for good mental health.

The researchers also used neuroimaging data to examine the relationship between sleep duration and brain structure. Overall, greater changes were seen in the regions of the brain involved in cognitive processing and memory.

“The most significant cortical volumes nonlinearly associated with sleep duration included the precentral cortex, the superior frontal gyrus, the lateral orbitofrontal cortex, the pars orbitalis, the frontal pole, and the middle temporal cortex,” the researchers wrote (P < .05 for all).

The association between sleep duration and cognitive function diminished among individuals older than 65 years, compared with those aged approximately 40 years, which suggests that optimal sleep duration may be more beneficial in middle age, the researchers noted. However, no similar impact of age was seen for mental health. For brain structure, the nonlinear relationship between sleep duration and cortical volumes was greatest in those aged 44-59 years, and gradually flattened with older age.
 

Research supports sleep discussions with patients

“Primary care physicians can use this study in their discussions with middle-aged and older patients to recommend optimal sleep duration and measures to achieve this sleep target,” Noel Deep, MD, a general internist in group practice in Antigo, Wisc., who was not involved in the study, said in an interview.

“This study is important because it demonstrated that both inadequate and excessive sleep patterns were associated with cognitive and mental health changes,” said Dr. Deep. “It supported previous observations of cognitive decline and mental health disorders being linked to disturbed sleep. But this study was unique because it provides data supporting an optimal sleep duration of 7 hours and the ill effects of both insufficient and excessive sleep duration.

“The usual thought process has been to assume that older individuals may not require as much sleep as the younger individuals, but this study supports an optimal time duration of sleep of 7 hours that benefits the older individuals. It was also interesting to note the mental health effects caused by the inadequate and excessive sleep durations,” he added.

As for additional research, “I would like to look into the quality of the sleep, in addition to the duration of sleep,” said Dr. Deep. For example, whether the excessive sleep was caused by poor quality sleep or fragmented sleep leading to the structural and subsequent cognitive decline.
 

Study limitations

“The current study relied on self-reporting of the sleep duration and was not observed and recorded data,” Dr. Deep noted. “It would also be beneficial to not only rely on healthy volunteers reporting the sleep duration, but also obtain sleep data from individuals with known brain disorders.”

The study findings were limited by several other factors, including the use of total sleep duration only, without other measures of sleep hygiene, the researchers noted. More research is needed to investigate the mechanisms driving the association between too much and not enough sleep and poor mental health and cognitive function.

The study was supported by the National Key R&D Program of China, the Shanghai Municipal Science and Technology Major Project, the Shanghai Center for Brain Science and Brain-Inspired Technology, the 111 Project, the National Natural Sciences Foundation of China and the Shanghai Rising Star Program.

The researchers had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News.
 

Consistently sleeping 7 hours per night was associated with optimal cognitive function and mental health for middle-aged adults, a new study found.

Sleep disturbances are common in older age, and previous studies have shown associations between too much or too little sleep and increased risk of cognitive decline, but the ideal amount of sleep for preserving mental health has not been well described, according to the authors of the new paper.

In the study published in Nature Aging, the team of researchers from China and the United Kingdom reviewed data from the UK Biobank, a national database of individuals in the United Kingdom that includes cognitive assessments, mental health questionnaires, and brain imaging data, as well as genetic information.

Sleep is important for physical and psychological health, and also serves a neuroprotective function by clearing waste products from the brain, lead author Yuzhu Li of Fudan University, Shanghai, China, and colleagues wrote.

The study population included 498,277 participants, aged 38-73 years, who completed touchscreen questionnaires about sleep duration between 2006 and 2010. The average age at baseline was 56.5 years, 54% were female, and the mean sleep duration was 7.15 hours.

The researchers also reviewed brain imaging data and genetic data from 39,692 participants in 2014 to examine the relationships between sleep duration and brain structure and between sleep duration and genetic risk. In addition, 156,884 participants completed an online follow-up mental health questionnaire in 2016-2017 to assess the longitudinal impact of sleep on mental health.

Both excessive and insufficient sleep was associated with impaired cognitive performance, evidenced by the U-shaped curve found by the researchers in their data analysis, which used quadratic associations.

Specific cognitive functions including pair matching, trail making, prospective memory, and reaction time were significantly impaired with too much or too little sleep, the researchers said. “This demonstrated the positive association of both insufficient and excessive sleep duration with inferior performance on cognitive tasks.”

When the researchers analyzed the association between sleep duration and mental health, sleep duration also showed a U-shaped association with symptoms of anxiety, depression, mental distress, mania, and self-harm, while well-being showed an inverted U-shape. All associations between sleep duration and mental health were statistically significant after controlling for confounding variables (P < .001).

On further analysis (using two-line tests), the researchers determined that consistent sleep duration of approximately 7 hours per night was optimal for cognitive performance and for good mental health.

The researchers also used neuroimaging data to examine the relationship between sleep duration and brain structure. Overall, greater changes were seen in the regions of the brain involved in cognitive processing and memory.

“The most significant cortical volumes nonlinearly associated with sleep duration included the precentral cortex, the superior frontal gyrus, the lateral orbitofrontal cortex, the pars orbitalis, the frontal pole, and the middle temporal cortex,” the researchers wrote (P < .05 for all).

The association between sleep duration and cognitive function diminished among individuals older than 65 years, compared with those aged approximately 40 years, which suggests that optimal sleep duration may be more beneficial in middle age, the researchers noted. However, no similar impact of age was seen for mental health. For brain structure, the nonlinear relationship between sleep duration and cortical volumes was greatest in those aged 44-59 years, and gradually flattened with older age.
 

Research supports sleep discussions with patients

“Primary care physicians can use this study in their discussions with middle-aged and older patients to recommend optimal sleep duration and measures to achieve this sleep target,” Noel Deep, MD, a general internist in group practice in Antigo, Wisc., who was not involved in the study, said in an interview.

“This study is important because it demonstrated that both inadequate and excessive sleep patterns were associated with cognitive and mental health changes,” said Dr. Deep. “It supported previous observations of cognitive decline and mental health disorders being linked to disturbed sleep. But this study was unique because it provides data supporting an optimal sleep duration of 7 hours and the ill effects of both insufficient and excessive sleep duration.

“The usual thought process has been to assume that older individuals may not require as much sleep as the younger individuals, but this study supports an optimal time duration of sleep of 7 hours that benefits the older individuals. It was also interesting to note the mental health effects caused by the inadequate and excessive sleep durations,” he added.

As for additional research, “I would like to look into the quality of the sleep, in addition to the duration of sleep,” said Dr. Deep. For example, whether the excessive sleep was caused by poor quality sleep or fragmented sleep leading to the structural and subsequent cognitive decline.
 

Study limitations

“The current study relied on self-reporting of the sleep duration and was not observed and recorded data,” Dr. Deep noted. “It would also be beneficial to not only rely on healthy volunteers reporting the sleep duration, but also obtain sleep data from individuals with known brain disorders.”

The study findings were limited by several other factors, including the use of total sleep duration only, without other measures of sleep hygiene, the researchers noted. More research is needed to investigate the mechanisms driving the association between too much and not enough sleep and poor mental health and cognitive function.

The study was supported by the National Key R&D Program of China, the Shanghai Municipal Science and Technology Major Project, the Shanghai Center for Brain Science and Brain-Inspired Technology, the 111 Project, the National Natural Sciences Foundation of China and the Shanghai Rising Star Program.

The researchers had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News.
 

Cognitive impairment from severe COVID-19 is equivalent to 20 years of aging, report scientists behind a new study, adding that the impairment is “equivalent to losing 10 IQ points.”

In their study, published in eClinicalMedicine, a team of scientists from the University of Cambridge and Imperial College London said there is growing evidence that COVID-19 can cause lasting cognitive and mental health problems. Patients report fatigue, “brain fog,” problems recalling words, sleep disturbances, anxiety, and even posttraumatic stress disorder months after infection.

The researchers analyzed data from 46 individuals who received critical care for COVID-19 at Addenbrooke’s Hospital between March and July 2020 (27 females, 19 males, mean age 51 years, 16 of whom had mechanical ventilation) and were recruited to the NIHR COVID-19 BioResource project.

At an average of 6 months after acute COVID-19 illness, the study participants underwent detailed computerized cognitive tests via the Cognitron platform,  comprising eight tasks deployed on an iPad measuring mental function such as memory, attention, and reasoning. Also assessed were anxiety, depression, and posttraumatic stress disorder via standard mood, anxiety, and posttraumatic stress scales – specifically the Generalized Anxiety Disorder 7 (GAD-7), the Patient Health Questionnaire 9 (PHQ-9), and the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders 5 (PCL-5). Their data were compared against 460 controls – matched for age, sex, education, and first language – and the pattern of deficits across tasks was qualitatively compared with normal age-related decline and early-stage dementia.
 

Less accurate and slower response times

The authors highlighted how this was the first time a “rigorous assessment and comparison” had been carried out in relation to the after-effects of severe COVID-19.

“Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine aging, but the patterns we saw – the cognitive ‘fingerprint’ of COVID-19 – was distinct from all of these,” said David Menon, MD, division of anesthesia at the University of Cambridge, England, and the study’s senior author.

The scientists found that COVID-19 survivors were less accurate and had slower response times than the control population, and added that survivors scored particularly poorly on verbal analogical reasoning and showed slower processing speeds.

Critically, the scale of the cognitive deficits correlated with acute illness severity, but not fatigue or mental health status at the time of cognitive assessment, said the authors.
 

Recovery ‘at best gradual’

The effects were strongest for those with more severe acute illness, and who required mechanical ventilation, said the authors, who found that acute illness severity was “better at predicting the cognitive deficits.”

The authors pointed out how these deficits were still detectable when patients were followed up 6 months later, and that, although patients’ scores and reaction times began to improve over time, any recovery was “at best gradual” and likely to be influenced by factors such as illness severity and its neurological or psychological impacts.

“We followed some patients up as late as 10 months after their acute infection, so were able to see a very slow improvement,” Dr. Menon said. He explained how, while this improvement was not statistically significant, it was “at least heading in the right direction.”

However, he warned it is very possible that some of these individuals “will never fully recover.”

The cognitive deficits observed may be due to several factors in combination, said the authors, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds. They highlighted how the most important mechanism, however, may be “damage caused by the body’s own inflammatory response and immune system.”

Adam Hampshire, PhD, of the department of brain sciences at Imperial College London, one of the study’s authors, described how around 40,000 people have been through intensive care with COVID-19 in England alone, with many more despite having been very sick not admitted to hospital. This means there is a “large number of people out there still experiencing problems with cognition many months later,” he said. “We urgently need to look at what can be done to help these people.”

A version of this article first appeared on Univadis.

Cognitive impairment from severe COVID-19 is equivalent to 20 years of aging, report scientists behind a new study, adding that the impairment is “equivalent to losing 10 IQ points.”

In their study, published in eClinicalMedicine, a team of scientists from the University of Cambridge and Imperial College London said there is growing evidence that COVID-19 can cause lasting cognitive and mental health problems. Patients report fatigue, “brain fog,” problems recalling words, sleep disturbances, anxiety, and even posttraumatic stress disorder months after infection.

The researchers analyzed data from 46 individuals who received critical care for COVID-19 at Addenbrooke’s Hospital between March and July 2020 (27 females, 19 males, mean age 51 years, 16 of whom had mechanical ventilation) and were recruited to the NIHR COVID-19 BioResource project.

At an average of 6 months after acute COVID-19 illness, the study participants underwent detailed computerized cognitive tests via the Cognitron platform,  comprising eight tasks deployed on an iPad measuring mental function such as memory, attention, and reasoning. Also assessed were anxiety, depression, and posttraumatic stress disorder via standard mood, anxiety, and posttraumatic stress scales – specifically the Generalized Anxiety Disorder 7 (GAD-7), the Patient Health Questionnaire 9 (PHQ-9), and the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders 5 (PCL-5). Their data were compared against 460 controls – matched for age, sex, education, and first language – and the pattern of deficits across tasks was qualitatively compared with normal age-related decline and early-stage dementia.
 

Less accurate and slower response times

The authors highlighted how this was the first time a “rigorous assessment and comparison” had been carried out in relation to the after-effects of severe COVID-19.

“Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine aging, but the patterns we saw – the cognitive ‘fingerprint’ of COVID-19 – was distinct from all of these,” said David Menon, MD, division of anesthesia at the University of Cambridge, England, and the study’s senior author.

The scientists found that COVID-19 survivors were less accurate and had slower response times than the control population, and added that survivors scored particularly poorly on verbal analogical reasoning and showed slower processing speeds.

Critically, the scale of the cognitive deficits correlated with acute illness severity, but not fatigue or mental health status at the time of cognitive assessment, said the authors.
 

Recovery ‘at best gradual’

The effects were strongest for those with more severe acute illness, and who required mechanical ventilation, said the authors, who found that acute illness severity was “better at predicting the cognitive deficits.”

The authors pointed out how these deficits were still detectable when patients were followed up 6 months later, and that, although patients’ scores and reaction times began to improve over time, any recovery was “at best gradual” and likely to be influenced by factors such as illness severity and its neurological or psychological impacts.

“We followed some patients up as late as 10 months after their acute infection, so were able to see a very slow improvement,” Dr. Menon said. He explained how, while this improvement was not statistically significant, it was “at least heading in the right direction.”

However, he warned it is very possible that some of these individuals “will never fully recover.”

The cognitive deficits observed may be due to several factors in combination, said the authors, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds. They highlighted how the most important mechanism, however, may be “damage caused by the body’s own inflammatory response and immune system.”

Adam Hampshire, PhD, of the department of brain sciences at Imperial College London, one of the study’s authors, described how around 40,000 people have been through intensive care with COVID-19 in England alone, with many more despite having been very sick not admitted to hospital. This means there is a “large number of people out there still experiencing problems with cognition many months later,” he said. “We urgently need to look at what can be done to help these people.”

A version of this article first appeared on Univadis.

Cognitive impairment from severe COVID-19 is equivalent to 20 years of aging, report scientists behind a new study, adding that the impairment is “equivalent to losing 10 IQ points.”

In their study, published in eClinicalMedicine, a team of scientists from the University of Cambridge and Imperial College London said there is growing evidence that COVID-19 can cause lasting cognitive and mental health problems. Patients report fatigue, “brain fog,” problems recalling words, sleep disturbances, anxiety, and even posttraumatic stress disorder months after infection.

The researchers analyzed data from 46 individuals who received critical care for COVID-19 at Addenbrooke’s Hospital between March and July 2020 (27 females, 19 males, mean age 51 years, 16 of whom had mechanical ventilation) and were recruited to the NIHR COVID-19 BioResource project.

At an average of 6 months after acute COVID-19 illness, the study participants underwent detailed computerized cognitive tests via the Cognitron platform,  comprising eight tasks deployed on an iPad measuring mental function such as memory, attention, and reasoning. Also assessed were anxiety, depression, and posttraumatic stress disorder via standard mood, anxiety, and posttraumatic stress scales – specifically the Generalized Anxiety Disorder 7 (GAD-7), the Patient Health Questionnaire 9 (PHQ-9), and the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders 5 (PCL-5). Their data were compared against 460 controls – matched for age, sex, education, and first language – and the pattern of deficits across tasks was qualitatively compared with normal age-related decline and early-stage dementia.
 

Less accurate and slower response times

The authors highlighted how this was the first time a “rigorous assessment and comparison” had been carried out in relation to the after-effects of severe COVID-19.

“Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine aging, but the patterns we saw – the cognitive ‘fingerprint’ of COVID-19 – was distinct from all of these,” said David Menon, MD, division of anesthesia at the University of Cambridge, England, and the study’s senior author.

The scientists found that COVID-19 survivors were less accurate and had slower response times than the control population, and added that survivors scored particularly poorly on verbal analogical reasoning and showed slower processing speeds.

Critically, the scale of the cognitive deficits correlated with acute illness severity, but not fatigue or mental health status at the time of cognitive assessment, said the authors.
 

Recovery ‘at best gradual’

The effects were strongest for those with more severe acute illness, and who required mechanical ventilation, said the authors, who found that acute illness severity was “better at predicting the cognitive deficits.”

The authors pointed out how these deficits were still detectable when patients were followed up 6 months later, and that, although patients’ scores and reaction times began to improve over time, any recovery was “at best gradual” and likely to be influenced by factors such as illness severity and its neurological or psychological impacts.

“We followed some patients up as late as 10 months after their acute infection, so were able to see a very slow improvement,” Dr. Menon said. He explained how, while this improvement was not statistically significant, it was “at least heading in the right direction.”

However, he warned it is very possible that some of these individuals “will never fully recover.”

The cognitive deficits observed may be due to several factors in combination, said the authors, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds. They highlighted how the most important mechanism, however, may be “damage caused by the body’s own inflammatory response and immune system.”

Adam Hampshire, PhD, of the department of brain sciences at Imperial College London, one of the study’s authors, described how around 40,000 people have been through intensive care with COVID-19 in England alone, with many more despite having been very sick not admitted to hospital. This means there is a “large number of people out there still experiencing problems with cognition many months later,” he said. “We urgently need to look at what can be done to help these people.”

A version of this article first appeared on Univadis.

Approximately 7% of youth who chose gender identity social transition in early childhood had retransitioned 5 years later, based on data from 317 individuals.

“Increasing numbers of children are socially transitioning to live in line with their gender identity, rather than the gender assumed by their sex at birth – a process that typically involves changing a child’s pronouns, first name, hairstyle, and clothing,” wrote Kristina R. Olson, PhD, of Princeton (N.J.) University, and colleagues.

The question of whether early childhood social transitions will result in high rates of retransition continues to be a subject for debate, and long-term data on retransition rates and identity outcomes in children who transition are limited, they said.

To examine retransition in early-transitioning children, the researchers identified 317 binary socially transitioned transgender children to participate in a longitudinal study known as the Trans Youth Project (TYP) between July 2013 and December 2017. The study was published in Pediatrics. The mean age at baseline was 8 years. At study entry, participants had to have made a complete binary social transition, including changing their pronouns from those used at birth. During the 5-year follow-up period, children and parents were asked about use of puberty blockers and/or gender-affirming hormones. At study entry, 37 children had begun some type of puberty blockers. A total of 124 children initially socially transitioned before 6 years of age, and 193 initially socially transitioned at 6 years or older.

The study did not evaluate whether the participants met the DSM-5 criteria for gender dysphoria in childhood, the researchers noted. “Based on data collected at their initial visit, we do know that these participants showed signs of gender identification and gender-typed preferences commonly associated with their gender, not their sex assigned at birth,” they wrote.

Participants were classified as binary transgender, nonbinary, or cisgender based on their pronouns at follow-up. Binary transgender pronouns were associated with the other binary assigned sex, nonbinary pronouns were they/them or a mix of they/them and binary pronouns, and cisgender pronouns were those associated with assigned sex.

Overall, 7.3% of the participants had retransitioned at least once by 5 years after their initial binary social transition. The majority (94%) were living as binary transgender youth, including 1.3% who retransitioned to cisgender or nonbinary and then back to binary transgender during the follow-up period. A total of 2.5% were living as cisgender youth and 3.5% were living as nonbinary youth. These rates were similar across the initial population, as well as the 291 participants who continue to be in contact with the researchers, the 200 who had gone at least 5 years since their initial social transition, and the 280 participants who began the study before starting puberty blockers.

The researchers found no differences in retransition rates related to participant sex at birth. Rates of retransition were slightly higher among participants who made their initial social transition before 6 years of age, but these rates were low, the researchers noted.

The study findings were limited by several factors including the use of a volunteer community sample, with the potential for bias that may not generalize to the population at large, the researchers noted. Other limitations included the use of pronouns as the main criteria for retransition, and the classification of a change from binary transgender to nonbinary as a transition, they said. “Many nonbinary people consider themselves to be transgender,” they noted.

“If we had used a stricter criterion of retransition, more similar to the common use of terms like “detransition” or “desistence,” referring only to youth who are living as cisgender, then our retransition rate would have been lower (2.5%),” the researchers explained. Another limitation was the disproportionate number of trans girls, the researchers said. However, because no significant gender effect appeared in terms of retransition rates, “we do not predict any change in pattern of results if we had a different ratio of participants by sex at birth,” they said.

The researchers stated that they intend to follow the cohort through adolescence and into adulthood.

“As more youth are coming out and being supported in their transitions early in development, it is increasingly critical that clinicians understand the experiences of this cohort and not make assumptions about them as a function of older data from youth who lived under different circumstances,” the researchers emphasized. “Though we can never predict the exact gender trajectory of any child, these data suggest that many youth who identify as transgender early, and are supported through a social transition, will continue to identify as transgender 5 years after initial social transition.” They concluded that more research is needed to determine how best to support initial and later gender transitions in youth.
 

Study offers support for family discussions

“This study is important to help provide more data regarding the experiences of gender-diverse youth,” M. Brett Cooper, MD, of UT Southwestern Medical Center, Dallas, said in an interview. “The results of a study like this can be used by clinicians to help provide advice and guidance to parents and families as they support their children through their gender journey,” said Dr. Cooper, who was not involved in the study. The current study “also provides evidence to support that persistent, insistent, and consistent youth have an extremely low rate of retransition to a gender that aligns with their sex assigned at birth. This refutes suggestions by politicians and others that those who seek medical care have a high rate of regret or retransition,” Dr. Cooper emphasized.

“I was not surprised at all by their findings,” said Dr. Cooper. “These are very similar to what I have seen in my own panel of gender-diverse patients and what has been seen in other studies,” he noted.

The take-home message of the current study does not suggest any change in clinical practice, Dr. Cooper said. “Guidance already suggests supporting these youth on their gender journey and that for some youth, this may mean retransitioning to identify with their sex assigned at birth,” he explained.

The study was supported in part by grants to the researchers from the National Institutes of Health, the National Science Foundation, the Arcus Foundation, and the MacArthur Foundation. The researchers had no financial conflicts to disclose.

Approximately 7% of youth who chose gender identity social transition in early childhood had retransitioned 5 years later, based on data from 317 individuals.

“Increasing numbers of children are socially transitioning to live in line with their gender identity, rather than the gender assumed by their sex at birth – a process that typically involves changing a child’s pronouns, first name, hairstyle, and clothing,” wrote Kristina R. Olson, PhD, of Princeton (N.J.) University, and colleagues.

The question of whether early childhood social transitions will result in high rates of retransition continues to be a subject for debate, and long-term data on retransition rates and identity outcomes in children who transition are limited, they said.

To examine retransition in early-transitioning children, the researchers identified 317 binary socially transitioned transgender children to participate in a longitudinal study known as the Trans Youth Project (TYP) between July 2013 and December 2017. The study was published in Pediatrics. The mean age at baseline was 8 years. At study entry, participants had to have made a complete binary social transition, including changing their pronouns from those used at birth. During the 5-year follow-up period, children and parents were asked about use of puberty blockers and/or gender-affirming hormones. At study entry, 37 children had begun some type of puberty blockers. A total of 124 children initially socially transitioned before 6 years of age, and 193 initially socially transitioned at 6 years or older.

The study did not evaluate whether the participants met the DSM-5 criteria for gender dysphoria in childhood, the researchers noted. “Based on data collected at their initial visit, we do know that these participants showed signs of gender identification and gender-typed preferences commonly associated with their gender, not their sex assigned at birth,” they wrote.

Participants were classified as binary transgender, nonbinary, or cisgender based on their pronouns at follow-up. Binary transgender pronouns were associated with the other binary assigned sex, nonbinary pronouns were they/them or a mix of they/them and binary pronouns, and cisgender pronouns were those associated with assigned sex.

Overall, 7.3% of the participants had retransitioned at least once by 5 years after their initial binary social transition. The majority (94%) were living as binary transgender youth, including 1.3% who retransitioned to cisgender or nonbinary and then back to binary transgender during the follow-up period. A total of 2.5% were living as cisgender youth and 3.5% were living as nonbinary youth. These rates were similar across the initial population, as well as the 291 participants who continue to be in contact with the researchers, the 200 who had gone at least 5 years since their initial social transition, and the 280 participants who began the study before starting puberty blockers.

The researchers found no differences in retransition rates related to participant sex at birth. Rates of retransition were slightly higher among participants who made their initial social transition before 6 years of age, but these rates were low, the researchers noted.

The study findings were limited by several factors including the use of a volunteer community sample, with the potential for bias that may not generalize to the population at large, the researchers noted. Other limitations included the use of pronouns as the main criteria for retransition, and the classification of a change from binary transgender to nonbinary as a transition, they said. “Many nonbinary people consider themselves to be transgender,” they noted.

“If we had used a stricter criterion of retransition, more similar to the common use of terms like “detransition” or “desistence,” referring only to youth who are living as cisgender, then our retransition rate would have been lower (2.5%),” the researchers explained. Another limitation was the disproportionate number of trans girls, the researchers said. However, because no significant gender effect appeared in terms of retransition rates, “we do not predict any change in pattern of results if we had a different ratio of participants by sex at birth,” they said.

The researchers stated that they intend to follow the cohort through adolescence and into adulthood.

“As more youth are coming out and being supported in their transitions early in development, it is increasingly critical that clinicians understand the experiences of this cohort and not make assumptions about them as a function of older data from youth who lived under different circumstances,” the researchers emphasized. “Though we can never predict the exact gender trajectory of any child, these data suggest that many youth who identify as transgender early, and are supported through a social transition, will continue to identify as transgender 5 years after initial social transition.” They concluded that more research is needed to determine how best to support initial and later gender transitions in youth.
 

Study offers support for family discussions

“This study is important to help provide more data regarding the experiences of gender-diverse youth,” M. Brett Cooper, MD, of UT Southwestern Medical Center, Dallas, said in an interview. “The results of a study like this can be used by clinicians to help provide advice and guidance to parents and families as they support their children through their gender journey,” said Dr. Cooper, who was not involved in the study. The current study “also provides evidence to support that persistent, insistent, and consistent youth have an extremely low rate of retransition to a gender that aligns with their sex assigned at birth. This refutes suggestions by politicians and others that those who seek medical care have a high rate of regret or retransition,” Dr. Cooper emphasized.

“I was not surprised at all by their findings,” said Dr. Cooper. “These are very similar to what I have seen in my own panel of gender-diverse patients and what has been seen in other studies,” he noted.

The take-home message of the current study does not suggest any change in clinical practice, Dr. Cooper said. “Guidance already suggests supporting these youth on their gender journey and that for some youth, this may mean retransitioning to identify with their sex assigned at birth,” he explained.

The study was supported in part by grants to the researchers from the National Institutes of Health, the National Science Foundation, the Arcus Foundation, and the MacArthur Foundation. The researchers had no financial conflicts to disclose.

Approximately 7% of youth who chose gender identity social transition in early childhood had retransitioned 5 years later, based on data from 317 individuals.

“Increasing numbers of children are socially transitioning to live in line with their gender identity, rather than the gender assumed by their sex at birth – a process that typically involves changing a child’s pronouns, first name, hairstyle, and clothing,” wrote Kristina R. Olson, PhD, of Princeton (N.J.) University, and colleagues.

The question of whether early childhood social transitions will result in high rates of retransition continues to be a subject for debate, and long-term data on retransition rates and identity outcomes in children who transition are limited, they said.

To examine retransition in early-transitioning children, the researchers identified 317 binary socially transitioned transgender children to participate in a longitudinal study known as the Trans Youth Project (TYP) between July 2013 and December 2017. The study was published in Pediatrics. The mean age at baseline was 8 years. At study entry, participants had to have made a complete binary social transition, including changing their pronouns from those used at birth. During the 5-year follow-up period, children and parents were asked about use of puberty blockers and/or gender-affirming hormones. At study entry, 37 children had begun some type of puberty blockers. A total of 124 children initially socially transitioned before 6 years of age, and 193 initially socially transitioned at 6 years or older.

The study did not evaluate whether the participants met the DSM-5 criteria for gender dysphoria in childhood, the researchers noted. “Based on data collected at their initial visit, we do know that these participants showed signs of gender identification and gender-typed preferences commonly associated with their gender, not their sex assigned at birth,” they wrote.

Participants were classified as binary transgender, nonbinary, or cisgender based on their pronouns at follow-up. Binary transgender pronouns were associated with the other binary assigned sex, nonbinary pronouns were they/them or a mix of they/them and binary pronouns, and cisgender pronouns were those associated with assigned sex.

Overall, 7.3% of the participants had retransitioned at least once by 5 years after their initial binary social transition. The majority (94%) were living as binary transgender youth, including 1.3% who retransitioned to cisgender or nonbinary and then back to binary transgender during the follow-up period. A total of 2.5% were living as cisgender youth and 3.5% were living as nonbinary youth. These rates were similar across the initial population, as well as the 291 participants who continue to be in contact with the researchers, the 200 who had gone at least 5 years since their initial social transition, and the 280 participants who began the study before starting puberty blockers.

The researchers found no differences in retransition rates related to participant sex at birth. Rates of retransition were slightly higher among participants who made their initial social transition before 6 years of age, but these rates were low, the researchers noted.

The study findings were limited by several factors including the use of a volunteer community sample, with the potential for bias that may not generalize to the population at large, the researchers noted. Other limitations included the use of pronouns as the main criteria for retransition, and the classification of a change from binary transgender to nonbinary as a transition, they said. “Many nonbinary people consider themselves to be transgender,” they noted.

“If we had used a stricter criterion of retransition, more similar to the common use of terms like “detransition” or “desistence,” referring only to youth who are living as cisgender, then our retransition rate would have been lower (2.5%),” the researchers explained. Another limitation was the disproportionate number of trans girls, the researchers said. However, because no significant gender effect appeared in terms of retransition rates, “we do not predict any change in pattern of results if we had a different ratio of participants by sex at birth,” they said.

The researchers stated that they intend to follow the cohort through adolescence and into adulthood.

“As more youth are coming out and being supported in their transitions early in development, it is increasingly critical that clinicians understand the experiences of this cohort and not make assumptions about them as a function of older data from youth who lived under different circumstances,” the researchers emphasized. “Though we can never predict the exact gender trajectory of any child, these data suggest that many youth who identify as transgender early, and are supported through a social transition, will continue to identify as transgender 5 years after initial social transition.” They concluded that more research is needed to determine how best to support initial and later gender transitions in youth.
 

Study offers support for family discussions

“This study is important to help provide more data regarding the experiences of gender-diverse youth,” M. Brett Cooper, MD, of UT Southwestern Medical Center, Dallas, said in an interview. “The results of a study like this can be used by clinicians to help provide advice and guidance to parents and families as they support their children through their gender journey,” said Dr. Cooper, who was not involved in the study. The current study “also provides evidence to support that persistent, insistent, and consistent youth have an extremely low rate of retransition to a gender that aligns with their sex assigned at birth. This refutes suggestions by politicians and others that those who seek medical care have a high rate of regret or retransition,” Dr. Cooper emphasized.

“I was not surprised at all by their findings,” said Dr. Cooper. “These are very similar to what I have seen in my own panel of gender-diverse patients and what has been seen in other studies,” he noted.

The take-home message of the current study does not suggest any change in clinical practice, Dr. Cooper said. “Guidance already suggests supporting these youth on their gender journey and that for some youth, this may mean retransitioning to identify with their sex assigned at birth,” he explained.

The study was supported in part by grants to the researchers from the National Institutes of Health, the National Science Foundation, the Arcus Foundation, and the MacArthur Foundation. The researchers had no financial conflicts to disclose.

The US Preventive Services Task Force recently released its findings on screening for eating disorders—including binge eating, bulimia nervosa, and anorexia nervosa—in adolescents and adults.¹ This is the first time the Task Force has addressed this topic.

For those who have no signs or symptoms of an eating disorder, the Task Force found insufficient evidence to assess the benefits and harms of screening. Signs and symptoms of an eating disorder include rapid changes in weight (gain or loss), delayed puberty, bradycardia, oligomenorrhea, or amenorrhea.¹

Screening vs diagnostic work-up. The term screening means looking for the presence of a condition in an asymptomatic person. Those who have signs or symptoms that could be due to an eating disorder should be assessed for these conditions, but this would be classified as diagnostic testing rather than preventive screening.

Relatively uncommon but serious. The estimated lifetime prevalence of anorexia is 1.42% in women and 0.12% in men; for bulimia, 0.46% in women and 0.08% in men; and for binge eating, 1.25% in women and 0.42% in men.¹ Those suspected of having an eating disorder need psychological, behavioral, medical, and nutritional care provided by those with expertise in diagnosing and treating these disorders. (A systematic review of treatment options was recently published in American Family Physician.²)

If you suspect an eating disorder … Several tools for the assessment of eating disorders have been described in the literature, including the Eating Disorder Screen for Primary Care (EDS-PC) tool, but the Task Force identified enough evidence to comment on the accuracy of only one: the SCOFF questionnaire. There is adequate evidence on its accuracy for use in adult women but not in adolescents or males.¹

The SCOFF tool, which originated in the United Kingdom, consists of 5 questions³:

• Do you make yourself Sick because you feel uncomfortably full?
• Do you worry that you have lost Control over how much you eat?
• Have you recently lost more than One stone (14 lb) in a 3-month period?
• Do you believe yourself to be Fat when others say you are too thin?
• Would you say that Food dominates your life?

A threshold of 2 or more “Yes” answers on the SCOFF questionnaire has a pooled sensitivity of 84% for all 3 disorders combined and a pooled specificity of 80%.⁴

What should you do routinely? For adolescents and adults who have no indication of an eating disorder, there is no proven value to screening. Measuring height and weight, calculating body mass index, and continuing to track these measurements for all patients over time is considered standard practice. For those patients who have signs or symptoms that could be due to an eating disorder, administer the SCOFF tool; further assess those with 2 or more positive responses, and refer for diagnosis and treatment those suspected of having an eating disorder.

The US Preventive Services Task Force recently released its findings on screening for eating disorders—including binge eating, bulimia nervosa, and anorexia nervosa—in adolescents and adults.¹ This is the first time the Task Force has addressed this topic.

For those who have no signs or symptoms of an eating disorder, the Task Force found insufficient evidence to assess the benefits and harms of screening. Signs and symptoms of an eating disorder include rapid changes in weight (gain or loss), delayed puberty, bradycardia, oligomenorrhea, or amenorrhea.¹

Screening vs diagnostic work-up. The term screening means looking for the presence of a condition in an asymptomatic person. Those who have signs or symptoms that could be due to an eating disorder should be assessed for these conditions, but this would be classified as diagnostic testing rather than preventive screening.

Relatively uncommon but serious. The estimated lifetime prevalence of anorexia is 1.42% in women and 0.12% in men; for bulimia, 0.46% in women and 0.08% in men; and for binge eating, 1.25% in women and 0.42% in men.¹ Those suspected of having an eating disorder need psychological, behavioral, medical, and nutritional care provided by those with expertise in diagnosing and treating these disorders. (A systematic review of treatment options was recently published in American Family Physician.²)

If you suspect an eating disorder … Several tools for the assessment of eating disorders have been described in the literature, including the Eating Disorder Screen for Primary Care (EDS-PC) tool, but the Task Force identified enough evidence to comment on the accuracy of only one: the SCOFF questionnaire. There is adequate evidence on its accuracy for use in adult women but not in adolescents or males.¹

The SCOFF tool, which originated in the United Kingdom, consists of 5 questions³:

• Do you make yourself Sick because you feel uncomfortably full?
• Do you worry that you have lost Control over how much you eat?
• Have you recently lost more than One stone (14 lb) in a 3-month period?
• Do you believe yourself to be Fat when others say you are too thin?
• Would you say that Food dominates your life?

A threshold of 2 or more “Yes” answers on the SCOFF questionnaire has a pooled sensitivity of 84% for all 3 disorders combined and a pooled specificity of 80%.⁴

What should you do routinely? For adolescents and adults who have no indication of an eating disorder, there is no proven value to screening. Measuring height and weight, calculating body mass index, and continuing to track these measurements for all patients over time is considered standard practice. For those patients who have signs or symptoms that could be due to an eating disorder, administer the SCOFF tool; further assess those with 2 or more positive responses, and refer for diagnosis and treatment those suspected of having an eating disorder.

The US Preventive Services Task Force recently released its findings on screening for eating disorders—including binge eating, bulimia nervosa, and anorexia nervosa—in adolescents and adults.¹ This is the first time the Task Force has addressed this topic.

For those who have no signs or symptoms of an eating disorder, the Task Force found insufficient evidence to assess the benefits and harms of screening. Signs and symptoms of an eating disorder include rapid changes in weight (gain or loss), delayed puberty, bradycardia, oligomenorrhea, or amenorrhea.¹

Screening vs diagnostic work-up. The term screening means looking for the presence of a condition in an asymptomatic person. Those who have signs or symptoms that could be due to an eating disorder should be assessed for these conditions, but this would be classified as diagnostic testing rather than preventive screening.

Relatively uncommon but serious. The estimated lifetime prevalence of anorexia is 1.42% in women and 0.12% in men; for bulimia, 0.46% in women and 0.08% in men; and for binge eating, 1.25% in women and 0.42% in men.¹ Those suspected of having an eating disorder need psychological, behavioral, medical, and nutritional care provided by those with expertise in diagnosing and treating these disorders. (A systematic review of treatment options was recently published in American Family Physician.²)

If you suspect an eating disorder … Several tools for the assessment of eating disorders have been described in the literature, including the Eating Disorder Screen for Primary Care (EDS-PC) tool, but the Task Force identified enough evidence to comment on the accuracy of only one: the SCOFF questionnaire. There is adequate evidence on its accuracy for use in adult women but not in adolescents or males.¹

The SCOFF tool, which originated in the United Kingdom, consists of 5 questions³:

• Do you make yourself Sick because you feel uncomfortably full?
• Do you worry that you have lost Control over how much you eat?
• Have you recently lost more than One stone (14 lb) in a 3-month period?
• Do you believe yourself to be Fat when others say you are too thin?
• Would you say that Food dominates your life?

A threshold of 2 or more “Yes” answers on the SCOFF questionnaire has a pooled sensitivity of 84% for all 3 disorders combined and a pooled specificity of 80%.⁴

What should you do routinely? For adolescents and adults who have no indication of an eating disorder, there is no proven value to screening. Measuring height and weight, calculating body mass index, and continuing to track these measurements for all patients over time is considered standard practice. For those patients who have signs or symptoms that could be due to an eating disorder, administer the SCOFF tool; further assess those with 2 or more positive responses, and refer for diagnosis and treatment those suspected of having an eating disorder.

SAN DIEGO – Combining topical tyrosinase inhibitors with either a nonablative fractional laser or a fractional picosecond laser was safe and effective for treating postinflammatory hyperpigmentation (PIH) in patients with Fitzpatrick skin phototypes V and VI, results from a small retrospective case series suggest.

“Postinflammatory hyperpigmentation is a leading chief of complaint of many skin of color persons seeking a dermatologist,” Elizabeth J. Kream, MD, told this news organization in advance of the annual conference of American Society for Laser Medicine and Surgery. “I describe PIH to patients as the ‘ashes after a fire is extinguished.’ It’s the stubborn brown to gray/black spots that persist after conditions like acne and folliculitis, but it can be caused by any insult to the skin including external injury. In fact, there’s a risk of inciting PIH with lasers and energy-based devices and this risk is greater in skin of color given the greater melanin content. Unfortunately, we see patients present after visiting a med spa who were treated with the wrong devices and/or the wrong settings and they have disfiguring scarring and/or dyspigmentation.”

During an abstract session at the meeting, Dr. Kream, a dermatology resident at the University of Illinois at Chicago, discussed three patients with recalcitrant PIH and Fitzpatrick skin phototype V and VI who were treated in San Diego with a combination of topical and laser therapies. She presented the case series on behalf of coauthors Monica Boen, MD and Douglas C. Wu, MD, dermatologists who practice in San Diego.

The first patient was a 37-year-old Black female who presented for evaluation of longstanding hyperpigmentation on the face and neck determined to be PIH secondary to folliculitis on the chin and neck. She was started on 8% hydroquinone with kojic acid daily and received four treatments spaced 4-8 weeks apart with the 1,927-nm fractional nonablative diode laser. Laser settings were 5 mJ pulse energy and 5% coverage after eight passes. Triamcinolone 0.1% ointment was applied immediately after treatment and for 3 days following treatment, and the “patient experienced near complete resolution of PIH with no unexpected adverse events,” Dr. Kream said.

The second patient was a 20-year-old Black male who presented with a 3-month history of facial hyperpigmentation after suffering a laser-induced injury. He was started on a non-hydroquinone topical lightening agent and received five treatments spaced 2 weeks apart with a 1,927-nm fractional nonablative diode laser. The laser settings were 5 mJ pulse energy and 5% coverage after eight passes. The patient experienced 80%-90% resolution of his PIH with no unexpected adverse reactions.

The third patient in the series was a 39-year-old Black male who presented with a 6-month history of hyperpigmentation on his right shin and calf, secondary to minor occupational-related trauma. Treatment was initiated with a fractional 1,064-nm picosecond laser. The laser settings were 2.1 mJ per microbeam microwave pulse energy and a 450 picosecond pulse duration delivered at 2 Hz through a holographic beam splitter with a 6 x 6–mm spot size containing 101 microbeams, for an estimated coverage of 4% per pulse. Four passes were performed for each area. The endpoint was a mild erythema to several treated areas a few minutes following laser treatment. Postoperative care consisted of applying a non-hydroquinone topical lightening agent twice daily to the affected area for 1 month. Near-complete resolution of the PIH was achieved, with no unexpected adverse reactions.

“In our clinical experience, PIH can be treated with the combination of topical skin lighteners and low density, low fluence laser therapy in almost all skin types,” Dr. Kream said. “The rationale behind this combination is to treat and remove existing pigment with the laser therapy while minimizing and preventing any pigmentary recurrence with diligent topical therapy and photoprotection.”

It is important to identify the cause of PIH “because some cases are trickier than others,” such as a lichenoid process that deposits pigment “a little bit deeper into the dermis,” she said. “When selecting an appropriate laser modality for the treatment of PIH in skin types V and VI, it’s especially important to consider the mechanism of action, depth of penetration, degree of tissue damage, and the extent of disruption to the dermal-epidermal junction.”

Following the presentation, one of the session moderators, Albert Wolkerstorfer, MD, PhD, a dermatologist at Amsterdam University Medical Center, the Netherlands, emphasized the importance of proper patient selection for laser treatment of PIH. “Not every patient with PIH is adapted to treatment with the laser,” Dr. Wolkerstorfer said. “I think it’s also important to choose stable PIH, meaning you often see patients with an underlying disorder who want to get rid of the pigment. They often believe that the laser is the solution, but it often isn’t.”

During a question-and-answer session, a meeting attendee pointed out that the study lacked a control area to compare the treatment results to. “This was a retrospective case series,” Dr. Kream replied. “I’d like to see more elegant studies in the future, with a control [area],” she said.

Dr. Kream reported having no financial disclosures, Dr. Boen has no disclosures, and Dr. Wu has conducted research for many pharmaceutical and device companies. Dr. Wolkerstorfer disclosed that he has received grant or research funding from Lumenis, Novartis, and Avita Medical, and is an advisory board member for Incyte.

SAN DIEGO – Combining topical tyrosinase inhibitors with either a nonablative fractional laser or a fractional picosecond laser was safe and effective for treating postinflammatory hyperpigmentation (PIH) in patients with Fitzpatrick skin phototypes V and VI, results from a small retrospective case series suggest.

“Postinflammatory hyperpigmentation is a leading chief of complaint of many skin of color persons seeking a dermatologist,” Elizabeth J. Kream, MD, told this news organization in advance of the annual conference of American Society for Laser Medicine and Surgery. “I describe PIH to patients as the ‘ashes after a fire is extinguished.’ It’s the stubborn brown to gray/black spots that persist after conditions like acne and folliculitis, but it can be caused by any insult to the skin including external injury. In fact, there’s a risk of inciting PIH with lasers and energy-based devices and this risk is greater in skin of color given the greater melanin content. Unfortunately, we see patients present after visiting a med spa who were treated with the wrong devices and/or the wrong settings and they have disfiguring scarring and/or dyspigmentation.”

During an abstract session at the meeting, Dr. Kream, a dermatology resident at the University of Illinois at Chicago, discussed three patients with recalcitrant PIH and Fitzpatrick skin phototype V and VI who were treated in San Diego with a combination of topical and laser therapies. She presented the case series on behalf of coauthors Monica Boen, MD and Douglas C. Wu, MD, dermatologists who practice in San Diego.

The first patient was a 37-year-old Black female who presented for evaluation of longstanding hyperpigmentation on the face and neck determined to be PIH secondary to folliculitis on the chin and neck. She was started on 8% hydroquinone with kojic acid daily and received four treatments spaced 4-8 weeks apart with the 1,927-nm fractional nonablative diode laser. Laser settings were 5 mJ pulse energy and 5% coverage after eight passes. Triamcinolone 0.1% ointment was applied immediately after treatment and for 3 days following treatment, and the “patient experienced near complete resolution of PIH with no unexpected adverse events,” Dr. Kream said.

The second patient was a 20-year-old Black male who presented with a 3-month history of facial hyperpigmentation after suffering a laser-induced injury. He was started on a non-hydroquinone topical lightening agent and received five treatments spaced 2 weeks apart with a 1,927-nm fractional nonablative diode laser. The laser settings were 5 mJ pulse energy and 5% coverage after eight passes. The patient experienced 80%-90% resolution of his PIH with no unexpected adverse reactions.

The third patient in the series was a 39-year-old Black male who presented with a 6-month history of hyperpigmentation on his right shin and calf, secondary to minor occupational-related trauma. Treatment was initiated with a fractional 1,064-nm picosecond laser. The laser settings were 2.1 mJ per microbeam microwave pulse energy and a 450 picosecond pulse duration delivered at 2 Hz through a holographic beam splitter with a 6 x 6–mm spot size containing 101 microbeams, for an estimated coverage of 4% per pulse. Four passes were performed for each area. The endpoint was a mild erythema to several treated areas a few minutes following laser treatment. Postoperative care consisted of applying a non-hydroquinone topical lightening agent twice daily to the affected area for 1 month. Near-complete resolution of the PIH was achieved, with no unexpected adverse reactions.

“In our clinical experience, PIH can be treated with the combination of topical skin lighteners and low density, low fluence laser therapy in almost all skin types,” Dr. Kream said. “The rationale behind this combination is to treat and remove existing pigment with the laser therapy while minimizing and preventing any pigmentary recurrence with diligent topical therapy and photoprotection.”

It is important to identify the cause of PIH “because some cases are trickier than others,” such as a lichenoid process that deposits pigment “a little bit deeper into the dermis,” she said. “When selecting an appropriate laser modality for the treatment of PIH in skin types V and VI, it’s especially important to consider the mechanism of action, depth of penetration, degree of tissue damage, and the extent of disruption to the dermal-epidermal junction.”

Following the presentation, one of the session moderators, Albert Wolkerstorfer, MD, PhD, a dermatologist at Amsterdam University Medical Center, the Netherlands, emphasized the importance of proper patient selection for laser treatment of PIH. “Not every patient with PIH is adapted to treatment with the laser,” Dr. Wolkerstorfer said. “I think it’s also important to choose stable PIH, meaning you often see patients with an underlying disorder who want to get rid of the pigment. They often believe that the laser is the solution, but it often isn’t.”

During a question-and-answer session, a meeting attendee pointed out that the study lacked a control area to compare the treatment results to. “This was a retrospective case series,” Dr. Kream replied. “I’d like to see more elegant studies in the future, with a control [area],” she said.

Dr. Kream reported having no financial disclosures, Dr. Boen has no disclosures, and Dr. Wu has conducted research for many pharmaceutical and device companies. Dr. Wolkerstorfer disclosed that he has received grant or research funding from Lumenis, Novartis, and Avita Medical, and is an advisory board member for Incyte.

SAN DIEGO – Combining topical tyrosinase inhibitors with either a nonablative fractional laser or a fractional picosecond laser was safe and effective for treating postinflammatory hyperpigmentation (PIH) in patients with Fitzpatrick skin phototypes V and VI, results from a small retrospective case series suggest.

“Postinflammatory hyperpigmentation is a leading chief of complaint of many skin of color persons seeking a dermatologist,” Elizabeth J. Kream, MD, told this news organization in advance of the annual conference of American Society for Laser Medicine and Surgery. “I describe PIH to patients as the ‘ashes after a fire is extinguished.’ It’s the stubborn brown to gray/black spots that persist after conditions like acne and folliculitis, but it can be caused by any insult to the skin including external injury. In fact, there’s a risk of inciting PIH with lasers and energy-based devices and this risk is greater in skin of color given the greater melanin content. Unfortunately, we see patients present after visiting a med spa who were treated with the wrong devices and/or the wrong settings and they have disfiguring scarring and/or dyspigmentation.”

During an abstract session at the meeting, Dr. Kream, a dermatology resident at the University of Illinois at Chicago, discussed three patients with recalcitrant PIH and Fitzpatrick skin phototype V and VI who were treated in San Diego with a combination of topical and laser therapies. She presented the case series on behalf of coauthors Monica Boen, MD and Douglas C. Wu, MD, dermatologists who practice in San Diego.

The first patient was a 37-year-old Black female who presented for evaluation of longstanding hyperpigmentation on the face and neck determined to be PIH secondary to folliculitis on the chin and neck. She was started on 8% hydroquinone with kojic acid daily and received four treatments spaced 4-8 weeks apart with the 1,927-nm fractional nonablative diode laser. Laser settings were 5 mJ pulse energy and 5% coverage after eight passes. Triamcinolone 0.1% ointment was applied immediately after treatment and for 3 days following treatment, and the “patient experienced near complete resolution of PIH with no unexpected adverse events,” Dr. Kream said.

The second patient was a 20-year-old Black male who presented with a 3-month history of facial hyperpigmentation after suffering a laser-induced injury. He was started on a non-hydroquinone topical lightening agent and received five treatments spaced 2 weeks apart with a 1,927-nm fractional nonablative diode laser. The laser settings were 5 mJ pulse energy and 5% coverage after eight passes. The patient experienced 80%-90% resolution of his PIH with no unexpected adverse reactions.

The third patient in the series was a 39-year-old Black male who presented with a 6-month history of hyperpigmentation on his right shin and calf, secondary to minor occupational-related trauma. Treatment was initiated with a fractional 1,064-nm picosecond laser. The laser settings were 2.1 mJ per microbeam microwave pulse energy and a 450 picosecond pulse duration delivered at 2 Hz through a holographic beam splitter with a 6 x 6–mm spot size containing 101 microbeams, for an estimated coverage of 4% per pulse. Four passes were performed for each area. The endpoint was a mild erythema to several treated areas a few minutes following laser treatment. Postoperative care consisted of applying a non-hydroquinone topical lightening agent twice daily to the affected area for 1 month. Near-complete resolution of the PIH was achieved, with no unexpected adverse reactions.

“In our clinical experience, PIH can be treated with the combination of topical skin lighteners and low density, low fluence laser therapy in almost all skin types,” Dr. Kream said. “The rationale behind this combination is to treat and remove existing pigment with the laser therapy while minimizing and preventing any pigmentary recurrence with diligent topical therapy and photoprotection.”

It is important to identify the cause of PIH “because some cases are trickier than others,” such as a lichenoid process that deposits pigment “a little bit deeper into the dermis,” she said. “When selecting an appropriate laser modality for the treatment of PIH in skin types V and VI, it’s especially important to consider the mechanism of action, depth of penetration, degree of tissue damage, and the extent of disruption to the dermal-epidermal junction.”

Following the presentation, one of the session moderators, Albert Wolkerstorfer, MD, PhD, a dermatologist at Amsterdam University Medical Center, the Netherlands, emphasized the importance of proper patient selection for laser treatment of PIH. “Not every patient with PIH is adapted to treatment with the laser,” Dr. Wolkerstorfer said. “I think it’s also important to choose stable PIH, meaning you often see patients with an underlying disorder who want to get rid of the pigment. They often believe that the laser is the solution, but it often isn’t.”

During a question-and-answer session, a meeting attendee pointed out that the study lacked a control area to compare the treatment results to. “This was a retrospective case series,” Dr. Kream replied. “I’d like to see more elegant studies in the future, with a control [area],” she said.

Dr. Kream reported having no financial disclosures, Dr. Boen has no disclosures, and Dr. Wu has conducted research for many pharmaceutical and device companies. Dr. Wolkerstorfer disclosed that he has received grant or research funding from Lumenis, Novartis, and Avita Medical, and is an advisory board member for Incyte.

BOZEMAN, Mont. – In a busy downtown coffee shop, a drawing of a ski lift with intrauterine devices for chairs draws the eyes of sleepy customers getting their morning underway with a caffeine jolt.

The flyer touts the services of Bridgercare, a nonprofit reproductive health clinic a few miles up the road. The clinic offers wellness exams, birth control, and LGBTQ+ services – and, starting in April, it oversees the state’s multimillion-dollar share of federal family planning program funding.

In March, Bridgercare beat out the state health department to become administrator of Montana’s $2.3 million Title X program, which helps pay for family planning and preventive health services. The organization applied for the grant because its leaders were concerned about a new state law that sought to restrict which local providers are funded.

What is happening in Montana is the latest example of an ongoing power struggle between nonprofits and conservative-leaning states over who receives federal family planning money. That has intensified in recent years as the Title X program has increasingly become entangled with the politics of abortion.

This year, the federal government set aside $257 million for family planning and preventive care. The providers that get that funding often serve families with low incomes, and Title X is one of the few federal programs in which people without legal permission to be in the United States can participate.

“The program permeates into communities that otherwise would be unreached by public health efforts,” said Rebecca Kreitzer, an associate professor of public policy at the University of North Carolina at Chapel Hill.

The Montana Department of Public Health and Human Services controlled the distribution of the state’s Title X funds for decades. Bridgercare sought the administrator role to circumvent a Republican-sponsored law passed last year that required the state to prioritize the money for local health departments and federally qualified health centers. That would have put the nonprofit – which doesn’t provide abortion procedures – and similar organizations at the bottom of the list. The law also banned clinics that perform abortions from receiving Title X funds from the state health department.

Bridgercare Executive Director Stephanie McDowell said the group applied for the grant to try to protect the program from decisions coming out of the state capitol. “Because of the politicization of Title X, we’re seeing how it’s run, swinging back and forth based on partisan leadership,” Ms. McDowell said.

A U.S. Department of Health & Human Services spokesperson, Tara Broido, didn’t answer a question about whether the agency intentionally awarded grants to nonprofits to avoid state politics. Instead, she said in a statement that applicants were evaluated in a competitive process by a panel of independent reviewers based on criteria to deliver high-quality, client-centered services.

Federal law prohibits the money from being used to perform abortions. But it can cover other services provided by groups that offer abortions – the largest and best-known by far is Planned Parenthood. In recent years, conservative politicians have tried to keep such providers from receiving Title X funding.

In some cases, contraception has entered the debate around which family planning services government should help fund. Some abortion opponents have raised concerns that long-lasting forms of birth control, such as IUDs, lead to abortions. Those claims are disputed by reproductive health experts.

In 2019, the Trump administration introduced several new rules for Title X, including disqualifying from receiving the funding family planning clinics that also offered abortion services or referrals. Many clinics across the nation left the program instead of conforming to the rules. Simultaneously, the spread of COVID-19 interrupted routine care. The number of patients served by Title X plummeted.

The Biden administration reversed most of those rules, including allowing providers with abortion services back into the Title X program. States also try to influence the funding’s reach, either through legislation or budget rules.

The current Title X funding cycle is 5 years, and the amount of money available each year could shift based on the state’s network of providers or federal budget changes. Jon Ebelt, a spokesperson for the Montana Department of Public Health and Human Services, didn’t answer when asked whether the state planned to reapply to administer the funding in 2027. He said the department was disappointed with the Biden administration’s “refusal” to renew the state’s funding.

“We recognize, however, that recent proabortion federal rule changes have distorted Title X and conflict with Montana law,” he said.

Conservative states have been tangling with nonprofits and the federal government over Title X funding for more than a decade. In 2011, during the Obama administration, Texas whittled down the state’s family planning spending and prioritized sending the federal money to general primary care providers over reproductive health clinics. As a result, 25% of family planning clinics in Texas closed. In 2013, a nonprofit now called Every Body Texas joined the competition to distribute the state’s Title X dollars and won.

“Filling and rebuilding those holes have taken this last decade, essentially,” said Berna Mason, director of service delivery improvement for Every Body Texas.

In 2019, the governor of Nebraska proposed a budget that would have prohibited the money from going to any organization that provided abortions or referred patients for abortions outside of an emergency. It also would have required that funding recipients be legally and financially separate from such clinics, a restriction that would have gone further than the Trump administration’s rules. Afterward, a family planning council won the right to administer Title X money.

In 2017, the nonprofit Arizona Family Health Partnership lost its status as that state’s only Title X administrator when the state health department was given 25% of the funding to deliver to providers. That came after Arizona lawmakers ordered the department to apply for the funds and distribute them first to state- or county-owned clinics, with the remaining money going to primary care facilities. The change was backed by groups that were opposed to abortion, and reproductive health care providers saw it as an attempt to weaken clinics that offer abortion services.

However, the state left nearly all the money it received untouched, and although it’s still required by law to apply for Title X funding, it hasn’t received a portion of the grant since.

Bré Thomas, CEO of Arizona Family Health Partnership, said that, even though the nonprofit is the sole administrator of the Title X funding again, the threat remains that some or all could be taken away because of politics. “We’re at the will of who’s in charge,” Ms. Thomas said.

Nonprofits say they have an advantage over state agencies in expanding services because they have more flexibility in fundraising and fewer administrative hurdles.

In April, Mississippi nonprofit Converge took over administration of Title X funds, a role the state had held for decades. The organization’s founders said they weren’t worried that conservative politicians would restrict access to services but simply believed they could do a better job. “Service quality was very low, and it was very hard to get appointments,” said cofounder Danielle Lampton.

A Mississippi State Department of Health spokesperson, Liz Sharlot, said the agency looks forward to working with Converge.

In Montana, Bridgercare plans to restore funding to Planned Parenthood clinics that have been cut off from the program since 2019, recruit more health centers to participate, and expand the program’s reach in rural, frontier, and tribal communities using telehealth services, Ms. McDowell said.

The organization’s goal is to increase the number of patients benefiting from the federal program by at least 10% in each year of the 5-year grant cycle. The clinic also plans to apply to keep its Title X role beyond this grant.

“In 5 years, our grant application should be a clear front-runner for funding,” she said. “It’s less about ‘How do we beat someone in 5 years?’ And more about ‘How do we grow this program to serve patients?’”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

BOZEMAN, Mont. – In a busy downtown coffee shop, a drawing of a ski lift with intrauterine devices for chairs draws the eyes of sleepy customers getting their morning underway with a caffeine jolt.

The flyer touts the services of Bridgercare, a nonprofit reproductive health clinic a few miles up the road. The clinic offers wellness exams, birth control, and LGBTQ+ services – and, starting in April, it oversees the state’s multimillion-dollar share of federal family planning program funding.

In March, Bridgercare beat out the state health department to become administrator of Montana’s $2.3 million Title X program, which helps pay for family planning and preventive health services. The organization applied for the grant because its leaders were concerned about a new state law that sought to restrict which local providers are funded.

What is happening in Montana is the latest example of an ongoing power struggle between nonprofits and conservative-leaning states over who receives federal family planning money. That has intensified in recent years as the Title X program has increasingly become entangled with the politics of abortion.

This year, the federal government set aside $257 million for family planning and preventive care. The providers that get that funding often serve families with low incomes, and Title X is one of the few federal programs in which people without legal permission to be in the United States can participate.

“The program permeates into communities that otherwise would be unreached by public health efforts,” said Rebecca Kreitzer, an associate professor of public policy at the University of North Carolina at Chapel Hill.

The Montana Department of Public Health and Human Services controlled the distribution of the state’s Title X funds for decades. Bridgercare sought the administrator role to circumvent a Republican-sponsored law passed last year that required the state to prioritize the money for local health departments and federally qualified health centers. That would have put the nonprofit – which doesn’t provide abortion procedures – and similar organizations at the bottom of the list. The law also banned clinics that perform abortions from receiving Title X funds from the state health department.

Bridgercare Executive Director Stephanie McDowell said the group applied for the grant to try to protect the program from decisions coming out of the state capitol. “Because of the politicization of Title X, we’re seeing how it’s run, swinging back and forth based on partisan leadership,” Ms. McDowell said.

A U.S. Department of Health & Human Services spokesperson, Tara Broido, didn’t answer a question about whether the agency intentionally awarded grants to nonprofits to avoid state politics. Instead, she said in a statement that applicants were evaluated in a competitive process by a panel of independent reviewers based on criteria to deliver high-quality, client-centered services.

Federal law prohibits the money from being used to perform abortions. But it can cover other services provided by groups that offer abortions – the largest and best-known by far is Planned Parenthood. In recent years, conservative politicians have tried to keep such providers from receiving Title X funding.

In some cases, contraception has entered the debate around which family planning services government should help fund. Some abortion opponents have raised concerns that long-lasting forms of birth control, such as IUDs, lead to abortions. Those claims are disputed by reproductive health experts.

In 2019, the Trump administration introduced several new rules for Title X, including disqualifying from receiving the funding family planning clinics that also offered abortion services or referrals. Many clinics across the nation left the program instead of conforming to the rules. Simultaneously, the spread of COVID-19 interrupted routine care. The number of patients served by Title X plummeted.

The Biden administration reversed most of those rules, including allowing providers with abortion services back into the Title X program. States also try to influence the funding’s reach, either through legislation or budget rules.

The current Title X funding cycle is 5 years, and the amount of money available each year could shift based on the state’s network of providers or federal budget changes. Jon Ebelt, a spokesperson for the Montana Department of Public Health and Human Services, didn’t answer when asked whether the state planned to reapply to administer the funding in 2027. He said the department was disappointed with the Biden administration’s “refusal” to renew the state’s funding.

“We recognize, however, that recent proabortion federal rule changes have distorted Title X and conflict with Montana law,” he said.

Conservative states have been tangling with nonprofits and the federal government over Title X funding for more than a decade. In 2011, during the Obama administration, Texas whittled down the state’s family planning spending and prioritized sending the federal money to general primary care providers over reproductive health clinics. As a result, 25% of family planning clinics in Texas closed. In 2013, a nonprofit now called Every Body Texas joined the competition to distribute the state’s Title X dollars and won.

“Filling and rebuilding those holes have taken this last decade, essentially,” said Berna Mason, director of service delivery improvement for Every Body Texas.

In 2019, the governor of Nebraska proposed a budget that would have prohibited the money from going to any organization that provided abortions or referred patients for abortions outside of an emergency. It also would have required that funding recipients be legally and financially separate from such clinics, a restriction that would have gone further than the Trump administration’s rules. Afterward, a family planning council won the right to administer Title X money.

In 2017, the nonprofit Arizona Family Health Partnership lost its status as that state’s only Title X administrator when the state health department was given 25% of the funding to deliver to providers. That came after Arizona lawmakers ordered the department to apply for the funds and distribute them first to state- or county-owned clinics, with the remaining money going to primary care facilities. The change was backed by groups that were opposed to abortion, and reproductive health care providers saw it as an attempt to weaken clinics that offer abortion services.

However, the state left nearly all the money it received untouched, and although it’s still required by law to apply for Title X funding, it hasn’t received a portion of the grant since.

Bré Thomas, CEO of Arizona Family Health Partnership, said that, even though the nonprofit is the sole administrator of the Title X funding again, the threat remains that some or all could be taken away because of politics. “We’re at the will of who’s in charge,” Ms. Thomas said.

Nonprofits say they have an advantage over state agencies in expanding services because they have more flexibility in fundraising and fewer administrative hurdles.

In April, Mississippi nonprofit Converge took over administration of Title X funds, a role the state had held for decades. The organization’s founders said they weren’t worried that conservative politicians would restrict access to services but simply believed they could do a better job. “Service quality was very low, and it was very hard to get appointments,” said cofounder Danielle Lampton.

A Mississippi State Department of Health spokesperson, Liz Sharlot, said the agency looks forward to working with Converge.

In Montana, Bridgercare plans to restore funding to Planned Parenthood clinics that have been cut off from the program since 2019, recruit more health centers to participate, and expand the program’s reach in rural, frontier, and tribal communities using telehealth services, Ms. McDowell said.

The organization’s goal is to increase the number of patients benefiting from the federal program by at least 10% in each year of the 5-year grant cycle. The clinic also plans to apply to keep its Title X role beyond this grant.

“In 5 years, our grant application should be a clear front-runner for funding,” she said. “It’s less about ‘How do we beat someone in 5 years?’ And more about ‘How do we grow this program to serve patients?’”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

BOZEMAN, Mont. – In a busy downtown coffee shop, a drawing of a ski lift with intrauterine devices for chairs draws the eyes of sleepy customers getting their morning underway with a caffeine jolt.

The flyer touts the services of Bridgercare, a nonprofit reproductive health clinic a few miles up the road. The clinic offers wellness exams, birth control, and LGBTQ+ services – and, starting in April, it oversees the state’s multimillion-dollar share of federal family planning program funding.

In March, Bridgercare beat out the state health department to become administrator of Montana’s $2.3 million Title X program, which helps pay for family planning and preventive health services. The organization applied for the grant because its leaders were concerned about a new state law that sought to restrict which local providers are funded.

What is happening in Montana is the latest example of an ongoing power struggle between nonprofits and conservative-leaning states over who receives federal family planning money. That has intensified in recent years as the Title X program has increasingly become entangled with the politics of abortion.

This year, the federal government set aside $257 million for family planning and preventive care. The providers that get that funding often serve families with low incomes, and Title X is one of the few federal programs in which people without legal permission to be in the United States can participate.

“The program permeates into communities that otherwise would be unreached by public health efforts,” said Rebecca Kreitzer, an associate professor of public policy at the University of North Carolina at Chapel Hill.

The Montana Department of Public Health and Human Services controlled the distribution of the state’s Title X funds for decades. Bridgercare sought the administrator role to circumvent a Republican-sponsored law passed last year that required the state to prioritize the money for local health departments and federally qualified health centers. That would have put the nonprofit – which doesn’t provide abortion procedures – and similar organizations at the bottom of the list. The law also banned clinics that perform abortions from receiving Title X funds from the state health department.

Bridgercare Executive Director Stephanie McDowell said the group applied for the grant to try to protect the program from decisions coming out of the state capitol. “Because of the politicization of Title X, we’re seeing how it’s run, swinging back and forth based on partisan leadership,” Ms. McDowell said.

A U.S. Department of Health & Human Services spokesperson, Tara Broido, didn’t answer a question about whether the agency intentionally awarded grants to nonprofits to avoid state politics. Instead, she said in a statement that applicants were evaluated in a competitive process by a panel of independent reviewers based on criteria to deliver high-quality, client-centered services.

Federal law prohibits the money from being used to perform abortions. But it can cover other services provided by groups that offer abortions – the largest and best-known by far is Planned Parenthood. In recent years, conservative politicians have tried to keep such providers from receiving Title X funding.

In some cases, contraception has entered the debate around which family planning services government should help fund. Some abortion opponents have raised concerns that long-lasting forms of birth control, such as IUDs, lead to abortions. Those claims are disputed by reproductive health experts.

In 2019, the Trump administration introduced several new rules for Title X, including disqualifying from receiving the funding family planning clinics that also offered abortion services or referrals. Many clinics across the nation left the program instead of conforming to the rules. Simultaneously, the spread of COVID-19 interrupted routine care. The number of patients served by Title X plummeted.

The Biden administration reversed most of those rules, including allowing providers with abortion services back into the Title X program. States also try to influence the funding’s reach, either through legislation or budget rules.

The current Title X funding cycle is 5 years, and the amount of money available each year could shift based on the state’s network of providers or federal budget changes. Jon Ebelt, a spokesperson for the Montana Department of Public Health and Human Services, didn’t answer when asked whether the state planned to reapply to administer the funding in 2027. He said the department was disappointed with the Biden administration’s “refusal” to renew the state’s funding.

“We recognize, however, that recent proabortion federal rule changes have distorted Title X and conflict with Montana law,” he said.

Conservative states have been tangling with nonprofits and the federal government over Title X funding for more than a decade. In 2011, during the Obama administration, Texas whittled down the state’s family planning spending and prioritized sending the federal money to general primary care providers over reproductive health clinics. As a result, 25% of family planning clinics in Texas closed. In 2013, a nonprofit now called Every Body Texas joined the competition to distribute the state’s Title X dollars and won.

“Filling and rebuilding those holes have taken this last decade, essentially,” said Berna Mason, director of service delivery improvement for Every Body Texas.

In 2019, the governor of Nebraska proposed a budget that would have prohibited the money from going to any organization that provided abortions or referred patients for abortions outside of an emergency. It also would have required that funding recipients be legally and financially separate from such clinics, a restriction that would have gone further than the Trump administration’s rules. Afterward, a family planning council won the right to administer Title X money.

In 2017, the nonprofit Arizona Family Health Partnership lost its status as that state’s only Title X administrator when the state health department was given 25% of the funding to deliver to providers. That came after Arizona lawmakers ordered the department to apply for the funds and distribute them first to state- or county-owned clinics, with the remaining money going to primary care facilities. The change was backed by groups that were opposed to abortion, and reproductive health care providers saw it as an attempt to weaken clinics that offer abortion services.

However, the state left nearly all the money it received untouched, and although it’s still required by law to apply for Title X funding, it hasn’t received a portion of the grant since.

Bré Thomas, CEO of Arizona Family Health Partnership, said that, even though the nonprofit is the sole administrator of the Title X funding again, the threat remains that some or all could be taken away because of politics. “We’re at the will of who’s in charge,” Ms. Thomas said.

Nonprofits say they have an advantage over state agencies in expanding services because they have more flexibility in fundraising and fewer administrative hurdles.

In April, Mississippi nonprofit Converge took over administration of Title X funds, a role the state had held for decades. The organization’s founders said they weren’t worried that conservative politicians would restrict access to services but simply believed they could do a better job. “Service quality was very low, and it was very hard to get appointments,” said cofounder Danielle Lampton.

A Mississippi State Department of Health spokesperson, Liz Sharlot, said the agency looks forward to working with Converge.

In Montana, Bridgercare plans to restore funding to Planned Parenthood clinics that have been cut off from the program since 2019, recruit more health centers to participate, and expand the program’s reach in rural, frontier, and tribal communities using telehealth services, Ms. McDowell said.

The organization’s goal is to increase the number of patients benefiting from the federal program by at least 10% in each year of the 5-year grant cycle. The clinic also plans to apply to keep its Title X role beyond this grant.

“In 5 years, our grant application should be a clear front-runner for funding,” she said. “It’s less about ‘How do we beat someone in 5 years?’ And more about ‘How do we grow this program to serve patients?’”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

In a European Society for Medical Oncology Virtual Plenary session, Dr Paz-Ares and colleagues presented interim analysis of the PEARLS/KEYNOTE-091 study of adjuvant pembrolizumab. In this triple-blind phase 3 trial, 1177 patients with stage IB (tumor ≥ 4 cm) to IIIA non–small cell lung cancer (NSCLC) (per American Joint Committee on Cancer [AJCC], version 7) were randomly assigned to receive pembrolizumab vs placebo. The dual primary endpoints were disease-free survival (DFS) in the overall population and in the population with high programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥ 50%). The study met its primary endpoint where improved DFS was observed in the overall population that included lung cancers, whether they were PD-L1–negative (TPS = 0%) or –positive (TPS  ≥ 1%) (53.6 months in the pembrolizumab group vs 42.0 months in the placebo group [hazard ratio (HR) 0.76; P = .0014]). Overall survival data are not yet clear. Of note, in the interim analysis presented, the subset of patients with high PD-L1 NSCLC (TPS ≥ 50%) did not show a DFS benefit whereas in other adjuvant and neoadjuvant studies, such as IMpower010 and CheckMate 816, the subset of high PD-L1 patients appeared to derive the most benefit. The results from the high PD-L1 subset and other subsets may change with future updated analyses as more events occur. The major co-primary endpoint was clearly met with the overall population clearly showing a positive DFS benefit. The results of the PEARLS trial adds to the current landscape of systemic treatment of early-stage NSCLC where neoadjuvant chemotherapy plus nivolumab is US Food and Drug Administration (FDA)–approved for stage IB (≥ 4 cm) to IIIA resected NSCLC regardless of level of PD-L1 expression, as is adjuvant atezolizumab after consideration of adjuvant chemotherapy in patients that are PD-L1–positive (≥ 1%) on the basis of a DFS benefit observed in this population.^1,2 For the future, it is important to see if the DFS benefit observed in these studies translates into a meaningful overall survival benefit.

Plasma cfDNA Levels as a Prognostic Marker in ALK+ NSCLC in the ALEX Trial

The ALEX trial is a pivotal global phase 3 randomized control trial that demonstrated superior progression-free survival (PFS) with the next-generation ALK inhibitor alectinib compared with the first-generation ALK inhibitor crizotinib as first-line treatment of ALK-positive NSCLC (HR 0.43; 95% CI 0.32-0.58; median PFS 34.8 vs 10.9 months crizotinib).³ In a study recently published in Clinical Cancer Research, Dr Dziadziuszko and colleagues retrospectively assessed the prognostic value of baseline cell-free DNA (cfDNA) levels in patients treated in the ALEX trial. Baseline plasma for cfDNA was quantified by the Foundation ACT next-generation sequencing assay. Clinical outcomes were assessed by quantitative cfDNA level stratified by the median value. In both the alectinib and crizotinib treatment arms, patients with cfDNA levels above the median were more likely to experience disease progression (alectinib adjusted HR 2.04; 95% CI 1.07-3.89; P = .03 and crizotinib adjusted HR 1.83; 95% CI 1.11-3.00, P = .016). Though survival data are incomplete, the study also suggested survival probability was lower when baseline cfDNA was above the median in both the alectinib and crizotinib treatment arms. Regardless of cfDNA levels, PFS was improved with alectinib compared with crizotinib. Previous studies have shown the value of cfDNA analysis at the time of progression to guide further treatment and target resistance mechanisms to ALK tyrosine kinase inhibitors (TKI), such as G1202R, or bypass tract pathways, such as MET amplification.^4,5 Assessment of the EML4-ALK variant type (V1 vs V3) has been shown to associate with certain types of resistance mechanisms (ie, on target ALK mutations, such as G1202R in V3) and clinical activity of specific ALK TKI (V3 > V1 for PFS with lorlatinib).⁶ This study examining baseline cfDNA levels and clinical outcomes on the ALEX trial shows the potential utility of baseline cfDNA levels as a prognostic factor for ALK TKI.

Lorlatinib in ROS1-Rearranged NSCLC After Progression on Prior ROS1 TKI

ROS1 rearrangements represent about 1.5% of lung adenocarcinoma. In advanced disease, both crizotinib and entrectinib are FDA-approved as agents targeting ROS1 with robust PFS. The third-generation TKI lorlatinib is approved and has substantial activity in ALK-rearranged NSCLC. In a recently published retrospective real-world cohort study by Girard and colleagues (LORLATU), 80 patients with ROS1-rearranged NSCLC were treated with lorlatinib as second-line treatment or beyond and after failure on at least one prior ROS1 TKI. Median PFS was 7.1 months (95% CI 5.0-9.9) and median overall survival was 19.6 months (95% CI 12.3-27.5). The overall response rate was 45% and the disease control rate was 82%. The central nervous system response rate was 72%. There were no new safety signals. This retrospective cohort study demonstrates that lorlatinib is a major targeted therapy treatment option in ROS1-rearranged NSCLC.

Checkmate 816: Neoadjuvant Nivolumab Plus Chemotherapy in Resectable NSCLC

In this open-label, phase 3 trial, 358 patients with stage IB (T ³ 4cm) to IIIA (per AJCC v7) resectable NSCLC were randomized 1:1 to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone for three cycles, followed by surgical resection. The primary endpoints were event-free survival (EFS) and pathological complete response (pCR) (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. The median EFS was significantly increased in the nivolumab plus chemotherapy arm compared to chemotherapy alone: 31.6 months (95% CI 30.2 to not reached) vs 20.8 months (95% CI 14.0 to 26.7) (HR 0.63; 97.38% CI 0.43 to 0.91; P = .005). pCR rate was also increased in the nivolumab plus chemotherapy arm (24.0% vs 2.2%, respectively; odds ratio 13.94; 99% CI 3.49 to 55.75; P < .001). At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI 0.30 to 1.07), which currently does not meet the criterion for statistical significance. Of the randomized patients, 83.2% of those in the nivolumab-plus chemotherapy group and 75.4% of those in the chemotherapy-alone group were able to undergo surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. In an exploratory analysis, EFS was longer in patients with pCR than patients without a pCR. In a subset analysis, patients with high PD-L1 expression (³50%) stood out in terms of particular benefit (HR 0.24, 95% CI 0.10–0.61). The Checkmate 816 trial is a landmark study. Neoadjuvant nivolumab plus chemotherapy represents a new standard of care in the systemic treatment of resectable NSCLC that is at a stage that warrants systemic treatment. It is FDA approved regardless of PD-L1 expression level including PD-L1 negative (0%) patients.² Adjuvant atezolizumab after adjuvant chemotherapy is also an FDA-approved treatment option for patients that are PD-L1 positive (³1%) based upon the IMpower 010 study.¹ It will be important to assess the overall survival benefit as the trial data matures, which seems to be trending in the right direction. Additional neoadjuvant clinical trials with chemoimmunotherapy have completed accrual and some of these trials also continued PD-(L)1 immune checkpoint inhibitor therapy in the adjuvant setting after surgery. An important question for the future is if combination of PD-(L)1 immune checkpoint blockade with chemotherapy in the neoadjuvant setting along with continuation of immunotherapy in the adjuvant setting post-surgery will further improve clinical outcomes.

References

1. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-57. Doi: 10.1016/S0140-6736(21)02098-5  Source

2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. April 11, 2022. Doi: 10.1056/NEJMoa2202170 Source
    
3. Mok T, Camige DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31:1056-1064. Doi: 10.1016/j.annonc.2020.04.478 Source

4. Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20:1691-1701. Doi: 10.1016/S1470-2045(19)30655-2 Source
    
5. Lawrence MN, Tamen RM, Martinez P, et al. SPACEWALK: A remote participation study of ALK resistance leveraging plasma cell-free DNA genotyping. JTO Clin Res Rep. 2021;2:100151. Doi: 10.1016/j.jtocrr.2021.100151 Source
    
6. Lin JJ, Zhu VW, Yoda S, et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J Clin Oncol. 2018;36:1199-1206. Doi: 10.1200/JCO.2017.76.2294 Source

In a European Society for Medical Oncology Virtual Plenary session, Dr Paz-Ares and colleagues presented interim analysis of the PEARLS/KEYNOTE-091 study of adjuvant pembrolizumab. In this triple-blind phase 3 trial, 1177 patients with stage IB (tumor ≥ 4 cm) to IIIA non–small cell lung cancer (NSCLC) (per American Joint Committee on Cancer [AJCC], version 7) were randomly assigned to receive pembrolizumab vs placebo. The dual primary endpoints were disease-free survival (DFS) in the overall population and in the population with high programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥ 50%). The study met its primary endpoint where improved DFS was observed in the overall population that included lung cancers, whether they were PD-L1–negative (TPS = 0%) or –positive (TPS  ≥ 1%) (53.6 months in the pembrolizumab group vs 42.0 months in the placebo group [hazard ratio (HR) 0.76; P = .0014]). Overall survival data are not yet clear. Of note, in the interim analysis presented, the subset of patients with high PD-L1 NSCLC (TPS ≥ 50%) did not show a DFS benefit whereas in other adjuvant and neoadjuvant studies, such as IMpower010 and CheckMate 816, the subset of high PD-L1 patients appeared to derive the most benefit. The results from the high PD-L1 subset and other subsets may change with future updated analyses as more events occur. The major co-primary endpoint was clearly met with the overall population clearly showing a positive DFS benefit. The results of the PEARLS trial adds to the current landscape of systemic treatment of early-stage NSCLC where neoadjuvant chemotherapy plus nivolumab is US Food and Drug Administration (FDA)–approved for stage IB (≥ 4 cm) to IIIA resected NSCLC regardless of level of PD-L1 expression, as is adjuvant atezolizumab after consideration of adjuvant chemotherapy in patients that are PD-L1–positive (≥ 1%) on the basis of a DFS benefit observed in this population.^1,2 For the future, it is important to see if the DFS benefit observed in these studies translates into a meaningful overall survival benefit.

Plasma cfDNA Levels as a Prognostic Marker in ALK+ NSCLC in the ALEX Trial

The ALEX trial is a pivotal global phase 3 randomized control trial that demonstrated superior progression-free survival (PFS) with the next-generation ALK inhibitor alectinib compared with the first-generation ALK inhibitor crizotinib as first-line treatment of ALK-positive NSCLC (HR 0.43; 95% CI 0.32-0.58; median PFS 34.8 vs 10.9 months crizotinib).³ In a study recently published in Clinical Cancer Research, Dr Dziadziuszko and colleagues retrospectively assessed the prognostic value of baseline cell-free DNA (cfDNA) levels in patients treated in the ALEX trial. Baseline plasma for cfDNA was quantified by the Foundation ACT next-generation sequencing assay. Clinical outcomes were assessed by quantitative cfDNA level stratified by the median value. In both the alectinib and crizotinib treatment arms, patients with cfDNA levels above the median were more likely to experience disease progression (alectinib adjusted HR 2.04; 95% CI 1.07-3.89; P = .03 and crizotinib adjusted HR 1.83; 95% CI 1.11-3.00, P = .016). Though survival data are incomplete, the study also suggested survival probability was lower when baseline cfDNA was above the median in both the alectinib and crizotinib treatment arms. Regardless of cfDNA levels, PFS was improved with alectinib compared with crizotinib. Previous studies have shown the value of cfDNA analysis at the time of progression to guide further treatment and target resistance mechanisms to ALK tyrosine kinase inhibitors (TKI), such as G1202R, or bypass tract pathways, such as MET amplification.^4,5 Assessment of the EML4-ALK variant type (V1 vs V3) has been shown to associate with certain types of resistance mechanisms (ie, on target ALK mutations, such as G1202R in V3) and clinical activity of specific ALK TKI (V3 > V1 for PFS with lorlatinib).⁶ This study examining baseline cfDNA levels and clinical outcomes on the ALEX trial shows the potential utility of baseline cfDNA levels as a prognostic factor for ALK TKI.

Lorlatinib in ROS1-Rearranged NSCLC After Progression on Prior ROS1 TKI

ROS1 rearrangements represent about 1.5% of lung adenocarcinoma. In advanced disease, both crizotinib and entrectinib are FDA-approved as agents targeting ROS1 with robust PFS. The third-generation TKI lorlatinib is approved and has substantial activity in ALK-rearranged NSCLC. In a recently published retrospective real-world cohort study by Girard and colleagues (LORLATU), 80 patients with ROS1-rearranged NSCLC were treated with lorlatinib as second-line treatment or beyond and after failure on at least one prior ROS1 TKI. Median PFS was 7.1 months (95% CI 5.0-9.9) and median overall survival was 19.6 months (95% CI 12.3-27.5). The overall response rate was 45% and the disease control rate was 82%. The central nervous system response rate was 72%. There were no new safety signals. This retrospective cohort study demonstrates that lorlatinib is a major targeted therapy treatment option in ROS1-rearranged NSCLC.

Checkmate 816: Neoadjuvant Nivolumab Plus Chemotherapy in Resectable NSCLC

In this open-label, phase 3 trial, 358 patients with stage IB (T ³ 4cm) to IIIA (per AJCC v7) resectable NSCLC were randomized 1:1 to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone for three cycles, followed by surgical resection. The primary endpoints were event-free survival (EFS) and pathological complete response (pCR) (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. The median EFS was significantly increased in the nivolumab plus chemotherapy arm compared to chemotherapy alone: 31.6 months (95% CI 30.2 to not reached) vs 20.8 months (95% CI 14.0 to 26.7) (HR 0.63; 97.38% CI 0.43 to 0.91; P = .005). pCR rate was also increased in the nivolumab plus chemotherapy arm (24.0% vs 2.2%, respectively; odds ratio 13.94; 99% CI 3.49 to 55.75; P < .001). At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI 0.30 to 1.07), which currently does not meet the criterion for statistical significance. Of the randomized patients, 83.2% of those in the nivolumab-plus chemotherapy group and 75.4% of those in the chemotherapy-alone group were able to undergo surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. In an exploratory analysis, EFS was longer in patients with pCR than patients without a pCR. In a subset analysis, patients with high PD-L1 expression (³50%) stood out in terms of particular benefit (HR 0.24, 95% CI 0.10–0.61). The Checkmate 816 trial is a landmark study. Neoadjuvant nivolumab plus chemotherapy represents a new standard of care in the systemic treatment of resectable NSCLC that is at a stage that warrants systemic treatment. It is FDA approved regardless of PD-L1 expression level including PD-L1 negative (0%) patients.² Adjuvant atezolizumab after adjuvant chemotherapy is also an FDA-approved treatment option for patients that are PD-L1 positive (³1%) based upon the IMpower 010 study.¹ It will be important to assess the overall survival benefit as the trial data matures, which seems to be trending in the right direction. Additional neoadjuvant clinical trials with chemoimmunotherapy have completed accrual and some of these trials also continued PD-(L)1 immune checkpoint inhibitor therapy in the adjuvant setting after surgery. An important question for the future is if combination of PD-(L)1 immune checkpoint blockade with chemotherapy in the neoadjuvant setting along with continuation of immunotherapy in the adjuvant setting post-surgery will further improve clinical outcomes.

References

1. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-57. Doi: 10.1016/S0140-6736(21)02098-5  Source

2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. April 11, 2022. Doi: 10.1056/NEJMoa2202170 Source
    
3. Mok T, Camige DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31:1056-1064. Doi: 10.1016/j.annonc.2020.04.478 Source

4. Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20:1691-1701. Doi: 10.1016/S1470-2045(19)30655-2 Source
    
5. Lawrence MN, Tamen RM, Martinez P, et al. SPACEWALK: A remote participation study of ALK resistance leveraging plasma cell-free DNA genotyping. JTO Clin Res Rep. 2021;2:100151. Doi: 10.1016/j.jtocrr.2021.100151 Source
    
6. Lin JJ, Zhu VW, Yoda S, et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J Clin Oncol. 2018;36:1199-1206. Doi: 10.1200/JCO.2017.76.2294 Source

In a European Society for Medical Oncology Virtual Plenary session, Dr Paz-Ares and colleagues presented interim analysis of the PEARLS/KEYNOTE-091 study of adjuvant pembrolizumab. In this triple-blind phase 3 trial, 1177 patients with stage IB (tumor ≥ 4 cm) to IIIA non–small cell lung cancer (NSCLC) (per American Joint Committee on Cancer [AJCC], version 7) were randomly assigned to receive pembrolizumab vs placebo. The dual primary endpoints were disease-free survival (DFS) in the overall population and in the population with high programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥ 50%). The study met its primary endpoint where improved DFS was observed in the overall population that included lung cancers, whether they were PD-L1–negative (TPS = 0%) or –positive (TPS  ≥ 1%) (53.6 months in the pembrolizumab group vs 42.0 months in the placebo group [hazard ratio (HR) 0.76; P = .0014]). Overall survival data are not yet clear. Of note, in the interim analysis presented, the subset of patients with high PD-L1 NSCLC (TPS ≥ 50%) did not show a DFS benefit whereas in other adjuvant and neoadjuvant studies, such as IMpower010 and CheckMate 816, the subset of high PD-L1 patients appeared to derive the most benefit. The results from the high PD-L1 subset and other subsets may change with future updated analyses as more events occur. The major co-primary endpoint was clearly met with the overall population clearly showing a positive DFS benefit. The results of the PEARLS trial adds to the current landscape of systemic treatment of early-stage NSCLC where neoadjuvant chemotherapy plus nivolumab is US Food and Drug Administration (FDA)–approved for stage IB (≥ 4 cm) to IIIA resected NSCLC regardless of level of PD-L1 expression, as is adjuvant atezolizumab after consideration of adjuvant chemotherapy in patients that are PD-L1–positive (≥ 1%) on the basis of a DFS benefit observed in this population.^1,2 For the future, it is important to see if the DFS benefit observed in these studies translates into a meaningful overall survival benefit.

Plasma cfDNA Levels as a Prognostic Marker in ALK+ NSCLC in the ALEX Trial

The ALEX trial is a pivotal global phase 3 randomized control trial that demonstrated superior progression-free survival (PFS) with the next-generation ALK inhibitor alectinib compared with the first-generation ALK inhibitor crizotinib as first-line treatment of ALK-positive NSCLC (HR 0.43; 95% CI 0.32-0.58; median PFS 34.8 vs 10.9 months crizotinib).³ In a study recently published in Clinical Cancer Research, Dr Dziadziuszko and colleagues retrospectively assessed the prognostic value of baseline cell-free DNA (cfDNA) levels in patients treated in the ALEX trial. Baseline plasma for cfDNA was quantified by the Foundation ACT next-generation sequencing assay. Clinical outcomes were assessed by quantitative cfDNA level stratified by the median value. In both the alectinib and crizotinib treatment arms, patients with cfDNA levels above the median were more likely to experience disease progression (alectinib adjusted HR 2.04; 95% CI 1.07-3.89; P = .03 and crizotinib adjusted HR 1.83; 95% CI 1.11-3.00, P = .016). Though survival data are incomplete, the study also suggested survival probability was lower when baseline cfDNA was above the median in both the alectinib and crizotinib treatment arms. Regardless of cfDNA levels, PFS was improved with alectinib compared with crizotinib. Previous studies have shown the value of cfDNA analysis at the time of progression to guide further treatment and target resistance mechanisms to ALK tyrosine kinase inhibitors (TKI), such as G1202R, or bypass tract pathways, such as MET amplification.^4,5 Assessment of the EML4-ALK variant type (V1 vs V3) has been shown to associate with certain types of resistance mechanisms (ie, on target ALK mutations, such as G1202R in V3) and clinical activity of specific ALK TKI (V3 > V1 for PFS with lorlatinib).⁶ This study examining baseline cfDNA levels and clinical outcomes on the ALEX trial shows the potential utility of baseline cfDNA levels as a prognostic factor for ALK TKI.

Lorlatinib in ROS1-Rearranged NSCLC After Progression on Prior ROS1 TKI

ROS1 rearrangements represent about 1.5% of lung adenocarcinoma. In advanced disease, both crizotinib and entrectinib are FDA-approved as agents targeting ROS1 with robust PFS. The third-generation TKI lorlatinib is approved and has substantial activity in ALK-rearranged NSCLC. In a recently published retrospective real-world cohort study by Girard and colleagues (LORLATU), 80 patients with ROS1-rearranged NSCLC were treated with lorlatinib as second-line treatment or beyond and after failure on at least one prior ROS1 TKI. Median PFS was 7.1 months (95% CI 5.0-9.9) and median overall survival was 19.6 months (95% CI 12.3-27.5). The overall response rate was 45% and the disease control rate was 82%. The central nervous system response rate was 72%. There were no new safety signals. This retrospective cohort study demonstrates that lorlatinib is a major targeted therapy treatment option in ROS1-rearranged NSCLC.

Checkmate 816: Neoadjuvant Nivolumab Plus Chemotherapy in Resectable NSCLC

In this open-label, phase 3 trial, 358 patients with stage IB (T ³ 4cm) to IIIA (per AJCC v7) resectable NSCLC were randomized 1:1 to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone for three cycles, followed by surgical resection. The primary endpoints were event-free survival (EFS) and pathological complete response (pCR) (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. The median EFS was significantly increased in the nivolumab plus chemotherapy arm compared to chemotherapy alone: 31.6 months (95% CI 30.2 to not reached) vs 20.8 months (95% CI 14.0 to 26.7) (HR 0.63; 97.38% CI 0.43 to 0.91; P = .005). pCR rate was also increased in the nivolumab plus chemotherapy arm (24.0% vs 2.2%, respectively; odds ratio 13.94; 99% CI 3.49 to 55.75; P < .001). At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI 0.30 to 1.07), which currently does not meet the criterion for statistical significance. Of the randomized patients, 83.2% of those in the nivolumab-plus chemotherapy group and 75.4% of those in the chemotherapy-alone group were able to undergo surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. In an exploratory analysis, EFS was longer in patients with pCR than patients without a pCR. In a subset analysis, patients with high PD-L1 expression (³50%) stood out in terms of particular benefit (HR 0.24, 95% CI 0.10–0.61). The Checkmate 816 trial is a landmark study. Neoadjuvant nivolumab plus chemotherapy represents a new standard of care in the systemic treatment of resectable NSCLC that is at a stage that warrants systemic treatment. It is FDA approved regardless of PD-L1 expression level including PD-L1 negative (0%) patients.² Adjuvant atezolizumab after adjuvant chemotherapy is also an FDA-approved treatment option for patients that are PD-L1 positive (³1%) based upon the IMpower 010 study.¹ It will be important to assess the overall survival benefit as the trial data matures, which seems to be trending in the right direction. Additional neoadjuvant clinical trials with chemoimmunotherapy have completed accrual and some of these trials also continued PD-(L)1 immune checkpoint inhibitor therapy in the adjuvant setting after surgery. An important question for the future is if combination of PD-(L)1 immune checkpoint blockade with chemotherapy in the neoadjuvant setting along with continuation of immunotherapy in the adjuvant setting post-surgery will further improve clinical outcomes.

References

1. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-57. Doi: 10.1016/S0140-6736(21)02098-5  Source

2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. April 11, 2022. Doi: 10.1056/NEJMoa2202170 Source
    
3. Mok T, Camige DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31:1056-1064. Doi: 10.1016/j.annonc.2020.04.478 Source

4. Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20:1691-1701. Doi: 10.1016/S1470-2045(19)30655-2 Source
    
5. Lawrence MN, Tamen RM, Martinez P, et al. SPACEWALK: A remote participation study of ALK resistance leveraging plasma cell-free DNA genotyping. JTO Clin Res Rep. 2021;2:100151. Doi: 10.1016/j.jtocrr.2021.100151 Source
    
6. Lin JJ, Zhu VW, Yoda S, et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J Clin Oncol. 2018;36:1199-1206. Doi: 10.1200/JCO.2017.76.2294 Source