Clinician Reviews

TOPLINE:

Dupilumab improved the signs and symptoms and quality of life in adults and adolescents with moderate to severe atopic hand and foot dermatitis compared with placebo.

METHODOLOGY:

• The multinational phase 3 LIBERTY-AD-HAFT trial of adults and adolescents with moderate to severe chronic atopic dermatitis (AD) of the hands, feet, or both included 67 participants at 48 sites randomized to dupilumab monotherapy and 66 to placebo.
• The primary endpoint was the proportion of patients scoring 0 or 1 on Hand and Foot Investigator’s Global Assessment (HF-IGA) at week 16.
• Secondary endpoints were severity and extent of signs, symptom intensity (itch and pain), sleep, and quality of life.

TAKEAWAY:

• At week 16, 27 patients receiving dupilumab vs 11 receiving placebo achieved an HF-IGA score of 0 or 1 (40.3% vs 16.7%; P = .003).
• At week 16, 35 participants receiving dupilumab vs nine receiving placebo improved at least four points in the weekly average of daily HF-Peak Pruritus Numeric Rating Scale (52.2% vs 13.6%; P < .0001).
• At week 16, Quality of Life Hand Eczema Questionnaire results improved in the dupilumab group compared with controls (P < .0001), and weekly average of daily Sleep Numeric Rating Scale results improved in the dupilumab group compared with controls (P < .05).
• The safety profile was similar to the known profile in adults and adolescents with moderate to severe AD.

IN PRACTICE:

The results of the study “support dupilumab” as an “efficacious systemic therapy for moderate to severe H/F AD,” the authors wrote.

SOURCE:

The study, led by Eric L. Simpson, MD, MCR, professor of dermatology at the Oregon Health & Science University in Portland, was published on January 29, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The short duration of the study and the large proportion of patients with positive patch tests (31 of 133) suggested that some participants may have had concurrent AD and allergic contact dermatitis, so the effect of dupilumab on those patients needs further evaluation.

DISCLOSURES:

The study was sponsored by Sanofi and Regeneron. All but one author had financial relationships with Sanofi, Regeneron, or both. Several authors were employees of, and may hold stocks or stock options in, Sanofi or Regeneron.

TOPLINE:

Dupilumab improved the signs and symptoms and quality of life in adults and adolescents with moderate to severe atopic hand and foot dermatitis compared with placebo.

METHODOLOGY:

• The multinational phase 3 LIBERTY-AD-HAFT trial of adults and adolescents with moderate to severe chronic atopic dermatitis (AD) of the hands, feet, or both included 67 participants at 48 sites randomized to dupilumab monotherapy and 66 to placebo.
• The primary endpoint was the proportion of patients scoring 0 or 1 on Hand and Foot Investigator’s Global Assessment (HF-IGA) at week 16.
• Secondary endpoints were severity and extent of signs, symptom intensity (itch and pain), sleep, and quality of life.

TAKEAWAY:

• At week 16, 27 patients receiving dupilumab vs 11 receiving placebo achieved an HF-IGA score of 0 or 1 (40.3% vs 16.7%; P = .003).
• At week 16, 35 participants receiving dupilumab vs nine receiving placebo improved at least four points in the weekly average of daily HF-Peak Pruritus Numeric Rating Scale (52.2% vs 13.6%; P < .0001).
• At week 16, Quality of Life Hand Eczema Questionnaire results improved in the dupilumab group compared with controls (P < .0001), and weekly average of daily Sleep Numeric Rating Scale results improved in the dupilumab group compared with controls (P < .05).
• The safety profile was similar to the known profile in adults and adolescents with moderate to severe AD.

IN PRACTICE:

The results of the study “support dupilumab” as an “efficacious systemic therapy for moderate to severe H/F AD,” the authors wrote.

SOURCE:

The study, led by Eric L. Simpson, MD, MCR, professor of dermatology at the Oregon Health & Science University in Portland, was published on January 29, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The short duration of the study and the large proportion of patients with positive patch tests (31 of 133) suggested that some participants may have had concurrent AD and allergic contact dermatitis, so the effect of dupilumab on those patients needs further evaluation.

DISCLOSURES:

The study was sponsored by Sanofi and Regeneron. All but one author had financial relationships with Sanofi, Regeneron, or both. Several authors were employees of, and may hold stocks or stock options in, Sanofi or Regeneron.

TOPLINE:

Dupilumab improved the signs and symptoms and quality of life in adults and adolescents with moderate to severe atopic hand and foot dermatitis compared with placebo.

METHODOLOGY:

• The multinational phase 3 LIBERTY-AD-HAFT trial of adults and adolescents with moderate to severe chronic atopic dermatitis (AD) of the hands, feet, or both included 67 participants at 48 sites randomized to dupilumab monotherapy and 66 to placebo.
• The primary endpoint was the proportion of patients scoring 0 or 1 on Hand and Foot Investigator’s Global Assessment (HF-IGA) at week 16.
• Secondary endpoints were severity and extent of signs, symptom intensity (itch and pain), sleep, and quality of life.

TAKEAWAY:

• At week 16, 27 patients receiving dupilumab vs 11 receiving placebo achieved an HF-IGA score of 0 or 1 (40.3% vs 16.7%; P = .003).
• At week 16, 35 participants receiving dupilumab vs nine receiving placebo improved at least four points in the weekly average of daily HF-Peak Pruritus Numeric Rating Scale (52.2% vs 13.6%; P < .0001).
• At week 16, Quality of Life Hand Eczema Questionnaire results improved in the dupilumab group compared with controls (P < .0001), and weekly average of daily Sleep Numeric Rating Scale results improved in the dupilumab group compared with controls (P < .05).
• The safety profile was similar to the known profile in adults and adolescents with moderate to severe AD.

IN PRACTICE:

The results of the study “support dupilumab” as an “efficacious systemic therapy for moderate to severe H/F AD,” the authors wrote.

SOURCE:

The study, led by Eric L. Simpson, MD, MCR, professor of dermatology at the Oregon Health & Science University in Portland, was published on January 29, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The short duration of the study and the large proportion of patients with positive patch tests (31 of 133) suggested that some participants may have had concurrent AD and allergic contact dermatitis, so the effect of dupilumab on those patients needs further evaluation.

DISCLOSURES:

The study was sponsored by Sanofi and Regeneron. All but one author had financial relationships with Sanofi, Regeneron, or both. Several authors were employees of, and may hold stocks or stock options in, Sanofi or Regeneron.

Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.

“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.

The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.

Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.

But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.

“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.

In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.

The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.

For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).

There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.

The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”

However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.

The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.

“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
 

Study ‘Overcomes Limitations of Prior Studies’

In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”

Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.

“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.

She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”

Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”

This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
 

A version of this article appeared on Medscape.com.

Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.

“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.

The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.

Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.

But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.

“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.

In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.

The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.

For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).

There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.

The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”

However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.

The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.

“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
 

Study ‘Overcomes Limitations of Prior Studies’

In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”

Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.

“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.

She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”

Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”

This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
 

A version of this article appeared on Medscape.com.

Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.

“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.

The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.

Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.

But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.

“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.

In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.

The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.

For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).

There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.

The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”

However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.

The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.

“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
 

Study ‘Overcomes Limitations of Prior Studies’

In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”

Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.

“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.

She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”

Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”

This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
 

A version of this article appeared on Medscape.com.

Patients with lactose intolerance are usually advised to avoid milk. However, many still consume dairy products despite experiencing gastrointestinal symptoms. Surprisingly, this "unreasonable" strategy may have the benefit of reducing the risk for type 2 diabetes, as shown in a recent American study.

“At first glance, the statement of the study seems counterintuitive,” said Robert Wagner, MD, head of the Clinical Studies Center at the German Diabetes Center-Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. “However, lactose intolerance has different manifestations.” Less severely affected individuals often consume milk and tolerate discomfort such as bloating or abdominal pain. “It is precisely these individuals that the study clearly shows have a lower incidence of diabetes associated with milk consumption,” said Dr. Wagner.
 

Milk’s Heterogeneous Effect

The effect of milk consumption on diabetes, among other factors, has been repeatedly studied in nutritional studies, with sometimes heterogeneous results in different countries. The reason for this is presumed to be that in Asia, most people — 60%-100% — are lactose intolerant, whereas in Europe, only as much as 40% of the population has lactose intolerance.

The authors, led by Kai Luo, PhD, research fellow in the Department of Epidemiology and Population Health at Albert Einstein College of Medicine in Bronx, New York, did not mention lactose tolerance and intolerance in their paper in Nature Metabolism. Instead, they divided the study population into lactase-persistent and non-lactase-persistent participants.

“Not being lactase-persistent does not necessarily exclude the ability to consume a certain amount of lactose,” said Lonneke Janssen Duijghuijsen, PhD, a nutrition scientist at Wageningen University, Wageningen, the Netherlands. “Studies have shown that many individuals who lack lactase can still consume up to 12 g of lactose per day — equivalent to the amount in a large glass of milk — without experiencing intolerance symptoms.”
 

Gut Microbiome and Metabolites

Dr. Luo and his colleagues analyzed data from 12,653 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing prospective cohort study involving adults with Hispanic backgrounds. It collects detailed information on nutrition and the occurrence of diseases.

The authors examined whether the study participants were lactase-persistent or non-lactase-persistent and how frequently they consumed milk. They also analyzed the gut microbiome and various metabolites in the blood over a median follow-up period of 6 years.

The data analysis showed that higher milk consumption in non-lactase-persistent participants — but not in lactase-persistent participants — is associated with about a 30% reduced risk for type 2 diabetes when socioeconomic, demographic, and behavioral factors are accounted for. Comparable results were obtained by Dr. Luo and his colleagues with data from the UK Biobank, which served as validation.

A higher milk consumption was associated not only with a lower diabetes risk in non-lactase-persistent individuals but also with a lower body mass index. “This could be one of the factors behind the diabetes protection,” said Dr. Wagner. “However, no formal mediation analyses were conducted in the study.”

Dr. Luo’s team primarily attributed the cause of the observed association between milk consumption and diabetes risk to the gut. Increased milk intake was also associated with changes in the gut microbiome. For example, there was an enrichment of Bifidobacterium, while Prevotella decreased. Changes were also observed in the circulating metabolites in the blood, such as an increase in indole-3-propionate and a decrease in branched-chain amino acids.

These metabolites, speculated the authors, could be more intensely produced by milk-associated bacteria and might be causally related to the association between milk consumption and reduced risk for type 2 diabetes in non-lactase-persistent individuals. “The authors have not been able to provide precise evidence of these mediators, but one possible mediator of these effects could be short-chain fatty acids, which can directly or indirectly influence appetite, insulin action, or liver fat beneficially,” said Dr. Wagner.
 

Bacteria in the Colon

For Dr. Janssen Duijghuijsen, the conclusion that milk consumption can influence the composition of the microbiome and thus the metabolic profile, especially in individuals without lactase persistence, is plausible.

“Individuals with lactase persistence efficiently digest lactose and absorb the resulting galactose and glucose molecules in the small intestine. In contrast, in non-lactase-persistent individuals, lactase is not expressed in the brush border of the small intestine. As a result, lactose remains undigested in the colon and can serve as an energy source for gut bacteria. This can influence the composition of the microbiome, which in turn can alter the concentration of circulating metabolites,” she said.

Dr. Janssen Duijghuijsen has investigated the effect of lactose intake on the microbiome. In a recently published study, she also showed that increasing lactose intake by non-lactase-persistent individuals leads to changes in the microbiome, including an increase in Bifidobacteria.

“In line with the current study, we also found a significant increase in fecal beta-galactosidase activity. Given the close relationship between the composition of the gut microbiome and the metabolite profile, it is likely that changes in one can affect the other,” said Dr. Janssen Duijghuijsen.
 

Nutritional Recommendations

The nutrition scientist warned against concluding that milk consumption can protect against type 2 diabetes in non-lactase-persistent individuals, however. “The study suggests a statistical association between milk consumption, certain metabolites, and the frequency of type 2 diabetes. These associations do not provide definitive evidence of a causal relationship,” she said. Any dietary recommendations cannot be derived from the study; much more research is needed for that.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Patients with lactose intolerance are usually advised to avoid milk. However, many still consume dairy products despite experiencing gastrointestinal symptoms. Surprisingly, this "unreasonable" strategy may have the benefit of reducing the risk for type 2 diabetes, as shown in a recent American study.

“At first glance, the statement of the study seems counterintuitive,” said Robert Wagner, MD, head of the Clinical Studies Center at the German Diabetes Center-Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. “However, lactose intolerance has different manifestations.” Less severely affected individuals often consume milk and tolerate discomfort such as bloating or abdominal pain. “It is precisely these individuals that the study clearly shows have a lower incidence of diabetes associated with milk consumption,” said Dr. Wagner.
 

Milk’s Heterogeneous Effect

The effect of milk consumption on diabetes, among other factors, has been repeatedly studied in nutritional studies, with sometimes heterogeneous results in different countries. The reason for this is presumed to be that in Asia, most people — 60%-100% — are lactose intolerant, whereas in Europe, only as much as 40% of the population has lactose intolerance.

The authors, led by Kai Luo, PhD, research fellow in the Department of Epidemiology and Population Health at Albert Einstein College of Medicine in Bronx, New York, did not mention lactose tolerance and intolerance in their paper in Nature Metabolism. Instead, they divided the study population into lactase-persistent and non-lactase-persistent participants.

“Not being lactase-persistent does not necessarily exclude the ability to consume a certain amount of lactose,” said Lonneke Janssen Duijghuijsen, PhD, a nutrition scientist at Wageningen University, Wageningen, the Netherlands. “Studies have shown that many individuals who lack lactase can still consume up to 12 g of lactose per day — equivalent to the amount in a large glass of milk — without experiencing intolerance symptoms.”
 

Gut Microbiome and Metabolites

Dr. Luo and his colleagues analyzed data from 12,653 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing prospective cohort study involving adults with Hispanic backgrounds. It collects detailed information on nutrition and the occurrence of diseases.

The authors examined whether the study participants were lactase-persistent or non-lactase-persistent and how frequently they consumed milk. They also analyzed the gut microbiome and various metabolites in the blood over a median follow-up period of 6 years.

The data analysis showed that higher milk consumption in non-lactase-persistent participants — but not in lactase-persistent participants — is associated with about a 30% reduced risk for type 2 diabetes when socioeconomic, demographic, and behavioral factors are accounted for. Comparable results were obtained by Dr. Luo and his colleagues with data from the UK Biobank, which served as validation.

A higher milk consumption was associated not only with a lower diabetes risk in non-lactase-persistent individuals but also with a lower body mass index. “This could be one of the factors behind the diabetes protection,” said Dr. Wagner. “However, no formal mediation analyses were conducted in the study.”

Dr. Luo’s team primarily attributed the cause of the observed association between milk consumption and diabetes risk to the gut. Increased milk intake was also associated with changes in the gut microbiome. For example, there was an enrichment of Bifidobacterium, while Prevotella decreased. Changes were also observed in the circulating metabolites in the blood, such as an increase in indole-3-propionate and a decrease in branched-chain amino acids.

These metabolites, speculated the authors, could be more intensely produced by milk-associated bacteria and might be causally related to the association between milk consumption and reduced risk for type 2 diabetes in non-lactase-persistent individuals. “The authors have not been able to provide precise evidence of these mediators, but one possible mediator of these effects could be short-chain fatty acids, which can directly or indirectly influence appetite, insulin action, or liver fat beneficially,” said Dr. Wagner.
 

Bacteria in the Colon

For Dr. Janssen Duijghuijsen, the conclusion that milk consumption can influence the composition of the microbiome and thus the metabolic profile, especially in individuals without lactase persistence, is plausible.

“Individuals with lactase persistence efficiently digest lactose and absorb the resulting galactose and glucose molecules in the small intestine. In contrast, in non-lactase-persistent individuals, lactase is not expressed in the brush border of the small intestine. As a result, lactose remains undigested in the colon and can serve as an energy source for gut bacteria. This can influence the composition of the microbiome, which in turn can alter the concentration of circulating metabolites,” she said.

Dr. Janssen Duijghuijsen has investigated the effect of lactose intake on the microbiome. In a recently published study, she also showed that increasing lactose intake by non-lactase-persistent individuals leads to changes in the microbiome, including an increase in Bifidobacteria.

“In line with the current study, we also found a significant increase in fecal beta-galactosidase activity. Given the close relationship between the composition of the gut microbiome and the metabolite profile, it is likely that changes in one can affect the other,” said Dr. Janssen Duijghuijsen.
 

Nutritional Recommendations

The nutrition scientist warned against concluding that milk consumption can protect against type 2 diabetes in non-lactase-persistent individuals, however. “The study suggests a statistical association between milk consumption, certain metabolites, and the frequency of type 2 diabetes. These associations do not provide definitive evidence of a causal relationship,” she said. Any dietary recommendations cannot be derived from the study; much more research is needed for that.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Patients with lactose intolerance are usually advised to avoid milk. However, many still consume dairy products despite experiencing gastrointestinal symptoms. Surprisingly, this "unreasonable" strategy may have the benefit of reducing the risk for type 2 diabetes, as shown in a recent American study.

“At first glance, the statement of the study seems counterintuitive,” said Robert Wagner, MD, head of the Clinical Studies Center at the German Diabetes Center-Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. “However, lactose intolerance has different manifestations.” Less severely affected individuals often consume milk and tolerate discomfort such as bloating or abdominal pain. “It is precisely these individuals that the study clearly shows have a lower incidence of diabetes associated with milk consumption,” said Dr. Wagner.
 

Milk’s Heterogeneous Effect

The effect of milk consumption on diabetes, among other factors, has been repeatedly studied in nutritional studies, with sometimes heterogeneous results in different countries. The reason for this is presumed to be that in Asia, most people — 60%-100% — are lactose intolerant, whereas in Europe, only as much as 40% of the population has lactose intolerance.

The authors, led by Kai Luo, PhD, research fellow in the Department of Epidemiology and Population Health at Albert Einstein College of Medicine in Bronx, New York, did not mention lactose tolerance and intolerance in their paper in Nature Metabolism. Instead, they divided the study population into lactase-persistent and non-lactase-persistent participants.

“Not being lactase-persistent does not necessarily exclude the ability to consume a certain amount of lactose,” said Lonneke Janssen Duijghuijsen, PhD, a nutrition scientist at Wageningen University, Wageningen, the Netherlands. “Studies have shown that many individuals who lack lactase can still consume up to 12 g of lactose per day — equivalent to the amount in a large glass of milk — without experiencing intolerance symptoms.”
 

Gut Microbiome and Metabolites

Dr. Luo and his colleagues analyzed data from 12,653 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing prospective cohort study involving adults with Hispanic backgrounds. It collects detailed information on nutrition and the occurrence of diseases.

The authors examined whether the study participants were lactase-persistent or non-lactase-persistent and how frequently they consumed milk. They also analyzed the gut microbiome and various metabolites in the blood over a median follow-up period of 6 years.

The data analysis showed that higher milk consumption in non-lactase-persistent participants — but not in lactase-persistent participants — is associated with about a 30% reduced risk for type 2 diabetes when socioeconomic, demographic, and behavioral factors are accounted for. Comparable results were obtained by Dr. Luo and his colleagues with data from the UK Biobank, which served as validation.

A higher milk consumption was associated not only with a lower diabetes risk in non-lactase-persistent individuals but also with a lower body mass index. “This could be one of the factors behind the diabetes protection,” said Dr. Wagner. “However, no formal mediation analyses were conducted in the study.”

Dr. Luo’s team primarily attributed the cause of the observed association between milk consumption and diabetes risk to the gut. Increased milk intake was also associated with changes in the gut microbiome. For example, there was an enrichment of Bifidobacterium, while Prevotella decreased. Changes were also observed in the circulating metabolites in the blood, such as an increase in indole-3-propionate and a decrease in branched-chain amino acids.

These metabolites, speculated the authors, could be more intensely produced by milk-associated bacteria and might be causally related to the association between milk consumption and reduced risk for type 2 diabetes in non-lactase-persistent individuals. “The authors have not been able to provide precise evidence of these mediators, but one possible mediator of these effects could be short-chain fatty acids, which can directly or indirectly influence appetite, insulin action, or liver fat beneficially,” said Dr. Wagner.
 

Bacteria in the Colon

For Dr. Janssen Duijghuijsen, the conclusion that milk consumption can influence the composition of the microbiome and thus the metabolic profile, especially in individuals without lactase persistence, is plausible.

“Individuals with lactase persistence efficiently digest lactose and absorb the resulting galactose and glucose molecules in the small intestine. In contrast, in non-lactase-persistent individuals, lactase is not expressed in the brush border of the small intestine. As a result, lactose remains undigested in the colon and can serve as an energy source for gut bacteria. This can influence the composition of the microbiome, which in turn can alter the concentration of circulating metabolites,” she said.

Dr. Janssen Duijghuijsen has investigated the effect of lactose intake on the microbiome. In a recently published study, she also showed that increasing lactose intake by non-lactase-persistent individuals leads to changes in the microbiome, including an increase in Bifidobacteria.

“In line with the current study, we also found a significant increase in fecal beta-galactosidase activity. Given the close relationship between the composition of the gut microbiome and the metabolite profile, it is likely that changes in one can affect the other,” said Dr. Janssen Duijghuijsen.
 

Nutritional Recommendations

The nutrition scientist warned against concluding that milk consumption can protect against type 2 diabetes in non-lactase-persistent individuals, however. “The study suggests a statistical association between milk consumption, certain metabolites, and the frequency of type 2 diabetes. These associations do not provide definitive evidence of a causal relationship,” she said. Any dietary recommendations cannot be derived from the study; much more research is needed for that.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

TOPLINE:

A diagnosis of type 2 diabetes (T2D) at a younger age is associated with an increased cancer risk, while the risk drops for T2D diagnosed at age 75 and older.

METHODOLOGY:

• A T2D diagnosis at a younger age is associated with a greater risk for complications and comorbidities, such as cardiovascular and kidney diseases, retinopathy, and dementia than that occurring at an older age.
• The study evaluated the association between the age at T2D diagnosis and subsequent risk for overall and 14 site-specific cancers in a Shanghai, China, cohort of 428,568 patients newly diagnosed with T2D (about half women) from 2011 to 2018.
• New cases of cancer from the T2D diagnosis to 2018 were identified through a tumor registry.
• Patients were categorized into six groups based on their age at T2D diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥ 75 years.
• The incidence rates of overall and 14 site-specific cancers were compared between patients with T2D and the general Shanghai population (older than 20 years).

TAKEAWAY:

• Compared to the general population, T2D increased the relative risk for all-cause cancer by 10% (standardized incidence ratios [SIRs], 1.10; 95% CI, 1.09-1.12).
• Compared with the general population, the overall cancer incidence risk (SIR) was higher among those diagnosed with T2D at a younger age:
• 20-54 years: 1.48 (95% CI, 1.41-1.54)
• 55-59 years: 1.30 (95% CI, 1.25-1.35)
• 60-64 years: 1.19 (95% CI, 1.15-1.23)
• 65-69 years: 1.16 (95% CI, 1.12-1.20)
• 70-74 years: 1.06 (95% CI, 1.02-1.10)
• The overall cancer incidence risk in patients diagnosed with T2D at age ≥ 75 years was even lower than that in the general population (SIR, 0.86; 95% CI, 0.84-0.89).
• The risk (SIR) for most site-specific cancers (including respiratory, colorectal, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancers and lymphoma) decreased with increasing age at T2D diagnosis.

IN PRACTICE:

“Our findings suggest that the carcinogenicity of T2D differs markedly by age at diagnosis and highlights the necessity of stratifying patients according to diagnosis age in management, screening, and preventative strategies,” wrote the authors.

SOURCE:

The study, led by Yanyun Li, Division of Chronic Non-Communicable Disease and Injury, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

Data on smoking history, alcohol consumption, and physical activity were available for nearly 60% of patients with T2D. The findings might only apply to patients with T2D who survive longer than the average and are therefore less applicable to the general population with diabetes. Patients with young-onset T2D had not reached the age where cancers are more prevalent despite as many as 8 years of follow-up.

DISCLOSURES:

This work was supported by the Foundation of National Facility for Translational Medicine, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Three-Year Action Plan of Shanghai Public Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A diagnosis of type 2 diabetes (T2D) at a younger age is associated with an increased cancer risk, while the risk drops for T2D diagnosed at age 75 and older.

METHODOLOGY:

• A T2D diagnosis at a younger age is associated with a greater risk for complications and comorbidities, such as cardiovascular and kidney diseases, retinopathy, and dementia than that occurring at an older age.
• The study evaluated the association between the age at T2D diagnosis and subsequent risk for overall and 14 site-specific cancers in a Shanghai, China, cohort of 428,568 patients newly diagnosed with T2D (about half women) from 2011 to 2018.
• New cases of cancer from the T2D diagnosis to 2018 were identified through a tumor registry.
• Patients were categorized into six groups based on their age at T2D diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥ 75 years.
• The incidence rates of overall and 14 site-specific cancers were compared between patients with T2D and the general Shanghai population (older than 20 years).

TAKEAWAY:

• Compared to the general population, T2D increased the relative risk for all-cause cancer by 10% (standardized incidence ratios [SIRs], 1.10; 95% CI, 1.09-1.12).
• Compared with the general population, the overall cancer incidence risk (SIR) was higher among those diagnosed with T2D at a younger age:
• 20-54 years: 1.48 (95% CI, 1.41-1.54)
• 55-59 years: 1.30 (95% CI, 1.25-1.35)
• 60-64 years: 1.19 (95% CI, 1.15-1.23)
• 65-69 years: 1.16 (95% CI, 1.12-1.20)
• 70-74 years: 1.06 (95% CI, 1.02-1.10)
• The overall cancer incidence risk in patients diagnosed with T2D at age ≥ 75 years was even lower than that in the general population (SIR, 0.86; 95% CI, 0.84-0.89).
• The risk (SIR) for most site-specific cancers (including respiratory, colorectal, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancers and lymphoma) decreased with increasing age at T2D diagnosis.

IN PRACTICE:

“Our findings suggest that the carcinogenicity of T2D differs markedly by age at diagnosis and highlights the necessity of stratifying patients according to diagnosis age in management, screening, and preventative strategies,” wrote the authors.

SOURCE:

The study, led by Yanyun Li, Division of Chronic Non-Communicable Disease and Injury, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

Data on smoking history, alcohol consumption, and physical activity were available for nearly 60% of patients with T2D. The findings might only apply to patients with T2D who survive longer than the average and are therefore less applicable to the general population with diabetes. Patients with young-onset T2D had not reached the age where cancers are more prevalent despite as many as 8 years of follow-up.

DISCLOSURES:

This work was supported by the Foundation of National Facility for Translational Medicine, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Three-Year Action Plan of Shanghai Public Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A diagnosis of type 2 diabetes (T2D) at a younger age is associated with an increased cancer risk, while the risk drops for T2D diagnosed at age 75 and older.

METHODOLOGY:

• A T2D diagnosis at a younger age is associated with a greater risk for complications and comorbidities, such as cardiovascular and kidney diseases, retinopathy, and dementia than that occurring at an older age.
• The study evaluated the association between the age at T2D diagnosis and subsequent risk for overall and 14 site-specific cancers in a Shanghai, China, cohort of 428,568 patients newly diagnosed with T2D (about half women) from 2011 to 2018.
• New cases of cancer from the T2D diagnosis to 2018 were identified through a tumor registry.
• Patients were categorized into six groups based on their age at T2D diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥ 75 years.
• The incidence rates of overall and 14 site-specific cancers were compared between patients with T2D and the general Shanghai population (older than 20 years).

TAKEAWAY:

• Compared to the general population, T2D increased the relative risk for all-cause cancer by 10% (standardized incidence ratios [SIRs], 1.10; 95% CI, 1.09-1.12).
• Compared with the general population, the overall cancer incidence risk (SIR) was higher among those diagnosed with T2D at a younger age:
• 20-54 years: 1.48 (95% CI, 1.41-1.54)
• 55-59 years: 1.30 (95% CI, 1.25-1.35)
• 60-64 years: 1.19 (95% CI, 1.15-1.23)
• 65-69 years: 1.16 (95% CI, 1.12-1.20)
• 70-74 years: 1.06 (95% CI, 1.02-1.10)
• The overall cancer incidence risk in patients diagnosed with T2D at age ≥ 75 years was even lower than that in the general population (SIR, 0.86; 95% CI, 0.84-0.89).
• The risk (SIR) for most site-specific cancers (including respiratory, colorectal, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancers and lymphoma) decreased with increasing age at T2D diagnosis.

IN PRACTICE:

“Our findings suggest that the carcinogenicity of T2D differs markedly by age at diagnosis and highlights the necessity of stratifying patients according to diagnosis age in management, screening, and preventative strategies,” wrote the authors.

SOURCE:

The study, led by Yanyun Li, Division of Chronic Non-Communicable Disease and Injury, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

Data on smoking history, alcohol consumption, and physical activity were available for nearly 60% of patients with T2D. The findings might only apply to patients with T2D who survive longer than the average and are therefore less applicable to the general population with diabetes. Patients with young-onset T2D had not reached the age where cancers are more prevalent despite as many as 8 years of follow-up.

DISCLOSURES:

This work was supported by the Foundation of National Facility for Translational Medicine, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Three-Year Action Plan of Shanghai Public Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Adolescents with severe obesity who undergo bariatric surgery may have a continuing need for mental health treatment and an increased risk for alcohol use disorder after the procedure.

METHODOLOGY:

• Researchers evaluated the long-term effects of bariatric surgery on the mental health of 1554 adolescents (75% women) with severe obesity who underwent bariatric surgery in Sweden between 2007 and 2017.
• At the time of surgery, the mean age was 19.0 years, and the mean body mass index was 43.7.
• A general population reference group of 15,540 adolescents was created by matching 10 comparators each to adolescents in the surgery group by age, sex, and country of residence.
• Information on psychiatric healthcare use and filled psychiatric drug prescriptions for 5 years before surgery and the first 10 years after surgery were obtained from national registers.
• The number of visits for self-harm and substance use disorder and the number of filled prescriptions for any psychiatric drug, antidepressants, and anxiolytics were other outcomes of interest.

TAKEAWAY:

• At 5 years before surgery, the prevalence of psychiatric healthcare visits (prevalence difference [Δ], 3.7%) and of psychiatric drug use (Δ, 6.2%) was higher in the surgery vs reference group.
• The preoperative trajectories continued and grew post-surgery, with the differences in psychiatric healthcare visits (Δ, ~12%) and psychiatric drug use (Δ, 20.4%) between the groups peaking at 9 and 10 years post surgery, respectively.
• A low prevalence of healthcare visits for substance use disorder in both groups grew to about 5% of adolescents in the surgery group after 10 years, driven primarily by alcohol use, compared with about 1% of adolescents in the reference group (Δ, 4.3%).
• Surgery is an obesity treatment, leading to sustainable weight loss, cardiometabolic health, and physical quality of life, but mental health improvements cannot be expected at the group level.

IN PRACTICE:

“Adolescent patients should be informed of the increased risk for alcohol use disorder and that they might continue needing mental health treatment,” the authors wrote.

SOURCE:

Gustaf Bruze, PhD, from the Department of Medicine, Clinical Epidemiology Division, Karolinska Institutet, Solna, and Kajsa Jarvholm, PhD, from the Department of Psychology, Lund University, Lund, Sweden, led this study, which was published online in The Lancet Child & Adolescent Health.

LIMITATIONS:

The findings may have limited generalizability to other settings, as the study was performed in Sweden with a predominantly White population undergoing Roux-en-Y gastric bypass in a universally accessible healthcare system. Moreover, there was a shortage of nonsurgically treated adolescents with severe obesity for comparison. Patients undergoing surgery may have easier access to healthcare than the general population, which could account for an increase in healthcare visits.

DISCLOSURES:

This study was supported by the Swedish Research Council and the Swedish Research Council for Health, Working Life, and Welfare. Two authors were the current or previous director of the Scandinavian Obesity Surgery Registry. Several authors declared receiving personal fees, participating in advisory boards and educational activities, and having other ties with Ethicon Johnson & Johnson, and Novo Nordisk.

A version of this article appeared on Medscape.com.

TOPLINE:

Adolescents with severe obesity who undergo bariatric surgery may have a continuing need for mental health treatment and an increased risk for alcohol use disorder after the procedure.

METHODOLOGY:

• Researchers evaluated the long-term effects of bariatric surgery on the mental health of 1554 adolescents (75% women) with severe obesity who underwent bariatric surgery in Sweden between 2007 and 2017.
• At the time of surgery, the mean age was 19.0 years, and the mean body mass index was 43.7.
• A general population reference group of 15,540 adolescents was created by matching 10 comparators each to adolescents in the surgery group by age, sex, and country of residence.
• Information on psychiatric healthcare use and filled psychiatric drug prescriptions for 5 years before surgery and the first 10 years after surgery were obtained from national registers.
• The number of visits for self-harm and substance use disorder and the number of filled prescriptions for any psychiatric drug, antidepressants, and anxiolytics were other outcomes of interest.

TAKEAWAY:

• At 5 years before surgery, the prevalence of psychiatric healthcare visits (prevalence difference [Δ], 3.7%) and of psychiatric drug use (Δ, 6.2%) was higher in the surgery vs reference group.
• The preoperative trajectories continued and grew post-surgery, with the differences in psychiatric healthcare visits (Δ, ~12%) and psychiatric drug use (Δ, 20.4%) between the groups peaking at 9 and 10 years post surgery, respectively.
• A low prevalence of healthcare visits for substance use disorder in both groups grew to about 5% of adolescents in the surgery group after 10 years, driven primarily by alcohol use, compared with about 1% of adolescents in the reference group (Δ, 4.3%).
• Surgery is an obesity treatment, leading to sustainable weight loss, cardiometabolic health, and physical quality of life, but mental health improvements cannot be expected at the group level.

IN PRACTICE:

“Adolescent patients should be informed of the increased risk for alcohol use disorder and that they might continue needing mental health treatment,” the authors wrote.

SOURCE:

Gustaf Bruze, PhD, from the Department of Medicine, Clinical Epidemiology Division, Karolinska Institutet, Solna, and Kajsa Jarvholm, PhD, from the Department of Psychology, Lund University, Lund, Sweden, led this study, which was published online in The Lancet Child & Adolescent Health.

LIMITATIONS:

The findings may have limited generalizability to other settings, as the study was performed in Sweden with a predominantly White population undergoing Roux-en-Y gastric bypass in a universally accessible healthcare system. Moreover, there was a shortage of nonsurgically treated adolescents with severe obesity for comparison. Patients undergoing surgery may have easier access to healthcare than the general population, which could account for an increase in healthcare visits.

DISCLOSURES:

This study was supported by the Swedish Research Council and the Swedish Research Council for Health, Working Life, and Welfare. Two authors were the current or previous director of the Scandinavian Obesity Surgery Registry. Several authors declared receiving personal fees, participating in advisory boards and educational activities, and having other ties with Ethicon Johnson & Johnson, and Novo Nordisk.

A version of this article appeared on Medscape.com.

TOPLINE:

Adolescents with severe obesity who undergo bariatric surgery may have a continuing need for mental health treatment and an increased risk for alcohol use disorder after the procedure.

METHODOLOGY:

• Researchers evaluated the long-term effects of bariatric surgery on the mental health of 1554 adolescents (75% women) with severe obesity who underwent bariatric surgery in Sweden between 2007 and 2017.
• At the time of surgery, the mean age was 19.0 years, and the mean body mass index was 43.7.
• A general population reference group of 15,540 adolescents was created by matching 10 comparators each to adolescents in the surgery group by age, sex, and country of residence.
• Information on psychiatric healthcare use and filled psychiatric drug prescriptions for 5 years before surgery and the first 10 years after surgery were obtained from national registers.
• The number of visits for self-harm and substance use disorder and the number of filled prescriptions for any psychiatric drug, antidepressants, and anxiolytics were other outcomes of interest.

TAKEAWAY:

• At 5 years before surgery, the prevalence of psychiatric healthcare visits (prevalence difference [Δ], 3.7%) and of psychiatric drug use (Δ, 6.2%) was higher in the surgery vs reference group.
• The preoperative trajectories continued and grew post-surgery, with the differences in psychiatric healthcare visits (Δ, ~12%) and psychiatric drug use (Δ, 20.4%) between the groups peaking at 9 and 10 years post surgery, respectively.
• A low prevalence of healthcare visits for substance use disorder in both groups grew to about 5% of adolescents in the surgery group after 10 years, driven primarily by alcohol use, compared with about 1% of adolescents in the reference group (Δ, 4.3%).
• Surgery is an obesity treatment, leading to sustainable weight loss, cardiometabolic health, and physical quality of life, but mental health improvements cannot be expected at the group level.

IN PRACTICE:

“Adolescent patients should be informed of the increased risk for alcohol use disorder and that they might continue needing mental health treatment,” the authors wrote.

SOURCE:

Gustaf Bruze, PhD, from the Department of Medicine, Clinical Epidemiology Division, Karolinska Institutet, Solna, and Kajsa Jarvholm, PhD, from the Department of Psychology, Lund University, Lund, Sweden, led this study, which was published online in The Lancet Child & Adolescent Health.

LIMITATIONS:

The findings may have limited generalizability to other settings, as the study was performed in Sweden with a predominantly White population undergoing Roux-en-Y gastric bypass in a universally accessible healthcare system. Moreover, there was a shortage of nonsurgically treated adolescents with severe obesity for comparison. Patients undergoing surgery may have easier access to healthcare than the general population, which could account for an increase in healthcare visits.

DISCLOSURES:

This study was supported by the Swedish Research Council and the Swedish Research Council for Health, Working Life, and Welfare. Two authors were the current or previous director of the Scandinavian Obesity Surgery Registry. Several authors declared receiving personal fees, participating in advisory boards and educational activities, and having other ties with Ethicon Johnson & Johnson, and Novo Nordisk.

A version of this article appeared on Medscape.com.

Exposure to even moderate concentrations of radon is associated with a significant increase in stroke risk, new research suggests.

An analysis of radon exposures in more than 150,000 postmenopausal women in the Women’s Health Initiative revealed a 14% higher stroke risk in those exposed to the highest concentrations compared with those exposed to the lowest concentrations. Even moderate concentrations of radon were associated with a 6% higher stroke risk.

Radon is the second leading cause of lung cancer, but little was known about how exposure to the gas might affect stroke risk in women. 

“Our research found an increased risk of stroke among participants exposed to radon above — and as many as 2 picocuries per liter (pCi/L) below — concentrations that usually trigger Environmental Protection Agency recommendations to install a home radon mitigation system,” senior author Eric A. Whitsel, MD, MPH, professor of epidemiology and medicine, University of North Carolina, Chapel Hill, said in a news release.

The study was published online on January 31, 2024, in Neurology.

Women Particularly Affected

Radon is a naturally occurring odorless radioactive gas produced when uranium or radium break down in rocks and soil. Its presence is increasing as a result of climate change, and it is increasingly being found in people’s homes. When inhaled, this air pollutant releases ionizing radiation in the lungs and is seen as second only to smoking as an established cause of lung cancer.

The National Radon Action Plan of the US Environmental Protection Agency (EPA) lays out testing and mitigation guidelines based on the known role of radon in lung carcinogenesis. But radon testing and mitigation are less common than recommended, and the EPA’s action plan doesn’t cover diseases other than lung cancer.

Compared with men, women have a higher rate of stroke and, in the US, typically spend about 11% more hours per day indoors at home, which investigators note highlights a “potential role of the residential environment among other risk factors specific to women.”

Researchers examined longitudinal associations between home radon exposure and incident stroke in 158,910 women at baseline (mean age 63.2 years; 83% White) over a mean follow-up of 13.4 years. During this time, participants experienced a total of 6979 strokes.

Participants’ home addresses were linked to radon concentration data drawn from the US Geological Survey and the EPA, which recommends that average indoor radon concentrations not exceed 4 pCi/L. 

The highest radon exposure group resided in areas where average radon concentrations were < 4 pCi/L; the middle exposure group lived in regions with average concentrations of 2-4 pCi/L; and the lowest exposure group lived in areas with average concentrations < 2 pCi/L. 

The researchers adjusted for demographic, social, behavioral, and clinical characteristics.

Public Health Implications

The incidence rates of stroke per 100,000 women in the lowest, middle, and highest radon concentration areas were 333, 343, and 349, respectively.

Stroke risk was 6% higher among those in the middle exposure group (adjusted hazard ratio [aHR], 1.06; 95% CI, 0.99-1.13) and 14% higher in the highest exposure group (aHR, 1.14; 95% CI, 1.05-1.22) compared with the lowest exposure group.

Notably, stroke risk was significant even at concentrations ranging from 2 to 4 pCi/L (P = .0004) vs < 2 pCi/L, which is below the EPA›s Radon Action Level for mitigation. 

The findings remained robust in sensitivity analyses, although the associations were slightly stronger for ischemic stroke (especially cardioembolic, small-vessel occlusive, and very large artery atherosclerotic) compared with hemorrhagic stroke.

“Radon is an indoor air pollutant that can only be detected through testing that measures concentrations of the gas in homes,” Dr. Whitsel said in the release. “More studies are needed to confirm our findings. Confirmation would present an opportunity to improve public health by addressing an emerging risk factor for stroke.”

The study lacked gender and racial/ethnic diversity, so the findings may not be generalizable to other populations. 

“Replication studies of individual-level radon exposures are needed to confirm this positive radon-stroke association,” the authors write. “Confirmation would present a potential opportunity to affect public health by addressing a pervasive environmental risk factor for stroke and thereby merit reconsideration of extant radon policy.”

The study was funded by the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute. Dr. Whitsel and coauthors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Exposure to even moderate concentrations of radon is associated with a significant increase in stroke risk, new research suggests.

An analysis of radon exposures in more than 150,000 postmenopausal women in the Women’s Health Initiative revealed a 14% higher stroke risk in those exposed to the highest concentrations compared with those exposed to the lowest concentrations. Even moderate concentrations of radon were associated with a 6% higher stroke risk.

Radon is the second leading cause of lung cancer, but little was known about how exposure to the gas might affect stroke risk in women. 

“Our research found an increased risk of stroke among participants exposed to radon above — and as many as 2 picocuries per liter (pCi/L) below — concentrations that usually trigger Environmental Protection Agency recommendations to install a home radon mitigation system,” senior author Eric A. Whitsel, MD, MPH, professor of epidemiology and medicine, University of North Carolina, Chapel Hill, said in a news release.

The study was published online on January 31, 2024, in Neurology.

Women Particularly Affected

Radon is a naturally occurring odorless radioactive gas produced when uranium or radium break down in rocks and soil. Its presence is increasing as a result of climate change, and it is increasingly being found in people’s homes. When inhaled, this air pollutant releases ionizing radiation in the lungs and is seen as second only to smoking as an established cause of lung cancer.

The National Radon Action Plan of the US Environmental Protection Agency (EPA) lays out testing and mitigation guidelines based on the known role of radon in lung carcinogenesis. But radon testing and mitigation are less common than recommended, and the EPA’s action plan doesn’t cover diseases other than lung cancer.

Compared with men, women have a higher rate of stroke and, in the US, typically spend about 11% more hours per day indoors at home, which investigators note highlights a “potential role of the residential environment among other risk factors specific to women.”

Researchers examined longitudinal associations between home radon exposure and incident stroke in 158,910 women at baseline (mean age 63.2 years; 83% White) over a mean follow-up of 13.4 years. During this time, participants experienced a total of 6979 strokes.

Participants’ home addresses were linked to radon concentration data drawn from the US Geological Survey and the EPA, which recommends that average indoor radon concentrations not exceed 4 pCi/L. 

The highest radon exposure group resided in areas where average radon concentrations were < 4 pCi/L; the middle exposure group lived in regions with average concentrations of 2-4 pCi/L; and the lowest exposure group lived in areas with average concentrations < 2 pCi/L. 

The researchers adjusted for demographic, social, behavioral, and clinical characteristics.

Public Health Implications

The incidence rates of stroke per 100,000 women in the lowest, middle, and highest radon concentration areas were 333, 343, and 349, respectively.

Stroke risk was 6% higher among those in the middle exposure group (adjusted hazard ratio [aHR], 1.06; 95% CI, 0.99-1.13) and 14% higher in the highest exposure group (aHR, 1.14; 95% CI, 1.05-1.22) compared with the lowest exposure group.

Notably, stroke risk was significant even at concentrations ranging from 2 to 4 pCi/L (P = .0004) vs < 2 pCi/L, which is below the EPA›s Radon Action Level for mitigation. 

The findings remained robust in sensitivity analyses, although the associations were slightly stronger for ischemic stroke (especially cardioembolic, small-vessel occlusive, and very large artery atherosclerotic) compared with hemorrhagic stroke.

“Radon is an indoor air pollutant that can only be detected through testing that measures concentrations of the gas in homes,” Dr. Whitsel said in the release. “More studies are needed to confirm our findings. Confirmation would present an opportunity to improve public health by addressing an emerging risk factor for stroke.”

The study lacked gender and racial/ethnic diversity, so the findings may not be generalizable to other populations. 

“Replication studies of individual-level radon exposures are needed to confirm this positive radon-stroke association,” the authors write. “Confirmation would present a potential opportunity to affect public health by addressing a pervasive environmental risk factor for stroke and thereby merit reconsideration of extant radon policy.”

The study was funded by the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute. Dr. Whitsel and coauthors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Exposure to even moderate concentrations of radon is associated with a significant increase in stroke risk, new research suggests.

An analysis of radon exposures in more than 150,000 postmenopausal women in the Women’s Health Initiative revealed a 14% higher stroke risk in those exposed to the highest concentrations compared with those exposed to the lowest concentrations. Even moderate concentrations of radon were associated with a 6% higher stroke risk.

Radon is the second leading cause of lung cancer, but little was known about how exposure to the gas might affect stroke risk in women. 

“Our research found an increased risk of stroke among participants exposed to radon above — and as many as 2 picocuries per liter (pCi/L) below — concentrations that usually trigger Environmental Protection Agency recommendations to install a home radon mitigation system,” senior author Eric A. Whitsel, MD, MPH, professor of epidemiology and medicine, University of North Carolina, Chapel Hill, said in a news release.

The study was published online on January 31, 2024, in Neurology.

Women Particularly Affected

Radon is a naturally occurring odorless radioactive gas produced when uranium or radium break down in rocks and soil. Its presence is increasing as a result of climate change, and it is increasingly being found in people’s homes. When inhaled, this air pollutant releases ionizing radiation in the lungs and is seen as second only to smoking as an established cause of lung cancer.

The National Radon Action Plan of the US Environmental Protection Agency (EPA) lays out testing and mitigation guidelines based on the known role of radon in lung carcinogenesis. But radon testing and mitigation are less common than recommended, and the EPA’s action plan doesn’t cover diseases other than lung cancer.

Compared with men, women have a higher rate of stroke and, in the US, typically spend about 11% more hours per day indoors at home, which investigators note highlights a “potential role of the residential environment among other risk factors specific to women.”

Researchers examined longitudinal associations between home radon exposure and incident stroke in 158,910 women at baseline (mean age 63.2 years; 83% White) over a mean follow-up of 13.4 years. During this time, participants experienced a total of 6979 strokes.

Participants’ home addresses were linked to radon concentration data drawn from the US Geological Survey and the EPA, which recommends that average indoor radon concentrations not exceed 4 pCi/L. 

The highest radon exposure group resided in areas where average radon concentrations were < 4 pCi/L; the middle exposure group lived in regions with average concentrations of 2-4 pCi/L; and the lowest exposure group lived in areas with average concentrations < 2 pCi/L. 

The researchers adjusted for demographic, social, behavioral, and clinical characteristics.

Public Health Implications

The incidence rates of stroke per 100,000 women in the lowest, middle, and highest radon concentration areas were 333, 343, and 349, respectively.

Stroke risk was 6% higher among those in the middle exposure group (adjusted hazard ratio [aHR], 1.06; 95% CI, 0.99-1.13) and 14% higher in the highest exposure group (aHR, 1.14; 95% CI, 1.05-1.22) compared with the lowest exposure group.

Notably, stroke risk was significant even at concentrations ranging from 2 to 4 pCi/L (P = .0004) vs < 2 pCi/L, which is below the EPA›s Radon Action Level for mitigation. 

The findings remained robust in sensitivity analyses, although the associations were slightly stronger for ischemic stroke (especially cardioembolic, small-vessel occlusive, and very large artery atherosclerotic) compared with hemorrhagic stroke.

“Radon is an indoor air pollutant that can only be detected through testing that measures concentrations of the gas in homes,” Dr. Whitsel said in the release. “More studies are needed to confirm our findings. Confirmation would present an opportunity to improve public health by addressing an emerging risk factor for stroke.”

The study lacked gender and racial/ethnic diversity, so the findings may not be generalizable to other populations. 

“Replication studies of individual-level radon exposures are needed to confirm this positive radon-stroke association,” the authors write. “Confirmation would present a potential opportunity to affect public health by addressing a pervasive environmental risk factor for stroke and thereby merit reconsideration of extant radon policy.”

The study was funded by the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute. Dr. Whitsel and coauthors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Men prescribed drugs to treat newly diagnosed erectile dysfunction (ED) are 18% less likely to develop Alzheimer’s disease (AD) during a 5-year follow-up period, new research shows. 

The study is the second in recent years to suggest an association between the use of phosphodiesterase type 5 inhibitors (PDE5Is) such as sildenafil (Viagra) or tadalafil (Cialis) and AD risk. The findings contradict those in a third study, reported by this news organization, that showed no link between the two. 

Although the research is interesting, outside experts noted that there is no evidence that the drugs can treat AD and urge caution when interpreting the findings. 

Investigators agree but believe that the results offer a direction for future studies and underscore the importance of investigating whether existing approved therapies can be repurposed to treat AD. 

“The positive findings from our large study in over 250,000 men is promising and can be used to enhance research capacity and knowledge, with a potential future impact on clinical use and public health policy,” senior author Ruth Brauer, PhD, of the University College London, told this news organization.

“However, before recommending PDE5I are used to reduce the risk of AD, more work is required to validate the findings of our work, particularly in a more generalizable population that includes women and men without erectile dysfunction,” she continued.

The findings were published online February 7 in Neurology.

Strong Association

The study drew on primary healthcare data from the United Kingdom and included 269,725 men (average age, 59 years) with newly diagnosed ED, 55% of whom had received prescriptions for PDE5Is. 

Participants were free from memory or cognitive issues when the study began and were followed for a median of 5.1 years. Investigators accounted for a range of potential AD risk factors, including smoking status, alcohol use, body mass index, hypertension, diabetes, depression, anxiety, and concomitant medication use.

During the study period, 749 in the PDE5I group were diagnosed with AD, corresponding to a rate of 8.1 cases per 10,000 person-years. Among those who did not take the drugs, 370 developed AD, corresponding to a rate of 9.7 cases per 10,000 person-years.

Overall, initiation of a PDE5I was associated with an 18% lower risk for AD (adjusted hazard ration [aHR], 0.82; 95% CI, 0.72-0.93) compared with those with no prescriptions. 

The association was stronger in people aged 70 years or older and those with a history of hypertension or diabetes. The greatest risk reduction was found in people with the most prescriptions during the study period. Those with 21-50 prescriptions had a 44% lower risk for AD (aHR, 0.56; 95% CI, 0.43-0.73) and those with more than 50 were 35% less likely to be diagnosed with AD (aHR, 0.65; 95% CI, 0.49-0.87).

There was no association with AD risk in individuals who received fewer than 20 prescriptions. 

Investigators also analyzed associations after introducing a 1- and 3-year lag period after cohort entry to address the latent period between AD onset and diagnosis. The primary findings held with a 1-year lag period but lost significance with the inclusion of a 3-year lag period.

In subgroup analyses, investigators found evidence of reduced AD risk in those who received prescriptions for sildenafil (aHR, 0.81; 95% CI, 0.71-0.93), but there was no evidence for reduced risk compared with nonusers in those who received tadalafil and vardenafil.

Lower AD risk was found in patients with hypertension, diabetes, and in men aged 70 years or older, but there was no association in younger men or those with no history of hypertension or diabetes. 

Although investigators controlled for a wide range of potential risk factors, Dr. Brauer noted that unmeasured confounders such as physical and sexual activity, which were not tracked and may predict PDE5I exposure, may have affected the results. 

Interpret With Caution

Commenting on the findings, Ozama Ismail, PhD, Alzheimer’s Association director of scientific programs, noted that in addition to the limitations cited by the study authors, AD diagnoses were not made with the “gold standard” testing that typically includes imaging biomarkers and postmortem assessments. 

“While this study is interesting and adds to a potential association, there is no evidence that these drugs are able to treat Alzheimer’s disease,” said Dr. Brauer, who was not part of the current study. 

“People should not use over-the-counter phosphodiesterase type 5 inhibitors for prevention of Alzheimer’s or other dementias based on this very preliminary finding. Always consult with your physician before starting or changing your medications,” he cautioned.

However, Dr. Ismael added that the study does highlight a potential new avenue for drug repurposing. 

“Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects,” which can decrease cost and time needed for studies, he said. 

“When considering repurposing an existing drug to an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismael said.

Randomized Trials Needed

Dr. Brauer agreed, offering that such a trial should also include people with mild cognitive impairment and measure the effects of PDE5Is given in predefined doses plus an acetylcholinesterase inhibitor or placebo plus an acetylcholinesterase inhibitor. 

“The primary outcome would be the change in baseline cognitive function,” she said. “This approach would provide a comprehensive understanding of the potential therapeutic benefits of PDE5I and AD.”

Studies are also needed to better understand the mechanisms by which these drugs might influence AD risk, Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, from the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, noted in an accompanying editorial.

The strong association between PDE5I use and AD risk in people with a history of hypertension or diabetes suggests “a potential neuroprotective effect through a vascular pathway,” they wrote.

In vitro studies on the role of inflammation and clearance of beta-amyloid could strengthen findings from studies like this one, and in vivo studies could help explain the mechanisms behind PDE5I use and lower AD risk, Dr. Yasar and Dr. Nidadavolu noted. 

“In the end, however, further observational studies exploring mechanisms will not prove a causal association,” they wrote. “A well-designed randomized controlled trial is needed before PDE5I drugs can be prescribed for AD prevention.”

The study was unfunded. The study and editorial authors and Dr. Ismail report no relevant financial conflicts. 
 

A version of this article appeared on Medscape.com.

Men prescribed drugs to treat newly diagnosed erectile dysfunction (ED) are 18% less likely to develop Alzheimer’s disease (AD) during a 5-year follow-up period, new research shows. 

The study is the second in recent years to suggest an association between the use of phosphodiesterase type 5 inhibitors (PDE5Is) such as sildenafil (Viagra) or tadalafil (Cialis) and AD risk. The findings contradict those in a third study, reported by this news organization, that showed no link between the two. 

Although the research is interesting, outside experts noted that there is no evidence that the drugs can treat AD and urge caution when interpreting the findings. 

Investigators agree but believe that the results offer a direction for future studies and underscore the importance of investigating whether existing approved therapies can be repurposed to treat AD. 

“The positive findings from our large study in over 250,000 men is promising and can be used to enhance research capacity and knowledge, with a potential future impact on clinical use and public health policy,” senior author Ruth Brauer, PhD, of the University College London, told this news organization.

“However, before recommending PDE5I are used to reduce the risk of AD, more work is required to validate the findings of our work, particularly in a more generalizable population that includes women and men without erectile dysfunction,” she continued.

The findings were published online February 7 in Neurology.

Strong Association

The study drew on primary healthcare data from the United Kingdom and included 269,725 men (average age, 59 years) with newly diagnosed ED, 55% of whom had received prescriptions for PDE5Is. 

Participants were free from memory or cognitive issues when the study began and were followed for a median of 5.1 years. Investigators accounted for a range of potential AD risk factors, including smoking status, alcohol use, body mass index, hypertension, diabetes, depression, anxiety, and concomitant medication use.

During the study period, 749 in the PDE5I group were diagnosed with AD, corresponding to a rate of 8.1 cases per 10,000 person-years. Among those who did not take the drugs, 370 developed AD, corresponding to a rate of 9.7 cases per 10,000 person-years.

Overall, initiation of a PDE5I was associated with an 18% lower risk for AD (adjusted hazard ration [aHR], 0.82; 95% CI, 0.72-0.93) compared with those with no prescriptions. 

The association was stronger in people aged 70 years or older and those with a history of hypertension or diabetes. The greatest risk reduction was found in people with the most prescriptions during the study period. Those with 21-50 prescriptions had a 44% lower risk for AD (aHR, 0.56; 95% CI, 0.43-0.73) and those with more than 50 were 35% less likely to be diagnosed with AD (aHR, 0.65; 95% CI, 0.49-0.87).

There was no association with AD risk in individuals who received fewer than 20 prescriptions. 

Investigators also analyzed associations after introducing a 1- and 3-year lag period after cohort entry to address the latent period between AD onset and diagnosis. The primary findings held with a 1-year lag period but lost significance with the inclusion of a 3-year lag period.

In subgroup analyses, investigators found evidence of reduced AD risk in those who received prescriptions for sildenafil (aHR, 0.81; 95% CI, 0.71-0.93), but there was no evidence for reduced risk compared with nonusers in those who received tadalafil and vardenafil.

Lower AD risk was found in patients with hypertension, diabetes, and in men aged 70 years or older, but there was no association in younger men or those with no history of hypertension or diabetes. 

Although investigators controlled for a wide range of potential risk factors, Dr. Brauer noted that unmeasured confounders such as physical and sexual activity, which were not tracked and may predict PDE5I exposure, may have affected the results. 

Interpret With Caution

Commenting on the findings, Ozama Ismail, PhD, Alzheimer’s Association director of scientific programs, noted that in addition to the limitations cited by the study authors, AD diagnoses were not made with the “gold standard” testing that typically includes imaging biomarkers and postmortem assessments. 

“While this study is interesting and adds to a potential association, there is no evidence that these drugs are able to treat Alzheimer’s disease,” said Dr. Brauer, who was not part of the current study. 

“People should not use over-the-counter phosphodiesterase type 5 inhibitors for prevention of Alzheimer’s or other dementias based on this very preliminary finding. Always consult with your physician before starting or changing your medications,” he cautioned.

However, Dr. Ismael added that the study does highlight a potential new avenue for drug repurposing. 

“Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects,” which can decrease cost and time needed for studies, he said. 

“When considering repurposing an existing drug to an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismael said.

Randomized Trials Needed

Dr. Brauer agreed, offering that such a trial should also include people with mild cognitive impairment and measure the effects of PDE5Is given in predefined doses plus an acetylcholinesterase inhibitor or placebo plus an acetylcholinesterase inhibitor. 

“The primary outcome would be the change in baseline cognitive function,” she said. “This approach would provide a comprehensive understanding of the potential therapeutic benefits of PDE5I and AD.”

Studies are also needed to better understand the mechanisms by which these drugs might influence AD risk, Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, from the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, noted in an accompanying editorial.

The strong association between PDE5I use and AD risk in people with a history of hypertension or diabetes suggests “a potential neuroprotective effect through a vascular pathway,” they wrote.

In vitro studies on the role of inflammation and clearance of beta-amyloid could strengthen findings from studies like this one, and in vivo studies could help explain the mechanisms behind PDE5I use and lower AD risk, Dr. Yasar and Dr. Nidadavolu noted. 

“In the end, however, further observational studies exploring mechanisms will not prove a causal association,” they wrote. “A well-designed randomized controlled trial is needed before PDE5I drugs can be prescribed for AD prevention.”

The study was unfunded. The study and editorial authors and Dr. Ismail report no relevant financial conflicts. 
 

A version of this article appeared on Medscape.com.

Men prescribed drugs to treat newly diagnosed erectile dysfunction (ED) are 18% less likely to develop Alzheimer’s disease (AD) during a 5-year follow-up period, new research shows. 

The study is the second in recent years to suggest an association between the use of phosphodiesterase type 5 inhibitors (PDE5Is) such as sildenafil (Viagra) or tadalafil (Cialis) and AD risk. The findings contradict those in a third study, reported by this news organization, that showed no link between the two. 

Although the research is interesting, outside experts noted that there is no evidence that the drugs can treat AD and urge caution when interpreting the findings. 

Investigators agree but believe that the results offer a direction for future studies and underscore the importance of investigating whether existing approved therapies can be repurposed to treat AD. 

“The positive findings from our large study in over 250,000 men is promising and can be used to enhance research capacity and knowledge, with a potential future impact on clinical use and public health policy,” senior author Ruth Brauer, PhD, of the University College London, told this news organization.

“However, before recommending PDE5I are used to reduce the risk of AD, more work is required to validate the findings of our work, particularly in a more generalizable population that includes women and men without erectile dysfunction,” she continued.

The findings were published online February 7 in Neurology.

Strong Association

The study drew on primary healthcare data from the United Kingdom and included 269,725 men (average age, 59 years) with newly diagnosed ED, 55% of whom had received prescriptions for PDE5Is. 

Participants were free from memory or cognitive issues when the study began and were followed for a median of 5.1 years. Investigators accounted for a range of potential AD risk factors, including smoking status, alcohol use, body mass index, hypertension, diabetes, depression, anxiety, and concomitant medication use.

During the study period, 749 in the PDE5I group were diagnosed with AD, corresponding to a rate of 8.1 cases per 10,000 person-years. Among those who did not take the drugs, 370 developed AD, corresponding to a rate of 9.7 cases per 10,000 person-years.

Overall, initiation of a PDE5I was associated with an 18% lower risk for AD (adjusted hazard ration [aHR], 0.82; 95% CI, 0.72-0.93) compared with those with no prescriptions. 

The association was stronger in people aged 70 years or older and those with a history of hypertension or diabetes. The greatest risk reduction was found in people with the most prescriptions during the study period. Those with 21-50 prescriptions had a 44% lower risk for AD (aHR, 0.56; 95% CI, 0.43-0.73) and those with more than 50 were 35% less likely to be diagnosed with AD (aHR, 0.65; 95% CI, 0.49-0.87).

There was no association with AD risk in individuals who received fewer than 20 prescriptions. 

Investigators also analyzed associations after introducing a 1- and 3-year lag period after cohort entry to address the latent period between AD onset and diagnosis. The primary findings held with a 1-year lag period but lost significance with the inclusion of a 3-year lag period.

In subgroup analyses, investigators found evidence of reduced AD risk in those who received prescriptions for sildenafil (aHR, 0.81; 95% CI, 0.71-0.93), but there was no evidence for reduced risk compared with nonusers in those who received tadalafil and vardenafil.

Lower AD risk was found in patients with hypertension, diabetes, and in men aged 70 years or older, but there was no association in younger men or those with no history of hypertension or diabetes. 

Although investigators controlled for a wide range of potential risk factors, Dr. Brauer noted that unmeasured confounders such as physical and sexual activity, which were not tracked and may predict PDE5I exposure, may have affected the results. 

Interpret With Caution

Commenting on the findings, Ozama Ismail, PhD, Alzheimer’s Association director of scientific programs, noted that in addition to the limitations cited by the study authors, AD diagnoses were not made with the “gold standard” testing that typically includes imaging biomarkers and postmortem assessments. 

“While this study is interesting and adds to a potential association, there is no evidence that these drugs are able to treat Alzheimer’s disease,” said Dr. Brauer, who was not part of the current study. 

“People should not use over-the-counter phosphodiesterase type 5 inhibitors for prevention of Alzheimer’s or other dementias based on this very preliminary finding. Always consult with your physician before starting or changing your medications,” he cautioned.

However, Dr. Ismael added that the study does highlight a potential new avenue for drug repurposing. 

“Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects,” which can decrease cost and time needed for studies, he said. 

“When considering repurposing an existing drug to an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismael said.

Randomized Trials Needed

Dr. Brauer agreed, offering that such a trial should also include people with mild cognitive impairment and measure the effects of PDE5Is given in predefined doses plus an acetylcholinesterase inhibitor or placebo plus an acetylcholinesterase inhibitor. 

“The primary outcome would be the change in baseline cognitive function,” she said. “This approach would provide a comprehensive understanding of the potential therapeutic benefits of PDE5I and AD.”

Studies are also needed to better understand the mechanisms by which these drugs might influence AD risk, Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, from the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, noted in an accompanying editorial.

The strong association between PDE5I use and AD risk in people with a history of hypertension or diabetes suggests “a potential neuroprotective effect through a vascular pathway,” they wrote.

In vitro studies on the role of inflammation and clearance of beta-amyloid could strengthen findings from studies like this one, and in vivo studies could help explain the mechanisms behind PDE5I use and lower AD risk, Dr. Yasar and Dr. Nidadavolu noted. 

“In the end, however, further observational studies exploring mechanisms will not prove a causal association,” they wrote. “A well-designed randomized controlled trial is needed before PDE5I drugs can be prescribed for AD prevention.”

The study was unfunded. The study and editorial authors and Dr. Ismail report no relevant financial conflicts. 
 

A version of this article appeared on Medscape.com.

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

Clinical efforts to get patients with a history of gout to reach specific target serum urate (SU) levels less than either 5 or 6 mg/dL could prevent the great majority of gout flares and hospitalizations for them, according to a new study that tracked patients for a mean of 8.3 years.

The findings, which appeared February 6 in JAMA, “support the value of target serum urate levels in gout flare prevention in primary care, where most gout patients are treated,” rheumatologist and study coauthor Hyon K. Choi, MD, DrPH, of Harvard Medical School and Massachusetts General Hospital, Boston, told this news organization. However, Dr. Choi noted that “the value of relying on target urate levels is not accepted in primary care practice,” and the author of an accompanying commentary said that the jury is still out about the best strategy to prevent flares.

Gout is caused by monosodium urate crystallization within the joints, which occurs when SU levels exceed the saturation point for uric acid crystallization in the body: approximately 6.8 mg/dL. “Studies have found strongly graded associations between serum urate levels above the saturation point and the risk of developing new cases of gout among individuals without gout at baseline,” Dr. Choi said. “However, associations between serum urate levels and the risk of recurrent flares among preexisting gout patients, which is relevant to clinical gout care practice, has not been established.”

Dr. Choi added that “despite the emphasis in US and European rheumatology guidelines on the use of urate-lowering therapy to treat-to-target serum urate level — eg, under 6 or 5 mg/dL — the proportions of flares associated with such target urate levels remained unknown.”
 

Study Shows Relationship Between SU Levels and Recurrent Flares

For the study, researchers tracked 3613 patients aged 40-69 with gout in the UK Biobank database from 2006-2010 to 2017 or 2020. The patients, 86% of whom were men, had a mean age of 60 years and about 96% were White.

Among the patients, 1773 new episodes of acute gout occurred in 27% of the patients (16% had one episode, 6% had two episodes, and 5% had at least three episodes). These were treated in primary care or required hospitalizations. The other 73% of patients had no new acute gout episodes.

Overall, 95% of flares occurred in those with baseline SU levels ≥ 6 mg/dL, and 98% occurred in those with levels ≥ 5 mg/dL.

Patients with baseline SU levels < 6.0 mg/dL had an acute gout flare rate of 10.6 per 1000 person-years. In comparison, relative risks for acute gout flares per 1000 person-years were 3.16 at baseline SU levels of 6.0-6.9 mg/dL, 6.20 for 7.0-7.9 mg/dL, 7.70 for 8.0-8.9 mg/dL, 9.80 for 9.0-9.9 mg/dL, and 11.26 for > 10 mg/dL after adjustment for various possible confounders (P < .001).

The researchers identified 64 hospitalizations with gout as the main discharge diagnosis, and 97% occurred in patients with baseline SU levels ≥ 6 mg/dL. All were in patients with baseline SU levels ≥ 5 mg/dL.

“An important feature of this study was that serum urate measurements were obtained from all gout patients at the study baseline, irrespective of clinical needs or flare status,” Dr. Choi said. “Prior studies failed to reveal the truly compelling nature of relations between serum urate levels and recurrent flares among preexisting gout patients.”

As for the cost of SU tests, Dr. Choi said they can run as low as $2. “Portable tests similar to home glucose measurement for diabetes patients are also being adopted by certain gout care practices,” he said.

The findings matter, Dr. Choi said, because SU is not tracked in the “vast majority of gout patients” in primary care. Instead, primary care doctors — as per the guidelines of the American College of Physicians — often adopt an approach that treats symptoms as needed instead of tracking and lowering SU levels, he said. In fact, “95% and 98% of gout flares can be potentially preventable at the population level if serum urate levels < 6 and < 5 mg/dL can be met, respectively, and 100% of hospitalizations for gout could be preventable with serum urate < 5 mg/dL,” he said.

As for limitations, the authors noted that participants in the UK Biobank “typically have a better socioeconomic status and are healthier than the UK general population,” and they added that “these data may underestimate the number of acute gout flares in the cohort.” Also, 55% of the total 502,490 patients in the UK Biobank were excluded owing to lack of primary care data.
 

Study ‘Offers the Kind of Evidence That We Need’

In an accompanying commentary, University of Alabama at Birmingham rheumatologist Angelo L. Gaffo, MD, MSPH, also noted that the study population was overwhelmingly White, had a low mean SU level (6.9 mg/dL), and had a low level of comorbidities, making the sample “poorly representative of the most commonly described gout populations.”

However, he also noted that there is “growing evidence linking serum urate levels with clinical outcomes,” with a pair of studies — one from 2021 and the other from 2022 — linking reductions in SU to < 6 md/dL to lower flare rates.

Dr. Gaffo told this news organization that although rheumatology guidelines support a treat-to-target strategy, “we haven›t generated a whole lot of important evidence to support it.”

The new study “offers the kind of evidence that we need,” he said, “but this is not going to be the ultimate answer.” That will only come from randomized clinical trials in the works that will pit the treat-to-target approach vs the primary care–favored strategy of titrating treatment until flares are controlled, he said.

Even though evidence is sparse, Dr. Gaffo said he still believes in the treat-to-target strategy: “I believe it is the best way to treat gout.”

What’s next? Researchers hope to understand how to better reach target SU goals in clinical practice, Dr. Choi said. “Involving nurses, pharmacists, or interactive online or app systems — as in other chronic treat-to-target care such as anticoagulation care, blood pressure, or lipid care — is actively being researched.”

He added that “we are trying to find the effective and safe medications and nonpharmacologic measures to reduce the urate burden, which can also simultaneously take care of gout’s frequent cardiovascular-kidney comorbidities.”

The US National Institutes of Health supported the study. Dr. Choi reports receiving grants from Horizon and serving on a board or committee for LG Chem, Shanton, and ANI Pharmaceuticals. Some other authors report an employment and stockholder relationship with Regeneron and support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Rheumatology Research Foundation. Dr. Gaffo reports personal fees from PK MED, SOBI/Selecta, Atom, and UpToDate.

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

Clinical efforts to get patients with a history of gout to reach specific target serum urate (SU) levels less than either 5 or 6 mg/dL could prevent the great majority of gout flares and hospitalizations for them, according to a new study that tracked patients for a mean of 8.3 years.

The findings, which appeared February 6 in JAMA, “support the value of target serum urate levels in gout flare prevention in primary care, where most gout patients are treated,” rheumatologist and study coauthor Hyon K. Choi, MD, DrPH, of Harvard Medical School and Massachusetts General Hospital, Boston, told this news organization. However, Dr. Choi noted that “the value of relying on target urate levels is not accepted in primary care practice,” and the author of an accompanying commentary said that the jury is still out about the best strategy to prevent flares.

Gout is caused by monosodium urate crystallization within the joints, which occurs when SU levels exceed the saturation point for uric acid crystallization in the body: approximately 6.8 mg/dL. “Studies have found strongly graded associations between serum urate levels above the saturation point and the risk of developing new cases of gout among individuals without gout at baseline,” Dr. Choi said. “However, associations between serum urate levels and the risk of recurrent flares among preexisting gout patients, which is relevant to clinical gout care practice, has not been established.”

Dr. Choi added that “despite the emphasis in US and European rheumatology guidelines on the use of urate-lowering therapy to treat-to-target serum urate level — eg, under 6 or 5 mg/dL — the proportions of flares associated with such target urate levels remained unknown.”
 

Study Shows Relationship Between SU Levels and Recurrent Flares

For the study, researchers tracked 3613 patients aged 40-69 with gout in the UK Biobank database from 2006-2010 to 2017 or 2020. The patients, 86% of whom were men, had a mean age of 60 years and about 96% were White.

Among the patients, 1773 new episodes of acute gout occurred in 27% of the patients (16% had one episode, 6% had two episodes, and 5% had at least three episodes). These were treated in primary care or required hospitalizations. The other 73% of patients had no new acute gout episodes.

Overall, 95% of flares occurred in those with baseline SU levels ≥ 6 mg/dL, and 98% occurred in those with levels ≥ 5 mg/dL.

Patients with baseline SU levels < 6.0 mg/dL had an acute gout flare rate of 10.6 per 1000 person-years. In comparison, relative risks for acute gout flares per 1000 person-years were 3.16 at baseline SU levels of 6.0-6.9 mg/dL, 6.20 for 7.0-7.9 mg/dL, 7.70 for 8.0-8.9 mg/dL, 9.80 for 9.0-9.9 mg/dL, and 11.26 for > 10 mg/dL after adjustment for various possible confounders (P < .001).

The researchers identified 64 hospitalizations with gout as the main discharge diagnosis, and 97% occurred in patients with baseline SU levels ≥ 6 mg/dL. All were in patients with baseline SU levels ≥ 5 mg/dL.

“An important feature of this study was that serum urate measurements were obtained from all gout patients at the study baseline, irrespective of clinical needs or flare status,” Dr. Choi said. “Prior studies failed to reveal the truly compelling nature of relations between serum urate levels and recurrent flares among preexisting gout patients.”

As for the cost of SU tests, Dr. Choi said they can run as low as $2. “Portable tests similar to home glucose measurement for diabetes patients are also being adopted by certain gout care practices,” he said.

The findings matter, Dr. Choi said, because SU is not tracked in the “vast majority of gout patients” in primary care. Instead, primary care doctors — as per the guidelines of the American College of Physicians — often adopt an approach that treats symptoms as needed instead of tracking and lowering SU levels, he said. In fact, “95% and 98% of gout flares can be potentially preventable at the population level if serum urate levels < 6 and < 5 mg/dL can be met, respectively, and 100% of hospitalizations for gout could be preventable with serum urate < 5 mg/dL,” he said.

As for limitations, the authors noted that participants in the UK Biobank “typically have a better socioeconomic status and are healthier than the UK general population,” and they added that “these data may underestimate the number of acute gout flares in the cohort.” Also, 55% of the total 502,490 patients in the UK Biobank were excluded owing to lack of primary care data.
 

Study ‘Offers the Kind of Evidence That We Need’

In an accompanying commentary, University of Alabama at Birmingham rheumatologist Angelo L. Gaffo, MD, MSPH, also noted that the study population was overwhelmingly White, had a low mean SU level (6.9 mg/dL), and had a low level of comorbidities, making the sample “poorly representative of the most commonly described gout populations.”

However, he also noted that there is “growing evidence linking serum urate levels with clinical outcomes,” with a pair of studies — one from 2021 and the other from 2022 — linking reductions in SU to < 6 md/dL to lower flare rates.

Dr. Gaffo told this news organization that although rheumatology guidelines support a treat-to-target strategy, “we haven›t generated a whole lot of important evidence to support it.”

The new study “offers the kind of evidence that we need,” he said, “but this is not going to be the ultimate answer.” That will only come from randomized clinical trials in the works that will pit the treat-to-target approach vs the primary care–favored strategy of titrating treatment until flares are controlled, he said.

Even though evidence is sparse, Dr. Gaffo said he still believes in the treat-to-target strategy: “I believe it is the best way to treat gout.”

What’s next? Researchers hope to understand how to better reach target SU goals in clinical practice, Dr. Choi said. “Involving nurses, pharmacists, or interactive online or app systems — as in other chronic treat-to-target care such as anticoagulation care, blood pressure, or lipid care — is actively being researched.”

He added that “we are trying to find the effective and safe medications and nonpharmacologic measures to reduce the urate burden, which can also simultaneously take care of gout’s frequent cardiovascular-kidney comorbidities.”

The US National Institutes of Health supported the study. Dr. Choi reports receiving grants from Horizon and serving on a board or committee for LG Chem, Shanton, and ANI Pharmaceuticals. Some other authors report an employment and stockholder relationship with Regeneron and support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Rheumatology Research Foundation. Dr. Gaffo reports personal fees from PK MED, SOBI/Selecta, Atom, and UpToDate.

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

Clinical efforts to get patients with a history of gout to reach specific target serum urate (SU) levels less than either 5 or 6 mg/dL could prevent the great majority of gout flares and hospitalizations for them, according to a new study that tracked patients for a mean of 8.3 years.

The findings, which appeared February 6 in JAMA, “support the value of target serum urate levels in gout flare prevention in primary care, where most gout patients are treated,” rheumatologist and study coauthor Hyon K. Choi, MD, DrPH, of Harvard Medical School and Massachusetts General Hospital, Boston, told this news organization. However, Dr. Choi noted that “the value of relying on target urate levels is not accepted in primary care practice,” and the author of an accompanying commentary said that the jury is still out about the best strategy to prevent flares.

Gout is caused by monosodium urate crystallization within the joints, which occurs when SU levels exceed the saturation point for uric acid crystallization in the body: approximately 6.8 mg/dL. “Studies have found strongly graded associations between serum urate levels above the saturation point and the risk of developing new cases of gout among individuals without gout at baseline,” Dr. Choi said. “However, associations between serum urate levels and the risk of recurrent flares among preexisting gout patients, which is relevant to clinical gout care practice, has not been established.”

Dr. Choi added that “despite the emphasis in US and European rheumatology guidelines on the use of urate-lowering therapy to treat-to-target serum urate level — eg, under 6 or 5 mg/dL — the proportions of flares associated with such target urate levels remained unknown.”
 

Study Shows Relationship Between SU Levels and Recurrent Flares

For the study, researchers tracked 3613 patients aged 40-69 with gout in the UK Biobank database from 2006-2010 to 2017 or 2020. The patients, 86% of whom were men, had a mean age of 60 years and about 96% were White.

Among the patients, 1773 new episodes of acute gout occurred in 27% of the patients (16% had one episode, 6% had two episodes, and 5% had at least three episodes). These were treated in primary care or required hospitalizations. The other 73% of patients had no new acute gout episodes.

Overall, 95% of flares occurred in those with baseline SU levels ≥ 6 mg/dL, and 98% occurred in those with levels ≥ 5 mg/dL.

Patients with baseline SU levels < 6.0 mg/dL had an acute gout flare rate of 10.6 per 1000 person-years. In comparison, relative risks for acute gout flares per 1000 person-years were 3.16 at baseline SU levels of 6.0-6.9 mg/dL, 6.20 for 7.0-7.9 mg/dL, 7.70 for 8.0-8.9 mg/dL, 9.80 for 9.0-9.9 mg/dL, and 11.26 for > 10 mg/dL after adjustment for various possible confounders (P < .001).

The researchers identified 64 hospitalizations with gout as the main discharge diagnosis, and 97% occurred in patients with baseline SU levels ≥ 6 mg/dL. All were in patients with baseline SU levels ≥ 5 mg/dL.

“An important feature of this study was that serum urate measurements were obtained from all gout patients at the study baseline, irrespective of clinical needs or flare status,” Dr. Choi said. “Prior studies failed to reveal the truly compelling nature of relations between serum urate levels and recurrent flares among preexisting gout patients.”

As for the cost of SU tests, Dr. Choi said they can run as low as $2. “Portable tests similar to home glucose measurement for diabetes patients are also being adopted by certain gout care practices,” he said.

The findings matter, Dr. Choi said, because SU is not tracked in the “vast majority of gout patients” in primary care. Instead, primary care doctors — as per the guidelines of the American College of Physicians — often adopt an approach that treats symptoms as needed instead of tracking and lowering SU levels, he said. In fact, “95% and 98% of gout flares can be potentially preventable at the population level if serum urate levels < 6 and < 5 mg/dL can be met, respectively, and 100% of hospitalizations for gout could be preventable with serum urate < 5 mg/dL,” he said.

As for limitations, the authors noted that participants in the UK Biobank “typically have a better socioeconomic status and are healthier than the UK general population,” and they added that “these data may underestimate the number of acute gout flares in the cohort.” Also, 55% of the total 502,490 patients in the UK Biobank were excluded owing to lack of primary care data.
 

Study ‘Offers the Kind of Evidence That We Need’

In an accompanying commentary, University of Alabama at Birmingham rheumatologist Angelo L. Gaffo, MD, MSPH, also noted that the study population was overwhelmingly White, had a low mean SU level (6.9 mg/dL), and had a low level of comorbidities, making the sample “poorly representative of the most commonly described gout populations.”

However, he also noted that there is “growing evidence linking serum urate levels with clinical outcomes,” with a pair of studies — one from 2021 and the other from 2022 — linking reductions in SU to < 6 md/dL to lower flare rates.

Dr. Gaffo told this news organization that although rheumatology guidelines support a treat-to-target strategy, “we haven›t generated a whole lot of important evidence to support it.”

The new study “offers the kind of evidence that we need,” he said, “but this is not going to be the ultimate answer.” That will only come from randomized clinical trials in the works that will pit the treat-to-target approach vs the primary care–favored strategy of titrating treatment until flares are controlled, he said.

Even though evidence is sparse, Dr. Gaffo said he still believes in the treat-to-target strategy: “I believe it is the best way to treat gout.”

What’s next? Researchers hope to understand how to better reach target SU goals in clinical practice, Dr. Choi said. “Involving nurses, pharmacists, or interactive online or app systems — as in other chronic treat-to-target care such as anticoagulation care, blood pressure, or lipid care — is actively being researched.”

He added that “we are trying to find the effective and safe medications and nonpharmacologic measures to reduce the urate burden, which can also simultaneously take care of gout’s frequent cardiovascular-kidney comorbidities.”

The US National Institutes of Health supported the study. Dr. Choi reports receiving grants from Horizon and serving on a board or committee for LG Chem, Shanton, and ANI Pharmaceuticals. Some other authors report an employment and stockholder relationship with Regeneron and support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Rheumatology Research Foundation. Dr. Gaffo reports personal fees from PK MED, SOBI/Selecta, Atom, and UpToDate.

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