From the Journals

TOPLINE:

Tumor necrosis factor (TNF) inhibitors led to no significant difference in survival or respiratory-related hospitalizations, compared with non-TNF inhibitors, in patients with rheumatoid arthritis–associated interstitial lung disease (RA-ILD).

METHODOLOGY:

• Guidelines from the American College of Rheumatology and the American College of Chest Physicians conditionally advise against the use of TNF inhibitors for treating ILD in patients with RA-ILD, with persisting uncertainty about the safety of TNF inhibitors.
• Researchers conducted a retrospective cohort study using data from the US Department of Veterans Affairs, with a focus on comparing outcomes in patients with RA-ILD who initiated TNF or non-TNF inhibitors between 2006 and 2018.
• A total of 1047 US veterans with RA-ILD were included, with 237 who initiated TNF inhibitors propensity matched in a 1:1 ratio with 237 who initiated non-TNF inhibitors (mean age, 68 years; 92% men).
• The primary composite outcome was time to death or respiratory-related hospitalization over a follow-up period of up to 3 years.
• The secondary outcomes included all-cause mortality, respiratory-related mortality, and respiratory-related hospitalization, with additional assessments over a 1-year period.

TAKEAWAY:

• No significant difference was observed in the composite outcome of death or respiratory-related hospitalization between the TNF and non-TNF inhibitor groups (adjusted hazard ratio, 1.21; 95% CI, 0.92-1.58).
• No significant differences in the risk for respiratory-related hospitalization and all-cause or respiratory-related mortality were found between the TNF and non-TNF inhibitor groups. Similar findings were observed for all the outcomes during 1 year of follow-up.
• The mean duration of medication use prior to discontinuation, the time to discontinuation, and the mean predicted forced vital capacity percentage were similar for both groups.
• In a subgroup analysis of patients aged ≥ 65 years, those treated with non-TNF inhibitors had a higher risk for the composite outcome and all-cause and respiratory-related mortality than those treated with TNF inhibitors. No significant differences in outcomes were observed between the two treatment groups among patients aged < 65 years.

IN PRACTICE:

“Our results do not suggest that systematic avoidance of TNF inhibitors is required in all patients with rheumatoid arthritis–associated ILD. However, given disease heterogeneity and imprecision of our estimates, some subpopulations of patients with rheumatoid arthritis–associated ILD might benefit from specific biological or targeted synthetic DMARD [disease-modifying antirheumatic drug] treatment strategies,” the authors wrote.

SOURCE:

The study was led by Bryant R. England, MD, PhD, University of Nebraska Medical Center, Omaha It was published online on January 7, 2025, in The Lancet Rheumatology.

LIMITATIONS:

Administrative algorithms were used for identifying RA-ILD, potentially leading to misclassification and limiting phenotyping accuracy. Even with the use of propensity score methods, there might still be residual selection bias or unmeasured confounding. The study lacked comprehensive measures of posttreatment forced vital capacity and other indicators of ILD severity. The study population, predominantly men and those with a smoking history, may limit the generalizability of the findings to other groups.

DISCLOSURES:

The study was primarily funded by the US Department of Veterans Affairs. Some authors reported having financial relationships with pharmaceutical companies unrelated to the submitted work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Tumor necrosis factor (TNF) inhibitors led to no significant difference in survival or respiratory-related hospitalizations, compared with non-TNF inhibitors, in patients with rheumatoid arthritis–associated interstitial lung disease (RA-ILD).

METHODOLOGY:

• Guidelines from the American College of Rheumatology and the American College of Chest Physicians conditionally advise against the use of TNF inhibitors for treating ILD in patients with RA-ILD, with persisting uncertainty about the safety of TNF inhibitors.
• Researchers conducted a retrospective cohort study using data from the US Department of Veterans Affairs, with a focus on comparing outcomes in patients with RA-ILD who initiated TNF or non-TNF inhibitors between 2006 and 2018.
• A total of 1047 US veterans with RA-ILD were included, with 237 who initiated TNF inhibitors propensity matched in a 1:1 ratio with 237 who initiated non-TNF inhibitors (mean age, 68 years; 92% men).
• The primary composite outcome was time to death or respiratory-related hospitalization over a follow-up period of up to 3 years.
• The secondary outcomes included all-cause mortality, respiratory-related mortality, and respiratory-related hospitalization, with additional assessments over a 1-year period.

TAKEAWAY:

• No significant difference was observed in the composite outcome of death or respiratory-related hospitalization between the TNF and non-TNF inhibitor groups (adjusted hazard ratio, 1.21; 95% CI, 0.92-1.58).
• No significant differences in the risk for respiratory-related hospitalization and all-cause or respiratory-related mortality were found between the TNF and non-TNF inhibitor groups. Similar findings were observed for all the outcomes during 1 year of follow-up.
• The mean duration of medication use prior to discontinuation, the time to discontinuation, and the mean predicted forced vital capacity percentage were similar for both groups.
• In a subgroup analysis of patients aged ≥ 65 years, those treated with non-TNF inhibitors had a higher risk for the composite outcome and all-cause and respiratory-related mortality than those treated with TNF inhibitors. No significant differences in outcomes were observed between the two treatment groups among patients aged < 65 years.

IN PRACTICE:

“Our results do not suggest that systematic avoidance of TNF inhibitors is required in all patients with rheumatoid arthritis–associated ILD. However, given disease heterogeneity and imprecision of our estimates, some subpopulations of patients with rheumatoid arthritis–associated ILD might benefit from specific biological or targeted synthetic DMARD [disease-modifying antirheumatic drug] treatment strategies,” the authors wrote.

SOURCE:

The study was led by Bryant R. England, MD, PhD, University of Nebraska Medical Center, Omaha It was published online on January 7, 2025, in The Lancet Rheumatology.

LIMITATIONS:

Administrative algorithms were used for identifying RA-ILD, potentially leading to misclassification and limiting phenotyping accuracy. Even with the use of propensity score methods, there might still be residual selection bias or unmeasured confounding. The study lacked comprehensive measures of posttreatment forced vital capacity and other indicators of ILD severity. The study population, predominantly men and those with a smoking history, may limit the generalizability of the findings to other groups.

DISCLOSURES:

The study was primarily funded by the US Department of Veterans Affairs. Some authors reported having financial relationships with pharmaceutical companies unrelated to the submitted work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Tumor necrosis factor (TNF) inhibitors led to no significant difference in survival or respiratory-related hospitalizations, compared with non-TNF inhibitors, in patients with rheumatoid arthritis–associated interstitial lung disease (RA-ILD).

METHODOLOGY:

• Guidelines from the American College of Rheumatology and the American College of Chest Physicians conditionally advise against the use of TNF inhibitors for treating ILD in patients with RA-ILD, with persisting uncertainty about the safety of TNF inhibitors.
• Researchers conducted a retrospective cohort study using data from the US Department of Veterans Affairs, with a focus on comparing outcomes in patients with RA-ILD who initiated TNF or non-TNF inhibitors between 2006 and 2018.
• A total of 1047 US veterans with RA-ILD were included, with 237 who initiated TNF inhibitors propensity matched in a 1:1 ratio with 237 who initiated non-TNF inhibitors (mean age, 68 years; 92% men).
• The primary composite outcome was time to death or respiratory-related hospitalization over a follow-up period of up to 3 years.
• The secondary outcomes included all-cause mortality, respiratory-related mortality, and respiratory-related hospitalization, with additional assessments over a 1-year period.

TAKEAWAY:

• No significant difference was observed in the composite outcome of death or respiratory-related hospitalization between the TNF and non-TNF inhibitor groups (adjusted hazard ratio, 1.21; 95% CI, 0.92-1.58).
• No significant differences in the risk for respiratory-related hospitalization and all-cause or respiratory-related mortality were found between the TNF and non-TNF inhibitor groups. Similar findings were observed for all the outcomes during 1 year of follow-up.
• The mean duration of medication use prior to discontinuation, the time to discontinuation, and the mean predicted forced vital capacity percentage were similar for both groups.
• In a subgroup analysis of patients aged ≥ 65 years, those treated with non-TNF inhibitors had a higher risk for the composite outcome and all-cause and respiratory-related mortality than those treated with TNF inhibitors. No significant differences in outcomes were observed between the two treatment groups among patients aged < 65 years.

IN PRACTICE:

“Our results do not suggest that systematic avoidance of TNF inhibitors is required in all patients with rheumatoid arthritis–associated ILD. However, given disease heterogeneity and imprecision of our estimates, some subpopulations of patients with rheumatoid arthritis–associated ILD might benefit from specific biological or targeted synthetic DMARD [disease-modifying antirheumatic drug] treatment strategies,” the authors wrote.

SOURCE:

The study was led by Bryant R. England, MD, PhD, University of Nebraska Medical Center, Omaha It was published online on January 7, 2025, in The Lancet Rheumatology.

LIMITATIONS:

Administrative algorithms were used for identifying RA-ILD, potentially leading to misclassification and limiting phenotyping accuracy. Even with the use of propensity score methods, there might still be residual selection bias or unmeasured confounding. The study lacked comprehensive measures of posttreatment forced vital capacity and other indicators of ILD severity. The study population, predominantly men and those with a smoking history, may limit the generalizability of the findings to other groups.

DISCLOSURES:

The study was primarily funded by the US Department of Veterans Affairs. Some authors reported having financial relationships with pharmaceutical companies unrelated to the submitted work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Children who were severely ill with multisystem inflammatory syndrome in children (MIS-C) related to COVID-19 infection appear to show excellent cardiovascular and noncardiovascular outcomes by 6 months, according to data published in JAMA Pediatrics.

MIS-C is a life-threatening complication of COVID-19 infection and data on outcomes are limited, wrote the authors, led by Dongngan T. Truong, MD, MSSI, with Children’s Healthcare of Atlanta Cardiology, Emory University School of Medicine in Atlanta, Georgia. These 6-month results are from the Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC) study, sponsored by the National Heart, Lung, and Blood Institute.

Researchers found in this cohort study of 1204 participants that by 6 months after hospital discharge, 99% had normalization of left ventricular systolic function, and 92.3% had normalized coronary artery dimensions. More than 95% reported being more than 90% back to baseline health.

Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health scores were at least equivalent to prepandemic population normative values. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months: fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3 (P < .001).

The most common symptoms reported at 2 weeks were fatigue (15.9%) and low stamina/energy (9.2%); both decreased to 3.4% and 3.3%, respectively, by 6 months. The most common cardiovascular symptom at 2 weeks was palpitations (1.5%), which decreased to 0.6%.

 

Chest Pain Increased Over Time

Reports of chest pain, however, reportedly increased over time, with 1.3% reporting chest pain at rest at 2 weeks and 2.2% at 6 months. Although gastrointestinal symptoms were common during the acute MIS-C, only 5.3% of respondents reported those symptoms at 2 weeks.

Children in the cohort had a median age of 9 years, and 60% were men. They self-identified with the following races and ethnicities: American Indian or Alaska Native (0.1%), Asian (3.3%), Black (27.0%), Hawaiian Native or Other Pacific Islander (0.2%), Hispanic or Latino (26.9%), multiracial (2.7%), White (31.2%), other (1.0%), and unknown or refused to specify (7.6%). Authors wrote that the cohort was followed-up to 2 years after illness onset and long-term results are not yet known.

 

Time to Exhale

David J. Goldberg, MD, with the Cardiac Center, Children’s Hospital of Philadelphia, Pennsylvania, and colleagues, wrote in an accompanying editorial that “the decreased frequency of the disease along (with) the reassuring reports on midterm outcomes can allow the pediatric community a moment of collective exhale.”

The editorialists note that of those who initially presented with myocardial dysfunction, all but one patient evaluated had a normal ejection fraction at follow-up. Energy, sleep, appetite, cognition, and mood also normalized by midterm.

“The results of the MUSIC study add to the emerging midterm outcomes data suggesting a near-complete cardiovascular recovery in the overwhelming majority of patients who develop MIS-C,” Goldberg and colleagues wrote. “Despite initial concerns, driven by the severity of acute presentation at diagnosis and longer-term questions that remain (for example, does coronary microvascular dysfunction persist even after normalization of coronary artery z score?), these data suggest an encouraging outlook for the long-term health of affected children.”

The Centers for Disease Control and Prevention and other agencies have reported a declining overall incidence of MIS-C and highlighted the protective value of vaccination. 

The editorialists add, however, that while the drop in MIS-C cases is encouraging, cases are still reported, especially amid high viral activity periods, “and nearly half of affected children continue to require intensive care in the acute phase of illness.”

Truong reported grants from the National Institutes of Health and serving as coprincipal investigator for Pfizer for research on COVID-19 vaccine-associated myocarditis funded by Pfizer and occurring through the framework of the National Heart, Lung, and Blood Institute’s Pediatric Heart Network outside the submitted work. One coauthor reported grants from Pfizer and Boston Scientific outside the submitted work. One coauthor reported receiving grants from Additional Ventures Foundation outside the submitted work. One coauthor reported receiving consultant fees from Amryt Pharma, Chiesi, Esperion, and Ultragenyx outside the submitted work. A coauthor reported receiving consultant fees from Larimar Therapeutics for mitochondrial therapies outside the submitted work. One coauthor reported being an employee of Takeda Pharmaceuticals since July 2023. One editorialist reported grants from Childhood Arthritis and Rheumatology Research Alliance and the Arthritis Foundation, Academy Health, and the Gordon and Betty Moore Foundation during the conduct of the study.

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

Children who were severely ill with multisystem inflammatory syndrome in children (MIS-C) related to COVID-19 infection appear to show excellent cardiovascular and noncardiovascular outcomes by 6 months, according to data published in JAMA Pediatrics.

MIS-C is a life-threatening complication of COVID-19 infection and data on outcomes are limited, wrote the authors, led by Dongngan T. Truong, MD, MSSI, with Children’s Healthcare of Atlanta Cardiology, Emory University School of Medicine in Atlanta, Georgia. These 6-month results are from the Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC) study, sponsored by the National Heart, Lung, and Blood Institute.

Researchers found in this cohort study of 1204 participants that by 6 months after hospital discharge, 99% had normalization of left ventricular systolic function, and 92.3% had normalized coronary artery dimensions. More than 95% reported being more than 90% back to baseline health.

Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health scores were at least equivalent to prepandemic population normative values. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months: fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3 (P < .001).

The most common symptoms reported at 2 weeks were fatigue (15.9%) and low stamina/energy (9.2%); both decreased to 3.4% and 3.3%, respectively, by 6 months. The most common cardiovascular symptom at 2 weeks was palpitations (1.5%), which decreased to 0.6%.

 

Chest Pain Increased Over Time

Reports of chest pain, however, reportedly increased over time, with 1.3% reporting chest pain at rest at 2 weeks and 2.2% at 6 months. Although gastrointestinal symptoms were common during the acute MIS-C, only 5.3% of respondents reported those symptoms at 2 weeks.

Children in the cohort had a median age of 9 years, and 60% were men. They self-identified with the following races and ethnicities: American Indian or Alaska Native (0.1%), Asian (3.3%), Black (27.0%), Hawaiian Native or Other Pacific Islander (0.2%), Hispanic or Latino (26.9%), multiracial (2.7%), White (31.2%), other (1.0%), and unknown or refused to specify (7.6%). Authors wrote that the cohort was followed-up to 2 years after illness onset and long-term results are not yet known.

 

Time to Exhale

David J. Goldberg, MD, with the Cardiac Center, Children’s Hospital of Philadelphia, Pennsylvania, and colleagues, wrote in an accompanying editorial that “the decreased frequency of the disease along (with) the reassuring reports on midterm outcomes can allow the pediatric community a moment of collective exhale.”

The editorialists note that of those who initially presented with myocardial dysfunction, all but one patient evaluated had a normal ejection fraction at follow-up. Energy, sleep, appetite, cognition, and mood also normalized by midterm.

“The results of the MUSIC study add to the emerging midterm outcomes data suggesting a near-complete cardiovascular recovery in the overwhelming majority of patients who develop MIS-C,” Goldberg and colleagues wrote. “Despite initial concerns, driven by the severity of acute presentation at diagnosis and longer-term questions that remain (for example, does coronary microvascular dysfunction persist even after normalization of coronary artery z score?), these data suggest an encouraging outlook for the long-term health of affected children.”

The Centers for Disease Control and Prevention and other agencies have reported a declining overall incidence of MIS-C and highlighted the protective value of vaccination. 

The editorialists add, however, that while the drop in MIS-C cases is encouraging, cases are still reported, especially amid high viral activity periods, “and nearly half of affected children continue to require intensive care in the acute phase of illness.”

Truong reported grants from the National Institutes of Health and serving as coprincipal investigator for Pfizer for research on COVID-19 vaccine-associated myocarditis funded by Pfizer and occurring through the framework of the National Heart, Lung, and Blood Institute’s Pediatric Heart Network outside the submitted work. One coauthor reported grants from Pfizer and Boston Scientific outside the submitted work. One coauthor reported receiving grants from Additional Ventures Foundation outside the submitted work. One coauthor reported receiving consultant fees from Amryt Pharma, Chiesi, Esperion, and Ultragenyx outside the submitted work. A coauthor reported receiving consultant fees from Larimar Therapeutics for mitochondrial therapies outside the submitted work. One coauthor reported being an employee of Takeda Pharmaceuticals since July 2023. One editorialist reported grants from Childhood Arthritis and Rheumatology Research Alliance and the Arthritis Foundation, Academy Health, and the Gordon and Betty Moore Foundation during the conduct of the study.

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

Children who were severely ill with multisystem inflammatory syndrome in children (MIS-C) related to COVID-19 infection appear to show excellent cardiovascular and noncardiovascular outcomes by 6 months, according to data published in JAMA Pediatrics.

MIS-C is a life-threatening complication of COVID-19 infection and data on outcomes are limited, wrote the authors, led by Dongngan T. Truong, MD, MSSI, with Children’s Healthcare of Atlanta Cardiology, Emory University School of Medicine in Atlanta, Georgia. These 6-month results are from the Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC) study, sponsored by the National Heart, Lung, and Blood Institute.

Researchers found in this cohort study of 1204 participants that by 6 months after hospital discharge, 99% had normalization of left ventricular systolic function, and 92.3% had normalized coronary artery dimensions. More than 95% reported being more than 90% back to baseline health.

Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health scores were at least equivalent to prepandemic population normative values. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months: fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3 (P < .001).

The most common symptoms reported at 2 weeks were fatigue (15.9%) and low stamina/energy (9.2%); both decreased to 3.4% and 3.3%, respectively, by 6 months. The most common cardiovascular symptom at 2 weeks was palpitations (1.5%), which decreased to 0.6%.

 

Chest Pain Increased Over Time

Reports of chest pain, however, reportedly increased over time, with 1.3% reporting chest pain at rest at 2 weeks and 2.2% at 6 months. Although gastrointestinal symptoms were common during the acute MIS-C, only 5.3% of respondents reported those symptoms at 2 weeks.

Children in the cohort had a median age of 9 years, and 60% were men. They self-identified with the following races and ethnicities: American Indian or Alaska Native (0.1%), Asian (3.3%), Black (27.0%), Hawaiian Native or Other Pacific Islander (0.2%), Hispanic or Latino (26.9%), multiracial (2.7%), White (31.2%), other (1.0%), and unknown or refused to specify (7.6%). Authors wrote that the cohort was followed-up to 2 years after illness onset and long-term results are not yet known.

 

Time to Exhale

David J. Goldberg, MD, with the Cardiac Center, Children’s Hospital of Philadelphia, Pennsylvania, and colleagues, wrote in an accompanying editorial that “the decreased frequency of the disease along (with) the reassuring reports on midterm outcomes can allow the pediatric community a moment of collective exhale.”

The editorialists note that of those who initially presented with myocardial dysfunction, all but one patient evaluated had a normal ejection fraction at follow-up. Energy, sleep, appetite, cognition, and mood also normalized by midterm.

“The results of the MUSIC study add to the emerging midterm outcomes data suggesting a near-complete cardiovascular recovery in the overwhelming majority of patients who develop MIS-C,” Goldberg and colleagues wrote. “Despite initial concerns, driven by the severity of acute presentation at diagnosis and longer-term questions that remain (for example, does coronary microvascular dysfunction persist even after normalization of coronary artery z score?), these data suggest an encouraging outlook for the long-term health of affected children.”

The Centers for Disease Control and Prevention and other agencies have reported a declining overall incidence of MIS-C and highlighted the protective value of vaccination. 

The editorialists add, however, that while the drop in MIS-C cases is encouraging, cases are still reported, especially amid high viral activity periods, “and nearly half of affected children continue to require intensive care in the acute phase of illness.”

Truong reported grants from the National Institutes of Health and serving as coprincipal investigator for Pfizer for research on COVID-19 vaccine-associated myocarditis funded by Pfizer and occurring through the framework of the National Heart, Lung, and Blood Institute’s Pediatric Heart Network outside the submitted work. One coauthor reported grants from Pfizer and Boston Scientific outside the submitted work. One coauthor reported receiving grants from Additional Ventures Foundation outside the submitted work. One coauthor reported receiving consultant fees from Amryt Pharma, Chiesi, Esperion, and Ultragenyx outside the submitted work. A coauthor reported receiving consultant fees from Larimar Therapeutics for mitochondrial therapies outside the submitted work. One coauthor reported being an employee of Takeda Pharmaceuticals since July 2023. One editorialist reported grants from Childhood Arthritis and Rheumatology Research Alliance and the Arthritis Foundation, Academy Health, and the Gordon and Betty Moore Foundation during the conduct of the study.

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

TOPLINE:

The use of valaciclovir as prophylaxis prevents herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) receiving anifrolumab treatment, with no cases of zoster reported during the follow-up period in patients receiving valaciclovir.

METHODOLOGY:

• Anifrolumab, a human monoclonal antibody binding to type I interferon receptor subunit 1, increases the risk for HZ in patients with SLE; however, specific recommendations to prevent HZ are currently nonexistent for patients with SLE receiving anifrolumab.
• Researchers conducted a multicenter observational study in France from November 2021 to July 2024 to evaluate the prophylactic benefits of valaciclovir in 132 patients with SLE (mean age, 42 years; 92% women) treated with anifrolumab for ≥ 3 months.
• Among these patients, 87 received either 500 mg/d valaciclovir (n = 69) or 1000 mg/d valaciclovir (n = 18) as prophylaxis, whereas 45 did not receive valaciclovir.
• The patients were followed up for a median duration of 234 days under anifrolumab treatment, with monitoring for the development of herpes zoster.

TAKEAWAY:

• The risk for HZ was significantly lower in patients who received valaciclovir than in those who did not (hazard ratio, 0.08; P = .01).
• None of the patients treated with valaciclovir developed HZ during the survey period.
• The frequency of HZ in patients who did not receive valaciclovir increased progressively from 2.2% at 3 months to 6.2% at 6 months, reaching 23% at 12 months.
• None of the reported cases of HZ required hospitalization or led to anifrolumab discontinuation, although one patient developed neuralgia.

IN PRACTICE:

“Prophylactic treatment with valaciclovir is effective for preventing HZ [herpes zoster] infection in SLE patients treated with anifrolumab,” the authors wrote. “This finding is particularly relevant for SLE patients who cannot receive the recombinant HZ vaccine or for whom it is unavailable,” they added.

SOURCE:

The study was led by Ludovic Trefond, MD, PhD, Centre Hospitalier Universitaire de Clermont-Ferrand in France. It was published online on January 4, 2025, in RMD Open.

LIMITATIONS:

The observational design of the study and the low number of herpes zoster events during the follow-up period may have affected the robustness of the findings.

DISCLOSURES:

The authors did not receive any specific grants. Some authors reported having financial relationships with various pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The use of valaciclovir as prophylaxis prevents herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) receiving anifrolumab treatment, with no cases of zoster reported during the follow-up period in patients receiving valaciclovir.

METHODOLOGY:

• Anifrolumab, a human monoclonal antibody binding to type I interferon receptor subunit 1, increases the risk for HZ in patients with SLE; however, specific recommendations to prevent HZ are currently nonexistent for patients with SLE receiving anifrolumab.
• Researchers conducted a multicenter observational study in France from November 2021 to July 2024 to evaluate the prophylactic benefits of valaciclovir in 132 patients with SLE (mean age, 42 years; 92% women) treated with anifrolumab for ≥ 3 months.
• Among these patients, 87 received either 500 mg/d valaciclovir (n = 69) or 1000 mg/d valaciclovir (n = 18) as prophylaxis, whereas 45 did not receive valaciclovir.
• The patients were followed up for a median duration of 234 days under anifrolumab treatment, with monitoring for the development of herpes zoster.

TAKEAWAY:

• The risk for HZ was significantly lower in patients who received valaciclovir than in those who did not (hazard ratio, 0.08; P = .01).
• None of the patients treated with valaciclovir developed HZ during the survey period.
• The frequency of HZ in patients who did not receive valaciclovir increased progressively from 2.2% at 3 months to 6.2% at 6 months, reaching 23% at 12 months.
• None of the reported cases of HZ required hospitalization or led to anifrolumab discontinuation, although one patient developed neuralgia.

IN PRACTICE:

“Prophylactic treatment with valaciclovir is effective for preventing HZ [herpes zoster] infection in SLE patients treated with anifrolumab,” the authors wrote. “This finding is particularly relevant for SLE patients who cannot receive the recombinant HZ vaccine or for whom it is unavailable,” they added.

SOURCE:

The study was led by Ludovic Trefond, MD, PhD, Centre Hospitalier Universitaire de Clermont-Ferrand in France. It was published online on January 4, 2025, in RMD Open.

LIMITATIONS:

The observational design of the study and the low number of herpes zoster events during the follow-up period may have affected the robustness of the findings.

DISCLOSURES:

The authors did not receive any specific grants. Some authors reported having financial relationships with various pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The use of valaciclovir as prophylaxis prevents herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) receiving anifrolumab treatment, with no cases of zoster reported during the follow-up period in patients receiving valaciclovir.

METHODOLOGY:

• Anifrolumab, a human monoclonal antibody binding to type I interferon receptor subunit 1, increases the risk for HZ in patients with SLE; however, specific recommendations to prevent HZ are currently nonexistent for patients with SLE receiving anifrolumab.
• Researchers conducted a multicenter observational study in France from November 2021 to July 2024 to evaluate the prophylactic benefits of valaciclovir in 132 patients with SLE (mean age, 42 years; 92% women) treated with anifrolumab for ≥ 3 months.
• Among these patients, 87 received either 500 mg/d valaciclovir (n = 69) or 1000 mg/d valaciclovir (n = 18) as prophylaxis, whereas 45 did not receive valaciclovir.
• The patients were followed up for a median duration of 234 days under anifrolumab treatment, with monitoring for the development of herpes zoster.

TAKEAWAY:

• The risk for HZ was significantly lower in patients who received valaciclovir than in those who did not (hazard ratio, 0.08; P = .01).
• None of the patients treated with valaciclovir developed HZ during the survey period.
• The frequency of HZ in patients who did not receive valaciclovir increased progressively from 2.2% at 3 months to 6.2% at 6 months, reaching 23% at 12 months.
• None of the reported cases of HZ required hospitalization or led to anifrolumab discontinuation, although one patient developed neuralgia.

IN PRACTICE:

“Prophylactic treatment with valaciclovir is effective for preventing HZ [herpes zoster] infection in SLE patients treated with anifrolumab,” the authors wrote. “This finding is particularly relevant for SLE patients who cannot receive the recombinant HZ vaccine or for whom it is unavailable,” they added.

SOURCE:

The study was led by Ludovic Trefond, MD, PhD, Centre Hospitalier Universitaire de Clermont-Ferrand in France. It was published online on January 4, 2025, in RMD Open.

LIMITATIONS:

The observational design of the study and the low number of herpes zoster events during the follow-up period may have affected the robustness of the findings.

DISCLOSURES:

The authors did not receive any specific grants. Some authors reported having financial relationships with various pharmaceutical companies.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

According to a secondary analysis of the 24-month Myopia Outcome Study of Atropine in Children (MOSAIC) trial, 0.05% atropine eye drops were more effective in controlling myopia progression and axial elongation than placebo eye drops in children despite causing blurred vision and photophobia in some participants.

METHODOLOGY:

• Researchers conducted a secondary analysis of the 3-year results of the MOSAIC trial to investigate the efficacy and safety of different atropine regimens in treatment-naive children aged 6-16 years with a spherical equivalent ≤ −0.50 diopters (D).
• They analyzed data of 199 children in Europe with myopia (mean age, 13.9 years; 60.8% girls) who were randomly assigned to either group 1 (nightly placebo for 2 years followed by 0.05% atropine eye drops for 1 year; n = 66) or group 2 (nightly 0.01% atropine eye drops for 2 years followed by another random assignment to nightly placebo, tapering placebo, or tapering of 0.01% atropine eye drops for 1 year; n = 133).
• The nightly and tapered placebo groups were combined as a single treatment group for the sake of analysis.
• The primary outcome measures included observed changes in the progression of myopia, assessed using cycloplegic spherical equivalent refraction and axial length from month 24 to month 36.

TAKEAWAY:

• Children in the 0.01% atropine then placebo groups showed greater spherical equivalent progression (adjusted difference, –0.13 D; P = .01) and axial elongation (adjusted difference, 0.06 mm; P = .008) than those in the placebo then 0.05% atropine group.
• Children in the placebo then 0.05% atropine group also experienced less axial elongation (P = .04) than those in the 0.01% atropine then tapering 0.01% atropine group.
• Among participants using 0.05% atropine, 15% reported blurred near vision and 8% reported photophobia, whereas 3% reported blurred near vision and 0% reported photophobia in the 0.01% atropine then tapering 0.01% atropine group.
• Despite experiencing adverse events, no participants in the placebo then 0.05% atropine group discontinued treatment, with 92% completing the 36-month visit and 81% adhering to the treatment regimen.

IN PRACTICE:

“Recognizing a 2-year delay in treatment initiation in the group of children originally assigned to placebo, 0.05% atropine eyedrops slowed both myopia progression and axial eye growth over the course of a 1-year period,” the authors of the study wrote.

SOURCE:

This study was led by James Loughman, PhD, of the Centre for Eye Research Ireland, Dublin. It was published online in JAMA Ophthalmology.

LIMITATIONS:

Limitations included smaller sample sizes across treatment groups in year 3 and potential carry-over effects for participants transitioning from 0.01% atropine to placebo or tapered dosing. Because the study lacked an untreated control group, rebound myopia progression could be measured based only on the expected third-year results from the 0.01% atropine then placebo groups. The age of participants during the third year may have affected the ability to detect rebound progression.

DISCLOSURES:

This study was supported partly by a grant from the Health Research Board; Fighting Blindness, Ireland; and Vyluma. Some authors reported receiving grants, nonfinancial support, or consultant fees or having several other ties with Vyluma and other sources.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

According to a secondary analysis of the 24-month Myopia Outcome Study of Atropine in Children (MOSAIC) trial, 0.05% atropine eye drops were more effective in controlling myopia progression and axial elongation than placebo eye drops in children despite causing blurred vision and photophobia in some participants.

METHODOLOGY:

• Researchers conducted a secondary analysis of the 3-year results of the MOSAIC trial to investigate the efficacy and safety of different atropine regimens in treatment-naive children aged 6-16 years with a spherical equivalent ≤ −0.50 diopters (D).
• They analyzed data of 199 children in Europe with myopia (mean age, 13.9 years; 60.8% girls) who were randomly assigned to either group 1 (nightly placebo for 2 years followed by 0.05% atropine eye drops for 1 year; n = 66) or group 2 (nightly 0.01% atropine eye drops for 2 years followed by another random assignment to nightly placebo, tapering placebo, or tapering of 0.01% atropine eye drops for 1 year; n = 133).
• The nightly and tapered placebo groups were combined as a single treatment group for the sake of analysis.
• The primary outcome measures included observed changes in the progression of myopia, assessed using cycloplegic spherical equivalent refraction and axial length from month 24 to month 36.

TAKEAWAY:

• Children in the 0.01% atropine then placebo groups showed greater spherical equivalent progression (adjusted difference, –0.13 D; P = .01) and axial elongation (adjusted difference, 0.06 mm; P = .008) than those in the placebo then 0.05% atropine group.
• Children in the placebo then 0.05% atropine group also experienced less axial elongation (P = .04) than those in the 0.01% atropine then tapering 0.01% atropine group.
• Among participants using 0.05% atropine, 15% reported blurred near vision and 8% reported photophobia, whereas 3% reported blurred near vision and 0% reported photophobia in the 0.01% atropine then tapering 0.01% atropine group.
• Despite experiencing adverse events, no participants in the placebo then 0.05% atropine group discontinued treatment, with 92% completing the 36-month visit and 81% adhering to the treatment regimen.

IN PRACTICE:

“Recognizing a 2-year delay in treatment initiation in the group of children originally assigned to placebo, 0.05% atropine eyedrops slowed both myopia progression and axial eye growth over the course of a 1-year period,” the authors of the study wrote.

SOURCE:

This study was led by James Loughman, PhD, of the Centre for Eye Research Ireland, Dublin. It was published online in JAMA Ophthalmology.

LIMITATIONS:

Limitations included smaller sample sizes across treatment groups in year 3 and potential carry-over effects for participants transitioning from 0.01% atropine to placebo or tapered dosing. Because the study lacked an untreated control group, rebound myopia progression could be measured based only on the expected third-year results from the 0.01% atropine then placebo groups. The age of participants during the third year may have affected the ability to detect rebound progression.

DISCLOSURES:

This study was supported partly by a grant from the Health Research Board; Fighting Blindness, Ireland; and Vyluma. Some authors reported receiving grants, nonfinancial support, or consultant fees or having several other ties with Vyluma and other sources.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

According to a secondary analysis of the 24-month Myopia Outcome Study of Atropine in Children (MOSAIC) trial, 0.05% atropine eye drops were more effective in controlling myopia progression and axial elongation than placebo eye drops in children despite causing blurred vision and photophobia in some participants.

METHODOLOGY:

• Researchers conducted a secondary analysis of the 3-year results of the MOSAIC trial to investigate the efficacy and safety of different atropine regimens in treatment-naive children aged 6-16 years with a spherical equivalent ≤ −0.50 diopters (D).
• They analyzed data of 199 children in Europe with myopia (mean age, 13.9 years; 60.8% girls) who were randomly assigned to either group 1 (nightly placebo for 2 years followed by 0.05% atropine eye drops for 1 year; n = 66) or group 2 (nightly 0.01% atropine eye drops for 2 years followed by another random assignment to nightly placebo, tapering placebo, or tapering of 0.01% atropine eye drops for 1 year; n = 133).
• The nightly and tapered placebo groups were combined as a single treatment group for the sake of analysis.
• The primary outcome measures included observed changes in the progression of myopia, assessed using cycloplegic spherical equivalent refraction and axial length from month 24 to month 36.

TAKEAWAY:

• Children in the 0.01% atropine then placebo groups showed greater spherical equivalent progression (adjusted difference, –0.13 D; P = .01) and axial elongation (adjusted difference, 0.06 mm; P = .008) than those in the placebo then 0.05% atropine group.
• Children in the placebo then 0.05% atropine group also experienced less axial elongation (P = .04) than those in the 0.01% atropine then tapering 0.01% atropine group.
• Among participants using 0.05% atropine, 15% reported blurred near vision and 8% reported photophobia, whereas 3% reported blurred near vision and 0% reported photophobia in the 0.01% atropine then tapering 0.01% atropine group.
• Despite experiencing adverse events, no participants in the placebo then 0.05% atropine group discontinued treatment, with 92% completing the 36-month visit and 81% adhering to the treatment regimen.

IN PRACTICE:

“Recognizing a 2-year delay in treatment initiation in the group of children originally assigned to placebo, 0.05% atropine eyedrops slowed both myopia progression and axial eye growth over the course of a 1-year period,” the authors of the study wrote.

SOURCE:

This study was led by James Loughman, PhD, of the Centre for Eye Research Ireland, Dublin. It was published online in JAMA Ophthalmology.

LIMITATIONS:

Limitations included smaller sample sizes across treatment groups in year 3 and potential carry-over effects for participants transitioning from 0.01% atropine to placebo or tapered dosing. Because the study lacked an untreated control group, rebound myopia progression could be measured based only on the expected third-year results from the 0.01% atropine then placebo groups. The age of participants during the third year may have affected the ability to detect rebound progression.

DISCLOSURES:

This study was supported partly by a grant from the Health Research Board; Fighting Blindness, Ireland; and Vyluma. Some authors reported receiving grants, nonfinancial support, or consultant fees or having several other ties with Vyluma and other sources.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Higher rates of leaving the emergency department (ED) without being seen are linked to increased short-term mortality or hospitalization, according to a cohort study in Ontario, Canada.

“We found that after 2020, there was a 14% higher risk for death or hospitalization within 7 days” among patients who left without being seen (LWBS), Candace McNaughton, MD, PhD, associate professor of medicine at the University of Toronto and scientist at Sunnybrook Research Institute, both in Toronto, Ontario, Canada, told this news organization.

“When we looked at death by itself, there was a 46% higher risk after 2020,” she said. “Even 30 days after a LWBS ED visit, there was still a 5% increased risk for death/hospitalization and a 24% increased risk for death.”

The study was published in the Journal of the American College of Emergency Physicians Open.

 

LWBS Rates Increased 

Researchers used linked administrative data to analyze temporal trends in monthly rates of ED and LWBS visits for adults in Ontario from 2014 to 2023.

They compared the composite outcome of 7-day all-cause mortality or hospitalization following an LWBS ED visit in April 2022‒March 2023 (recent period) with that following an LWBS ED visit in April 2014‒March 2020 (baseline period), after adjustment for age, sex, and Charlson Comorbidity Index (CCI).

In the two periods, patient characteristics were similar across age, sex, neighborhood-level income quartile, history of being unhoused, rurality, CCI, day, time, and mode of arrival. The median age was 40 years for the baseline period and 42 years for the recent period.

Temporal trends showed sustained increases in monthly LWBS rates after 2020, despite fewer monthly ED visits. The rate of LWBS ED visits after April 1, 2020, exceeded the baseline period’s single-month LWBS maximum of 4% in 15 of 36 months.

The rate of 7-day all-cause mortality or hospitalization was 3.4% in the recent period vs 2.9% in the baseline period (adjusted risk ratio [aRR], 1.14), despite similar rates of post-ED outpatient visits (7-day recent and baseline, 38.9% and 39.7%, respectively).

Similar trends were seen at 30 days for all-cause mortality or hospitalization (6.2% in the recent period vs 5.8% at baseline; aRR, 1.05) despite similar rates of post-ED outpatient visits (59.4% and 59.7%, respectively).

After April 1, 2020, monthly ED visits and the proportion of patients who LWBS varied widely.

The proportion of LWBS visits categorized as emergent on the Canadian Triage and Acuity Scale was higher during the recent period (12.9% vs 9.2% in the baseline period), and fewer visits were categorized as semiurgent (22.6% vs 31.9%, respectively). This finding suggested a higher acuity of illness among patients who LWBS in the recent period.

 

LWBS Visits ‘Not Benign’

Results of a preplanned subgroup analysis examining the risk for all-cause mortality after an LWBS visit were “particularly notable,” the authors wrote, with a 46% higher adjusted risk for death at 7 days and 24% higher adjusted risk at 30 days.

The observational study had several limitations, however. The authors could not draw conclusions regarding direct causes of the increased risk for severe short-term adverse health outcomes after an LWBS ED visit, and residual confounding is possible. Cause-of-death information was not available to generate hypotheses for future studies of potential causes. Furthermore, the findings may not be generalizable to systems without universal access to healthcare.

Nevertheless, the findings are a “concerning signal [and] should prompt interventions to address system- and population-level causes,” the authors wrote.

“Unfortunately, because of politics, since 2020, ED closures in Ontario have become more and more common and seem to be affecting more and more Ontarians,” said McNaughton. “It would be surprising if ED closure didn’t play some role in our findings.”

She added, “It is important to note that people in our study were relatively young, with a median age in their 40s; this makes our findings all the more concerning. Clinicians should be aware that LWBS ED visits are not necessarily benign, particularly when rates of LWBS ED visits are high.”

 

Unanswered Questions

The study raised the following questions that the authors are or will be investigating, according to McNaughton: 

• Which patients are at greatest risk for bad outcomes if they leave the ED without being seen, and why?
• How much of the findings might be related to recent ED closures, longer ED wait times, or other factors? Are there geographic variations in risk?
• What can be done in the ED to prevent LWBS ED visits, and what can be changed outside the ED to prevent LWBS ED visits? For example, what can hospitals do to reduce boarding in the ED? If patients leave without being seen, should they be contacted to try to meet their health needs in other ways?
• What worked in terms of maintaining access to outpatient medical care, despite the considerable disruptions starting in 2020, and how can continued success be ensured?

To address the current situation, McNaughton said, “We need consistent, predictable, and sustained investment in our public healthcare system. We need long-term, consistent funding for primary care, ED care, as well as hospital and long-term care.”

“It takes years to recruit and train the teams of people necessary to provide the high-quality medical care that Canadians have a right to. There are no shortcuts,” she concluded.

 

‘Tragic Situation’

American College of Emergency Physicians (ACEP) spokesperson Jesse Pines, MD, chief of clinical innovation at US Acute Care Solutions; clinical professor of emergency medicine at George Washington University in Washington, DC; and professor of emergency medicine at Drexel University in Philadelphia, commented on the study for this news organization.

“Similar to what the authors found in their report, LWBS and other metrics — specifically boarding — have progressively increased in the United States, in particular, since the early part of 2021,” he said. “The primary factor in the US driving this, and one that ACEP is trying to address on a national scale, is the boarding of admitted patients.”

When the number of boarded patients increases, there is less space in the ED for new patients, and waits increase, Pines explained. Some patients leave without being seen, and a subset of those patients experience poor outcomes. “It’s a tragic situation that is worsening.”

“Emergency physicians like me always worry when patients leave without being seen,” he said. While some of those patients have self-limited conditions that will improve on their own, “some have critical life-threatening conditions that require care and hospitalization. The worry is that these patients experience poorer outcomes,” Pines said. “The authors showed that this is increasingly the case in Canada. The same is likely true in the US.”

The study was funded by the Canadian Institutes of Health Research. McNaughton and Pines declared no relevant financial relationships.

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

Higher rates of leaving the emergency department (ED) without being seen are linked to increased short-term mortality or hospitalization, according to a cohort study in Ontario, Canada.

“We found that after 2020, there was a 14% higher risk for death or hospitalization within 7 days” among patients who left without being seen (LWBS), Candace McNaughton, MD, PhD, associate professor of medicine at the University of Toronto and scientist at Sunnybrook Research Institute, both in Toronto, Ontario, Canada, told this news organization.

“When we looked at death by itself, there was a 46% higher risk after 2020,” she said. “Even 30 days after a LWBS ED visit, there was still a 5% increased risk for death/hospitalization and a 24% increased risk for death.”

The study was published in the Journal of the American College of Emergency Physicians Open.

 

LWBS Rates Increased 

Researchers used linked administrative data to analyze temporal trends in monthly rates of ED and LWBS visits for adults in Ontario from 2014 to 2023.

They compared the composite outcome of 7-day all-cause mortality or hospitalization following an LWBS ED visit in April 2022‒March 2023 (recent period) with that following an LWBS ED visit in April 2014‒March 2020 (baseline period), after adjustment for age, sex, and Charlson Comorbidity Index (CCI).

In the two periods, patient characteristics were similar across age, sex, neighborhood-level income quartile, history of being unhoused, rurality, CCI, day, time, and mode of arrival. The median age was 40 years for the baseline period and 42 years for the recent period.

Temporal trends showed sustained increases in monthly LWBS rates after 2020, despite fewer monthly ED visits. The rate of LWBS ED visits after April 1, 2020, exceeded the baseline period’s single-month LWBS maximum of 4% in 15 of 36 months.

The rate of 7-day all-cause mortality or hospitalization was 3.4% in the recent period vs 2.9% in the baseline period (adjusted risk ratio [aRR], 1.14), despite similar rates of post-ED outpatient visits (7-day recent and baseline, 38.9% and 39.7%, respectively).

Similar trends were seen at 30 days for all-cause mortality or hospitalization (6.2% in the recent period vs 5.8% at baseline; aRR, 1.05) despite similar rates of post-ED outpatient visits (59.4% and 59.7%, respectively).

After April 1, 2020, monthly ED visits and the proportion of patients who LWBS varied widely.

The proportion of LWBS visits categorized as emergent on the Canadian Triage and Acuity Scale was higher during the recent period (12.9% vs 9.2% in the baseline period), and fewer visits were categorized as semiurgent (22.6% vs 31.9%, respectively). This finding suggested a higher acuity of illness among patients who LWBS in the recent period.

 

LWBS Visits ‘Not Benign’

Results of a preplanned subgroup analysis examining the risk for all-cause mortality after an LWBS visit were “particularly notable,” the authors wrote, with a 46% higher adjusted risk for death at 7 days and 24% higher adjusted risk at 30 days.

The observational study had several limitations, however. The authors could not draw conclusions regarding direct causes of the increased risk for severe short-term adverse health outcomes after an LWBS ED visit, and residual confounding is possible. Cause-of-death information was not available to generate hypotheses for future studies of potential causes. Furthermore, the findings may not be generalizable to systems without universal access to healthcare.

Nevertheless, the findings are a “concerning signal [and] should prompt interventions to address system- and population-level causes,” the authors wrote.

“Unfortunately, because of politics, since 2020, ED closures in Ontario have become more and more common and seem to be affecting more and more Ontarians,” said McNaughton. “It would be surprising if ED closure didn’t play some role in our findings.”

She added, “It is important to note that people in our study were relatively young, with a median age in their 40s; this makes our findings all the more concerning. Clinicians should be aware that LWBS ED visits are not necessarily benign, particularly when rates of LWBS ED visits are high.”

 

Unanswered Questions

The study raised the following questions that the authors are or will be investigating, according to McNaughton: 

• Which patients are at greatest risk for bad outcomes if they leave the ED without being seen, and why?
• How much of the findings might be related to recent ED closures, longer ED wait times, or other factors? Are there geographic variations in risk?
• What can be done in the ED to prevent LWBS ED visits, and what can be changed outside the ED to prevent LWBS ED visits? For example, what can hospitals do to reduce boarding in the ED? If patients leave without being seen, should they be contacted to try to meet their health needs in other ways?
• What worked in terms of maintaining access to outpatient medical care, despite the considerable disruptions starting in 2020, and how can continued success be ensured?

To address the current situation, McNaughton said, “We need consistent, predictable, and sustained investment in our public healthcare system. We need long-term, consistent funding for primary care, ED care, as well as hospital and long-term care.”

“It takes years to recruit and train the teams of people necessary to provide the high-quality medical care that Canadians have a right to. There are no shortcuts,” she concluded.

 

‘Tragic Situation’

American College of Emergency Physicians (ACEP) spokesperson Jesse Pines, MD, chief of clinical innovation at US Acute Care Solutions; clinical professor of emergency medicine at George Washington University in Washington, DC; and professor of emergency medicine at Drexel University in Philadelphia, commented on the study for this news organization.

“Similar to what the authors found in their report, LWBS and other metrics — specifically boarding — have progressively increased in the United States, in particular, since the early part of 2021,” he said. “The primary factor in the US driving this, and one that ACEP is trying to address on a national scale, is the boarding of admitted patients.”

When the number of boarded patients increases, there is less space in the ED for new patients, and waits increase, Pines explained. Some patients leave without being seen, and a subset of those patients experience poor outcomes. “It’s a tragic situation that is worsening.”

“Emergency physicians like me always worry when patients leave without being seen,” he said. While some of those patients have self-limited conditions that will improve on their own, “some have critical life-threatening conditions that require care and hospitalization. The worry is that these patients experience poorer outcomes,” Pines said. “The authors showed that this is increasingly the case in Canada. The same is likely true in the US.”

The study was funded by the Canadian Institutes of Health Research. McNaughton and Pines declared no relevant financial relationships.

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

Higher rates of leaving the emergency department (ED) without being seen are linked to increased short-term mortality or hospitalization, according to a cohort study in Ontario, Canada.

“We found that after 2020, there was a 14% higher risk for death or hospitalization within 7 days” among patients who left without being seen (LWBS), Candace McNaughton, MD, PhD, associate professor of medicine at the University of Toronto and scientist at Sunnybrook Research Institute, both in Toronto, Ontario, Canada, told this news organization.

“When we looked at death by itself, there was a 46% higher risk after 2020,” she said. “Even 30 days after a LWBS ED visit, there was still a 5% increased risk for death/hospitalization and a 24% increased risk for death.”

The study was published in the Journal of the American College of Emergency Physicians Open.

 

LWBS Rates Increased 

Researchers used linked administrative data to analyze temporal trends in monthly rates of ED and LWBS visits for adults in Ontario from 2014 to 2023.

They compared the composite outcome of 7-day all-cause mortality or hospitalization following an LWBS ED visit in April 2022‒March 2023 (recent period) with that following an LWBS ED visit in April 2014‒March 2020 (baseline period), after adjustment for age, sex, and Charlson Comorbidity Index (CCI).

In the two periods, patient characteristics were similar across age, sex, neighborhood-level income quartile, history of being unhoused, rurality, CCI, day, time, and mode of arrival. The median age was 40 years for the baseline period and 42 years for the recent period.

Temporal trends showed sustained increases in monthly LWBS rates after 2020, despite fewer monthly ED visits. The rate of LWBS ED visits after April 1, 2020, exceeded the baseline period’s single-month LWBS maximum of 4% in 15 of 36 months.

The rate of 7-day all-cause mortality or hospitalization was 3.4% in the recent period vs 2.9% in the baseline period (adjusted risk ratio [aRR], 1.14), despite similar rates of post-ED outpatient visits (7-day recent and baseline, 38.9% and 39.7%, respectively).

Similar trends were seen at 30 days for all-cause mortality or hospitalization (6.2% in the recent period vs 5.8% at baseline; aRR, 1.05) despite similar rates of post-ED outpatient visits (59.4% and 59.7%, respectively).

After April 1, 2020, monthly ED visits and the proportion of patients who LWBS varied widely.

The proportion of LWBS visits categorized as emergent on the Canadian Triage and Acuity Scale was higher during the recent period (12.9% vs 9.2% in the baseline period), and fewer visits were categorized as semiurgent (22.6% vs 31.9%, respectively). This finding suggested a higher acuity of illness among patients who LWBS in the recent period.

 

LWBS Visits ‘Not Benign’

Results of a preplanned subgroup analysis examining the risk for all-cause mortality after an LWBS visit were “particularly notable,” the authors wrote, with a 46% higher adjusted risk for death at 7 days and 24% higher adjusted risk at 30 days.

The observational study had several limitations, however. The authors could not draw conclusions regarding direct causes of the increased risk for severe short-term adverse health outcomes after an LWBS ED visit, and residual confounding is possible. Cause-of-death information was not available to generate hypotheses for future studies of potential causes. Furthermore, the findings may not be generalizable to systems without universal access to healthcare.

Nevertheless, the findings are a “concerning signal [and] should prompt interventions to address system- and population-level causes,” the authors wrote.

“Unfortunately, because of politics, since 2020, ED closures in Ontario have become more and more common and seem to be affecting more and more Ontarians,” said McNaughton. “It would be surprising if ED closure didn’t play some role in our findings.”

She added, “It is important to note that people in our study were relatively young, with a median age in their 40s; this makes our findings all the more concerning. Clinicians should be aware that LWBS ED visits are not necessarily benign, particularly when rates of LWBS ED visits are high.”

 

Unanswered Questions

The study raised the following questions that the authors are or will be investigating, according to McNaughton: 

• Which patients are at greatest risk for bad outcomes if they leave the ED without being seen, and why?
• How much of the findings might be related to recent ED closures, longer ED wait times, or other factors? Are there geographic variations in risk?
• What can be done in the ED to prevent LWBS ED visits, and what can be changed outside the ED to prevent LWBS ED visits? For example, what can hospitals do to reduce boarding in the ED? If patients leave without being seen, should they be contacted to try to meet their health needs in other ways?
• What worked in terms of maintaining access to outpatient medical care, despite the considerable disruptions starting in 2020, and how can continued success be ensured?

To address the current situation, McNaughton said, “We need consistent, predictable, and sustained investment in our public healthcare system. We need long-term, consistent funding for primary care, ED care, as well as hospital and long-term care.”

“It takes years to recruit and train the teams of people necessary to provide the high-quality medical care that Canadians have a right to. There are no shortcuts,” she concluded.

 

‘Tragic Situation’

American College of Emergency Physicians (ACEP) spokesperson Jesse Pines, MD, chief of clinical innovation at US Acute Care Solutions; clinical professor of emergency medicine at George Washington University in Washington, DC; and professor of emergency medicine at Drexel University in Philadelphia, commented on the study for this news organization.

“Similar to what the authors found in their report, LWBS and other metrics — specifically boarding — have progressively increased in the United States, in particular, since the early part of 2021,” he said. “The primary factor in the US driving this, and one that ACEP is trying to address on a national scale, is the boarding of admitted patients.”

When the number of boarded patients increases, there is less space in the ED for new patients, and waits increase, Pines explained. Some patients leave without being seen, and a subset of those patients experience poor outcomes. “It’s a tragic situation that is worsening.”

“Emergency physicians like me always worry when patients leave without being seen,” he said. While some of those patients have self-limited conditions that will improve on their own, “some have critical life-threatening conditions that require care and hospitalization. The worry is that these patients experience poorer outcomes,” Pines said. “The authors showed that this is increasingly the case in Canada. The same is likely true in the US.”

The study was funded by the Canadian Institutes of Health Research. McNaughton and Pines declared no relevant financial relationships.

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

A few items bring back unpleasant memories of COVID-19, such as masks. However, they are among the simplest and most effective ways to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). If everyone had worn them correctly, the transmission could have been reduced as much as ninefold, according to a theoretical study published in Physical Review E by Richard P. Sear, PhD, from the University of Surrey, Guildford, England.

Study Overcomes Limitations

This study aimed to address the limitations of epidemiological investigations of masks, which can be complex and error-prone. Sear used data obtained from the UK’s COVID-19 app, totaling 7 million contacts, to create a mathematical model of virus transmission, focusing on the correlation between contact duration and infection. The model estimates that if all UK residents had worn masks during every potential exposure, virus transmission would have been approximately nine times lower.

Although this is a mathematical model, it adds to the growing evidence that supports the benefits of masks. Masks are among the best strategies for treating SARS-CoV-2. This conclusion has been supported by several systematic reviews and additional statistical studies. Conversely, the decision to relax and eliminate mask regulations has had consequences that have received little attention.

As expected, removing the mask mandate leads to increased virus transmission, resulting in more hospitalizations and deaths. A 2024 study estimated that in Japan, where cultural factors lead to much higher mask use in public than in Europe, the decline in mask use from 97% of the population in 2022 to 63% in October 2023 may have caused an additional 3500 deaths.

 

Impact Beyond SARS-CoV-2

One remarkable effect of non-pharmaceutical interventions during the pandemic was the probable extinction of an entire influenza strain (B/Yamagata), which could improve future influenza vaccines and significantly reduce the spread of respiratory syncytial virus. While this was not solely caused by masks, it was also influenced by emergency measures such as lockdowns and social distancing. These behavioral changes can positively alter the landscape of infectious diseases.

Masks play a role in reducing influenza transmission during pandemics. Their effectiveness has been supported by several studies and systematic reviews on a wide range of respiratory viruses. A randomized clinical trial involving 4647 Norwegian participants from February to April 2023, published in May 2024 by the British Medical Journal, suggested that wearing a mask reduces the incidence of respiratory symptoms. Specifically, 8.9% of those who wore masks reported respiratory symptoms during the study period compared with 12.2% of those who did not, representing a relative risk reduction of 27%.

Widespread mask use could also protect against other factors such as fine particulate matter, indirectly reducing the risk for various health conditions. A retrospective study involving 7.8 million residents in the Chinese city of Weifang, published in December 2024 by BMC Public Health, suggested that mask use during the pandemic may have also protected the population from pollution, reducing the number of stroke cases by 38.6% over 33 months of follow-up.

Although there are still voices in bioethics calling for the reintroduction of mask mandates in public places, it is unlikely that, barring emergencies, mask mandates are politically and socially acceptable today. Mask use is also considered a politically polarizing topic in several Western countries. Nevertheless, it is worth considering whether, as we move away from the acute phase of the COVID-19 pandemic, we can more objectively promote the use of masks in public places.

Communicating the importance of public health initiatives and persuading people to support them is a well-known challenge. However, scientific literature offers valuable insights. These include encouraging people to rely on rational thinking rather than emotions and providing information on how masks protect those around them. The fact that East Asian cultures tend to have a more positive relationship with the use of masks shows that, in principle, it is possible to make them acceptable. Data from studies suggest that, as we prepare for potential future pandemics, it may be time to move past polarization and reintroduce masks — not as a universal mandate but as an individual choice for many.

This story was translated from Univadis Italy 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.

A few items bring back unpleasant memories of COVID-19, such as masks. However, they are among the simplest and most effective ways to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). If everyone had worn them correctly, the transmission could have been reduced as much as ninefold, according to a theoretical study published in Physical Review E by Richard P. Sear, PhD, from the University of Surrey, Guildford, England.

Study Overcomes Limitations

This study aimed to address the limitations of epidemiological investigations of masks, which can be complex and error-prone. Sear used data obtained from the UK’s COVID-19 app, totaling 7 million contacts, to create a mathematical model of virus transmission, focusing on the correlation between contact duration and infection. The model estimates that if all UK residents had worn masks during every potential exposure, virus transmission would have been approximately nine times lower.

Although this is a mathematical model, it adds to the growing evidence that supports the benefits of masks. Masks are among the best strategies for treating SARS-CoV-2. This conclusion has been supported by several systematic reviews and additional statistical studies. Conversely, the decision to relax and eliminate mask regulations has had consequences that have received little attention.

As expected, removing the mask mandate leads to increased virus transmission, resulting in more hospitalizations and deaths. A 2024 study estimated that in Japan, where cultural factors lead to much higher mask use in public than in Europe, the decline in mask use from 97% of the population in 2022 to 63% in October 2023 may have caused an additional 3500 deaths.

 

Impact Beyond SARS-CoV-2

One remarkable effect of non-pharmaceutical interventions during the pandemic was the probable extinction of an entire influenza strain (B/Yamagata), which could improve future influenza vaccines and significantly reduce the spread of respiratory syncytial virus. While this was not solely caused by masks, it was also influenced by emergency measures such as lockdowns and social distancing. These behavioral changes can positively alter the landscape of infectious diseases.

Masks play a role in reducing influenza transmission during pandemics. Their effectiveness has been supported by several studies and systematic reviews on a wide range of respiratory viruses. A randomized clinical trial involving 4647 Norwegian participants from February to April 2023, published in May 2024 by the British Medical Journal, suggested that wearing a mask reduces the incidence of respiratory symptoms. Specifically, 8.9% of those who wore masks reported respiratory symptoms during the study period compared with 12.2% of those who did not, representing a relative risk reduction of 27%.

Widespread mask use could also protect against other factors such as fine particulate matter, indirectly reducing the risk for various health conditions. A retrospective study involving 7.8 million residents in the Chinese city of Weifang, published in December 2024 by BMC Public Health, suggested that mask use during the pandemic may have also protected the population from pollution, reducing the number of stroke cases by 38.6% over 33 months of follow-up.

Although there are still voices in bioethics calling for the reintroduction of mask mandates in public places, it is unlikely that, barring emergencies, mask mandates are politically and socially acceptable today. Mask use is also considered a politically polarizing topic in several Western countries. Nevertheless, it is worth considering whether, as we move away from the acute phase of the COVID-19 pandemic, we can more objectively promote the use of masks in public places.

Communicating the importance of public health initiatives and persuading people to support them is a well-known challenge. However, scientific literature offers valuable insights. These include encouraging people to rely on rational thinking rather than emotions and providing information on how masks protect those around them. The fact that East Asian cultures tend to have a more positive relationship with the use of masks shows that, in principle, it is possible to make them acceptable. Data from studies suggest that, as we prepare for potential future pandemics, it may be time to move past polarization and reintroduce masks — not as a universal mandate but as an individual choice for many.

This story was translated from Univadis Italy 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.

A few items bring back unpleasant memories of COVID-19, such as masks. However, they are among the simplest and most effective ways to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). If everyone had worn them correctly, the transmission could have been reduced as much as ninefold, according to a theoretical study published in Physical Review E by Richard P. Sear, PhD, from the University of Surrey, Guildford, England.

Study Overcomes Limitations

This study aimed to address the limitations of epidemiological investigations of masks, which can be complex and error-prone. Sear used data obtained from the UK’s COVID-19 app, totaling 7 million contacts, to create a mathematical model of virus transmission, focusing on the correlation between contact duration and infection. The model estimates that if all UK residents had worn masks during every potential exposure, virus transmission would have been approximately nine times lower.

Although this is a mathematical model, it adds to the growing evidence that supports the benefits of masks. Masks are among the best strategies for treating SARS-CoV-2. This conclusion has been supported by several systematic reviews and additional statistical studies. Conversely, the decision to relax and eliminate mask regulations has had consequences that have received little attention.

As expected, removing the mask mandate leads to increased virus transmission, resulting in more hospitalizations and deaths. A 2024 study estimated that in Japan, where cultural factors lead to much higher mask use in public than in Europe, the decline in mask use from 97% of the population in 2022 to 63% in October 2023 may have caused an additional 3500 deaths.

 

Impact Beyond SARS-CoV-2

One remarkable effect of non-pharmaceutical interventions during the pandemic was the probable extinction of an entire influenza strain (B/Yamagata), which could improve future influenza vaccines and significantly reduce the spread of respiratory syncytial virus. While this was not solely caused by masks, it was also influenced by emergency measures such as lockdowns and social distancing. These behavioral changes can positively alter the landscape of infectious diseases.

Masks play a role in reducing influenza transmission during pandemics. Their effectiveness has been supported by several studies and systematic reviews on a wide range of respiratory viruses. A randomized clinical trial involving 4647 Norwegian participants from February to April 2023, published in May 2024 by the British Medical Journal, suggested that wearing a mask reduces the incidence of respiratory symptoms. Specifically, 8.9% of those who wore masks reported respiratory symptoms during the study period compared with 12.2% of those who did not, representing a relative risk reduction of 27%.

Widespread mask use could also protect against other factors such as fine particulate matter, indirectly reducing the risk for various health conditions. A retrospective study involving 7.8 million residents in the Chinese city of Weifang, published in December 2024 by BMC Public Health, suggested that mask use during the pandemic may have also protected the population from pollution, reducing the number of stroke cases by 38.6% over 33 months of follow-up.

Although there are still voices in bioethics calling for the reintroduction of mask mandates in public places, it is unlikely that, barring emergencies, mask mandates are politically and socially acceptable today. Mask use is also considered a politically polarizing topic in several Western countries. Nevertheless, it is worth considering whether, as we move away from the acute phase of the COVID-19 pandemic, we can more objectively promote the use of masks in public places.

Communicating the importance of public health initiatives and persuading people to support them is a well-known challenge. However, scientific literature offers valuable insights. These include encouraging people to rely on rational thinking rather than emotions and providing information on how masks protect those around them. The fact that East Asian cultures tend to have a more positive relationship with the use of masks shows that, in principle, it is possible to make them acceptable. Data from studies suggest that, as we prepare for potential future pandemics, it may be time to move past polarization and reintroduce masks — not as a universal mandate but as an individual choice for many.

This story was translated from Univadis Italy 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.

Results published from a systematic review and meta-analysis find an inverse association and a dose-response link between fluoride exposure and children’s IQ scores.

Kyla W. Taylor, PhD, with the Division of Translational Toxicology at the National Institutes of Health, Morrisville, North Carolina, led the multicountry study published online in JAMA Pediatrics.

Two accompanying editorials offer two very different perspectives on how to interpret the researchers’ conclusions.
 

Study Results

The authors noted that, of the 74 studies included in the review (64 cross-sectional and 10 cohort studies), most (45) were conducted in China. Other countries included were Canada (3), Denmark (1), India (12), Iran (4), Mexico (4), New Zealand (1), Pakistan (2), Spain (1), and Taiwan (1). “Fifty-two studies were rated high risk of bias, and 22 were rated low risk of bias,” the authors stated.

Researchers found that 64 of the 74 studies reported inverse associations between fluoride exposure measures and children’s IQ scores. Their analysis of 59 studies with group-level measures of fluoride in drinking water, dental fluorosis, or other measures of fluoride exposure showed an inverse relationship between fluoride exposure and IQ (pooled standardized mean difference [SMD], −0.45; 95% CI, −0.57 to −0.33; P < .001). Of those 59 studies, encompassing 20,932 children, 47 had high risk for bias and 12 had low risk for bias.

In 31 studies that reported fluoride measurements in drinking water, a dose-response relationship was found between exposed and reference groups (SMD, –0.15; 95% CI, –0.20 to –0.11; P < .001). That relationship remained inverse when exposed groups were limited to less than 4 mg fluoride/L and less than 2 mg/L. However, the association was not seen at less than 1.5 mg/L.

In 20 studies reporting fluoride measured in urine, there was an inverse dose-response association (SMD, –0.15; 95% CI, –0.23 to –0.07; P < .001). Those inverse relationships held at levels less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in urine.

For perspective, in the United States, the US Public Health Service in 2015 lowered the recommended concentration of fluoride in drinking water from a range of 0.7-1.2 mg/L to 0.7 mg/L to reduce the risk for dental fluorosis while keeping its protective effect against dental caries. 

When Taylor’s team analyzed 13 studies with individual-level measures, they found an IQ score decrease of 1.63 points (95% CI, –2.33 to –0.93; P < .001) per 1-mg/L increase in urinary fluoride. Among studies with a low risk for bias, they observed an IQ score decrease of 1.14 points (95% CI, –1.68 to –0.61; P < .001). The inverse relationship remained when stratified by factors including risk for bias, sex, age, country, outcome assessment type, exposure timing (prenatal or postnatal), and exposure matrix (urinary fluoride, intake and water fluoride), the authors wrote.

The authors conclude both that inverse relationships and a dose-response association between fluoride measured in urine and drinking water and children’s IQs were found across the literature examined but also that “there were limited data and uncertainty in the dose-response association between fluoride exposure and children’s IQ when fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L.”

The authors point out that, “To our knowledge, no studies of fluoride exposure and children’s IQ have been performed in the United States and no nationally representative urinary fluoride levels are available, hindering application of these findings to the US population.”
 

Editorial: Time to Reassess Systemic Fluoride

Bruce P. Lanphear, MD, MPH, with Simon Fraser University, Vancouver, British Columbia, Canada, is the lead author on an editorial that suggests these data point to the need to reassess systemic fluoride exposure.

“Their study is the largest and includes the most rigorous series of meta-analyses of fluoride ever conducted,” Lanphear and colleagues wrote. “It is time for health organizations and regulatory bodies to reassess the risks and benefits of fluoride, particularly for pregnant women and infants.”

Lanphear’s team says distinguishing between water fluoride and urinary fluoride levels is important in these results “because regulatory and public health agencies must consider total fluoride intake when assessing risks.”

Taylor and colleagues’ finding that there was no statistically significant association between water fluoride les than 1.5 mg/L and children’s IQ scores in the dose-response meta-analysis doesn’t mean fluoride is not a potential risk for lower IQ scores in fluoridated communities, they wrote. “Water fluoride concentration does not capture the amount of water ingested or other sources of ingested fluoride. In contrast, urinary fluoride is a biological measure of total fluoride exposure, including the dynamic interface between bone fluoride stores and blood fluoride.”
 

Editorial: Be Cautious About the Conclusions

Steven M. Levy, DDS, MPH, cites “major areas of concern” in the meta-analysis in his editorial.

He points to the large majority of studies in the meta-analysis that were at “high risk of bias” (47 high risk vs 12 that were low risk). He also cited information from a further look at the low-risk-of-bias studies included in the supplement.

“The studies with lower risk of bias showed a negligible effect (standardized mean difference [SMD], −0.19; 95% CI, −0.35 to −0.04) with very high heterogeneity (I2 = 87%), and a majority of publications (8 of 12) did not show a negative association between fluoride and childhood IQ,” Levy wrote. 

“Taylor et al do not adequately justify selection or omission of studies or explain or justify the calculated individual effect sizes presented in the main analysis. Also, readers are not told which studies with lower risk of bias are included in the subanalyses for water fluoride levels less than 1.5 mg/L, less than 2.0 mg/L, and less than 4.0 mg/L; therefore, readers cannot independently consider important differences across these studies.”

Levy also states that the magnitudes of the possible IQ differences are unfairly inflated. For the United Staes and most of the world, he points out, the recommended community water fluoridation level is 0.7 mg/L. Therefore, the difference between a community with low fluoride levels (about 0.2 mg/L) and one with optimal levels is about 0.5 mg/L. 

“However, Taylor and colleagues use a difference of 1.0 mg/L in their calculations, artificially doubling the estimated impact on IQ,” Levy wrote.

The meta-analysis should not affect public policy on adding fluoride to community water systems “and the widespread use of fluoride for caries prevention should continue,” Levy concluded.
 

Concerns About Quality of Studies Included

Charlotte Lewis, MD, MPH, associate professor of pediatrics at the University of Washington School of Medicine and part of Seattle Children’s Multidisciplinary Infant Nutrition and Feeding Team, Seattle, who was not involved in the meta-analysis or editorials, said that systemic fluoridation should not change based on these results, citing what she said are problems with methodology.

“There are many concerns about the quality of studies included in this meta-analysis,” Lewis said. “Although the authors claim to have separated out low-bias studies, it is important to note that many of these same studies have substantial methodological flaws.”

She said studies deemed low-bias and included in the meta-analysis “relied on multiple examiners for cognitive testing without consideration for inter-rater variation or reliability measures.” She added that “a number of the studies failed to account for maternal IQ scores, breastfeeding, lead exposure, or other factors that could affect cognitive development, further contributing to biased conclusions.”

Importantly, she said, many of the studies, including one by Rivka Green and colleagues published in JAMA Pediatrics, relied on maternal spot urinary fluoride to assess fetal exposure to fluoride. “This is not a valid way to assess fetal exposure to fluoride and including such studies in this meta-analysis has led to inappropriate conclusions because they are based on studies using a flawed exposure measure.” 

She pointed to recent longitudinal, population-based studies, including one by Jayant V Kumar and colleagues that have found no adverse impact on IQ, or other cognitive tests, of drinking water with low levels of fluoride present, comparable to US community water fluoridation standards. 

“Relative to the small convenience-sample, cross-sectional studies included in this meta-analysis, longitudinal, population-based studies are considered significantly more reliable for establishing cause and effect,” she said.
 

Fluoride Levels Different Globally

Lewis said in some parts of the world fluoride is present in the environment in much higher levels than in fluoridated water in the United States.

“There are known adverse health effects of high fluoride ingestion in these endemic regions found primarily in China, India, and Iran. This points to the importance of dose response. What is beneficial at low levels can be toxic at high levels and that appears to be the case, not surprisingly, for fluoride as well. However, at 0.7 ppm, the level of fluoride in community water fluoridation, we experience fluoride’s beneficial effects when we regularly drink optimally fluoridated water.”

“Water fluoridation is an important public health approach available and beneficial to all, even those unable to afford or access dental care,” she said. “Water fluoridation diminishes oral health disparities, and its removal threatens to worsen disparities and increased suffering from dental disease. I remain confident in the benefits and safety of community water fluoridation.”

Taylor and colleagues reported no relevant financial relationships. Lanphear reported grants from the National Institute of Environmental Health Sciences and the Canadian Institute for Health Research and having served as a nonretained and unpaid expert witness in a federal fluoride suit against the US EPA. Levy reported past grants from the National Institute of Dental and Craniofacial Research related to fluoride, dental caries, dental fluorosis, and bone development. He reported small grant funding from the Centers for Disease Control and Prevention related to fluoride, dental caries, and fluorosis. He consults for the Centers for Disease Control and Prevention and the National Institute of Dental and Craniofacial Research and serves on the National Fluoride Advisory Committee for the American Dental Association.

A version of this article appeared on Medscape.com.

Results published from a systematic review and meta-analysis find an inverse association and a dose-response link between fluoride exposure and children’s IQ scores.

Kyla W. Taylor, PhD, with the Division of Translational Toxicology at the National Institutes of Health, Morrisville, North Carolina, led the multicountry study published online in JAMA Pediatrics.

Two accompanying editorials offer two very different perspectives on how to interpret the researchers’ conclusions.
 

Study Results

The authors noted that, of the 74 studies included in the review (64 cross-sectional and 10 cohort studies), most (45) were conducted in China. Other countries included were Canada (3), Denmark (1), India (12), Iran (4), Mexico (4), New Zealand (1), Pakistan (2), Spain (1), and Taiwan (1). “Fifty-two studies were rated high risk of bias, and 22 were rated low risk of bias,” the authors stated.

Researchers found that 64 of the 74 studies reported inverse associations between fluoride exposure measures and children’s IQ scores. Their analysis of 59 studies with group-level measures of fluoride in drinking water, dental fluorosis, or other measures of fluoride exposure showed an inverse relationship between fluoride exposure and IQ (pooled standardized mean difference [SMD], −0.45; 95% CI, −0.57 to −0.33; P < .001). Of those 59 studies, encompassing 20,932 children, 47 had high risk for bias and 12 had low risk for bias.

In 31 studies that reported fluoride measurements in drinking water, a dose-response relationship was found between exposed and reference groups (SMD, –0.15; 95% CI, –0.20 to –0.11; P < .001). That relationship remained inverse when exposed groups were limited to less than 4 mg fluoride/L and less than 2 mg/L. However, the association was not seen at less than 1.5 mg/L.

In 20 studies reporting fluoride measured in urine, there was an inverse dose-response association (SMD, –0.15; 95% CI, –0.23 to –0.07; P < .001). Those inverse relationships held at levels less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in urine.

For perspective, in the United States, the US Public Health Service in 2015 lowered the recommended concentration of fluoride in drinking water from a range of 0.7-1.2 mg/L to 0.7 mg/L to reduce the risk for dental fluorosis while keeping its protective effect against dental caries. 

When Taylor’s team analyzed 13 studies with individual-level measures, they found an IQ score decrease of 1.63 points (95% CI, –2.33 to –0.93; P < .001) per 1-mg/L increase in urinary fluoride. Among studies with a low risk for bias, they observed an IQ score decrease of 1.14 points (95% CI, –1.68 to –0.61; P < .001). The inverse relationship remained when stratified by factors including risk for bias, sex, age, country, outcome assessment type, exposure timing (prenatal or postnatal), and exposure matrix (urinary fluoride, intake and water fluoride), the authors wrote.

The authors conclude both that inverse relationships and a dose-response association between fluoride measured in urine and drinking water and children’s IQs were found across the literature examined but also that “there were limited data and uncertainty in the dose-response association between fluoride exposure and children’s IQ when fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L.”

The authors point out that, “To our knowledge, no studies of fluoride exposure and children’s IQ have been performed in the United States and no nationally representative urinary fluoride levels are available, hindering application of these findings to the US population.”
 

Editorial: Time to Reassess Systemic Fluoride

Bruce P. Lanphear, MD, MPH, with Simon Fraser University, Vancouver, British Columbia, Canada, is the lead author on an editorial that suggests these data point to the need to reassess systemic fluoride exposure.

“Their study is the largest and includes the most rigorous series of meta-analyses of fluoride ever conducted,” Lanphear and colleagues wrote. “It is time for health organizations and regulatory bodies to reassess the risks and benefits of fluoride, particularly for pregnant women and infants.”

Lanphear’s team says distinguishing between water fluoride and urinary fluoride levels is important in these results “because regulatory and public health agencies must consider total fluoride intake when assessing risks.”

Taylor and colleagues’ finding that there was no statistically significant association between water fluoride les than 1.5 mg/L and children’s IQ scores in the dose-response meta-analysis doesn’t mean fluoride is not a potential risk for lower IQ scores in fluoridated communities, they wrote. “Water fluoride concentration does not capture the amount of water ingested or other sources of ingested fluoride. In contrast, urinary fluoride is a biological measure of total fluoride exposure, including the dynamic interface between bone fluoride stores and blood fluoride.”
 

Editorial: Be Cautious About the Conclusions

Steven M. Levy, DDS, MPH, cites “major areas of concern” in the meta-analysis in his editorial.

He points to the large majority of studies in the meta-analysis that were at “high risk of bias” (47 high risk vs 12 that were low risk). He also cited information from a further look at the low-risk-of-bias studies included in the supplement.

“The studies with lower risk of bias showed a negligible effect (standardized mean difference [SMD], −0.19; 95% CI, −0.35 to −0.04) with very high heterogeneity (I2 = 87%), and a majority of publications (8 of 12) did not show a negative association between fluoride and childhood IQ,” Levy wrote. 

“Taylor et al do not adequately justify selection or omission of studies or explain or justify the calculated individual effect sizes presented in the main analysis. Also, readers are not told which studies with lower risk of bias are included in the subanalyses for water fluoride levels less than 1.5 mg/L, less than 2.0 mg/L, and less than 4.0 mg/L; therefore, readers cannot independently consider important differences across these studies.”

Levy also states that the magnitudes of the possible IQ differences are unfairly inflated. For the United Staes and most of the world, he points out, the recommended community water fluoridation level is 0.7 mg/L. Therefore, the difference between a community with low fluoride levels (about 0.2 mg/L) and one with optimal levels is about 0.5 mg/L. 

“However, Taylor and colleagues use a difference of 1.0 mg/L in their calculations, artificially doubling the estimated impact on IQ,” Levy wrote.

The meta-analysis should not affect public policy on adding fluoride to community water systems “and the widespread use of fluoride for caries prevention should continue,” Levy concluded.
 

Concerns About Quality of Studies Included

Charlotte Lewis, MD, MPH, associate professor of pediatrics at the University of Washington School of Medicine and part of Seattle Children’s Multidisciplinary Infant Nutrition and Feeding Team, Seattle, who was not involved in the meta-analysis or editorials, said that systemic fluoridation should not change based on these results, citing what she said are problems with methodology.

“There are many concerns about the quality of studies included in this meta-analysis,” Lewis said. “Although the authors claim to have separated out low-bias studies, it is important to note that many of these same studies have substantial methodological flaws.”

She said studies deemed low-bias and included in the meta-analysis “relied on multiple examiners for cognitive testing without consideration for inter-rater variation or reliability measures.” She added that “a number of the studies failed to account for maternal IQ scores, breastfeeding, lead exposure, or other factors that could affect cognitive development, further contributing to biased conclusions.”

Importantly, she said, many of the studies, including one by Rivka Green and colleagues published in JAMA Pediatrics, relied on maternal spot urinary fluoride to assess fetal exposure to fluoride. “This is not a valid way to assess fetal exposure to fluoride and including such studies in this meta-analysis has led to inappropriate conclusions because they are based on studies using a flawed exposure measure.” 

She pointed to recent longitudinal, population-based studies, including one by Jayant V Kumar and colleagues that have found no adverse impact on IQ, or other cognitive tests, of drinking water with low levels of fluoride present, comparable to US community water fluoridation standards. 

“Relative to the small convenience-sample, cross-sectional studies included in this meta-analysis, longitudinal, population-based studies are considered significantly more reliable for establishing cause and effect,” she said.
 

Fluoride Levels Different Globally

Lewis said in some parts of the world fluoride is present in the environment in much higher levels than in fluoridated water in the United States.

“There are known adverse health effects of high fluoride ingestion in these endemic regions found primarily in China, India, and Iran. This points to the importance of dose response. What is beneficial at low levels can be toxic at high levels and that appears to be the case, not surprisingly, for fluoride as well. However, at 0.7 ppm, the level of fluoride in community water fluoridation, we experience fluoride’s beneficial effects when we regularly drink optimally fluoridated water.”

“Water fluoridation is an important public health approach available and beneficial to all, even those unable to afford or access dental care,” she said. “Water fluoridation diminishes oral health disparities, and its removal threatens to worsen disparities and increased suffering from dental disease. I remain confident in the benefits and safety of community water fluoridation.”

Taylor and colleagues reported no relevant financial relationships. Lanphear reported grants from the National Institute of Environmental Health Sciences and the Canadian Institute for Health Research and having served as a nonretained and unpaid expert witness in a federal fluoride suit against the US EPA. Levy reported past grants from the National Institute of Dental and Craniofacial Research related to fluoride, dental caries, dental fluorosis, and bone development. He reported small grant funding from the Centers for Disease Control and Prevention related to fluoride, dental caries, and fluorosis. He consults for the Centers for Disease Control and Prevention and the National Institute of Dental and Craniofacial Research and serves on the National Fluoride Advisory Committee for the American Dental Association.

A version of this article appeared on Medscape.com.

Results published from a systematic review and meta-analysis find an inverse association and a dose-response link between fluoride exposure and children’s IQ scores.

Kyla W. Taylor, PhD, with the Division of Translational Toxicology at the National Institutes of Health, Morrisville, North Carolina, led the multicountry study published online in JAMA Pediatrics.

Two accompanying editorials offer two very different perspectives on how to interpret the researchers’ conclusions.
 

Study Results

The authors noted that, of the 74 studies included in the review (64 cross-sectional and 10 cohort studies), most (45) were conducted in China. Other countries included were Canada (3), Denmark (1), India (12), Iran (4), Mexico (4), New Zealand (1), Pakistan (2), Spain (1), and Taiwan (1). “Fifty-two studies were rated high risk of bias, and 22 were rated low risk of bias,” the authors stated.

Researchers found that 64 of the 74 studies reported inverse associations between fluoride exposure measures and children’s IQ scores. Their analysis of 59 studies with group-level measures of fluoride in drinking water, dental fluorosis, or other measures of fluoride exposure showed an inverse relationship between fluoride exposure and IQ (pooled standardized mean difference [SMD], −0.45; 95% CI, −0.57 to −0.33; P < .001). Of those 59 studies, encompassing 20,932 children, 47 had high risk for bias and 12 had low risk for bias.

In 31 studies that reported fluoride measurements in drinking water, a dose-response relationship was found between exposed and reference groups (SMD, –0.15; 95% CI, –0.20 to –0.11; P < .001). That relationship remained inverse when exposed groups were limited to less than 4 mg fluoride/L and less than 2 mg/L. However, the association was not seen at less than 1.5 mg/L.

In 20 studies reporting fluoride measured in urine, there was an inverse dose-response association (SMD, –0.15; 95% CI, –0.23 to –0.07; P < .001). Those inverse relationships held at levels less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in urine.

For perspective, in the United States, the US Public Health Service in 2015 lowered the recommended concentration of fluoride in drinking water from a range of 0.7-1.2 mg/L to 0.7 mg/L to reduce the risk for dental fluorosis while keeping its protective effect against dental caries. 

When Taylor’s team analyzed 13 studies with individual-level measures, they found an IQ score decrease of 1.63 points (95% CI, –2.33 to –0.93; P < .001) per 1-mg/L increase in urinary fluoride. Among studies with a low risk for bias, they observed an IQ score decrease of 1.14 points (95% CI, –1.68 to –0.61; P < .001). The inverse relationship remained when stratified by factors including risk for bias, sex, age, country, outcome assessment type, exposure timing (prenatal or postnatal), and exposure matrix (urinary fluoride, intake and water fluoride), the authors wrote.

The authors conclude both that inverse relationships and a dose-response association between fluoride measured in urine and drinking water and children’s IQs were found across the literature examined but also that “there were limited data and uncertainty in the dose-response association between fluoride exposure and children’s IQ when fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L.”

The authors point out that, “To our knowledge, no studies of fluoride exposure and children’s IQ have been performed in the United States and no nationally representative urinary fluoride levels are available, hindering application of these findings to the US population.”
 

Editorial: Time to Reassess Systemic Fluoride

Bruce P. Lanphear, MD, MPH, with Simon Fraser University, Vancouver, British Columbia, Canada, is the lead author on an editorial that suggests these data point to the need to reassess systemic fluoride exposure.

“Their study is the largest and includes the most rigorous series of meta-analyses of fluoride ever conducted,” Lanphear and colleagues wrote. “It is time for health organizations and regulatory bodies to reassess the risks and benefits of fluoride, particularly for pregnant women and infants.”

Lanphear’s team says distinguishing between water fluoride and urinary fluoride levels is important in these results “because regulatory and public health agencies must consider total fluoride intake when assessing risks.”

Taylor and colleagues’ finding that there was no statistically significant association between water fluoride les than 1.5 mg/L and children’s IQ scores in the dose-response meta-analysis doesn’t mean fluoride is not a potential risk for lower IQ scores in fluoridated communities, they wrote. “Water fluoride concentration does not capture the amount of water ingested or other sources of ingested fluoride. In contrast, urinary fluoride is a biological measure of total fluoride exposure, including the dynamic interface between bone fluoride stores and blood fluoride.”
 

Editorial: Be Cautious About the Conclusions

Steven M. Levy, DDS, MPH, cites “major areas of concern” in the meta-analysis in his editorial.

He points to the large majority of studies in the meta-analysis that were at “high risk of bias” (47 high risk vs 12 that were low risk). He also cited information from a further look at the low-risk-of-bias studies included in the supplement.

“The studies with lower risk of bias showed a negligible effect (standardized mean difference [SMD], −0.19; 95% CI, −0.35 to −0.04) with very high heterogeneity (I2 = 87%), and a majority of publications (8 of 12) did not show a negative association between fluoride and childhood IQ,” Levy wrote. 

“Taylor et al do not adequately justify selection or omission of studies or explain or justify the calculated individual effect sizes presented in the main analysis. Also, readers are not told which studies with lower risk of bias are included in the subanalyses for water fluoride levels less than 1.5 mg/L, less than 2.0 mg/L, and less than 4.0 mg/L; therefore, readers cannot independently consider important differences across these studies.”

Levy also states that the magnitudes of the possible IQ differences are unfairly inflated. For the United Staes and most of the world, he points out, the recommended community water fluoridation level is 0.7 mg/L. Therefore, the difference between a community with low fluoride levels (about 0.2 mg/L) and one with optimal levels is about 0.5 mg/L. 

“However, Taylor and colleagues use a difference of 1.0 mg/L in their calculations, artificially doubling the estimated impact on IQ,” Levy wrote.

The meta-analysis should not affect public policy on adding fluoride to community water systems “and the widespread use of fluoride for caries prevention should continue,” Levy concluded.
 

Concerns About Quality of Studies Included

Charlotte Lewis, MD, MPH, associate professor of pediatrics at the University of Washington School of Medicine and part of Seattle Children’s Multidisciplinary Infant Nutrition and Feeding Team, Seattle, who was not involved in the meta-analysis or editorials, said that systemic fluoridation should not change based on these results, citing what she said are problems with methodology.

“There are many concerns about the quality of studies included in this meta-analysis,” Lewis said. “Although the authors claim to have separated out low-bias studies, it is important to note that many of these same studies have substantial methodological flaws.”

She said studies deemed low-bias and included in the meta-analysis “relied on multiple examiners for cognitive testing without consideration for inter-rater variation or reliability measures.” She added that “a number of the studies failed to account for maternal IQ scores, breastfeeding, lead exposure, or other factors that could affect cognitive development, further contributing to biased conclusions.”

Importantly, she said, many of the studies, including one by Rivka Green and colleagues published in JAMA Pediatrics, relied on maternal spot urinary fluoride to assess fetal exposure to fluoride. “This is not a valid way to assess fetal exposure to fluoride and including such studies in this meta-analysis has led to inappropriate conclusions because they are based on studies using a flawed exposure measure.” 

She pointed to recent longitudinal, population-based studies, including one by Jayant V Kumar and colleagues that have found no adverse impact on IQ, or other cognitive tests, of drinking water with low levels of fluoride present, comparable to US community water fluoridation standards. 

“Relative to the small convenience-sample, cross-sectional studies included in this meta-analysis, longitudinal, population-based studies are considered significantly more reliable for establishing cause and effect,” she said.
 

Fluoride Levels Different Globally

Lewis said in some parts of the world fluoride is present in the environment in much higher levels than in fluoridated water in the United States.

“There are known adverse health effects of high fluoride ingestion in these endemic regions found primarily in China, India, and Iran. This points to the importance of dose response. What is beneficial at low levels can be toxic at high levels and that appears to be the case, not surprisingly, for fluoride as well. However, at 0.7 ppm, the level of fluoride in community water fluoridation, we experience fluoride’s beneficial effects when we regularly drink optimally fluoridated water.”

“Water fluoridation is an important public health approach available and beneficial to all, even those unable to afford or access dental care,” she said. “Water fluoridation diminishes oral health disparities, and its removal threatens to worsen disparities and increased suffering from dental disease. I remain confident in the benefits and safety of community water fluoridation.”

Taylor and colleagues reported no relevant financial relationships. Lanphear reported grants from the National Institute of Environmental Health Sciences and the Canadian Institute for Health Research and having served as a nonretained and unpaid expert witness in a federal fluoride suit against the US EPA. Levy reported past grants from the National Institute of Dental and Craniofacial Research related to fluoride, dental caries, dental fluorosis, and bone development. He reported small grant funding from the Centers for Disease Control and Prevention related to fluoride, dental caries, and fluorosis. He consults for the Centers for Disease Control and Prevention and the National Institute of Dental and Craniofacial Research and serves on the National Fluoride Advisory Committee for the American Dental Association.

A version of this article appeared on Medscape.com.