Heidi Splete

Histologic remission using the Nancy Histologic Index (NHI) was superior to endoscopic mucosal healing in predicting relapse-free survival in ulcerative colitis (UC), based on data from 74 patients.

A growing body of evidence suggests that UC patients in both histologic and endoscopic remission experience longer relapse-free survival and improved outcomes, but data on specific histologic assessments are limited, wrote Hunter Wang, MBBS, of Canberra Hospital, Australia, and colleagues. The NHI is a validated score drawing interest as an option for predicting survival, they said.

In a retrospective cohort study published Feb. 28 in the Journal of Clinical Gastroenterology, the researchers identified 74 adults aged 18 years and older with UC who were treated at a single center between 2009 and 2017. All patients were in clinical and endoscopic remission without concurrent corticosteroid use. Mucosal healing was defined as Mayo endoscopic subscore (MES) of 1 or less, and clinical remission was defined as partial Mayo score (MSp) less than 2. The median age of the participants was 41 years, and the median disease duration was 8 years at the time of surveillance colonoscopy.

Over a median follow-up of 42 months, patients with an MES of 0 and histologic remission had significantly longer relapse-free survival compared to those with MES 1 and NHI 2 to 4, respectively.

Thirty-three patients relapsed during the study period. Clinical relapse rates were similar for patients with MES 0 and MES 1 (40% and 52%, respectively), but only 29% of patients in histologic remission at baseline relapsed vs. 64% of those with histologic activity at baseline (P = 0.0064).

Risk factors for earlier relapse on univariate analysis included MES 1 and NHI 2 to 4. Only histologic activity predicted future relapse in a multivariate analysis (hazard ratio, 4.36, P = 0.002).

The study findings reflect data from previous research supporting the prognostic value of histologic remission using NHI, the researchers noted in their discussion. Barriers to adoption of histologic indices include “their multiplicity, complexity, lack of validation, and inconsistent incorporation in randomized controlled trials,” which create challenges in interpreting and comparing research outcomes, they wrote.

The study findings were limited by several factors, including the retrospective design, collection of clinical and endoscopic variables from electronic medical records without objective measures of relapse, lack of standardization of colonic biopsies, and lack of power to detect differences in dysplasia and colectomy, the researchers noted.

The results suggest that histologic remission using the NHI serves as an effective predictor of longer relapse-free survival in UC patients with clinical and endoscopic remission, they said.

“Further prospective trials are needed to clarify whether histologic remission as a therapeutic endpoint in addition to endoscopic remission will alter disease course and patient outcomes,” while helping guide treatment management decisions for patients and clinicians, the researchers concluded.

Not the ultimate endpoint?

“There is ongoing interest in whether histological findings (biopsies) of the mucosa are a clinically important and reachable treatment goal in ulcerative colitis,” David T. Rubin, MD, of the University of Chicago, who was not involved in the study, said in an interview.

Questions about this approach remain, such as how findings should be incorporated into clinical care and whether histology offers advantages over patient-reported symptoms, endoscopic findings, or other surrogates of inflammation like calprotectin, a protein related to histology detected in stool, Dr. Rubin explained.

“A number of retrospective studies have demonstrated the clinical importance of achieving histological remission, but the details of how to get there are not yet clearly defined. In this study, using one of the established indices of histological activity, the Nancy Histological Index, those patients who achieved histological remission had better clinical outcomes (stable remission) than symptoms alone or endoscopy alone.”

According to Dr. Rubin, clinicians can inform patients that histological remission supports that the therapy is working and they have a very good likelihood of staying in remission over the next year.

“Importantly, this is not the same as saying we should treat to get to this endpoint,” Dr. Rubin emphasized. “If a patient is in clinical remission with normalized labs and endoscopy (or calprotectin) that show healing, we do not yet recommend adjusting therapy for histological endpoints. This was edified in the consensus paper called STRIDE 2, published in Gastroenterology in 2021.”

As for additional research, the ongoing prospective randomized VERDICT trial is exploring different endpoints of treatment, “one of which is the combination of symptoms, endoscopy, and histology to assess whether this is better than symptoms or endoscopy alone,” said Dr. Rubin. “We also need more work to understand the timing of this finding, the number of biopsies that may be required to get an adequate assessment of the bowel, how pathologists should read and interpret our findings, when we should relook if we adjust therapy, and whether some therapies are more or less likely to achieve this endpoint,” he said.

The study received no outside funding. Neither the researchers nor Dr. Rubin reported any financial disclosures.

Histologic remission using the Nancy Histologic Index (NHI) was superior to endoscopic mucosal healing in predicting relapse-free survival in ulcerative colitis (UC), based on data from 74 patients.

A growing body of evidence suggests that UC patients in both histologic and endoscopic remission experience longer relapse-free survival and improved outcomes, but data on specific histologic assessments are limited, wrote Hunter Wang, MBBS, of Canberra Hospital, Australia, and colleagues. The NHI is a validated score drawing interest as an option for predicting survival, they said.

In a retrospective cohort study published Feb. 28 in the Journal of Clinical Gastroenterology, the researchers identified 74 adults aged 18 years and older with UC who were treated at a single center between 2009 and 2017. All patients were in clinical and endoscopic remission without concurrent corticosteroid use. Mucosal healing was defined as Mayo endoscopic subscore (MES) of 1 or less, and clinical remission was defined as partial Mayo score (MSp) less than 2. The median age of the participants was 41 years, and the median disease duration was 8 years at the time of surveillance colonoscopy.

Over a median follow-up of 42 months, patients with an MES of 0 and histologic remission had significantly longer relapse-free survival compared to those with MES 1 and NHI 2 to 4, respectively.

Thirty-three patients relapsed during the study period. Clinical relapse rates were similar for patients with MES 0 and MES 1 (40% and 52%, respectively), but only 29% of patients in histologic remission at baseline relapsed vs. 64% of those with histologic activity at baseline (P = 0.0064).

Risk factors for earlier relapse on univariate analysis included MES 1 and NHI 2 to 4. Only histologic activity predicted future relapse in a multivariate analysis (hazard ratio, 4.36, P = 0.002).

The study findings reflect data from previous research supporting the prognostic value of histologic remission using NHI, the researchers noted in their discussion. Barriers to adoption of histologic indices include “their multiplicity, complexity, lack of validation, and inconsistent incorporation in randomized controlled trials,” which create challenges in interpreting and comparing research outcomes, they wrote.

The study findings were limited by several factors, including the retrospective design, collection of clinical and endoscopic variables from electronic medical records without objective measures of relapse, lack of standardization of colonic biopsies, and lack of power to detect differences in dysplasia and colectomy, the researchers noted.

The results suggest that histologic remission using the NHI serves as an effective predictor of longer relapse-free survival in UC patients with clinical and endoscopic remission, they said.

“Further prospective trials are needed to clarify whether histologic remission as a therapeutic endpoint in addition to endoscopic remission will alter disease course and patient outcomes,” while helping guide treatment management decisions for patients and clinicians, the researchers concluded.

Not the ultimate endpoint?

“There is ongoing interest in whether histological findings (biopsies) of the mucosa are a clinically important and reachable treatment goal in ulcerative colitis,” David T. Rubin, MD, of the University of Chicago, who was not involved in the study, said in an interview.

Questions about this approach remain, such as how findings should be incorporated into clinical care and whether histology offers advantages over patient-reported symptoms, endoscopic findings, or other surrogates of inflammation like calprotectin, a protein related to histology detected in stool, Dr. Rubin explained.

“A number of retrospective studies have demonstrated the clinical importance of achieving histological remission, but the details of how to get there are not yet clearly defined. In this study, using one of the established indices of histological activity, the Nancy Histological Index, those patients who achieved histological remission had better clinical outcomes (stable remission) than symptoms alone or endoscopy alone.”

According to Dr. Rubin, clinicians can inform patients that histological remission supports that the therapy is working and they have a very good likelihood of staying in remission over the next year.

“Importantly, this is not the same as saying we should treat to get to this endpoint,” Dr. Rubin emphasized. “If a patient is in clinical remission with normalized labs and endoscopy (or calprotectin) that show healing, we do not yet recommend adjusting therapy for histological endpoints. This was edified in the consensus paper called STRIDE 2, published in Gastroenterology in 2021.”

As for additional research, the ongoing prospective randomized VERDICT trial is exploring different endpoints of treatment, “one of which is the combination of symptoms, endoscopy, and histology to assess whether this is better than symptoms or endoscopy alone,” said Dr. Rubin. “We also need more work to understand the timing of this finding, the number of biopsies that may be required to get an adequate assessment of the bowel, how pathologists should read and interpret our findings, when we should relook if we adjust therapy, and whether some therapies are more or less likely to achieve this endpoint,” he said.

The study received no outside funding. Neither the researchers nor Dr. Rubin reported any financial disclosures.

Histologic remission using the Nancy Histologic Index (NHI) was superior to endoscopic mucosal healing in predicting relapse-free survival in ulcerative colitis (UC), based on data from 74 patients.

A growing body of evidence suggests that UC patients in both histologic and endoscopic remission experience longer relapse-free survival and improved outcomes, but data on specific histologic assessments are limited, wrote Hunter Wang, MBBS, of Canberra Hospital, Australia, and colleagues. The NHI is a validated score drawing interest as an option for predicting survival, they said.

In a retrospective cohort study published Feb. 28 in the Journal of Clinical Gastroenterology, the researchers identified 74 adults aged 18 years and older with UC who were treated at a single center between 2009 and 2017. All patients were in clinical and endoscopic remission without concurrent corticosteroid use. Mucosal healing was defined as Mayo endoscopic subscore (MES) of 1 or less, and clinical remission was defined as partial Mayo score (MSp) less than 2. The median age of the participants was 41 years, and the median disease duration was 8 years at the time of surveillance colonoscopy.

Over a median follow-up of 42 months, patients with an MES of 0 and histologic remission had significantly longer relapse-free survival compared to those with MES 1 and NHI 2 to 4, respectively.

Thirty-three patients relapsed during the study period. Clinical relapse rates were similar for patients with MES 0 and MES 1 (40% and 52%, respectively), but only 29% of patients in histologic remission at baseline relapsed vs. 64% of those with histologic activity at baseline (P = 0.0064).

Risk factors for earlier relapse on univariate analysis included MES 1 and NHI 2 to 4. Only histologic activity predicted future relapse in a multivariate analysis (hazard ratio, 4.36, P = 0.002).

The study findings reflect data from previous research supporting the prognostic value of histologic remission using NHI, the researchers noted in their discussion. Barriers to adoption of histologic indices include “their multiplicity, complexity, lack of validation, and inconsistent incorporation in randomized controlled trials,” which create challenges in interpreting and comparing research outcomes, they wrote.

The study findings were limited by several factors, including the retrospective design, collection of clinical and endoscopic variables from electronic medical records without objective measures of relapse, lack of standardization of colonic biopsies, and lack of power to detect differences in dysplasia and colectomy, the researchers noted.

The results suggest that histologic remission using the NHI serves as an effective predictor of longer relapse-free survival in UC patients with clinical and endoscopic remission, they said.

“Further prospective trials are needed to clarify whether histologic remission as a therapeutic endpoint in addition to endoscopic remission will alter disease course and patient outcomes,” while helping guide treatment management decisions for patients and clinicians, the researchers concluded.

Not the ultimate endpoint?

“There is ongoing interest in whether histological findings (biopsies) of the mucosa are a clinically important and reachable treatment goal in ulcerative colitis,” David T. Rubin, MD, of the University of Chicago, who was not involved in the study, said in an interview.

Questions about this approach remain, such as how findings should be incorporated into clinical care and whether histology offers advantages over patient-reported symptoms, endoscopic findings, or other surrogates of inflammation like calprotectin, a protein related to histology detected in stool, Dr. Rubin explained.

“A number of retrospective studies have demonstrated the clinical importance of achieving histological remission, but the details of how to get there are not yet clearly defined. In this study, using one of the established indices of histological activity, the Nancy Histological Index, those patients who achieved histological remission had better clinical outcomes (stable remission) than symptoms alone or endoscopy alone.”

According to Dr. Rubin, clinicians can inform patients that histological remission supports that the therapy is working and they have a very good likelihood of staying in remission over the next year.

“Importantly, this is not the same as saying we should treat to get to this endpoint,” Dr. Rubin emphasized. “If a patient is in clinical remission with normalized labs and endoscopy (or calprotectin) that show healing, we do not yet recommend adjusting therapy for histological endpoints. This was edified in the consensus paper called STRIDE 2, published in Gastroenterology in 2021.”

As for additional research, the ongoing prospective randomized VERDICT trial is exploring different endpoints of treatment, “one of which is the combination of symptoms, endoscopy, and histology to assess whether this is better than symptoms or endoscopy alone,” said Dr. Rubin. “We also need more work to understand the timing of this finding, the number of biopsies that may be required to get an adequate assessment of the bowel, how pathologists should read and interpret our findings, when we should relook if we adjust therapy, and whether some therapies are more or less likely to achieve this endpoint,” he said.

The study received no outside funding. Neither the researchers nor Dr. Rubin reported any financial disclosures.

The Food and Drug Administration has recommended thyroid monitoring for newborns and children through 3 years of age within 3 weeks of receiving injections of iodine-containing contrast media as part of imaging procedures.

A recent FDA review showed that “underactive thyroid or a temporary decrease in thyroid hormone levels were uncommon,” according to an updated Drug Safety Communication issued on March 30, 2022.

However, early monitoring will help identify and treat any thyroid abnormalities as a result of the injections to help prevent potential complications in the future, according to the FDA, as babies and children do not generally show visible signs of thyroid problems and may not do so after an iodinated contrast media (ICM) injection.

ICM have been approved and used for decades to enhance images on x-rays or computed tomography (CT) scans, according to the communication.

The new FDA warning and recommendation for monitoring applies to the prescribing information for the entire class of ICM products. The new communication is an update to the 2015 Drug Safety Communication that advised medical professionals of the potential for underactive thyroid in response to ICM injections in newborns and young children. The update reflects new studies since that time.

The recent research showed that most reported cases of adverse effects were transient subclinical hypothyroidism and did not require treatment, according to the FDA. “The reported rate ranged from 1 percent to 15 percent and tended to be higher in neonates, particularly preterm neonates,” they said. Others at increased risk are those with underlying medical conditions, especially those with cardiac conditions who often require higher doses of contrast during invasive procedures.

In the recent studies, the time from ICM exposure to a diagnosis of thyroid dysfunction ranged from 8.5 to 138 days, but most occurred within 3 weeks, according to the update.

Patients and clinicians can report any adverse events from ICM or other medications to the FDA via FDA MedWatch program.

For more information, read the complete Drug Safety Communication.

The Food and Drug Administration has recommended thyroid monitoring for newborns and children through 3 years of age within 3 weeks of receiving injections of iodine-containing contrast media as part of imaging procedures.

A recent FDA review showed that “underactive thyroid or a temporary decrease in thyroid hormone levels were uncommon,” according to an updated Drug Safety Communication issued on March 30, 2022.

However, early monitoring will help identify and treat any thyroid abnormalities as a result of the injections to help prevent potential complications in the future, according to the FDA, as babies and children do not generally show visible signs of thyroid problems and may not do so after an iodinated contrast media (ICM) injection.

ICM have been approved and used for decades to enhance images on x-rays or computed tomography (CT) scans, according to the communication.

The new FDA warning and recommendation for monitoring applies to the prescribing information for the entire class of ICM products. The new communication is an update to the 2015 Drug Safety Communication that advised medical professionals of the potential for underactive thyroid in response to ICM injections in newborns and young children. The update reflects new studies since that time.

The recent research showed that most reported cases of adverse effects were transient subclinical hypothyroidism and did not require treatment, according to the FDA. “The reported rate ranged from 1 percent to 15 percent and tended to be higher in neonates, particularly preterm neonates,” they said. Others at increased risk are those with underlying medical conditions, especially those with cardiac conditions who often require higher doses of contrast during invasive procedures.

In the recent studies, the time from ICM exposure to a diagnosis of thyroid dysfunction ranged from 8.5 to 138 days, but most occurred within 3 weeks, according to the update.

Patients and clinicians can report any adverse events from ICM or other medications to the FDA via FDA MedWatch program.

For more information, read the complete Drug Safety Communication.

The Food and Drug Administration has recommended thyroid monitoring for newborns and children through 3 years of age within 3 weeks of receiving injections of iodine-containing contrast media as part of imaging procedures.

A recent FDA review showed that “underactive thyroid or a temporary decrease in thyroid hormone levels were uncommon,” according to an updated Drug Safety Communication issued on March 30, 2022.

However, early monitoring will help identify and treat any thyroid abnormalities as a result of the injections to help prevent potential complications in the future, according to the FDA, as babies and children do not generally show visible signs of thyroid problems and may not do so after an iodinated contrast media (ICM) injection.

ICM have been approved and used for decades to enhance images on x-rays or computed tomography (CT) scans, according to the communication.

The new FDA warning and recommendation for monitoring applies to the prescribing information for the entire class of ICM products. The new communication is an update to the 2015 Drug Safety Communication that advised medical professionals of the potential for underactive thyroid in response to ICM injections in newborns and young children. The update reflects new studies since that time.

The recent research showed that most reported cases of adverse effects were transient subclinical hypothyroidism and did not require treatment, according to the FDA. “The reported rate ranged from 1 percent to 15 percent and tended to be higher in neonates, particularly preterm neonates,” they said. Others at increased risk are those with underlying medical conditions, especially those with cardiac conditions who often require higher doses of contrast during invasive procedures.

In the recent studies, the time from ICM exposure to a diagnosis of thyroid dysfunction ranged from 8.5 to 138 days, but most occurred within 3 weeks, according to the update.

Patients and clinicians can report any adverse events from ICM or other medications to the FDA via FDA MedWatch program.

For more information, read the complete Drug Safety Communication.

Children at risk of neonatal hypoglycemia who were screened and treated if needed showed no difference in educational achievement from controls at age 9-10 years, based on data from 480 children.

Previous studies have shown an increased risk of poor executive and visual-motor function in children with neonatal hypoglycemia, but the effect on later childhood academic performance remains unclear, wrote Rajesh Shah, PhD, of the University of Auckland, New Zealand, and colleagues.

In a prospective cohort study published in JAMA, the researchers enrolled moderate to late preterm and term infants born at increased risk for hypoglycemia; those with episodes of hypoglycemia were treated to maintain a blood glucose concentration of at least 47 mg/dL.

The study population was enrolled between 2006 and 2010 at a regional perinatal center in New Zealand, and their educational achievement was assessed 9-10 years later. The primary outcome of low educational achievement was defined as performing below the normal curriculum level in standardized tests of reading comprehension or math. The researchers also identified 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.

Rates of low educational achievement were not significantly different for children with and without neonatal hypoglycemia (47% vs. 48%, adjusted risk ratio 0.95).

No significant differences appeared between the two groups for any secondary outcomes, including reading comprehension, math, behavior manifestations of executive function, fine motor function, autism traits, and overall well-being, the researchers noted.

However, children with neonatal hypoglycemia were significantly less likely to be rated as below or well below reading curriculum level by teachers compared to those without neonatal hypoglycemia (24% vs. 31%).

The researchers cited a previous study of the same patient cohort at age 4.5 years, which suggested an association between adverse neurodevelopmental outcomes and infant hypoglycemia. However, the reason this association did not persist at age 9-10 years remains unclear, the researchers wrote in their discussion. “Early disturbances in brain development may have diminishing effects over time due to neuroplasticity, that is, reorganization of neural networks, or delayed maturation with mid-childhood catch-up in neurocognitive function,” they said.

The study findings were limited by several factors including the lack of data on several measures of cognition, notably processing speed, and a lack of adjustment for intelligence quotient at age 4.5 years, the lack of data on any treatment for developmental impairment, and the inclusion of a population with well-managed hypoglycemia, the researchers said.

However, the results were strengthened by having a sample size large enough to detect associations, the prospective design, and the accurate measure of neonatal glycemic exposure, they said. Although the results suggest that at-risk children reach similar endpoints by the end of primary school, “efforts to prevent and optimize adverse pregnancy conditions remain important, and developmental surveillance after birth should be considered for at-risk infants,” they concluded.

In a related study published in JAMA, Taygen Edwards and colleagues found that prophylactic oral dextrose gel had no significant effect on neurosensory function.

The study, a prospective follow-up of a multicenter randomized trial, included 1,197 later preterm or term infants deemed at risk for neonatal hypoglycemia. The infants (49% of whom were female) were randomized to prophylactic 40% dextrose gel or a placebo, massaged into the buccal mucosa at 1 hour after birth.

The primary outcome was neurosensory impairment at 2 years of age, which was assessed by neurologic examination, parent-reported medical questionnaires, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), performance-based executive function, Behavior Rating Inventory of Executive Function–Preschool Version, motion coherence thresholds, growth, and body composition.

At 2 years of age, the prevalence of neurosensory impairment was 21% and 19%, respectively, in infants randomized to prophylactic oral dextrose gel and placebo, a nonsignificant difference. No differences between the two groups were noted for cognitive and language delays, or low performance-based overall executive function. However, infants randomized to dextrose gel had significantly higher risk of motor delay compared to placebo (2.5% vs. 0.7%) and significantly lower Bayley-III composite scores for cognitive, language, and motor performance.

No significant differences were noted between the groups in the areas of moderate or severe neurosensory impairment, hearing impairment, cerebral palsy, developmental delay, above-average development, socioemotional and adaptive behavior, questionnaire-based executive function, low visual processing, history of seizures, allergic and infectious diseases, growth, and body composition.

The results are consistent with previous studies on the safety of dextrose gel, the researchers wrote in their discussion. However, the absolute difference of 7% in the primary outcome may be clinically important, they noted. “Caution is warranted before using prophylactic dextrose gel,” they said.

The researchers noted the results of a dose-finding trial that suggested improved scores on language, executive function, and motor skills in unadjusted analysis with higher doses of dextrose gel, but the reason for these findings remains unknown, they said.

The study findings were limited by the potential underpowering to detect small, but significant differences, and possible lack of generalizability because the majority of the participants were children of mothers with diabetes.

The results were strengthened by the high follow-up rate and comprehensive assessments, and highlight the need for additional research with longer follow-up, the researchers said.
 

Findings fuel further exploration

Although hypoglycemia is common in newborns, its management and potential outcomes remain subjects for debate, Paul J. Rozance, MD, of the University of Colorado, Aurora, wrote in an editorial accompanying both studies.

“Often, the same features that increase the risk of hypoglycemia in newborns also increase the risk for poor outcomes independent of hypoglycemia,” he said.

The study by Shah and colleagues was not a randomized trial of a specific management strategy, Dr. Rozance noted. However, the high rate of low educational attainment in children not exposed to dextrose gel emphasizes the need for more effective management of infant hypoglycemia, he said. “The findings also suggest that antenatal conditions that are associated with increased risk of hypoglycemia among newborns are associated with increased risk for impaired neurodevelopment and educational achievement, independent of neonatal hypoglycemia,” he said. The study findings contrast with those of an earlier study showing low academic achievement association with early transient hypoglycemia, which could argue for earlier intervention, he noted.

The study by Edwards and colleagues addressed the potential value of dextrose gel as an early intervention to prevent neonatal hypoglycemia, said Dr. Rozance.

“The 95% CI for the primary outcome of neurosensory impairment included up to a 7% increased risk for neurosensory impairment in the prophylactic dextrose gel group. The 7% increased risk was defined by the investigators as potentially clinically important, and the study may have been underpowered to detect small differences in the primary outcome,” he wrote.

Although the reasons for adverse outcomes in children given prophylactic dextrose gel remain unclear, “incorporation of prophylactic dextrose gel into clinical practice should await further research,” he said.

Regarding such research, Dr. Rozance proposed an “ideal study,” that would “randomize newborns with hypoglycemia to treatment or no treatment, although equipoise and ethical support for such a study are lacking. Another strategy would be to randomize newborns with hypoglycemia to receive low- or high-treatment glucose concentration goals,” he noted.

The relationship between hypoglycemia and impaired neurodevelopment is yet to be determined, but the two studies provide new evidence for the clinical importance and need for management of neonatal hypoglycemia and subsequent neurodevelopmental outcomes, he concluded.

The study by Shah and colleagues was supported by the Health Research Council of New Zealand and the Maurice and Phyllis Paykel Trust. Dr. Shah disclosed a doctoral fellowship from the University of Auckland. The study by Edwards and colleagues was supported by the Health Research Council of New Zealand and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Ms. Edwards had no financial conflicts to disclose. Dr. Rozance disclosed receiving a StatStrip from Nova Biomedical for use in his laboratory.

Children at risk of neonatal hypoglycemia who were screened and treated if needed showed no difference in educational achievement from controls at age 9-10 years, based on data from 480 children.

Previous studies have shown an increased risk of poor executive and visual-motor function in children with neonatal hypoglycemia, but the effect on later childhood academic performance remains unclear, wrote Rajesh Shah, PhD, of the University of Auckland, New Zealand, and colleagues.

In a prospective cohort study published in JAMA, the researchers enrolled moderate to late preterm and term infants born at increased risk for hypoglycemia; those with episodes of hypoglycemia were treated to maintain a blood glucose concentration of at least 47 mg/dL.

The study population was enrolled between 2006 and 2010 at a regional perinatal center in New Zealand, and their educational achievement was assessed 9-10 years later. The primary outcome of low educational achievement was defined as performing below the normal curriculum level in standardized tests of reading comprehension or math. The researchers also identified 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.

Rates of low educational achievement were not significantly different for children with and without neonatal hypoglycemia (47% vs. 48%, adjusted risk ratio 0.95).

No significant differences appeared between the two groups for any secondary outcomes, including reading comprehension, math, behavior manifestations of executive function, fine motor function, autism traits, and overall well-being, the researchers noted.

However, children with neonatal hypoglycemia were significantly less likely to be rated as below or well below reading curriculum level by teachers compared to those without neonatal hypoglycemia (24% vs. 31%).

The researchers cited a previous study of the same patient cohort at age 4.5 years, which suggested an association between adverse neurodevelopmental outcomes and infant hypoglycemia. However, the reason this association did not persist at age 9-10 years remains unclear, the researchers wrote in their discussion. “Early disturbances in brain development may have diminishing effects over time due to neuroplasticity, that is, reorganization of neural networks, or delayed maturation with mid-childhood catch-up in neurocognitive function,” they said.

The study findings were limited by several factors including the lack of data on several measures of cognition, notably processing speed, and a lack of adjustment for intelligence quotient at age 4.5 years, the lack of data on any treatment for developmental impairment, and the inclusion of a population with well-managed hypoglycemia, the researchers said.

However, the results were strengthened by having a sample size large enough to detect associations, the prospective design, and the accurate measure of neonatal glycemic exposure, they said. Although the results suggest that at-risk children reach similar endpoints by the end of primary school, “efforts to prevent and optimize adverse pregnancy conditions remain important, and developmental surveillance after birth should be considered for at-risk infants,” they concluded.

In a related study published in JAMA, Taygen Edwards and colleagues found that prophylactic oral dextrose gel had no significant effect on neurosensory function.

The study, a prospective follow-up of a multicenter randomized trial, included 1,197 later preterm or term infants deemed at risk for neonatal hypoglycemia. The infants (49% of whom were female) were randomized to prophylactic 40% dextrose gel or a placebo, massaged into the buccal mucosa at 1 hour after birth.

The primary outcome was neurosensory impairment at 2 years of age, which was assessed by neurologic examination, parent-reported medical questionnaires, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), performance-based executive function, Behavior Rating Inventory of Executive Function–Preschool Version, motion coherence thresholds, growth, and body composition.

At 2 years of age, the prevalence of neurosensory impairment was 21% and 19%, respectively, in infants randomized to prophylactic oral dextrose gel and placebo, a nonsignificant difference. No differences between the two groups were noted for cognitive and language delays, or low performance-based overall executive function. However, infants randomized to dextrose gel had significantly higher risk of motor delay compared to placebo (2.5% vs. 0.7%) and significantly lower Bayley-III composite scores for cognitive, language, and motor performance.

No significant differences were noted between the groups in the areas of moderate or severe neurosensory impairment, hearing impairment, cerebral palsy, developmental delay, above-average development, socioemotional and adaptive behavior, questionnaire-based executive function, low visual processing, history of seizures, allergic and infectious diseases, growth, and body composition.

The results are consistent with previous studies on the safety of dextrose gel, the researchers wrote in their discussion. However, the absolute difference of 7% in the primary outcome may be clinically important, they noted. “Caution is warranted before using prophylactic dextrose gel,” they said.

The researchers noted the results of a dose-finding trial that suggested improved scores on language, executive function, and motor skills in unadjusted analysis with higher doses of dextrose gel, but the reason for these findings remains unknown, they said.

The study findings were limited by the potential underpowering to detect small, but significant differences, and possible lack of generalizability because the majority of the participants were children of mothers with diabetes.

The results were strengthened by the high follow-up rate and comprehensive assessments, and highlight the need for additional research with longer follow-up, the researchers said.
 

Findings fuel further exploration

Although hypoglycemia is common in newborns, its management and potential outcomes remain subjects for debate, Paul J. Rozance, MD, of the University of Colorado, Aurora, wrote in an editorial accompanying both studies.

“Often, the same features that increase the risk of hypoglycemia in newborns also increase the risk for poor outcomes independent of hypoglycemia,” he said.

The study by Shah and colleagues was not a randomized trial of a specific management strategy, Dr. Rozance noted. However, the high rate of low educational attainment in children not exposed to dextrose gel emphasizes the need for more effective management of infant hypoglycemia, he said. “The findings also suggest that antenatal conditions that are associated with increased risk of hypoglycemia among newborns are associated with increased risk for impaired neurodevelopment and educational achievement, independent of neonatal hypoglycemia,” he said. The study findings contrast with those of an earlier study showing low academic achievement association with early transient hypoglycemia, which could argue for earlier intervention, he noted.

The study by Edwards and colleagues addressed the potential value of dextrose gel as an early intervention to prevent neonatal hypoglycemia, said Dr. Rozance.

“The 95% CI for the primary outcome of neurosensory impairment included up to a 7% increased risk for neurosensory impairment in the prophylactic dextrose gel group. The 7% increased risk was defined by the investigators as potentially clinically important, and the study may have been underpowered to detect small differences in the primary outcome,” he wrote.

Although the reasons for adverse outcomes in children given prophylactic dextrose gel remain unclear, “incorporation of prophylactic dextrose gel into clinical practice should await further research,” he said.

Regarding such research, Dr. Rozance proposed an “ideal study,” that would “randomize newborns with hypoglycemia to treatment or no treatment, although equipoise and ethical support for such a study are lacking. Another strategy would be to randomize newborns with hypoglycemia to receive low- or high-treatment glucose concentration goals,” he noted.

The relationship between hypoglycemia and impaired neurodevelopment is yet to be determined, but the two studies provide new evidence for the clinical importance and need for management of neonatal hypoglycemia and subsequent neurodevelopmental outcomes, he concluded.

The study by Shah and colleagues was supported by the Health Research Council of New Zealand and the Maurice and Phyllis Paykel Trust. Dr. Shah disclosed a doctoral fellowship from the University of Auckland. The study by Edwards and colleagues was supported by the Health Research Council of New Zealand and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Ms. Edwards had no financial conflicts to disclose. Dr. Rozance disclosed receiving a StatStrip from Nova Biomedical for use in his laboratory.

Children at risk of neonatal hypoglycemia who were screened and treated if needed showed no difference in educational achievement from controls at age 9-10 years, based on data from 480 children.

Previous studies have shown an increased risk of poor executive and visual-motor function in children with neonatal hypoglycemia, but the effect on later childhood academic performance remains unclear, wrote Rajesh Shah, PhD, of the University of Auckland, New Zealand, and colleagues.

In a prospective cohort study published in JAMA, the researchers enrolled moderate to late preterm and term infants born at increased risk for hypoglycemia; those with episodes of hypoglycemia were treated to maintain a blood glucose concentration of at least 47 mg/dL.

The study population was enrolled between 2006 and 2010 at a regional perinatal center in New Zealand, and their educational achievement was assessed 9-10 years later. The primary outcome of low educational achievement was defined as performing below the normal curriculum level in standardized tests of reading comprehension or math. The researchers also identified 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.

Rates of low educational achievement were not significantly different for children with and without neonatal hypoglycemia (47% vs. 48%, adjusted risk ratio 0.95).

No significant differences appeared between the two groups for any secondary outcomes, including reading comprehension, math, behavior manifestations of executive function, fine motor function, autism traits, and overall well-being, the researchers noted.

However, children with neonatal hypoglycemia were significantly less likely to be rated as below or well below reading curriculum level by teachers compared to those without neonatal hypoglycemia (24% vs. 31%).

The researchers cited a previous study of the same patient cohort at age 4.5 years, which suggested an association between adverse neurodevelopmental outcomes and infant hypoglycemia. However, the reason this association did not persist at age 9-10 years remains unclear, the researchers wrote in their discussion. “Early disturbances in brain development may have diminishing effects over time due to neuroplasticity, that is, reorganization of neural networks, or delayed maturation with mid-childhood catch-up in neurocognitive function,” they said.

The study findings were limited by several factors including the lack of data on several measures of cognition, notably processing speed, and a lack of adjustment for intelligence quotient at age 4.5 years, the lack of data on any treatment for developmental impairment, and the inclusion of a population with well-managed hypoglycemia, the researchers said.

However, the results were strengthened by having a sample size large enough to detect associations, the prospective design, and the accurate measure of neonatal glycemic exposure, they said. Although the results suggest that at-risk children reach similar endpoints by the end of primary school, “efforts to prevent and optimize adverse pregnancy conditions remain important, and developmental surveillance after birth should be considered for at-risk infants,” they concluded.

In a related study published in JAMA, Taygen Edwards and colleagues found that prophylactic oral dextrose gel had no significant effect on neurosensory function.

The study, a prospective follow-up of a multicenter randomized trial, included 1,197 later preterm or term infants deemed at risk for neonatal hypoglycemia. The infants (49% of whom were female) were randomized to prophylactic 40% dextrose gel or a placebo, massaged into the buccal mucosa at 1 hour after birth.

The primary outcome was neurosensory impairment at 2 years of age, which was assessed by neurologic examination, parent-reported medical questionnaires, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), performance-based executive function, Behavior Rating Inventory of Executive Function–Preschool Version, motion coherence thresholds, growth, and body composition.

At 2 years of age, the prevalence of neurosensory impairment was 21% and 19%, respectively, in infants randomized to prophylactic oral dextrose gel and placebo, a nonsignificant difference. No differences between the two groups were noted for cognitive and language delays, or low performance-based overall executive function. However, infants randomized to dextrose gel had significantly higher risk of motor delay compared to placebo (2.5% vs. 0.7%) and significantly lower Bayley-III composite scores for cognitive, language, and motor performance.

No significant differences were noted between the groups in the areas of moderate or severe neurosensory impairment, hearing impairment, cerebral palsy, developmental delay, above-average development, socioemotional and adaptive behavior, questionnaire-based executive function, low visual processing, history of seizures, allergic and infectious diseases, growth, and body composition.

The results are consistent with previous studies on the safety of dextrose gel, the researchers wrote in their discussion. However, the absolute difference of 7% in the primary outcome may be clinically important, they noted. “Caution is warranted before using prophylactic dextrose gel,” they said.

The researchers noted the results of a dose-finding trial that suggested improved scores on language, executive function, and motor skills in unadjusted analysis with higher doses of dextrose gel, but the reason for these findings remains unknown, they said.

The study findings were limited by the potential underpowering to detect small, but significant differences, and possible lack of generalizability because the majority of the participants were children of mothers with diabetes.

The results were strengthened by the high follow-up rate and comprehensive assessments, and highlight the need for additional research with longer follow-up, the researchers said.
 

Findings fuel further exploration

Although hypoglycemia is common in newborns, its management and potential outcomes remain subjects for debate, Paul J. Rozance, MD, of the University of Colorado, Aurora, wrote in an editorial accompanying both studies.

“Often, the same features that increase the risk of hypoglycemia in newborns also increase the risk for poor outcomes independent of hypoglycemia,” he said.

The study by Shah and colleagues was not a randomized trial of a specific management strategy, Dr. Rozance noted. However, the high rate of low educational attainment in children not exposed to dextrose gel emphasizes the need for more effective management of infant hypoglycemia, he said. “The findings also suggest that antenatal conditions that are associated with increased risk of hypoglycemia among newborns are associated with increased risk for impaired neurodevelopment and educational achievement, independent of neonatal hypoglycemia,” he said. The study findings contrast with those of an earlier study showing low academic achievement association with early transient hypoglycemia, which could argue for earlier intervention, he noted.

The study by Edwards and colleagues addressed the potential value of dextrose gel as an early intervention to prevent neonatal hypoglycemia, said Dr. Rozance.

“The 95% CI for the primary outcome of neurosensory impairment included up to a 7% increased risk for neurosensory impairment in the prophylactic dextrose gel group. The 7% increased risk was defined by the investigators as potentially clinically important, and the study may have been underpowered to detect small differences in the primary outcome,” he wrote.

Although the reasons for adverse outcomes in children given prophylactic dextrose gel remain unclear, “incorporation of prophylactic dextrose gel into clinical practice should await further research,” he said.

Regarding such research, Dr. Rozance proposed an “ideal study,” that would “randomize newborns with hypoglycemia to treatment or no treatment, although equipoise and ethical support for such a study are lacking. Another strategy would be to randomize newborns with hypoglycemia to receive low- or high-treatment glucose concentration goals,” he noted.

The relationship between hypoglycemia and impaired neurodevelopment is yet to be determined, but the two studies provide new evidence for the clinical importance and need for management of neonatal hypoglycemia and subsequent neurodevelopmental outcomes, he concluded.

The study by Shah and colleagues was supported by the Health Research Council of New Zealand and the Maurice and Phyllis Paykel Trust. Dr. Shah disclosed a doctoral fellowship from the University of Auckland. The study by Edwards and colleagues was supported by the Health Research Council of New Zealand and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Ms. Edwards had no financial conflicts to disclose. Dr. Rozance disclosed receiving a StatStrip from Nova Biomedical for use in his laboratory.

Initiating treatment may become easier for adults living with HIV. The Food and Drug Administration has approved a label update that allows adults living with HIV to begin treatment with Cabenuva, a combination injectable, without a lead-in period of oral tablets, according to a press release from Janssen Pharmaceuticals.

Cabenuva combines rilpivirine (Janssen) and cabotegravir (ViiV Healthcare). The change offers patients and clinicians an option for a streamlined entry to treatment without the burden of daily pill taking, according to the release.

Cabenuva injections may be given as few as six times a year to manage HIV, according to Janssen. HIV patients with viral suppression previously had to complete an oral treatment regimen before starting monthly or bimonthly injections.

The injectable combination of cabotegravir, an HIV-1 integrase strand transfer inhibitor, and rilpivirine, an HIV-1 nonnucleoside reverse transcriptase inhibitor, is currently indicated as a complete treatment regimen to replace the current antiretroviral regimen for adults with HIV who are virologically suppressed,” according to the press release.

“Janssen and ViiV are exploring the future possibility of an ultra–long-acting version of Cabenuva, which could reduce the frequency of injections even further, according to the press release.
 

Access may improve, but barriers persist

“Despite advances in HIV care, many barriers remain, particularly for the most vulnerable populations,” Lina Rosengren-Hovee, MD, of the University of North Carolina at Chapel Hill, said in an interview.

“Care engagement has improved with the use of bridge counselors, rapid ART [antiretroviral therapy] initiation policies, and contact tracing,” she said. “Similarly, increasing access to multiple modalities of HIV treatment is critical to increase engagement in care.

“For patients, removing the oral lead-in primarily reduces the number of clinical visits to start injectable ART,” Dr. Rosengren-Hovee added. “It may also remove adherence barriers for patients who have difficulty taking a daily oral medication.”

But Dr. Rosengren-Hovee (who has no financial connection to the manufacturers) pointed out that access to Cabenuva may not be seamless. “Unless the medication is stocked in clinics, patients are not likely to receive their first injection during the initial visit. Labs are also required prior to initiation to ensure there is no contraindication to the medication, such as viral resistance to one of its components. Cost and insurance coverage are also likely to remain major obstacles.”

Dr. Rosengren-Hovee has disclosed no relevant financial relationships.

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

Initiating treatment may become easier for adults living with HIV. The Food and Drug Administration has approved a label update that allows adults living with HIV to begin treatment with Cabenuva, a combination injectable, without a lead-in period of oral tablets, according to a press release from Janssen Pharmaceuticals.

Cabenuva combines rilpivirine (Janssen) and cabotegravir (ViiV Healthcare). The change offers patients and clinicians an option for a streamlined entry to treatment without the burden of daily pill taking, according to the release.

Cabenuva injections may be given as few as six times a year to manage HIV, according to Janssen. HIV patients with viral suppression previously had to complete an oral treatment regimen before starting monthly or bimonthly injections.

The injectable combination of cabotegravir, an HIV-1 integrase strand transfer inhibitor, and rilpivirine, an HIV-1 nonnucleoside reverse transcriptase inhibitor, is currently indicated as a complete treatment regimen to replace the current antiretroviral regimen for adults with HIV who are virologically suppressed,” according to the press release.

“Janssen and ViiV are exploring the future possibility of an ultra–long-acting version of Cabenuva, which could reduce the frequency of injections even further, according to the press release.
 

Access may improve, but barriers persist

“Despite advances in HIV care, many barriers remain, particularly for the most vulnerable populations,” Lina Rosengren-Hovee, MD, of the University of North Carolina at Chapel Hill, said in an interview.

“Care engagement has improved with the use of bridge counselors, rapid ART [antiretroviral therapy] initiation policies, and contact tracing,” she said. “Similarly, increasing access to multiple modalities of HIV treatment is critical to increase engagement in care.

“For patients, removing the oral lead-in primarily reduces the number of clinical visits to start injectable ART,” Dr. Rosengren-Hovee added. “It may also remove adherence barriers for patients who have difficulty taking a daily oral medication.”

But Dr. Rosengren-Hovee (who has no financial connection to the manufacturers) pointed out that access to Cabenuva may not be seamless. “Unless the medication is stocked in clinics, patients are not likely to receive their first injection during the initial visit. Labs are also required prior to initiation to ensure there is no contraindication to the medication, such as viral resistance to one of its components. Cost and insurance coverage are also likely to remain major obstacles.”

Dr. Rosengren-Hovee has disclosed no relevant financial relationships.

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

Initiating treatment may become easier for adults living with HIV. The Food and Drug Administration has approved a label update that allows adults living with HIV to begin treatment with Cabenuva, a combination injectable, without a lead-in period of oral tablets, according to a press release from Janssen Pharmaceuticals.

Cabenuva combines rilpivirine (Janssen) and cabotegravir (ViiV Healthcare). The change offers patients and clinicians an option for a streamlined entry to treatment without the burden of daily pill taking, according to the release.

Cabenuva injections may be given as few as six times a year to manage HIV, according to Janssen. HIV patients with viral suppression previously had to complete an oral treatment regimen before starting monthly or bimonthly injections.

The injectable combination of cabotegravir, an HIV-1 integrase strand transfer inhibitor, and rilpivirine, an HIV-1 nonnucleoside reverse transcriptase inhibitor, is currently indicated as a complete treatment regimen to replace the current antiretroviral regimen for adults with HIV who are virologically suppressed,” according to the press release.

“Janssen and ViiV are exploring the future possibility of an ultra–long-acting version of Cabenuva, which could reduce the frequency of injections even further, according to the press release.
 

Access may improve, but barriers persist

“Despite advances in HIV care, many barriers remain, particularly for the most vulnerable populations,” Lina Rosengren-Hovee, MD, of the University of North Carolina at Chapel Hill, said in an interview.

“Care engagement has improved with the use of bridge counselors, rapid ART [antiretroviral therapy] initiation policies, and contact tracing,” she said. “Similarly, increasing access to multiple modalities of HIV treatment is critical to increase engagement in care.

“For patients, removing the oral lead-in primarily reduces the number of clinical visits to start injectable ART,” Dr. Rosengren-Hovee added. “It may also remove adherence barriers for patients who have difficulty taking a daily oral medication.”

But Dr. Rosengren-Hovee (who has no financial connection to the manufacturers) pointed out that access to Cabenuva may not be seamless. “Unless the medication is stocked in clinics, patients are not likely to receive their first injection during the initial visit. Labs are also required prior to initiation to ensure there is no contraindication to the medication, such as viral resistance to one of its components. Cost and insurance coverage are also likely to remain major obstacles.”

Dr. Rosengren-Hovee has disclosed no relevant financial relationships.

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

A higher rate of serrated polyp detection was associated with a reduced risk of postcolonoscopy colorectal cancer, based on data from nearly 20,000 patients and 142 endoscopists, according to a study published in Gastrointestinal Endoscopy.

Higher rates of adenoma detection reduce the risk of postcolonoscopy colorectal cancer (PCCRC), but the data on detection rates for clinically significant serrated polyps and traditional serrated adenomas are limited, wrote Joseph C. Anderson, MD, of the Geisel School of Medicine at Dartmouth, Hanover, N.H., and colleagues.

“A unique challenge for endoscopists is that serrated polyps exhibit characteristics that can make them more difficult to detect than conventional adenomas. Thus, it is not surprising that several studies have demonstrated a wide variation in serrated polyp detection rates.” Even so, improved detection and resection of these polyps would likely improve CRC prevention, they noted.

The researchers reviewed data from the New Hampshire Colonoscopy Registry to explore the association between clinically significantly serrated polyp (CSSP) detection rates and subsequent PCCRC risk.

The study population included 19,532 patients with follow-up events at least 6 months after an index colonoscopy. Of these, 128 cases of CRC were diagnosed at least 6 months after an index exam. CSSP was defined as any sessile serrated polyp, traditional serrated adenoma, or any large hyperplastic polyp (> 1 cm) or proximal hyperplastic polyp > 5 mm. The exams were performed by 142 endoscopists, 92 of whom were gastroenterologists. The 50 nongastroenterologists included general surgeons, colorectal surgeons, and family practitioners.

The primary outcome was PCCRC, defined as any CRC diagnosis 6 months or longer after an index exam. Clinically significant serrated polyp detection rate (CSSDR) was determined by dividing the total number of complete screening exams with adequate prep and at least one CSSP by the total number of complete exams with adequate prep. CSSDR was divided into tertiles of less than 3%, 3% up to 9%, and 9% or higher.

Overall, the risk for PCCRC 6 months or more after an index exam was significantly lower for exams performed by endoscopists with detection rates of 3% up to 9% and for those with detection rates of 9% or higher compared to those with detection rates below 3% (hazard ratios 0.57 and 0.39, respectively).

Significantly more gastroenterologists were in the higher CSSDR categories compared to nongastroenterologists (P = .00005). The percentages of gastroenterologists in the three tertiles from lowest to highest detection were 15.2%, 50.0%, and 34.8%; compared to 46%, 44.0%, and 10.0%, respectively, for nongastroenterologists.

In adjusted analysis, higher detection rates were associated with lower CRC risk across all time periods.

The researchers also found higher CSSDR categories associated with lower PCCRC risk for exams by endoscopists with ADR rates of 25% or higher.

“It may be reasonable to question whether a separate serrated detection rate is needed in addition to ADR,” the researchers wrote in their discussion of the findings. “These data support our suggestion that endoscopists, even those with an ADR of 25% or higher, calculate their SDR at least once, a recommendation supported by a recent review of the American Gastroenterological Association,” they noted.

The study findings were limited by several factors, including the lack of information on specific endoscopic techniques, a lack of data on the molecular characteristics of the cancers, and potential residual confounding variables, the researchers noted.

However, the results were strengthened by the large number of participating endoscopists and by the longitudinal database that included detection rates for screening exams and detailed polyp pathology, they said. The results support the need for a serrated polyp detection rate benchmark to endure complete polyp detection and validate the use of CSSDR as a quality measure that adds to the knowledge of both colonoscopy quality and the role of the serrated pathway in colorectal cancer, they concluded.
 

Serrated pathway serves as predictor

The current study is an important addition to the knowledge of colorectal cancer risk, Atsushi Sakuraba, MD, PhD, associate professor of medicine at the University of Chicago, said in an interview.

“In addition to the conventional adenoma pathway, the serrated pathway has been recognized to account for a significant portion of colorectal cancer, but whether detection of serrated polyps [is] associated with reduction of CRC remains unknown,” he said.

Dr. Sakuraba said he was not surprised by the study findings. Given that the serrated pathway is now considered to account for approximately 10%-20% of all CRC cases, higher detection rates should result in lower risk of CRC, he noted.

The findings support the value of CSSDR in clinical practice, said Dr. Sakuraba. “The study has shown that a clinically significant serrated polyps detection rate of 3% was associated with lower postcolonoscopy CRC, so endoscopists should introduce this to their practice in addition to adenoma detection rates,” he said.

However, Dr. Sakuraba acknowledged the limitations of the current study and emphasized that it needs to be reproduced in other cohorts. Prospective studies might be helpful as well, he said.

The study received no outside funding. The researchers and Dr. Sakuraba had no financial conflicts to disclose.

A higher rate of serrated polyp detection was associated with a reduced risk of postcolonoscopy colorectal cancer, based on data from nearly 20,000 patients and 142 endoscopists, according to a study published in Gastrointestinal Endoscopy.

Higher rates of adenoma detection reduce the risk of postcolonoscopy colorectal cancer (PCCRC), but the data on detection rates for clinically significant serrated polyps and traditional serrated adenomas are limited, wrote Joseph C. Anderson, MD, of the Geisel School of Medicine at Dartmouth, Hanover, N.H., and colleagues.

“A unique challenge for endoscopists is that serrated polyps exhibit characteristics that can make them more difficult to detect than conventional adenomas. Thus, it is not surprising that several studies have demonstrated a wide variation in serrated polyp detection rates.” Even so, improved detection and resection of these polyps would likely improve CRC prevention, they noted.

The researchers reviewed data from the New Hampshire Colonoscopy Registry to explore the association between clinically significantly serrated polyp (CSSP) detection rates and subsequent PCCRC risk.

The study population included 19,532 patients with follow-up events at least 6 months after an index colonoscopy. Of these, 128 cases of CRC were diagnosed at least 6 months after an index exam. CSSP was defined as any sessile serrated polyp, traditional serrated adenoma, or any large hyperplastic polyp (> 1 cm) or proximal hyperplastic polyp > 5 mm. The exams were performed by 142 endoscopists, 92 of whom were gastroenterologists. The 50 nongastroenterologists included general surgeons, colorectal surgeons, and family practitioners.

The primary outcome was PCCRC, defined as any CRC diagnosis 6 months or longer after an index exam. Clinically significant serrated polyp detection rate (CSSDR) was determined by dividing the total number of complete screening exams with adequate prep and at least one CSSP by the total number of complete exams with adequate prep. CSSDR was divided into tertiles of less than 3%, 3% up to 9%, and 9% or higher.

Overall, the risk for PCCRC 6 months or more after an index exam was significantly lower for exams performed by endoscopists with detection rates of 3% up to 9% and for those with detection rates of 9% or higher compared to those with detection rates below 3% (hazard ratios 0.57 and 0.39, respectively).

Significantly more gastroenterologists were in the higher CSSDR categories compared to nongastroenterologists (P = .00005). The percentages of gastroenterologists in the three tertiles from lowest to highest detection were 15.2%, 50.0%, and 34.8%; compared to 46%, 44.0%, and 10.0%, respectively, for nongastroenterologists.

In adjusted analysis, higher detection rates were associated with lower CRC risk across all time periods.

The researchers also found higher CSSDR categories associated with lower PCCRC risk for exams by endoscopists with ADR rates of 25% or higher.

“It may be reasonable to question whether a separate serrated detection rate is needed in addition to ADR,” the researchers wrote in their discussion of the findings. “These data support our suggestion that endoscopists, even those with an ADR of 25% or higher, calculate their SDR at least once, a recommendation supported by a recent review of the American Gastroenterological Association,” they noted.

The study findings were limited by several factors, including the lack of information on specific endoscopic techniques, a lack of data on the molecular characteristics of the cancers, and potential residual confounding variables, the researchers noted.

However, the results were strengthened by the large number of participating endoscopists and by the longitudinal database that included detection rates for screening exams and detailed polyp pathology, they said. The results support the need for a serrated polyp detection rate benchmark to endure complete polyp detection and validate the use of CSSDR as a quality measure that adds to the knowledge of both colonoscopy quality and the role of the serrated pathway in colorectal cancer, they concluded.
 

Serrated pathway serves as predictor

The current study is an important addition to the knowledge of colorectal cancer risk, Atsushi Sakuraba, MD, PhD, associate professor of medicine at the University of Chicago, said in an interview.

“In addition to the conventional adenoma pathway, the serrated pathway has been recognized to account for a significant portion of colorectal cancer, but whether detection of serrated polyps [is] associated with reduction of CRC remains unknown,” he said.

Dr. Sakuraba said he was not surprised by the study findings. Given that the serrated pathway is now considered to account for approximately 10%-20% of all CRC cases, higher detection rates should result in lower risk of CRC, he noted.

The findings support the value of CSSDR in clinical practice, said Dr. Sakuraba. “The study has shown that a clinically significant serrated polyps detection rate of 3% was associated with lower postcolonoscopy CRC, so endoscopists should introduce this to their practice in addition to adenoma detection rates,” he said.

However, Dr. Sakuraba acknowledged the limitations of the current study and emphasized that it needs to be reproduced in other cohorts. Prospective studies might be helpful as well, he said.

The study received no outside funding. The researchers and Dr. Sakuraba had no financial conflicts to disclose.

A higher rate of serrated polyp detection was associated with a reduced risk of postcolonoscopy colorectal cancer, based on data from nearly 20,000 patients and 142 endoscopists, according to a study published in Gastrointestinal Endoscopy.

Higher rates of adenoma detection reduce the risk of postcolonoscopy colorectal cancer (PCCRC), but the data on detection rates for clinically significant serrated polyps and traditional serrated adenomas are limited, wrote Joseph C. Anderson, MD, of the Geisel School of Medicine at Dartmouth, Hanover, N.H., and colleagues.

“A unique challenge for endoscopists is that serrated polyps exhibit characteristics that can make them more difficult to detect than conventional adenomas. Thus, it is not surprising that several studies have demonstrated a wide variation in serrated polyp detection rates.” Even so, improved detection and resection of these polyps would likely improve CRC prevention, they noted.

The researchers reviewed data from the New Hampshire Colonoscopy Registry to explore the association between clinically significantly serrated polyp (CSSP) detection rates and subsequent PCCRC risk.

The study population included 19,532 patients with follow-up events at least 6 months after an index colonoscopy. Of these, 128 cases of CRC were diagnosed at least 6 months after an index exam. CSSP was defined as any sessile serrated polyp, traditional serrated adenoma, or any large hyperplastic polyp (> 1 cm) or proximal hyperplastic polyp > 5 mm. The exams were performed by 142 endoscopists, 92 of whom were gastroenterologists. The 50 nongastroenterologists included general surgeons, colorectal surgeons, and family practitioners.

The primary outcome was PCCRC, defined as any CRC diagnosis 6 months or longer after an index exam. Clinically significant serrated polyp detection rate (CSSDR) was determined by dividing the total number of complete screening exams with adequate prep and at least one CSSP by the total number of complete exams with adequate prep. CSSDR was divided into tertiles of less than 3%, 3% up to 9%, and 9% or higher.

Overall, the risk for PCCRC 6 months or more after an index exam was significantly lower for exams performed by endoscopists with detection rates of 3% up to 9% and for those with detection rates of 9% or higher compared to those with detection rates below 3% (hazard ratios 0.57 and 0.39, respectively).

Significantly more gastroenterologists were in the higher CSSDR categories compared to nongastroenterologists (P = .00005). The percentages of gastroenterologists in the three tertiles from lowest to highest detection were 15.2%, 50.0%, and 34.8%; compared to 46%, 44.0%, and 10.0%, respectively, for nongastroenterologists.

In adjusted analysis, higher detection rates were associated with lower CRC risk across all time periods.

The researchers also found higher CSSDR categories associated with lower PCCRC risk for exams by endoscopists with ADR rates of 25% or higher.

“It may be reasonable to question whether a separate serrated detection rate is needed in addition to ADR,” the researchers wrote in their discussion of the findings. “These data support our suggestion that endoscopists, even those with an ADR of 25% or higher, calculate their SDR at least once, a recommendation supported by a recent review of the American Gastroenterological Association,” they noted.

The study findings were limited by several factors, including the lack of information on specific endoscopic techniques, a lack of data on the molecular characteristics of the cancers, and potential residual confounding variables, the researchers noted.

However, the results were strengthened by the large number of participating endoscopists and by the longitudinal database that included detection rates for screening exams and detailed polyp pathology, they said. The results support the need for a serrated polyp detection rate benchmark to endure complete polyp detection and validate the use of CSSDR as a quality measure that adds to the knowledge of both colonoscopy quality and the role of the serrated pathway in colorectal cancer, they concluded.
 

Serrated pathway serves as predictor

The current study is an important addition to the knowledge of colorectal cancer risk, Atsushi Sakuraba, MD, PhD, associate professor of medicine at the University of Chicago, said in an interview.

“In addition to the conventional adenoma pathway, the serrated pathway has been recognized to account for a significant portion of colorectal cancer, but whether detection of serrated polyps [is] associated with reduction of CRC remains unknown,” he said.

Dr. Sakuraba said he was not surprised by the study findings. Given that the serrated pathway is now considered to account for approximately 10%-20% of all CRC cases, higher detection rates should result in lower risk of CRC, he noted.

The findings support the value of CSSDR in clinical practice, said Dr. Sakuraba. “The study has shown that a clinically significant serrated polyps detection rate of 3% was associated with lower postcolonoscopy CRC, so endoscopists should introduce this to their practice in addition to adenoma detection rates,” he said.

However, Dr. Sakuraba acknowledged the limitations of the current study and emphasized that it needs to be reproduced in other cohorts. Prospective studies might be helpful as well, he said.

The study received no outside funding. The researchers and Dr. Sakuraba had no financial conflicts to disclose.

Hospitalized COVID-19 survivors showed greater cognitive impairment 6 months later, compared with patients hospitalized for other causes, but the overall disease burden was similar, based on data from 85 adults with COVID-19.

Previous studies have shown that cognitive and neuropsychiatric symptoms can occur from 2-6 months after COVID-19 recovery, and such symptoms are known to be associated with hospitalization for other severe medical conditions, Vardan Nersesjan, MD, of Copenhagen University Hospital, and colleagues wrote.

However, it remains unknown if COVID-19 is associated with a unique pattern of cognitive and mental impairment compared with other similarly severe medical conditions, they said.

In a study published in JAMA Psychiatry (2022 Mar 23. doi: 10.1001/jamapsychiatry.2022.0284), the researchers identified 85 adult COVID-19 survivors and 61 controls with non-COVID medical conditions who were treated and released between July 2020 and July 2021. The COVID-19 patients and controls were matched for age, sex, and ICU status. Cognitive impairment was assessed using the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semistructured interview to determine subjective symptoms.

The primary outcomes were the total scores on the MoCA and any new-onset psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses such as depression, neurologic examination findings, and self-reported neuropsychiatric and cognitive symptoms. The mean age of the COVID-19 patients was 56.8 years, and 42% were women.

At 6 months’ follow-up, cognitive status was significantly lower in COVID-19 survivors, compared with controls, based on total geometric mean MoCA scores (26.7 vs. 27.5, P = .01). However, cognitive status improved significantly from 19.2 at hospital discharge to 26.1 at 6 months in 15 of the COVID-19 patients (P = .004), the researchers noted.

New-onset psychiatric diagnoses occurred in 16 COVID-19 patients and 12 of the controls (19% vs. 20%); this difference was not significant.

Secondary outcomes were not significantly different at 6 months between the groups, with the exception of anosmia, which was significantly more common in the COVID-19 patients; however, the significance disappeared in adjusted analysis, the researchers said.

The study findings were limited by several factors including the inability to prove causality because of the case-control feature and by the inability to detect small differences in neuropsychiatric outcomes, the researchers noted.

However, the results were strengthened by the use of a prospectively matched control group with similar disease severity admitted to the same hospital in the same time frame. Although the overall burden of neuropsychiatric and neurologic symptoms and diagnoses appeared similar in COVID-19 patients and those with other medical conditions, more research in larger populations is needed to determine smaller differences in neuropsychiatric profiles, the researchers noted.

Study fills research gap

The study is important at this time because, although prolonged neuropsychiatric and cognitive symptoms have been reported after COVID-19, the field lacked prospective case-control studies with well-matched controls to investigate whether these outcomes differed from those seen in other critical illnesses that had also required hospitalization, corresponding author Michael E. Benros, MD, of the Mental Health Center, Copenhagen, said in an interview.

“I was surprised that there was a significant worse cognitive functioning among COVID-19 patients 6 months after symptom onset also when compared to this well-matched control group that had been hospitalized for non–COVID-19 illness, although the absolute difference between the groups in cognition score were small,” said Dr. Benros. “Another notable finding is the large improvement in cognitive functioning from discharge to follow-up,” he added on behalf of himself and fellow corresponding author Daniel Kondziella, MD.

The study results show that cognitive function affected by COVID-19 and critical illness as observed at discharge showed a substantial improvement at 6 months after symptom onset, said Dr. Benros. “However, the cognitive function was significantly worse among severely ill COVID-19 patients 6 months after symptom onset when compared to a matched control group of individuals hospitalized for non–COVID-19 illness, although this difference in cognitive function was rather small in absolute numbers, and smaller than what had been suggested by other studies that lacked control groups. Strikingly, neuropsychiatric disorders were similar across the two groups, which was also the case when looking at neuropsychiatric symptoms.

“Larger prospective case-control studies of neuropsychiatric and cognitive functioning after COVID-19, compared with matched controls are still needed to detect smaller differences, and more detailed cognitive domains, and with longer follow-up time, which we are currently conducting,” Dr. Benros said.  
 

Controlled studies will help planning

“Lingering neuropsychiatric complications are common after COVID-19, but only controlled studies can tell us whether these complications are specific to COVID-19, rather than a general effect of having been medically ill,” Alasdair G. Rooney, MRCPsych MD PhD, of the University of Edinburgh, said in an interview. “The answer matters ultimately because COVID-19 is a new disease; societies and health care services need to be able to plan for its specific consequences.”

The health status of the control group is important as well. “Most previous studies had compared COVID-19 survivors against healthy controls or patients from a historical database. This new study compared COVID-19 survivors against those hospitalized for other medical causes over the same period,” Dr. Rooney said. “This is a more stringent test of whether COVID-19 has specific neurocognitive and neuropsychiatric consequences.

“The study found that new-onset neuropsychiatric diagnoses and symptoms were no more likely to occur after COVID-19 than after similarly severe medical illnesses,” Dr. Rooney said. “This negative finding runs counter to some earlier studies and may surprise some.” The findings need to be replicated in larger samples, but the current study shows the importance of prospectively recruiting active controls.

“In a subgroup analysis, some patients showed good improvement in cognitive scores between discharge and follow-up. While unsurprising, this is encouraging and suggests that the early postdischarge months are an important time for neurocognitive recovery,” Dr. Rooney noted.

“The findings suggest that COVID-19 may impair attention more selectively than other medical causes of hospitalization. COVID-19 survivors may also be at higher risk of significant overall cognitive impairment than survivors of similarly severe medical illnesses, after a similar duration,” said Dr. Rooney. “If the results are replicated by other prospective studies, they would suggest that there is something about COVID-19 that causes clinically significant neurocognitive difficulties in a minority of survivors.

“Larger well-controlled studies are required, with longer follow-up and more detailed neurocognitive testing,” as the duration of impairment and scope for further recovery are not known, Dr. Rooney added. Also unknown is whether COVID-19 affects attention permanently, or whether recovery is simply slower after COVID-19 compared to other medical illnesses.

“Knowing who is at the greatest risk of severe cognitive impairment after COVID-19 is important and likely to allow tailoring of more effective shielding strategies,” said Dr. Rooney. “This study was conducted before the widespread availability of vaccines for COVID-19. Long-term neuropsychiatric outcomes in vaccinated patients remain largely unknown. Arguably, these are now more important to understand, as future COVID-19 waves will occur mainly among vaccinated individuals.”

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation. Lead author Dr. Nersesjan had no financial conflicts to disclose. Dr. Benros reported grants from Lundbeck Foundation and Novo Nordisk Foundation during the conduct of the study. Dr. Rooney had no financial conflicts to disclose.

This article was updated 3/25/22.

Hospitalized COVID-19 survivors showed greater cognitive impairment 6 months later, compared with patients hospitalized for other causes, but the overall disease burden was similar, based on data from 85 adults with COVID-19.

Previous studies have shown that cognitive and neuropsychiatric symptoms can occur from 2-6 months after COVID-19 recovery, and such symptoms are known to be associated with hospitalization for other severe medical conditions, Vardan Nersesjan, MD, of Copenhagen University Hospital, and colleagues wrote.

However, it remains unknown if COVID-19 is associated with a unique pattern of cognitive and mental impairment compared with other similarly severe medical conditions, they said.

In a study published in JAMA Psychiatry (2022 Mar 23. doi: 10.1001/jamapsychiatry.2022.0284), the researchers identified 85 adult COVID-19 survivors and 61 controls with non-COVID medical conditions who were treated and released between July 2020 and July 2021. The COVID-19 patients and controls were matched for age, sex, and ICU status. Cognitive impairment was assessed using the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semistructured interview to determine subjective symptoms.

The primary outcomes were the total scores on the MoCA and any new-onset psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses such as depression, neurologic examination findings, and self-reported neuropsychiatric and cognitive symptoms. The mean age of the COVID-19 patients was 56.8 years, and 42% were women.

At 6 months’ follow-up, cognitive status was significantly lower in COVID-19 survivors, compared with controls, based on total geometric mean MoCA scores (26.7 vs. 27.5, P = .01). However, cognitive status improved significantly from 19.2 at hospital discharge to 26.1 at 6 months in 15 of the COVID-19 patients (P = .004), the researchers noted.

New-onset psychiatric diagnoses occurred in 16 COVID-19 patients and 12 of the controls (19% vs. 20%); this difference was not significant.

Secondary outcomes were not significantly different at 6 months between the groups, with the exception of anosmia, which was significantly more common in the COVID-19 patients; however, the significance disappeared in adjusted analysis, the researchers said.

The study findings were limited by several factors including the inability to prove causality because of the case-control feature and by the inability to detect small differences in neuropsychiatric outcomes, the researchers noted.

However, the results were strengthened by the use of a prospectively matched control group with similar disease severity admitted to the same hospital in the same time frame. Although the overall burden of neuropsychiatric and neurologic symptoms and diagnoses appeared similar in COVID-19 patients and those with other medical conditions, more research in larger populations is needed to determine smaller differences in neuropsychiatric profiles, the researchers noted.

Study fills research gap

The study is important at this time because, although prolonged neuropsychiatric and cognitive symptoms have been reported after COVID-19, the field lacked prospective case-control studies with well-matched controls to investigate whether these outcomes differed from those seen in other critical illnesses that had also required hospitalization, corresponding author Michael E. Benros, MD, of the Mental Health Center, Copenhagen, said in an interview.

“I was surprised that there was a significant worse cognitive functioning among COVID-19 patients 6 months after symptom onset also when compared to this well-matched control group that had been hospitalized for non–COVID-19 illness, although the absolute difference between the groups in cognition score were small,” said Dr. Benros. “Another notable finding is the large improvement in cognitive functioning from discharge to follow-up,” he added on behalf of himself and fellow corresponding author Daniel Kondziella, MD.

The study results show that cognitive function affected by COVID-19 and critical illness as observed at discharge showed a substantial improvement at 6 months after symptom onset, said Dr. Benros. “However, the cognitive function was significantly worse among severely ill COVID-19 patients 6 months after symptom onset when compared to a matched control group of individuals hospitalized for non–COVID-19 illness, although this difference in cognitive function was rather small in absolute numbers, and smaller than what had been suggested by other studies that lacked control groups. Strikingly, neuropsychiatric disorders were similar across the two groups, which was also the case when looking at neuropsychiatric symptoms.

“Larger prospective case-control studies of neuropsychiatric and cognitive functioning after COVID-19, compared with matched controls are still needed to detect smaller differences, and more detailed cognitive domains, and with longer follow-up time, which we are currently conducting,” Dr. Benros said.  
 

Controlled studies will help planning

“Lingering neuropsychiatric complications are common after COVID-19, but only controlled studies can tell us whether these complications are specific to COVID-19, rather than a general effect of having been medically ill,” Alasdair G. Rooney, MRCPsych MD PhD, of the University of Edinburgh, said in an interview. “The answer matters ultimately because COVID-19 is a new disease; societies and health care services need to be able to plan for its specific consequences.”

The health status of the control group is important as well. “Most previous studies had compared COVID-19 survivors against healthy controls or patients from a historical database. This new study compared COVID-19 survivors against those hospitalized for other medical causes over the same period,” Dr. Rooney said. “This is a more stringent test of whether COVID-19 has specific neurocognitive and neuropsychiatric consequences.

“The study found that new-onset neuropsychiatric diagnoses and symptoms were no more likely to occur after COVID-19 than after similarly severe medical illnesses,” Dr. Rooney said. “This negative finding runs counter to some earlier studies and may surprise some.” The findings need to be replicated in larger samples, but the current study shows the importance of prospectively recruiting active controls.

“In a subgroup analysis, some patients showed good improvement in cognitive scores between discharge and follow-up. While unsurprising, this is encouraging and suggests that the early postdischarge months are an important time for neurocognitive recovery,” Dr. Rooney noted.

“The findings suggest that COVID-19 may impair attention more selectively than other medical causes of hospitalization. COVID-19 survivors may also be at higher risk of significant overall cognitive impairment than survivors of similarly severe medical illnesses, after a similar duration,” said Dr. Rooney. “If the results are replicated by other prospective studies, they would suggest that there is something about COVID-19 that causes clinically significant neurocognitive difficulties in a minority of survivors.

“Larger well-controlled studies are required, with longer follow-up and more detailed neurocognitive testing,” as the duration of impairment and scope for further recovery are not known, Dr. Rooney added. Also unknown is whether COVID-19 affects attention permanently, or whether recovery is simply slower after COVID-19 compared to other medical illnesses.

“Knowing who is at the greatest risk of severe cognitive impairment after COVID-19 is important and likely to allow tailoring of more effective shielding strategies,” said Dr. Rooney. “This study was conducted before the widespread availability of vaccines for COVID-19. Long-term neuropsychiatric outcomes in vaccinated patients remain largely unknown. Arguably, these are now more important to understand, as future COVID-19 waves will occur mainly among vaccinated individuals.”

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation. Lead author Dr. Nersesjan had no financial conflicts to disclose. Dr. Benros reported grants from Lundbeck Foundation and Novo Nordisk Foundation during the conduct of the study. Dr. Rooney had no financial conflicts to disclose.

This article was updated 3/25/22.

Hospitalized COVID-19 survivors showed greater cognitive impairment 6 months later, compared with patients hospitalized for other causes, but the overall disease burden was similar, based on data from 85 adults with COVID-19.

Previous studies have shown that cognitive and neuropsychiatric symptoms can occur from 2-6 months after COVID-19 recovery, and such symptoms are known to be associated with hospitalization for other severe medical conditions, Vardan Nersesjan, MD, of Copenhagen University Hospital, and colleagues wrote.

However, it remains unknown if COVID-19 is associated with a unique pattern of cognitive and mental impairment compared with other similarly severe medical conditions, they said.

In a study published in JAMA Psychiatry (2022 Mar 23. doi: 10.1001/jamapsychiatry.2022.0284), the researchers identified 85 adult COVID-19 survivors and 61 controls with non-COVID medical conditions who were treated and released between July 2020 and July 2021. The COVID-19 patients and controls were matched for age, sex, and ICU status. Cognitive impairment was assessed using the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semistructured interview to determine subjective symptoms.

The primary outcomes were the total scores on the MoCA and any new-onset psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses such as depression, neurologic examination findings, and self-reported neuropsychiatric and cognitive symptoms. The mean age of the COVID-19 patients was 56.8 years, and 42% were women.

At 6 months’ follow-up, cognitive status was significantly lower in COVID-19 survivors, compared with controls, based on total geometric mean MoCA scores (26.7 vs. 27.5, P = .01). However, cognitive status improved significantly from 19.2 at hospital discharge to 26.1 at 6 months in 15 of the COVID-19 patients (P = .004), the researchers noted.

New-onset psychiatric diagnoses occurred in 16 COVID-19 patients and 12 of the controls (19% vs. 20%); this difference was not significant.

Secondary outcomes were not significantly different at 6 months between the groups, with the exception of anosmia, which was significantly more common in the COVID-19 patients; however, the significance disappeared in adjusted analysis, the researchers said.

The study findings were limited by several factors including the inability to prove causality because of the case-control feature and by the inability to detect small differences in neuropsychiatric outcomes, the researchers noted.

However, the results were strengthened by the use of a prospectively matched control group with similar disease severity admitted to the same hospital in the same time frame. Although the overall burden of neuropsychiatric and neurologic symptoms and diagnoses appeared similar in COVID-19 patients and those with other medical conditions, more research in larger populations is needed to determine smaller differences in neuropsychiatric profiles, the researchers noted.

Study fills research gap

The study is important at this time because, although prolonged neuropsychiatric and cognitive symptoms have been reported after COVID-19, the field lacked prospective case-control studies with well-matched controls to investigate whether these outcomes differed from those seen in other critical illnesses that had also required hospitalization, corresponding author Michael E. Benros, MD, of the Mental Health Center, Copenhagen, said in an interview.

“I was surprised that there was a significant worse cognitive functioning among COVID-19 patients 6 months after symptom onset also when compared to this well-matched control group that had been hospitalized for non–COVID-19 illness, although the absolute difference between the groups in cognition score were small,” said Dr. Benros. “Another notable finding is the large improvement in cognitive functioning from discharge to follow-up,” he added on behalf of himself and fellow corresponding author Daniel Kondziella, MD.

The study results show that cognitive function affected by COVID-19 and critical illness as observed at discharge showed a substantial improvement at 6 months after symptom onset, said Dr. Benros. “However, the cognitive function was significantly worse among severely ill COVID-19 patients 6 months after symptom onset when compared to a matched control group of individuals hospitalized for non–COVID-19 illness, although this difference in cognitive function was rather small in absolute numbers, and smaller than what had been suggested by other studies that lacked control groups. Strikingly, neuropsychiatric disorders were similar across the two groups, which was also the case when looking at neuropsychiatric symptoms.

“Larger prospective case-control studies of neuropsychiatric and cognitive functioning after COVID-19, compared with matched controls are still needed to detect smaller differences, and more detailed cognitive domains, and with longer follow-up time, which we are currently conducting,” Dr. Benros said.  
 

Controlled studies will help planning

“Lingering neuropsychiatric complications are common after COVID-19, but only controlled studies can tell us whether these complications are specific to COVID-19, rather than a general effect of having been medically ill,” Alasdair G. Rooney, MRCPsych MD PhD, of the University of Edinburgh, said in an interview. “The answer matters ultimately because COVID-19 is a new disease; societies and health care services need to be able to plan for its specific consequences.”

The health status of the control group is important as well. “Most previous studies had compared COVID-19 survivors against healthy controls or patients from a historical database. This new study compared COVID-19 survivors against those hospitalized for other medical causes over the same period,” Dr. Rooney said. “This is a more stringent test of whether COVID-19 has specific neurocognitive and neuropsychiatric consequences.

“The study found that new-onset neuropsychiatric diagnoses and symptoms were no more likely to occur after COVID-19 than after similarly severe medical illnesses,” Dr. Rooney said. “This negative finding runs counter to some earlier studies and may surprise some.” The findings need to be replicated in larger samples, but the current study shows the importance of prospectively recruiting active controls.

“In a subgroup analysis, some patients showed good improvement in cognitive scores between discharge and follow-up. While unsurprising, this is encouraging and suggests that the early postdischarge months are an important time for neurocognitive recovery,” Dr. Rooney noted.

“The findings suggest that COVID-19 may impair attention more selectively than other medical causes of hospitalization. COVID-19 survivors may also be at higher risk of significant overall cognitive impairment than survivors of similarly severe medical illnesses, after a similar duration,” said Dr. Rooney. “If the results are replicated by other prospective studies, they would suggest that there is something about COVID-19 that causes clinically significant neurocognitive difficulties in a minority of survivors.

“Larger well-controlled studies are required, with longer follow-up and more detailed neurocognitive testing,” as the duration of impairment and scope for further recovery are not known, Dr. Rooney added. Also unknown is whether COVID-19 affects attention permanently, or whether recovery is simply slower after COVID-19 compared to other medical illnesses.

“Knowing who is at the greatest risk of severe cognitive impairment after COVID-19 is important and likely to allow tailoring of more effective shielding strategies,” said Dr. Rooney. “This study was conducted before the widespread availability of vaccines for COVID-19. Long-term neuropsychiatric outcomes in vaccinated patients remain largely unknown. Arguably, these are now more important to understand, as future COVID-19 waves will occur mainly among vaccinated individuals.”

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation. Lead author Dr. Nersesjan had no financial conflicts to disclose. Dr. Benros reported grants from Lundbeck Foundation and Novo Nordisk Foundation during the conduct of the study. Dr. Rooney had no financial conflicts to disclose.

This article was updated 3/25/22.

There does not appear to be superiority of any type of biologic medication for patients with rheumatoid arthritis across different body mass index (BMI) groupings, with obesity and underweight both reducing the effects of the treatments after 6 months of use, according to findings from registry data on nearly 6,000 individuals.

Although interest in the precision use of biologics for RA is on the rise, few patient characteristics have been identified to inform therapeutic decisions, Joshua F. Baker, MD, of the Philadelphia Veterans Affairs Medical Center and the University of Pennsylvania, Philadelphia, and colleagues wrote.

Previous studies on the effect of obesity on RA treatments have been inconclusive, and a comparison of RA treatments across BMI categories would provide more definitive guidance, they said.

In a study published in Arthritis Care & Research, the researchers used the CorEvitas U.S. observational registry (formerly known as Corrona) to identify adults who initiated second- or third-line treatment for RA with tumor necrosis factor inhibitors (n = 2,891) or non-TNFi biologics (n = 3,010) between 2001 and April 30, 2021.

The study population included adults diagnosed with RA; those with low disease activity or without a 6-month follow-up visit were excluded. BMI was categorized as underweight (less than 18.5 kg/m²), normal weight (18.5-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), and severely obese (35 kg/m² or higher). The three measures of response were the achievement of low disease activity (LDA), a change at least as large as the minimum clinically important difference (MCID), and the absolute change on the Clinical Disease Activity Index (CDAI) from baseline.

A total of 2,712 patients were obese or severely obese at the time of treatment initiation.

Overall, patients with severe obesity had significantly lower odds of achieving either LDA or a change at least as large as the MCID, as well as less improvement in CDAI score, compared with other BMI categories. However, in adjusted models, the differences in these outcomes for patients with severe obesity were no longer statistically significant, whereas underweight was associated with lower odds of achieving LDA (odds ratio, 0.32; P = .005) or a change at least as large as the MCID (OR, 0.40; P = .005). The adjusted model also showed lesser improvement on CDAI in underweight patients, compared with patients of normal weight (P = .006).

Stratification by TNFi and non-TNFi therapies showed no differences in clinical response rates across BMI categories.

The study represents the first evidence of a similar reduction in therapeutic response with both TNFi and non-TNFi in severely obese patients, with estimates for non-TNFi biologics that fit within the 95% confidence interval for TNFi biologics, the researchers wrote. “Our current study suggests that a lack of response among obese patients is not specific to TNFi therapies, suggesting that this phenomenon is not biologically specific to the TNF pathway.”

The study findings were limited by several factors, including the focus on patients who were not naive to biologic treatments and by the relatively small number of underweight patients (n = 57), the researchers noted. Other limitations include unaddressed mediators of the relationship between obesity and disease activity and lack of data on off-label dosing strategies.

However, the results were strengthened by the large sample size, control for a range of confounding factors, and the direct comparison of RA therapies.

The researchers concluded that BMI should not influence the choice of TNF versus non-TNF therapy in terms of clinical efficacy.

The study was supported by the Corrona Research Foundation. Dr. Baker disclosed receiving support from a Veterans Affairs Clinical Science Research and Development Merit Award and a Rehabilitation Research and Development Merit Award, and consulting fees from Bristol-Myers Squibb, Pfizer, CorEvitas, and Burns-White. Two coauthors reported financial ties to CorEvitas.

There does not appear to be superiority of any type of biologic medication for patients with rheumatoid arthritis across different body mass index (BMI) groupings, with obesity and underweight both reducing the effects of the treatments after 6 months of use, according to findings from registry data on nearly 6,000 individuals.

Although interest in the precision use of biologics for RA is on the rise, few patient characteristics have been identified to inform therapeutic decisions, Joshua F. Baker, MD, of the Philadelphia Veterans Affairs Medical Center and the University of Pennsylvania, Philadelphia, and colleagues wrote.

Previous studies on the effect of obesity on RA treatments have been inconclusive, and a comparison of RA treatments across BMI categories would provide more definitive guidance, they said.

In a study published in Arthritis Care & Research, the researchers used the CorEvitas U.S. observational registry (formerly known as Corrona) to identify adults who initiated second- or third-line treatment for RA with tumor necrosis factor inhibitors (n = 2,891) or non-TNFi biologics (n = 3,010) between 2001 and April 30, 2021.

The study population included adults diagnosed with RA; those with low disease activity or without a 6-month follow-up visit were excluded. BMI was categorized as underweight (less than 18.5 kg/m²), normal weight (18.5-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), and severely obese (35 kg/m² or higher). The three measures of response were the achievement of low disease activity (LDA), a change at least as large as the minimum clinically important difference (MCID), and the absolute change on the Clinical Disease Activity Index (CDAI) from baseline.

A total of 2,712 patients were obese or severely obese at the time of treatment initiation.

Overall, patients with severe obesity had significantly lower odds of achieving either LDA or a change at least as large as the MCID, as well as less improvement in CDAI score, compared with other BMI categories. However, in adjusted models, the differences in these outcomes for patients with severe obesity were no longer statistically significant, whereas underweight was associated with lower odds of achieving LDA (odds ratio, 0.32; P = .005) or a change at least as large as the MCID (OR, 0.40; P = .005). The adjusted model also showed lesser improvement on CDAI in underweight patients, compared with patients of normal weight (P = .006).

Stratification by TNFi and non-TNFi therapies showed no differences in clinical response rates across BMI categories.

The study represents the first evidence of a similar reduction in therapeutic response with both TNFi and non-TNFi in severely obese patients, with estimates for non-TNFi biologics that fit within the 95% confidence interval for TNFi biologics, the researchers wrote. “Our current study suggests that a lack of response among obese patients is not specific to TNFi therapies, suggesting that this phenomenon is not biologically specific to the TNF pathway.”

The study findings were limited by several factors, including the focus on patients who were not naive to biologic treatments and by the relatively small number of underweight patients (n = 57), the researchers noted. Other limitations include unaddressed mediators of the relationship between obesity and disease activity and lack of data on off-label dosing strategies.

However, the results were strengthened by the large sample size, control for a range of confounding factors, and the direct comparison of RA therapies.

The researchers concluded that BMI should not influence the choice of TNF versus non-TNF therapy in terms of clinical efficacy.

The study was supported by the Corrona Research Foundation. Dr. Baker disclosed receiving support from a Veterans Affairs Clinical Science Research and Development Merit Award and a Rehabilitation Research and Development Merit Award, and consulting fees from Bristol-Myers Squibb, Pfizer, CorEvitas, and Burns-White. Two coauthors reported financial ties to CorEvitas.

There does not appear to be superiority of any type of biologic medication for patients with rheumatoid arthritis across different body mass index (BMI) groupings, with obesity and underweight both reducing the effects of the treatments after 6 months of use, according to findings from registry data on nearly 6,000 individuals.

Although interest in the precision use of biologics for RA is on the rise, few patient characteristics have been identified to inform therapeutic decisions, Joshua F. Baker, MD, of the Philadelphia Veterans Affairs Medical Center and the University of Pennsylvania, Philadelphia, and colleagues wrote.

Previous studies on the effect of obesity on RA treatments have been inconclusive, and a comparison of RA treatments across BMI categories would provide more definitive guidance, they said.

In a study published in Arthritis Care & Research, the researchers used the CorEvitas U.S. observational registry (formerly known as Corrona) to identify adults who initiated second- or third-line treatment for RA with tumor necrosis factor inhibitors (n = 2,891) or non-TNFi biologics (n = 3,010) between 2001 and April 30, 2021.

The study population included adults diagnosed with RA; those with low disease activity or without a 6-month follow-up visit were excluded. BMI was categorized as underweight (less than 18.5 kg/m²), normal weight (18.5-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), and severely obese (35 kg/m² or higher). The three measures of response were the achievement of low disease activity (LDA), a change at least as large as the minimum clinically important difference (MCID), and the absolute change on the Clinical Disease Activity Index (CDAI) from baseline.

A total of 2,712 patients were obese or severely obese at the time of treatment initiation.

Overall, patients with severe obesity had significantly lower odds of achieving either LDA or a change at least as large as the MCID, as well as less improvement in CDAI score, compared with other BMI categories. However, in adjusted models, the differences in these outcomes for patients with severe obesity were no longer statistically significant, whereas underweight was associated with lower odds of achieving LDA (odds ratio, 0.32; P = .005) or a change at least as large as the MCID (OR, 0.40; P = .005). The adjusted model also showed lesser improvement on CDAI in underweight patients, compared with patients of normal weight (P = .006).

Stratification by TNFi and non-TNFi therapies showed no differences in clinical response rates across BMI categories.

The study represents the first evidence of a similar reduction in therapeutic response with both TNFi and non-TNFi in severely obese patients, with estimates for non-TNFi biologics that fit within the 95% confidence interval for TNFi biologics, the researchers wrote. “Our current study suggests that a lack of response among obese patients is not specific to TNFi therapies, suggesting that this phenomenon is not biologically specific to the TNF pathway.”

The study findings were limited by several factors, including the focus on patients who were not naive to biologic treatments and by the relatively small number of underweight patients (n = 57), the researchers noted. Other limitations include unaddressed mediators of the relationship between obesity and disease activity and lack of data on off-label dosing strategies.

However, the results were strengthened by the large sample size, control for a range of confounding factors, and the direct comparison of RA therapies.

The researchers concluded that BMI should not influence the choice of TNF versus non-TNF therapy in terms of clinical efficacy.

The study was supported by the Corrona Research Foundation. Dr. Baker disclosed receiving support from a Veterans Affairs Clinical Science Research and Development Merit Award and a Rehabilitation Research and Development Merit Award, and consulting fees from Bristol-Myers Squibb, Pfizer, CorEvitas, and Burns-White. Two coauthors reported financial ties to CorEvitas.

The infants of obese pregnant women had a 55% higher adjusted perinatal death rate, compared with those of normal-weight pregnant women, but lower gestational age had a mediating effect, based on data from nearly 400,000 women-infant pairs.

“While some obesity-related causes of fetal death are known, the exact pathophysiology behind the effects of obesity on perinatal death are not completely understood,” Jeffrey N. Bone, MD, of the University of British Columbia, Vancouver, and colleagues wrote. Higher body mass index prior to pregnancy also is associated with preterm delivery, but the effect of gestational age on the association between BMI and infant mortality has not been well explored.

In a study published in PLOS ONE, the researchers reviewed data from nearly 400,000 women obtained through the British Columbia Perinatal Database Registry, which collects obstetric and neonatal data from hospital charts and from delivery records of home births. Births at less than 20 weeks’ gestation and late pregnancy terminations were excluded.

BMI was based on self-reported prepregnancy height and weight; of the 392,820 included women, 12.8% were classified as obese, 20.6% were overweight, 60.6% were normal weight, and 6.0% were underweight. Infants of women with higher BMI had a lower gestational age at delivery. Perinatal mortality occurred in 1,834 pregnancies (0.5%). In adjusted analysis, infant perinatal death was significantly more likely for obese women (adjusted odds ratio, 1.55) and overweight women (aOR, 1.22).

However, 63.1% of this association in obese women was mediated by gestational age of the infant at delivery, with aORs of 1.32 and 1.18 for natural indirect and natural direct effects, respectively, compared with that of normal-weight women. Similar, but lesser effects were noted for overweight women, with aORs of 1.11 and 1.10, respectively. “Direct effects were higher, and mediation was lower for stillbirth than for neonatal death, where the total effect was entirely indirect,” but the confidence intervals remained consistent with the primary analyses, the researchers noted.

The increased perinatal death rates of infants of obese and overweight women reflect data from previous studies, but the current study’s use of mediation analysis offers new insight on the mechanism by which perinatal death rates increase with higher maternal BMI, the researchers wrote.

The study findings were limited by several factors including the need to consider potential common risk factors for both perinatal death and early delivery that would be affected by maternal obesity, the researchers noted. Other limitations included the use of gestational age at stillbirth, which represents an approximation of fetal death in some cases, and the use of self-reports for prepregnancy maternal BMI.

However, the results were strengthened by the large, population-based design and information on potential confounding variables, and suggest that early gestational age at delivery may play a role in maternal obesity-related perinatal death risk.

“To better inform the pregnancy management in obese women, further studies should continue to disentangle the causal pathways under which obesity increases the risk of perinatal death, including, for example, gestational diabetes and other obesity-related pregnancy complications,” they concluded.
 

More testing and counseling are needed

The current study is important because obesity rates continue to increase in the reproductive-age population, Marissa Platner, MD, of Emory University, Atlanta, said in an interview. “Obesity has become a known risk factor for adverse pregnancy outcomes, specifically the risk of stillbirth and perinatal death. However, the authors correctly point out that the underlying cause of these perinatal deaths in women with obesity is unclear. Additionally, ACOG recently updated their clinical guidelines to recommend routine antenatal testing for women with obesity due to these increased rates of stillbirth.

“I was not surprised by these findings; similar to previous literature, the risks of perinatal death seem to have a dose-response relationship with increasing BMI. We know that women with prepregnancy obesity are also at higher risk of perinatal complications in the preterm period, which would increase the risk of perinatal death,” Dr. Platner said

“I think the take-home message for clinicians is twofold,” Dr. Platner said. First, “we need to take the updated antenatal testing guidelines from ACOG very seriously and implement these in our practices.” Second, “in the preconception or early antepartum period, these patients should be thoroughly counseled on the associated risks of pregnancy and discuss appropriate gestational weight gain guidelines and lifestyle modifications.”

However, “additional research is needed in a U.S. population with higher rates of obesity to determine the true effects of obesity on perinatal deaths and to further elucidate the underlying pathophysiology and disease processes that may lead to increased risk of both stillbirth and perinatal deaths,” Dr. Platner emphasized.

*This story was updated on March 23, 2022.

The study was supported by the Sick Kids Foundation and the Canadian Institute of Health Research. The researchers had no financial conflicts to disclose. Dr. Platner had no financial conflicts to disclose.

The infants of obese pregnant women had a 55% higher adjusted perinatal death rate, compared with those of normal-weight pregnant women, but lower gestational age had a mediating effect, based on data from nearly 400,000 women-infant pairs.

“While some obesity-related causes of fetal death are known, the exact pathophysiology behind the effects of obesity on perinatal death are not completely understood,” Jeffrey N. Bone, MD, of the University of British Columbia, Vancouver, and colleagues wrote. Higher body mass index prior to pregnancy also is associated with preterm delivery, but the effect of gestational age on the association between BMI and infant mortality has not been well explored.

In a study published in PLOS ONE, the researchers reviewed data from nearly 400,000 women obtained through the British Columbia Perinatal Database Registry, which collects obstetric and neonatal data from hospital charts and from delivery records of home births. Births at less than 20 weeks’ gestation and late pregnancy terminations were excluded.

BMI was based on self-reported prepregnancy height and weight; of the 392,820 included women, 12.8% were classified as obese, 20.6% were overweight, 60.6% were normal weight, and 6.0% were underweight. Infants of women with higher BMI had a lower gestational age at delivery. Perinatal mortality occurred in 1,834 pregnancies (0.5%). In adjusted analysis, infant perinatal death was significantly more likely for obese women (adjusted odds ratio, 1.55) and overweight women (aOR, 1.22).

However, 63.1% of this association in obese women was mediated by gestational age of the infant at delivery, with aORs of 1.32 and 1.18 for natural indirect and natural direct effects, respectively, compared with that of normal-weight women. Similar, but lesser effects were noted for overweight women, with aORs of 1.11 and 1.10, respectively. “Direct effects were higher, and mediation was lower for stillbirth than for neonatal death, where the total effect was entirely indirect,” but the confidence intervals remained consistent with the primary analyses, the researchers noted.

The increased perinatal death rates of infants of obese and overweight women reflect data from previous studies, but the current study’s use of mediation analysis offers new insight on the mechanism by which perinatal death rates increase with higher maternal BMI, the researchers wrote.

The study findings were limited by several factors including the need to consider potential common risk factors for both perinatal death and early delivery that would be affected by maternal obesity, the researchers noted. Other limitations included the use of gestational age at stillbirth, which represents an approximation of fetal death in some cases, and the use of self-reports for prepregnancy maternal BMI.

However, the results were strengthened by the large, population-based design and information on potential confounding variables, and suggest that early gestational age at delivery may play a role in maternal obesity-related perinatal death risk.

“To better inform the pregnancy management in obese women, further studies should continue to disentangle the causal pathways under which obesity increases the risk of perinatal death, including, for example, gestational diabetes and other obesity-related pregnancy complications,” they concluded.
 

More testing and counseling are needed

The current study is important because obesity rates continue to increase in the reproductive-age population, Marissa Platner, MD, of Emory University, Atlanta, said in an interview. “Obesity has become a known risk factor for adverse pregnancy outcomes, specifically the risk of stillbirth and perinatal death. However, the authors correctly point out that the underlying cause of these perinatal deaths in women with obesity is unclear. Additionally, ACOG recently updated their clinical guidelines to recommend routine antenatal testing for women with obesity due to these increased rates of stillbirth.

“I was not surprised by these findings; similar to previous literature, the risks of perinatal death seem to have a dose-response relationship with increasing BMI. We know that women with prepregnancy obesity are also at higher risk of perinatal complications in the preterm period, which would increase the risk of perinatal death,” Dr. Platner said

“I think the take-home message for clinicians is twofold,” Dr. Platner said. First, “we need to take the updated antenatal testing guidelines from ACOG very seriously and implement these in our practices.” Second, “in the preconception or early antepartum period, these patients should be thoroughly counseled on the associated risks of pregnancy and discuss appropriate gestational weight gain guidelines and lifestyle modifications.”

However, “additional research is needed in a U.S. population with higher rates of obesity to determine the true effects of obesity on perinatal deaths and to further elucidate the underlying pathophysiology and disease processes that may lead to increased risk of both stillbirth and perinatal deaths,” Dr. Platner emphasized.

*This story was updated on March 23, 2022.

The study was supported by the Sick Kids Foundation and the Canadian Institute of Health Research. The researchers had no financial conflicts to disclose. Dr. Platner had no financial conflicts to disclose.

The infants of obese pregnant women had a 55% higher adjusted perinatal death rate, compared with those of normal-weight pregnant women, but lower gestational age had a mediating effect, based on data from nearly 400,000 women-infant pairs.

“While some obesity-related causes of fetal death are known, the exact pathophysiology behind the effects of obesity on perinatal death are not completely understood,” Jeffrey N. Bone, MD, of the University of British Columbia, Vancouver, and colleagues wrote. Higher body mass index prior to pregnancy also is associated with preterm delivery, but the effect of gestational age on the association between BMI and infant mortality has not been well explored.

In a study published in PLOS ONE, the researchers reviewed data from nearly 400,000 women obtained through the British Columbia Perinatal Database Registry, which collects obstetric and neonatal data from hospital charts and from delivery records of home births. Births at less than 20 weeks’ gestation and late pregnancy terminations were excluded.

BMI was based on self-reported prepregnancy height and weight; of the 392,820 included women, 12.8% were classified as obese, 20.6% were overweight, 60.6% were normal weight, and 6.0% were underweight. Infants of women with higher BMI had a lower gestational age at delivery. Perinatal mortality occurred in 1,834 pregnancies (0.5%). In adjusted analysis, infant perinatal death was significantly more likely for obese women (adjusted odds ratio, 1.55) and overweight women (aOR, 1.22).

However, 63.1% of this association in obese women was mediated by gestational age of the infant at delivery, with aORs of 1.32 and 1.18 for natural indirect and natural direct effects, respectively, compared with that of normal-weight women. Similar, but lesser effects were noted for overweight women, with aORs of 1.11 and 1.10, respectively. “Direct effects were higher, and mediation was lower for stillbirth than for neonatal death, where the total effect was entirely indirect,” but the confidence intervals remained consistent with the primary analyses, the researchers noted.

The increased perinatal death rates of infants of obese and overweight women reflect data from previous studies, but the current study’s use of mediation analysis offers new insight on the mechanism by which perinatal death rates increase with higher maternal BMI, the researchers wrote.

The study findings were limited by several factors including the need to consider potential common risk factors for both perinatal death and early delivery that would be affected by maternal obesity, the researchers noted. Other limitations included the use of gestational age at stillbirth, which represents an approximation of fetal death in some cases, and the use of self-reports for prepregnancy maternal BMI.

However, the results were strengthened by the large, population-based design and information on potential confounding variables, and suggest that early gestational age at delivery may play a role in maternal obesity-related perinatal death risk.

“To better inform the pregnancy management in obese women, further studies should continue to disentangle the causal pathways under which obesity increases the risk of perinatal death, including, for example, gestational diabetes and other obesity-related pregnancy complications,” they concluded.
 

More testing and counseling are needed

The current study is important because obesity rates continue to increase in the reproductive-age population, Marissa Platner, MD, of Emory University, Atlanta, said in an interview. “Obesity has become a known risk factor for adverse pregnancy outcomes, specifically the risk of stillbirth and perinatal death. However, the authors correctly point out that the underlying cause of these perinatal deaths in women with obesity is unclear. Additionally, ACOG recently updated their clinical guidelines to recommend routine antenatal testing for women with obesity due to these increased rates of stillbirth.

“I was not surprised by these findings; similar to previous literature, the risks of perinatal death seem to have a dose-response relationship with increasing BMI. We know that women with prepregnancy obesity are also at higher risk of perinatal complications in the preterm period, which would increase the risk of perinatal death,” Dr. Platner said

“I think the take-home message for clinicians is twofold,” Dr. Platner said. First, “we need to take the updated antenatal testing guidelines from ACOG very seriously and implement these in our practices.” Second, “in the preconception or early antepartum period, these patients should be thoroughly counseled on the associated risks of pregnancy and discuss appropriate gestational weight gain guidelines and lifestyle modifications.”

However, “additional research is needed in a U.S. population with higher rates of obesity to determine the true effects of obesity on perinatal deaths and to further elucidate the underlying pathophysiology and disease processes that may lead to increased risk of both stillbirth and perinatal deaths,” Dr. Platner emphasized.

*This story was updated on March 23, 2022.

The study was supported by the Sick Kids Foundation and the Canadian Institute of Health Research. The researchers had no financial conflicts to disclose. Dr. Platner had no financial conflicts to disclose.

An intervention with extra virgin olive oil in a pilot study of 22 patients significantly improved biomarkers for early stage chronic lymphocytic leukemia (CLL).

Olive oil is a major component of the Mediterranean diet, and olive phenols have been shown to convey antioxidant, anti-inflammatory, anticancer, neuroprotective, and antidiabetic effects by modulating various molecular pathways, Andrea Paola Rojas Gil, PhD, of the University of Peloponnese, Tripoli, Greece, and colleagues wrote.

In most patients, CLL is incurable, but those at the early stages do not need immediate therapy and may benefit from an intervention to prevent disease progression, the authors wrote. Previous research suggested that dietary intervention exerts a salutary effect on early CLL, and in vitro studies suggested that oleocanthal, a component of extra virgin olive oil, induced anticancer activity.

In a study published in Frontiers in Oncology, the researchers enrolled adults with early stage CLL who had not undergone chemotherapy or other treatment. All patients adhered to a Mediterranean-style diet.

After a washout period of 9-12 months, the researchers randomized 22 patients to extra virgin olive oil high in oleocanthal and oleacein (high OC/OL-EVOO). Patients in the intervention group consumed 40 mL/day of high OC/OL-EVOO before meals. Their average age was 71 years; 10 were women and 12 were men.

The primary outcomes included changes in hematological, biochemical, and apoptotic markers. After 6 months, patients in the intervention group showed a statistically significant reduction in white blood cells and lymphocyte count, compared with measurements taken 3 months before the intervention. The WBC decrease was greatest among patients with the highest WBC levels at baseline.

As for biochemical markers, the researchers observed a significant decrease in glucose levels during the intervention, but no significant effects on metabolic indexes or renal function.

After 3 months and also after 6 months of the olive oil intervention, patients showed a significant increase in the apoptotic markers ccK18 and Apo1-Fas (P ≤ .05 for both), as well as an increase in the cell cycle negative regulator p21. The dietary intervention also was associated with significant decreases in expression of the antiapoptotic protein survivin and in cyclin D, a positive cell cycle regulator protein.

Further, patients who had a high ccK18 level at baseline showed a significantly greater increase in ccK18 after the intervention, compared with those with lower ccK18 at baseline (P = .001).

Notably, “a negative correlation of the WBC at the end of the dietary intervention with the fluctuation of the protein expression of the apoptotic marker ccK18 (final – initial) was observed,” the researchers wrote in their discussion.

The study findings were limited by several factors including the small sample size, short intervention time, and pilot design, the researchers said. Other limitations include the possible effect of other unmeasured properties of olive oil.

However, the results reflect previous studies showing the benefits of a Mediterranean-type diet, and they represent the first clinical trial to indicate possible beneficial effects from oleocanthal and oleacein on the progression of CLL. Therefore, the authors concluded, the study is worthy of a large, multicenter trial.
 

Pilot data merit more research

In an interview, corresponding author Prokopios Magiatis, PhD, noted that CLL is “the most commonly diagnosed adult leukemia in Western countries and is responsible for about one in four cases of all leukemias.” CLL remains incurable in most patients, and ways to delay disease progression are needed.

“Oleocanthal is the active ingredient of early harvest olive oil with proven anticancer activities in vitro and in vivo,” Dr. Magiatis explained. “For this reason, it was a unique challenge to investigate the anticancer activity of this compound for the first time in humans through the dietary consumption of specifically selected olive oil.” He expressed surprise at the beneficial effects of high-oleocanthal olive oil, not only to the white blood cells, but also to glucose levels.

“It seems that oleocanthal can activate mechanisms related to the apoptosis of cancer cells, and also mechanisms related to blood glucose regulation without affecting any normal cells of the body,” he said. “All anticancer drugs usually have severe side effects, however the administration of 25 mg of oleocanthal through the dietary consumption of olive oil did not present any harmful effects for at least 6 months of everyday use.

“The addition of naturally produced high-oleocanthal olive oil in the diet of early-stage CLL patients at a dose of three tablespoons per day [40 mL] is a practice that may lower the cancerous white blood cells of the patients without any risk,” said Dr. Magiatis. “High-oleocanthal early-harvest olive oil has been consumed for centuries, and may be the key of longevity of several Mediterranean populations.

“In our study, the number of the white blood cells returned back to the number it was one year before the initiation of the study; this clearly shows that it could be a significant factor for the delay of the progress of the disease,” he said.

The current trial was a pilot study in one hospital with only 22 patients for 6 months, said Dr. Magiatis. “We are currently preparing the expansion of the study to other hospitals and other countries, and we aim to include at least 100 patients for at least 1 year, to validate the already-obtained beneficial results.”

The clinical trial is supported by the nonprofit organization World Olive Center for Health, he added.

The current study received no outside funding. The researchers had no financial conflicts to disclose.

An intervention with extra virgin olive oil in a pilot study of 22 patients significantly improved biomarkers for early stage chronic lymphocytic leukemia (CLL).

Olive oil is a major component of the Mediterranean diet, and olive phenols have been shown to convey antioxidant, anti-inflammatory, anticancer, neuroprotective, and antidiabetic effects by modulating various molecular pathways, Andrea Paola Rojas Gil, PhD, of the University of Peloponnese, Tripoli, Greece, and colleagues wrote.

In most patients, CLL is incurable, but those at the early stages do not need immediate therapy and may benefit from an intervention to prevent disease progression, the authors wrote. Previous research suggested that dietary intervention exerts a salutary effect on early CLL, and in vitro studies suggested that oleocanthal, a component of extra virgin olive oil, induced anticancer activity.

In a study published in Frontiers in Oncology, the researchers enrolled adults with early stage CLL who had not undergone chemotherapy or other treatment. All patients adhered to a Mediterranean-style diet.

After a washout period of 9-12 months, the researchers randomized 22 patients to extra virgin olive oil high in oleocanthal and oleacein (high OC/OL-EVOO). Patients in the intervention group consumed 40 mL/day of high OC/OL-EVOO before meals. Their average age was 71 years; 10 were women and 12 were men.

The primary outcomes included changes in hematological, biochemical, and apoptotic markers. After 6 months, patients in the intervention group showed a statistically significant reduction in white blood cells and lymphocyte count, compared with measurements taken 3 months before the intervention. The WBC decrease was greatest among patients with the highest WBC levels at baseline.

As for biochemical markers, the researchers observed a significant decrease in glucose levels during the intervention, but no significant effects on metabolic indexes or renal function.

After 3 months and also after 6 months of the olive oil intervention, patients showed a significant increase in the apoptotic markers ccK18 and Apo1-Fas (P ≤ .05 for both), as well as an increase in the cell cycle negative regulator p21. The dietary intervention also was associated with significant decreases in expression of the antiapoptotic protein survivin and in cyclin D, a positive cell cycle regulator protein.

Further, patients who had a high ccK18 level at baseline showed a significantly greater increase in ccK18 after the intervention, compared with those with lower ccK18 at baseline (P = .001).

Notably, “a negative correlation of the WBC at the end of the dietary intervention with the fluctuation of the protein expression of the apoptotic marker ccK18 (final – initial) was observed,” the researchers wrote in their discussion.

The study findings were limited by several factors including the small sample size, short intervention time, and pilot design, the researchers said. Other limitations include the possible effect of other unmeasured properties of olive oil.

However, the results reflect previous studies showing the benefits of a Mediterranean-type diet, and they represent the first clinical trial to indicate possible beneficial effects from oleocanthal and oleacein on the progression of CLL. Therefore, the authors concluded, the study is worthy of a large, multicenter trial.
 

Pilot data merit more research

In an interview, corresponding author Prokopios Magiatis, PhD, noted that CLL is “the most commonly diagnosed adult leukemia in Western countries and is responsible for about one in four cases of all leukemias.” CLL remains incurable in most patients, and ways to delay disease progression are needed.

“Oleocanthal is the active ingredient of early harvest olive oil with proven anticancer activities in vitro and in vivo,” Dr. Magiatis explained. “For this reason, it was a unique challenge to investigate the anticancer activity of this compound for the first time in humans through the dietary consumption of specifically selected olive oil.” He expressed surprise at the beneficial effects of high-oleocanthal olive oil, not only to the white blood cells, but also to glucose levels.

“It seems that oleocanthal can activate mechanisms related to the apoptosis of cancer cells, and also mechanisms related to blood glucose regulation without affecting any normal cells of the body,” he said. “All anticancer drugs usually have severe side effects, however the administration of 25 mg of oleocanthal through the dietary consumption of olive oil did not present any harmful effects for at least 6 months of everyday use.

“The addition of naturally produced high-oleocanthal olive oil in the diet of early-stage CLL patients at a dose of three tablespoons per day [40 mL] is a practice that may lower the cancerous white blood cells of the patients without any risk,” said Dr. Magiatis. “High-oleocanthal early-harvest olive oil has been consumed for centuries, and may be the key of longevity of several Mediterranean populations.

“In our study, the number of the white blood cells returned back to the number it was one year before the initiation of the study; this clearly shows that it could be a significant factor for the delay of the progress of the disease,” he said.

The current trial was a pilot study in one hospital with only 22 patients for 6 months, said Dr. Magiatis. “We are currently preparing the expansion of the study to other hospitals and other countries, and we aim to include at least 100 patients for at least 1 year, to validate the already-obtained beneficial results.”

The clinical trial is supported by the nonprofit organization World Olive Center for Health, he added.

The current study received no outside funding. The researchers had no financial conflicts to disclose.

An intervention with extra virgin olive oil in a pilot study of 22 patients significantly improved biomarkers for early stage chronic lymphocytic leukemia (CLL).

Olive oil is a major component of the Mediterranean diet, and olive phenols have been shown to convey antioxidant, anti-inflammatory, anticancer, neuroprotective, and antidiabetic effects by modulating various molecular pathways, Andrea Paola Rojas Gil, PhD, of the University of Peloponnese, Tripoli, Greece, and colleagues wrote.

In most patients, CLL is incurable, but those at the early stages do not need immediate therapy and may benefit from an intervention to prevent disease progression, the authors wrote. Previous research suggested that dietary intervention exerts a salutary effect on early CLL, and in vitro studies suggested that oleocanthal, a component of extra virgin olive oil, induced anticancer activity.

In a study published in Frontiers in Oncology, the researchers enrolled adults with early stage CLL who had not undergone chemotherapy or other treatment. All patients adhered to a Mediterranean-style diet.

After a washout period of 9-12 months, the researchers randomized 22 patients to extra virgin olive oil high in oleocanthal and oleacein (high OC/OL-EVOO). Patients in the intervention group consumed 40 mL/day of high OC/OL-EVOO before meals. Their average age was 71 years; 10 were women and 12 were men.

The primary outcomes included changes in hematological, biochemical, and apoptotic markers. After 6 months, patients in the intervention group showed a statistically significant reduction in white blood cells and lymphocyte count, compared with measurements taken 3 months before the intervention. The WBC decrease was greatest among patients with the highest WBC levels at baseline.

As for biochemical markers, the researchers observed a significant decrease in glucose levels during the intervention, but no significant effects on metabolic indexes or renal function.

After 3 months and also after 6 months of the olive oil intervention, patients showed a significant increase in the apoptotic markers ccK18 and Apo1-Fas (P ≤ .05 for both), as well as an increase in the cell cycle negative regulator p21. The dietary intervention also was associated with significant decreases in expression of the antiapoptotic protein survivin and in cyclin D, a positive cell cycle regulator protein.

Further, patients who had a high ccK18 level at baseline showed a significantly greater increase in ccK18 after the intervention, compared with those with lower ccK18 at baseline (P = .001).

Notably, “a negative correlation of the WBC at the end of the dietary intervention with the fluctuation of the protein expression of the apoptotic marker ccK18 (final – initial) was observed,” the researchers wrote in their discussion.

The study findings were limited by several factors including the small sample size, short intervention time, and pilot design, the researchers said. Other limitations include the possible effect of other unmeasured properties of olive oil.

However, the results reflect previous studies showing the benefits of a Mediterranean-type diet, and they represent the first clinical trial to indicate possible beneficial effects from oleocanthal and oleacein on the progression of CLL. Therefore, the authors concluded, the study is worthy of a large, multicenter trial.
 

Pilot data merit more research

In an interview, corresponding author Prokopios Magiatis, PhD, noted that CLL is “the most commonly diagnosed adult leukemia in Western countries and is responsible for about one in four cases of all leukemias.” CLL remains incurable in most patients, and ways to delay disease progression are needed.

“Oleocanthal is the active ingredient of early harvest olive oil with proven anticancer activities in vitro and in vivo,” Dr. Magiatis explained. “For this reason, it was a unique challenge to investigate the anticancer activity of this compound for the first time in humans through the dietary consumption of specifically selected olive oil.” He expressed surprise at the beneficial effects of high-oleocanthal olive oil, not only to the white blood cells, but also to glucose levels.

“It seems that oleocanthal can activate mechanisms related to the apoptosis of cancer cells, and also mechanisms related to blood glucose regulation without affecting any normal cells of the body,” he said. “All anticancer drugs usually have severe side effects, however the administration of 25 mg of oleocanthal through the dietary consumption of olive oil did not present any harmful effects for at least 6 months of everyday use.

“The addition of naturally produced high-oleocanthal olive oil in the diet of early-stage CLL patients at a dose of three tablespoons per day [40 mL] is a practice that may lower the cancerous white blood cells of the patients without any risk,” said Dr. Magiatis. “High-oleocanthal early-harvest olive oil has been consumed for centuries, and may be the key of longevity of several Mediterranean populations.

“In our study, the number of the white blood cells returned back to the number it was one year before the initiation of the study; this clearly shows that it could be a significant factor for the delay of the progress of the disease,” he said.

The current trial was a pilot study in one hospital with only 22 patients for 6 months, said Dr. Magiatis. “We are currently preparing the expansion of the study to other hospitals and other countries, and we aim to include at least 100 patients for at least 1 year, to validate the already-obtained beneficial results.”

The clinical trial is supported by the nonprofit organization World Olive Center for Health, he added.

The current study received no outside funding. The researchers had no financial conflicts to disclose.

The incremental step test is a highly reliable measure of exercise capacity in patients with moderate to severe asthma, based on data from 50 individuals.

Asthma patients often limit their physical exercise to avoid respiratory symptoms, which creates a downward spiral of reduced exercise capacity and ability to perform activities of daily living, wrote Renata Cléia Claudino Barbosa of the University of Sao Paulo and colleagues. “However, exercise training has been shown to be an important adjunctive therapy for asthma treatment that improves exercise capacity and health-related quality of life,” they wrote.

Step tests have been identified as a simpler, less costly alternative to cardiopulmonary exercise tests to measure exercise capacity in patients with chronic obstructive pulmonary disease, but their effectiveness for asthma patients has not investigated, the researchers said.

In a study published in Pulmonology, the researchers recruited 50 adults with moderate or severe asthma during routine care at a university hospital. The participants had been clinically stable for at least 6 months, with no hospitalizations, emergency care, or medication changes in the past 30 days. All participants received short-acting and long-acting bronchodilators and inhaled corticosteroids. The patients ranged in age from 18 to 60 years, with body mass index measures from 20 kg/m² to 40 kg/m².

Participants were randomized to tests on 2 nonconsecutive days at least 48 hours apart. On the first day, patients completed asthma control questionnaires and lung function tests, then performed either a cardiopulmonary exercise test (CPET) or two incremental step tests (IST-1 and IST-2). On the second day, they performed the other test. Participants were instructed to use bronchodilators 15 minutes before each test.

The step test involved stepping up and down on a 20-cm high wooden bench.

Overall, the peak oxygen uptakes were 27.6 mL/kg per minute for the CPET, 22.3 mL/kg per minute for the first IST, and 23.3 mL/kg per minute for the second IST.

“The IST with better performance regarding the peak VO₂ value was called the best IST (b-IST),” and these values were used for validity and interpretability analyses, the researchers wrote.

In a reliability analysis, the intraclass correlation coefficient (ICC) was 0.93, the measurement error was 2.5%, and the construct validity for peak VO₂ was significantly more reliable than the CPET (P < 0.001), the researchers said. The ICC for total number of steps was 0.88.

Notably, “the present study also demonstrated that IST is not interchangeable with the CPET since the subjects with moderate to severe asthma did not reach the maximal exercise capacity,” the researchers said. However, “we believe that the IST is superior to walking tests in subjects with asthma because it is an activity that requires greater ventilation in a subject’s daily life,” they said.

The study findings were limited by several factors including the relatively small study population and the small number of male patients, which may limit generalizability to males with asthma or other asthma endotypes, the researchers said. However, the results were strengthened by the randomized design, and support the value of the IST as a cost-effective option for assessing exercise capacity, preferably with two step tests to minimize the learning effect, they said. Additional research is needed to determine whether IST can assess responsiveness to pharmacological and nonpharmalogical treatments in asthma patients, they noted.

The study was supported by the Sao Paulo Research Foundation, Conselho Nacional de Pesquisa, and Coordination of Improvement of Higher Level Personnel--Brazil. The researchers had no financial conflicts to disclose.

The incremental step test is a highly reliable measure of exercise capacity in patients with moderate to severe asthma, based on data from 50 individuals.

Asthma patients often limit their physical exercise to avoid respiratory symptoms, which creates a downward spiral of reduced exercise capacity and ability to perform activities of daily living, wrote Renata Cléia Claudino Barbosa of the University of Sao Paulo and colleagues. “However, exercise training has been shown to be an important adjunctive therapy for asthma treatment that improves exercise capacity and health-related quality of life,” they wrote.

Step tests have been identified as a simpler, less costly alternative to cardiopulmonary exercise tests to measure exercise capacity in patients with chronic obstructive pulmonary disease, but their effectiveness for asthma patients has not investigated, the researchers said.

In a study published in Pulmonology, the researchers recruited 50 adults with moderate or severe asthma during routine care at a university hospital. The participants had been clinically stable for at least 6 months, with no hospitalizations, emergency care, or medication changes in the past 30 days. All participants received short-acting and long-acting bronchodilators and inhaled corticosteroids. The patients ranged in age from 18 to 60 years, with body mass index measures from 20 kg/m² to 40 kg/m².

Participants were randomized to tests on 2 nonconsecutive days at least 48 hours apart. On the first day, patients completed asthma control questionnaires and lung function tests, then performed either a cardiopulmonary exercise test (CPET) or two incremental step tests (IST-1 and IST-2). On the second day, they performed the other test. Participants were instructed to use bronchodilators 15 minutes before each test.

The step test involved stepping up and down on a 20-cm high wooden bench.

Overall, the peak oxygen uptakes were 27.6 mL/kg per minute for the CPET, 22.3 mL/kg per minute for the first IST, and 23.3 mL/kg per minute for the second IST.

“The IST with better performance regarding the peak VO₂ value was called the best IST (b-IST),” and these values were used for validity and interpretability analyses, the researchers wrote.

In a reliability analysis, the intraclass correlation coefficient (ICC) was 0.93, the measurement error was 2.5%, and the construct validity for peak VO₂ was significantly more reliable than the CPET (P < 0.001), the researchers said. The ICC for total number of steps was 0.88.

Notably, “the present study also demonstrated that IST is not interchangeable with the CPET since the subjects with moderate to severe asthma did not reach the maximal exercise capacity,” the researchers said. However, “we believe that the IST is superior to walking tests in subjects with asthma because it is an activity that requires greater ventilation in a subject’s daily life,” they said.

The study findings were limited by several factors including the relatively small study population and the small number of male patients, which may limit generalizability to males with asthma or other asthma endotypes, the researchers said. However, the results were strengthened by the randomized design, and support the value of the IST as a cost-effective option for assessing exercise capacity, preferably with two step tests to minimize the learning effect, they said. Additional research is needed to determine whether IST can assess responsiveness to pharmacological and nonpharmalogical treatments in asthma patients, they noted.

The study was supported by the Sao Paulo Research Foundation, Conselho Nacional de Pesquisa, and Coordination of Improvement of Higher Level Personnel--Brazil. The researchers had no financial conflicts to disclose.

The incremental step test is a highly reliable measure of exercise capacity in patients with moderate to severe asthma, based on data from 50 individuals.

Asthma patients often limit their physical exercise to avoid respiratory symptoms, which creates a downward spiral of reduced exercise capacity and ability to perform activities of daily living, wrote Renata Cléia Claudino Barbosa of the University of Sao Paulo and colleagues. “However, exercise training has been shown to be an important adjunctive therapy for asthma treatment that improves exercise capacity and health-related quality of life,” they wrote.

Step tests have been identified as a simpler, less costly alternative to cardiopulmonary exercise tests to measure exercise capacity in patients with chronic obstructive pulmonary disease, but their effectiveness for asthma patients has not investigated, the researchers said.

In a study published in Pulmonology, the researchers recruited 50 adults with moderate or severe asthma during routine care at a university hospital. The participants had been clinically stable for at least 6 months, with no hospitalizations, emergency care, or medication changes in the past 30 days. All participants received short-acting and long-acting bronchodilators and inhaled corticosteroids. The patients ranged in age from 18 to 60 years, with body mass index measures from 20 kg/m² to 40 kg/m².

Participants were randomized to tests on 2 nonconsecutive days at least 48 hours apart. On the first day, patients completed asthma control questionnaires and lung function tests, then performed either a cardiopulmonary exercise test (CPET) or two incremental step tests (IST-1 and IST-2). On the second day, they performed the other test. Participants were instructed to use bronchodilators 15 minutes before each test.

The step test involved stepping up and down on a 20-cm high wooden bench.

Overall, the peak oxygen uptakes were 27.6 mL/kg per minute for the CPET, 22.3 mL/kg per minute for the first IST, and 23.3 mL/kg per minute for the second IST.

“The IST with better performance regarding the peak VO₂ value was called the best IST (b-IST),” and these values were used for validity and interpretability analyses, the researchers wrote.

In a reliability analysis, the intraclass correlation coefficient (ICC) was 0.93, the measurement error was 2.5%, and the construct validity for peak VO₂ was significantly more reliable than the CPET (P < 0.001), the researchers said. The ICC for total number of steps was 0.88.

Notably, “the present study also demonstrated that IST is not interchangeable with the CPET since the subjects with moderate to severe asthma did not reach the maximal exercise capacity,” the researchers said. However, “we believe that the IST is superior to walking tests in subjects with asthma because it is an activity that requires greater ventilation in a subject’s daily life,” they said.

The study findings were limited by several factors including the relatively small study population and the small number of male patients, which may limit generalizability to males with asthma or other asthma endotypes, the researchers said. However, the results were strengthened by the randomized design, and support the value of the IST as a cost-effective option for assessing exercise capacity, preferably with two step tests to minimize the learning effect, they said. Additional research is needed to determine whether IST can assess responsiveness to pharmacological and nonpharmalogical treatments in asthma patients, they noted.

The study was supported by the Sao Paulo Research Foundation, Conselho Nacional de Pesquisa, and Coordination of Improvement of Higher Level Personnel--Brazil. The researchers had no financial conflicts to disclose.