Jennie Smith

Adverse cognitive and psychiatric effects seen associated with the investigational Alzheimer’s drug atabecestat were reversed within 6 months of treatment cessation, according to follow-up results from a truncated clinical trial.

A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.

A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.

In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.

Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.

Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
 

Questions surround BACE inhibitors

Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.

Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.

While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue. 

“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
 

Research should continue

Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.

“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”

Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.

“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.

Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.

Adverse cognitive and psychiatric effects seen associated with the investigational Alzheimer’s drug atabecestat were reversed within 6 months of treatment cessation, according to follow-up results from a truncated clinical trial.

A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.

A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.

In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.

Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.

Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
 

Questions surround BACE inhibitors

Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.

Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.

While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue. 

“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
 

Research should continue

Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.

“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”

Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.

“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.

Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.

Adverse cognitive and psychiatric effects seen associated with the investigational Alzheimer’s drug atabecestat were reversed within 6 months of treatment cessation, according to follow-up results from a truncated clinical trial.

A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.

A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.

In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.

Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.

Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
 

Questions surround BACE inhibitors

Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.

Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.

While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue. 

“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
 

Research should continue

Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.

“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”

Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.

“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.

Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from a new analysis of trial data suggest that the EDSS, in use since 1983, may be a noisier or more variation-prone measure of MS disease progression than two other widely used measures: the timed 25-foot walk and the 9-hole peg test.

For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
 

Comparing three outcome measures

The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.

Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.

The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
 

‘Considerable implications’ for the design of future clinical trials

In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”

The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.

Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.

Oral agents are taking on an ever-greater role in the management of gynecologic cancers. However, women being treated for these cancers have less than ideal adherence to such medications, a new study has found – with just over half reporting taking them exactly as prescribed.

Ingram Publishing/Thinkstock

The findings reported in Obstetrics & Gynecology are consistent with reports from other populations taking oral anticancer agents, in which adherence is generally lower than with intravenous therapies.

For their research, Catherine Watson, MD, and colleagues at Duke University, Durham, N.C., recruited 100 women at their institution taking a variety of oral anticancer agents for uterine or ovarian cancer for 30 days or more (median time, 6 months). The women answered a questionnaire that measured adherence as well as health literacy, quality of life, and distress. The researchers also collected information on the subjects’ race, age, insurance type, medication burden, and medication costs.

Fourteen of the women in the study additionally underwent qualitative interviews about their experiences with oral anticancer drugs. The researchers also queried physicians and nurse practitioners about their thoughts on adherence.

Dr. Watson and colleagues reported that 54% of women self-reported perfect adherence to their medication in the previous week, while 21% had missed or skipped one dose, and 25% reported skipping or missing more than one dose.

The researchers saw no significant differences between the adherent and nonadherent groups corresponding with race, age, or other demographic or clinical characteristics, but they noted that their study was not powered to detect such associations. The small sample size and self-reported data were among this study’s limitations, Dr. Watson and colleagues acknowledged.

Interviews with patients revealed some surprising reasons for the less-than-optimal adherence, with 43% of women reporting feeling anxiety about the burden of administering medication at home. While patients acknowledged the convenience of oral regimens, some also expressed a wish for more physician contact and support. Some women who were nonadherent said they perceived the efficacy of oral agents to be less than intravenous therapies.

Physicians and nurse practitioners interviewed by the researchers “tended to assume that their patients were adherent to oral anticancer therapy because of the therapy’s importance, and many did not routinely ask their patients about adherence,” Dr. Watson and colleagues wrote.

Emma Rossi, MD, a gynecologic oncologist at the University of North Carolina at Chapel Hill, commented in an interview that the study highlighted “the importance of not generalizing our perception of patients. As providers we have to spend the time asking patients where they’re at and how they’re thinking about taking an oral medication, with special attention to their fears, their expectations, and their concerns. We should be touching base with them not just before starting drugs, but during the course of treatment.”

Dr. Rossi stressed that compliance in real-life settings is likely to be different from that seen in clinical trials of oral anticancer drugs. “It’s important to recognize that real-world efficacy of treatments may be different from trial efficacy. We see these differences a lot in medicine where studies show a large magnitude of effect that doesn’t play out in real life practice – because of factors like this.”

Some 57% of the women in the study were taking their medications as maintenance, while the rest were taking the medications as active treatment. This too might have an effect on adherence, she said, with the active-treatment group potentially more motivated to maintain perfect adherence.

“You see in the interviews that doctors assume patients would be compliant because of the seriousness of the disease,” Dr. Rossi said. “But some patients said they perceived oral drugs as less strong or effective. If a patient is cancer free on a scan and doesn’t have measurable disease, prescribing an oral medication may be sending the subliminal message that it’s not as important.”

Physicians “may need to take the extra steps to individualize our counseling of patients – especially with therapies that they’re responsible for administering,” Dr. Rossi continued. “As this study shows, every patient sees treatment through her own individual lens. We really need to meet them where they’re at to make them comfortable with their treatment and optimize compliance.”

Dr. Watson and colleagues’ study was supported by their institution. One coauthor reported financial ties with drug manufacturers in the form of grant and clinical trial support and honoraria. Another coauthor is the member of various boards and steering committees, which are uncompensated. Dr. Rossi reported no financial conflicts of interest.

SOURCE: Watson C et al. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000004170.

Oral agents are taking on an ever-greater role in the management of gynecologic cancers. However, women being treated for these cancers have less than ideal adherence to such medications, a new study has found – with just over half reporting taking them exactly as prescribed.

Ingram Publishing/Thinkstock

The findings reported in Obstetrics & Gynecology are consistent with reports from other populations taking oral anticancer agents, in which adherence is generally lower than with intravenous therapies.

For their research, Catherine Watson, MD, and colleagues at Duke University, Durham, N.C., recruited 100 women at their institution taking a variety of oral anticancer agents for uterine or ovarian cancer for 30 days or more (median time, 6 months). The women answered a questionnaire that measured adherence as well as health literacy, quality of life, and distress. The researchers also collected information on the subjects’ race, age, insurance type, medication burden, and medication costs.

Fourteen of the women in the study additionally underwent qualitative interviews about their experiences with oral anticancer drugs. The researchers also queried physicians and nurse practitioners about their thoughts on adherence.

Dr. Watson and colleagues reported that 54% of women self-reported perfect adherence to their medication in the previous week, while 21% had missed or skipped one dose, and 25% reported skipping or missing more than one dose.

The researchers saw no significant differences between the adherent and nonadherent groups corresponding with race, age, or other demographic or clinical characteristics, but they noted that their study was not powered to detect such associations. The small sample size and self-reported data were among this study’s limitations, Dr. Watson and colleagues acknowledged.

Interviews with patients revealed some surprising reasons for the less-than-optimal adherence, with 43% of women reporting feeling anxiety about the burden of administering medication at home. While patients acknowledged the convenience of oral regimens, some also expressed a wish for more physician contact and support. Some women who were nonadherent said they perceived the efficacy of oral agents to be less than intravenous therapies.

Physicians and nurse practitioners interviewed by the researchers “tended to assume that their patients were adherent to oral anticancer therapy because of the therapy’s importance, and many did not routinely ask their patients about adherence,” Dr. Watson and colleagues wrote.

Emma Rossi, MD, a gynecologic oncologist at the University of North Carolina at Chapel Hill, commented in an interview that the study highlighted “the importance of not generalizing our perception of patients. As providers we have to spend the time asking patients where they’re at and how they’re thinking about taking an oral medication, with special attention to their fears, their expectations, and their concerns. We should be touching base with them not just before starting drugs, but during the course of treatment.”

Dr. Rossi stressed that compliance in real-life settings is likely to be different from that seen in clinical trials of oral anticancer drugs. “It’s important to recognize that real-world efficacy of treatments may be different from trial efficacy. We see these differences a lot in medicine where studies show a large magnitude of effect that doesn’t play out in real life practice – because of factors like this.”

Some 57% of the women in the study were taking their medications as maintenance, while the rest were taking the medications as active treatment. This too might have an effect on adherence, she said, with the active-treatment group potentially more motivated to maintain perfect adherence.

“You see in the interviews that doctors assume patients would be compliant because of the seriousness of the disease,” Dr. Rossi said. “But some patients said they perceived oral drugs as less strong or effective. If a patient is cancer free on a scan and doesn’t have measurable disease, prescribing an oral medication may be sending the subliminal message that it’s not as important.”

Physicians “may need to take the extra steps to individualize our counseling of patients – especially with therapies that they’re responsible for administering,” Dr. Rossi continued. “As this study shows, every patient sees treatment through her own individual lens. We really need to meet them where they’re at to make them comfortable with their treatment and optimize compliance.”

Dr. Watson and colleagues’ study was supported by their institution. One coauthor reported financial ties with drug manufacturers in the form of grant and clinical trial support and honoraria. Another coauthor is the member of various boards and steering committees, which are uncompensated. Dr. Rossi reported no financial conflicts of interest.

SOURCE: Watson C et al. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000004170.

Oral agents are taking on an ever-greater role in the management of gynecologic cancers. However, women being treated for these cancers have less than ideal adherence to such medications, a new study has found – with just over half reporting taking them exactly as prescribed.

Ingram Publishing/Thinkstock

The findings reported in Obstetrics & Gynecology are consistent with reports from other populations taking oral anticancer agents, in which adherence is generally lower than with intravenous therapies.

For their research, Catherine Watson, MD, and colleagues at Duke University, Durham, N.C., recruited 100 women at their institution taking a variety of oral anticancer agents for uterine or ovarian cancer for 30 days or more (median time, 6 months). The women answered a questionnaire that measured adherence as well as health literacy, quality of life, and distress. The researchers also collected information on the subjects’ race, age, insurance type, medication burden, and medication costs.

Fourteen of the women in the study additionally underwent qualitative interviews about their experiences with oral anticancer drugs. The researchers also queried physicians and nurse practitioners about their thoughts on adherence.

Dr. Watson and colleagues reported that 54% of women self-reported perfect adherence to their medication in the previous week, while 21% had missed or skipped one dose, and 25% reported skipping or missing more than one dose.

The researchers saw no significant differences between the adherent and nonadherent groups corresponding with race, age, or other demographic or clinical characteristics, but they noted that their study was not powered to detect such associations. The small sample size and self-reported data were among this study’s limitations, Dr. Watson and colleagues acknowledged.

Interviews with patients revealed some surprising reasons for the less-than-optimal adherence, with 43% of women reporting feeling anxiety about the burden of administering medication at home. While patients acknowledged the convenience of oral regimens, some also expressed a wish for more physician contact and support. Some women who were nonadherent said they perceived the efficacy of oral agents to be less than intravenous therapies.

Physicians and nurse practitioners interviewed by the researchers “tended to assume that their patients were adherent to oral anticancer therapy because of the therapy’s importance, and many did not routinely ask their patients about adherence,” Dr. Watson and colleagues wrote.

Emma Rossi, MD, a gynecologic oncologist at the University of North Carolina at Chapel Hill, commented in an interview that the study highlighted “the importance of not generalizing our perception of patients. As providers we have to spend the time asking patients where they’re at and how they’re thinking about taking an oral medication, with special attention to their fears, their expectations, and their concerns. We should be touching base with them not just before starting drugs, but during the course of treatment.”

Dr. Rossi stressed that compliance in real-life settings is likely to be different from that seen in clinical trials of oral anticancer drugs. “It’s important to recognize that real-world efficacy of treatments may be different from trial efficacy. We see these differences a lot in medicine where studies show a large magnitude of effect that doesn’t play out in real life practice – because of factors like this.”

Some 57% of the women in the study were taking their medications as maintenance, while the rest were taking the medications as active treatment. This too might have an effect on adherence, she said, with the active-treatment group potentially more motivated to maintain perfect adherence.

“You see in the interviews that doctors assume patients would be compliant because of the seriousness of the disease,” Dr. Rossi said. “But some patients said they perceived oral drugs as less strong or effective. If a patient is cancer free on a scan and doesn’t have measurable disease, prescribing an oral medication may be sending the subliminal message that it’s not as important.”

Physicians “may need to take the extra steps to individualize our counseling of patients – especially with therapies that they’re responsible for administering,” Dr. Rossi continued. “As this study shows, every patient sees treatment through her own individual lens. We really need to meet them where they’re at to make them comfortable with their treatment and optimize compliance.”

Dr. Watson and colleagues’ study was supported by their institution. One coauthor reported financial ties with drug manufacturers in the form of grant and clinical trial support and honoraria. Another coauthor is the member of various boards and steering committees, which are uncompensated. Dr. Rossi reported no financial conflicts of interest.

SOURCE: Watson C et al. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000004170.

Nebulized delivery of surfactant reduced the need for intubation and liquid surfactant administration by half among newborns with signs of respiratory distress syndrome, according to results from a large randomized, multicenter trial.

Neonatologists have long sought alternatives to intubation for administering surfactant to newborns with respiratory distress syndrome (RDS). An effective noninvasive aerosolized treatment has remained elusive, with small clinical trials that have produced mixed results.

In research published in Pediatrics, James J. Cummings, MD, of Albany (N.Y.) Medical Center, and colleagues, randomized 457 infants (mean 33 weeks’ gestational age) with signs of RDS to either usual care or a nebulized bovine surfactant. Infants were recruited at 22 neonatal ICUs in the United States. Investigators were not blinded to treatment allocation and the decision to intubate was left up to the individual treating physician, because to do so, the authors wrote, would add “pragmatic strength” to the study, and “be ethically compliant with the infant’s best interest.”

Infants in the study received usual care or up to three treatments 4 or more hours apart of 35 mg/mL calfactant suspension, 210 mg phospholipid/kg body weight delivered into the mouth through a nebulizer modified with a pacifier. Dr. Cummings and colleagues found that intubation and liquid surfactant administration within the first 4 days after birth was 26% in the intervention group and 50% in the usual care group (P < .001).

The results remained significant after investigators adjusted for gestational age, birth weight, age when randomized, sex, delivery mode, and antenatal steroids. Rates of intubation for surfactant administration were lower for infants in the intervention group in all gestational age brackets except the youngest (23-24 weeks); all of these infants needed intubation. Respiratory support at days 3, 7, and 28 did not differ between study groups.

“Our study is the first to reveal the efficacy of an aerosolized surfactant delivery system that does not require a respiratory circuit interface,” the investigators wrote.

In previous trials of aerosolized surfactants, they noted, treatment was delivered with nasal continuous positive airway pressure. “By using a separate, pacifier interface, both the aerosol delivery and [nasal continuous positive airway pressure] flow can be managed independently, which should allow for safer patient care.”

Dr. Cummings and colleagues also acknowledged several important limitations of their study, including its nonmasked, nonblinded design, and that it enrolled few infants with less than 28 weeks’ gestation. It takes 1-2 hours to deliver aerosolized calfactant, and “we did not want to delay definitive treatment.”

In an editorial comment accompanying the study, Kirsten Glaser, MD, of the University of Leipzig (Germany), and Clyde Wright, MD of the University of Colorado at Denver, Aurora, called the results promising. “Importantly, application of surfactant aerosols was well tolerated by using a modified nebulizer with a pacifier interface.”

The editorialists cautioned, however, of the study’s strong potential for selection bias. “Clinicians were aware that every infant randomly assigned to the nebulized surfactant arm received the intervention,” they wrote. “It is possible that clinicians delayed intubation and endotracheal surfactant instillation in this group, being biased by aerosolization and the hypothesis of lower risk of air leak and lung injury.”

Dr. Glaser and Dr. Wright further lamented that there were no formal criteria for administering surfactant therapy, and that the infants in the study might not be representative of those most in need of treatment. Today, bronchopulmonary dysplasia “primarily affects infants born at less than 28 weeks’ gestational age,” a minority of the infants recruited for this study, they wrote, urging further investigation in this patient group.

In an interview, neonatologist Roger F. Soll, MD, the H. Wallace Professor of Neonatology at the Larner College of Medicine at University of Vermont in Burlington, echoed the editorialists’ concerns that the study’s pragmatic design left a number of key questions unanswered. “It’s a promising study that laudably recruited on an order of magnitude more infants than any like it in the past,” Dr. Soll said. “And the kids who got the therapy seemed to do better, which is exciting. But with the broad entry criteria, the lack of formal diagnosis of RDS, and the outcome measures ultimately potentially biased by lack of blinding, it doesn’t give us the answers we need yet to consider aerosolized treatment.”

ONY Biotech, manufacturer of the study drug Infasurf, sponsored the trial. Dr. Cummings and one coauthor disclosed consulting arrangements with the sponsor, and another coauthor is an employee of the sponsor. The remaining investigators had no relevant financial disclosures. Dr. Glaser and Dr. Wright disclosed no conflicts of interest related to their editorial; Dr. Wright’s work was supported by the National Institutes of Health. Dr. Soll is president of the Vermont Oxford Network and coordinating editor of Cochrane Neonatal.
 

SOURCE: Cummings JJ et al. Pediatrics. 2020;146(5):e2020021576.

Nebulized delivery of surfactant reduced the need for intubation and liquid surfactant administration by half among newborns with signs of respiratory distress syndrome, according to results from a large randomized, multicenter trial.

Neonatologists have long sought alternatives to intubation for administering surfactant to newborns with respiratory distress syndrome (RDS). An effective noninvasive aerosolized treatment has remained elusive, with small clinical trials that have produced mixed results.

In research published in Pediatrics, James J. Cummings, MD, of Albany (N.Y.) Medical Center, and colleagues, randomized 457 infants (mean 33 weeks’ gestational age) with signs of RDS to either usual care or a nebulized bovine surfactant. Infants were recruited at 22 neonatal ICUs in the United States. Investigators were not blinded to treatment allocation and the decision to intubate was left up to the individual treating physician, because to do so, the authors wrote, would add “pragmatic strength” to the study, and “be ethically compliant with the infant’s best interest.”

Infants in the study received usual care or up to three treatments 4 or more hours apart of 35 mg/mL calfactant suspension, 210 mg phospholipid/kg body weight delivered into the mouth through a nebulizer modified with a pacifier. Dr. Cummings and colleagues found that intubation and liquid surfactant administration within the first 4 days after birth was 26% in the intervention group and 50% in the usual care group (P < .001).

The results remained significant after investigators adjusted for gestational age, birth weight, age when randomized, sex, delivery mode, and antenatal steroids. Rates of intubation for surfactant administration were lower for infants in the intervention group in all gestational age brackets except the youngest (23-24 weeks); all of these infants needed intubation. Respiratory support at days 3, 7, and 28 did not differ between study groups.

“Our study is the first to reveal the efficacy of an aerosolized surfactant delivery system that does not require a respiratory circuit interface,” the investigators wrote.

In previous trials of aerosolized surfactants, they noted, treatment was delivered with nasal continuous positive airway pressure. “By using a separate, pacifier interface, both the aerosol delivery and [nasal continuous positive airway pressure] flow can be managed independently, which should allow for safer patient care.”

Dr. Cummings and colleagues also acknowledged several important limitations of their study, including its nonmasked, nonblinded design, and that it enrolled few infants with less than 28 weeks’ gestation. It takes 1-2 hours to deliver aerosolized calfactant, and “we did not want to delay definitive treatment.”

In an editorial comment accompanying the study, Kirsten Glaser, MD, of the University of Leipzig (Germany), and Clyde Wright, MD of the University of Colorado at Denver, Aurora, called the results promising. “Importantly, application of surfactant aerosols was well tolerated by using a modified nebulizer with a pacifier interface.”

The editorialists cautioned, however, of the study’s strong potential for selection bias. “Clinicians were aware that every infant randomly assigned to the nebulized surfactant arm received the intervention,” they wrote. “It is possible that clinicians delayed intubation and endotracheal surfactant instillation in this group, being biased by aerosolization and the hypothesis of lower risk of air leak and lung injury.”

Dr. Glaser and Dr. Wright further lamented that there were no formal criteria for administering surfactant therapy, and that the infants in the study might not be representative of those most in need of treatment. Today, bronchopulmonary dysplasia “primarily affects infants born at less than 28 weeks’ gestational age,” a minority of the infants recruited for this study, they wrote, urging further investigation in this patient group.

In an interview, neonatologist Roger F. Soll, MD, the H. Wallace Professor of Neonatology at the Larner College of Medicine at University of Vermont in Burlington, echoed the editorialists’ concerns that the study’s pragmatic design left a number of key questions unanswered. “It’s a promising study that laudably recruited on an order of magnitude more infants than any like it in the past,” Dr. Soll said. “And the kids who got the therapy seemed to do better, which is exciting. But with the broad entry criteria, the lack of formal diagnosis of RDS, and the outcome measures ultimately potentially biased by lack of blinding, it doesn’t give us the answers we need yet to consider aerosolized treatment.”

ONY Biotech, manufacturer of the study drug Infasurf, sponsored the trial. Dr. Cummings and one coauthor disclosed consulting arrangements with the sponsor, and another coauthor is an employee of the sponsor. The remaining investigators had no relevant financial disclosures. Dr. Glaser and Dr. Wright disclosed no conflicts of interest related to their editorial; Dr. Wright’s work was supported by the National Institutes of Health. Dr. Soll is president of the Vermont Oxford Network and coordinating editor of Cochrane Neonatal.
 

SOURCE: Cummings JJ et al. Pediatrics. 2020;146(5):e2020021576.

Nebulized delivery of surfactant reduced the need for intubation and liquid surfactant administration by half among newborns with signs of respiratory distress syndrome, according to results from a large randomized, multicenter trial.

Neonatologists have long sought alternatives to intubation for administering surfactant to newborns with respiratory distress syndrome (RDS). An effective noninvasive aerosolized treatment has remained elusive, with small clinical trials that have produced mixed results.

In research published in Pediatrics, James J. Cummings, MD, of Albany (N.Y.) Medical Center, and colleagues, randomized 457 infants (mean 33 weeks’ gestational age) with signs of RDS to either usual care or a nebulized bovine surfactant. Infants were recruited at 22 neonatal ICUs in the United States. Investigators were not blinded to treatment allocation and the decision to intubate was left up to the individual treating physician, because to do so, the authors wrote, would add “pragmatic strength” to the study, and “be ethically compliant with the infant’s best interest.”

Infants in the study received usual care or up to three treatments 4 or more hours apart of 35 mg/mL calfactant suspension, 210 mg phospholipid/kg body weight delivered into the mouth through a nebulizer modified with a pacifier. Dr. Cummings and colleagues found that intubation and liquid surfactant administration within the first 4 days after birth was 26% in the intervention group and 50% in the usual care group (P < .001).

The results remained significant after investigators adjusted for gestational age, birth weight, age when randomized, sex, delivery mode, and antenatal steroids. Rates of intubation for surfactant administration were lower for infants in the intervention group in all gestational age brackets except the youngest (23-24 weeks); all of these infants needed intubation. Respiratory support at days 3, 7, and 28 did not differ between study groups.

“Our study is the first to reveal the efficacy of an aerosolized surfactant delivery system that does not require a respiratory circuit interface,” the investigators wrote.

In previous trials of aerosolized surfactants, they noted, treatment was delivered with nasal continuous positive airway pressure. “By using a separate, pacifier interface, both the aerosol delivery and [nasal continuous positive airway pressure] flow can be managed independently, which should allow for safer patient care.”

Dr. Cummings and colleagues also acknowledged several important limitations of their study, including its nonmasked, nonblinded design, and that it enrolled few infants with less than 28 weeks’ gestation. It takes 1-2 hours to deliver aerosolized calfactant, and “we did not want to delay definitive treatment.”

In an editorial comment accompanying the study, Kirsten Glaser, MD, of the University of Leipzig (Germany), and Clyde Wright, MD of the University of Colorado at Denver, Aurora, called the results promising. “Importantly, application of surfactant aerosols was well tolerated by using a modified nebulizer with a pacifier interface.”

The editorialists cautioned, however, of the study’s strong potential for selection bias. “Clinicians were aware that every infant randomly assigned to the nebulized surfactant arm received the intervention,” they wrote. “It is possible that clinicians delayed intubation and endotracheal surfactant instillation in this group, being biased by aerosolization and the hypothesis of lower risk of air leak and lung injury.”

Dr. Glaser and Dr. Wright further lamented that there were no formal criteria for administering surfactant therapy, and that the infants in the study might not be representative of those most in need of treatment. Today, bronchopulmonary dysplasia “primarily affects infants born at less than 28 weeks’ gestational age,” a minority of the infants recruited for this study, they wrote, urging further investigation in this patient group.

In an interview, neonatologist Roger F. Soll, MD, the H. Wallace Professor of Neonatology at the Larner College of Medicine at University of Vermont in Burlington, echoed the editorialists’ concerns that the study’s pragmatic design left a number of key questions unanswered. “It’s a promising study that laudably recruited on an order of magnitude more infants than any like it in the past,” Dr. Soll said. “And the kids who got the therapy seemed to do better, which is exciting. But with the broad entry criteria, the lack of formal diagnosis of RDS, and the outcome measures ultimately potentially biased by lack of blinding, it doesn’t give us the answers we need yet to consider aerosolized treatment.”

ONY Biotech, manufacturer of the study drug Infasurf, sponsored the trial. Dr. Cummings and one coauthor disclosed consulting arrangements with the sponsor, and another coauthor is an employee of the sponsor. The remaining investigators had no relevant financial disclosures. Dr. Glaser and Dr. Wright disclosed no conflicts of interest related to their editorial; Dr. Wright’s work was supported by the National Institutes of Health. Dr. Soll is president of the Vermont Oxford Network and coordinating editor of Cochrane Neonatal.
 

SOURCE: Cummings JJ et al. Pediatrics. 2020;146(5):e2020021576.

A new report of mother-to-fetus transmission of SARS-CoV-2 through umbilical cord blood adds to a small but growing body of evidence that the virus can be transmitted in utero.

Further, this case suggests such infections may not be easily detectable in neonates until days after birth.
 

The data

In a report published in the Journal of The Pediatric Infectious Diseases Society, Isabelle Von Kohorn, MD, PhD, of Holy Cross Health in Silver Spring, Md., and colleagues, described a case of neonatal infection with SARS-CoV-2 in a boy delivered by C-section at 34 weeks to a mother diagnosed with COVID-19 some 14 hours before. The newborn was immediately removed to a neonatal ICU and reunited with his mother a week later, once the mother had recovered.

Dr. Von Kohorn and colleagues reported that, while the infant’s nasopharyngeal swab test for SARS-CoV-2 was negative at 24 hours after birth, repeat molecular tests (using different assays) from 49 hours on were positive and indicated an increasing viral burden, although the infant never developed symptoms of COVID-19. In addition to being found in the nasopharynx, viral RNA also was detected in cord blood and in urine. No viral RNA was found in the placenta.

The circumstances of the birth, and the care taken to keep mother and her infant at a safe distance along with masking of the mother, made it “extremely unlikely” that the infant acquired his infection by the respiratory route, Dr. Von Kohorn and colleagues wrote.

“While we cannot rule out microscopic maternal blood contamination of cord blood in this or any other delivery, cord blood collection procedures are designed to avoid gross contamination with maternal blood. Microscopic contamination would not explain the RNA levels observed in our patient’s cord blood,” they wrote.

Clinicians should note that a neonate born to a mother with COVID-19 may take time to test positive for SARS-CoV-2 , the investigators argued, though the current recommendation of the American Academy of Pediatrics is to test nasopharyngeal secretions of well newborns at 24 and 48 hours but not again in the absence of symptoms. “This case suggests that some cases of SARS-CoV-2 in newborns may be detectable only after 48 hours of life.”

The authors hypothesized that virus transmitted by cord blood “seeded the nasopharynx and required 2 days for incubation and replication sufficient for detection.”
 

Some perspective

In an interview, Andrea Edlow, MD, A maternal-fetal medicine specialist at Massachusetts General Hospital in Boston, called the findings provocative if not definitive in establishing in utero or vertical transmission of SARS-CoV-2 in the same way that a Nature Communications case report did in July 2020. In that case, of a baby born to a mother with COVID-19, virus was seen at high levels in the placenta.

With the current case, “the absence of detectable virus in the placenta is certainly inconsistent/confusing if the authors claim hematogenous spread from mother to baby,” Dr. Edlow commented, “but the authors do offer plausible explanations, such as examination of limited areas within the placenta (when we know infection is likely to be patchy) and possible degradation of RNA prior to attempting to measure placental viral presence.”

Dr. Von Kohorn and colleagues’ study was funded by the National Institutes of Health, and the investigators disclosed no financial conflicts of interest. Dr. Edlow had no relevant financial disclosures.

SOURCE: Von Kohorn I et al. J Pediat Inf Dis Soc. 2020 Oct 22. doi: 10.1093/jpids/piaa127

A new report of mother-to-fetus transmission of SARS-CoV-2 through umbilical cord blood adds to a small but growing body of evidence that the virus can be transmitted in utero.

Further, this case suggests such infections may not be easily detectable in neonates until days after birth.
 

The data

In a report published in the Journal of The Pediatric Infectious Diseases Society, Isabelle Von Kohorn, MD, PhD, of Holy Cross Health in Silver Spring, Md., and colleagues, described a case of neonatal infection with SARS-CoV-2 in a boy delivered by C-section at 34 weeks to a mother diagnosed with COVID-19 some 14 hours before. The newborn was immediately removed to a neonatal ICU and reunited with his mother a week later, once the mother had recovered.

Dr. Von Kohorn and colleagues reported that, while the infant’s nasopharyngeal swab test for SARS-CoV-2 was negative at 24 hours after birth, repeat molecular tests (using different assays) from 49 hours on were positive and indicated an increasing viral burden, although the infant never developed symptoms of COVID-19. In addition to being found in the nasopharynx, viral RNA also was detected in cord blood and in urine. No viral RNA was found in the placenta.

The circumstances of the birth, and the care taken to keep mother and her infant at a safe distance along with masking of the mother, made it “extremely unlikely” that the infant acquired his infection by the respiratory route, Dr. Von Kohorn and colleagues wrote.

“While we cannot rule out microscopic maternal blood contamination of cord blood in this or any other delivery, cord blood collection procedures are designed to avoid gross contamination with maternal blood. Microscopic contamination would not explain the RNA levels observed in our patient’s cord blood,” they wrote.

Clinicians should note that a neonate born to a mother with COVID-19 may take time to test positive for SARS-CoV-2 , the investigators argued, though the current recommendation of the American Academy of Pediatrics is to test nasopharyngeal secretions of well newborns at 24 and 48 hours but not again in the absence of symptoms. “This case suggests that some cases of SARS-CoV-2 in newborns may be detectable only after 48 hours of life.”

The authors hypothesized that virus transmitted by cord blood “seeded the nasopharynx and required 2 days for incubation and replication sufficient for detection.”
 

Some perspective

In an interview, Andrea Edlow, MD, A maternal-fetal medicine specialist at Massachusetts General Hospital in Boston, called the findings provocative if not definitive in establishing in utero or vertical transmission of SARS-CoV-2 in the same way that a Nature Communications case report did in July 2020. In that case, of a baby born to a mother with COVID-19, virus was seen at high levels in the placenta.

With the current case, “the absence of detectable virus in the placenta is certainly inconsistent/confusing if the authors claim hematogenous spread from mother to baby,” Dr. Edlow commented, “but the authors do offer plausible explanations, such as examination of limited areas within the placenta (when we know infection is likely to be patchy) and possible degradation of RNA prior to attempting to measure placental viral presence.”

Dr. Von Kohorn and colleagues’ study was funded by the National Institutes of Health, and the investigators disclosed no financial conflicts of interest. Dr. Edlow had no relevant financial disclosures.

SOURCE: Von Kohorn I et al. J Pediat Inf Dis Soc. 2020 Oct 22. doi: 10.1093/jpids/piaa127

A new report of mother-to-fetus transmission of SARS-CoV-2 through umbilical cord blood adds to a small but growing body of evidence that the virus can be transmitted in utero.

Further, this case suggests such infections may not be easily detectable in neonates until days after birth.
 

The data

In a report published in the Journal of The Pediatric Infectious Diseases Society, Isabelle Von Kohorn, MD, PhD, of Holy Cross Health in Silver Spring, Md., and colleagues, described a case of neonatal infection with SARS-CoV-2 in a boy delivered by C-section at 34 weeks to a mother diagnosed with COVID-19 some 14 hours before. The newborn was immediately removed to a neonatal ICU and reunited with his mother a week later, once the mother had recovered.

Dr. Von Kohorn and colleagues reported that, while the infant’s nasopharyngeal swab test for SARS-CoV-2 was negative at 24 hours after birth, repeat molecular tests (using different assays) from 49 hours on were positive and indicated an increasing viral burden, although the infant never developed symptoms of COVID-19. In addition to being found in the nasopharynx, viral RNA also was detected in cord blood and in urine. No viral RNA was found in the placenta.

The circumstances of the birth, and the care taken to keep mother and her infant at a safe distance along with masking of the mother, made it “extremely unlikely” that the infant acquired his infection by the respiratory route, Dr. Von Kohorn and colleagues wrote.

“While we cannot rule out microscopic maternal blood contamination of cord blood in this or any other delivery, cord blood collection procedures are designed to avoid gross contamination with maternal blood. Microscopic contamination would not explain the RNA levels observed in our patient’s cord blood,” they wrote.

Clinicians should note that a neonate born to a mother with COVID-19 may take time to test positive for SARS-CoV-2 , the investigators argued, though the current recommendation of the American Academy of Pediatrics is to test nasopharyngeal secretions of well newborns at 24 and 48 hours but not again in the absence of symptoms. “This case suggests that some cases of SARS-CoV-2 in newborns may be detectable only after 48 hours of life.”

The authors hypothesized that virus transmitted by cord blood “seeded the nasopharynx and required 2 days for incubation and replication sufficient for detection.”
 

Some perspective

In an interview, Andrea Edlow, MD, A maternal-fetal medicine specialist at Massachusetts General Hospital in Boston, called the findings provocative if not definitive in establishing in utero or vertical transmission of SARS-CoV-2 in the same way that a Nature Communications case report did in July 2020. In that case, of a baby born to a mother with COVID-19, virus was seen at high levels in the placenta.

With the current case, “the absence of detectable virus in the placenta is certainly inconsistent/confusing if the authors claim hematogenous spread from mother to baby,” Dr. Edlow commented, “but the authors do offer plausible explanations, such as examination of limited areas within the placenta (when we know infection is likely to be patchy) and possible degradation of RNA prior to attempting to measure placental viral presence.”

Dr. Von Kohorn and colleagues’ study was funded by the National Institutes of Health, and the investigators disclosed no financial conflicts of interest. Dr. Edlow had no relevant financial disclosures.

SOURCE: Von Kohorn I et al. J Pediat Inf Dis Soc. 2020 Oct 22. doi: 10.1093/jpids/piaa127

Half of Chinese American parents and their children report having experienced an in-person episode of racial discrimination related to the COVID-19 pandemic, according to results from a survey study.

In the United States, where public officials continue to refer to SARS-CoV-2 as the “China virus” and have often sought to draw attention to its origins in Wuhan, China, “the associations between discrimination triggered by the racialization of this acute public health crisis and mental health are unknown,” Charissa S.L. Cheah, PhD, of the University of Maryland, Baltimore County, and colleagues wrote.

For their research published Oct. 29 in Pediatrics, Dr. Cheah and colleagues recruited a cohort of 543 Chinese American parents of school-age children, and 230 of their children aged 10-18 years, to complete online surveys between mid-March and late May 2020. Parents in the cohort were largely foreign born, with all identifying as ethnically Chinese, while their children were mostly U.S. born.
 

Evidence of discrimination against Chinese Americans

Half of parents and their children (51% of parents and 50% of youth) reported experiencing at least one in-person incident of direct discrimination (assessed using questions derived from a validated scale of racial aggression) related to the pandemic. Dr. Cheah and colleagues also reported a high incidence of direct discrimination online (32% of parents and 46% of youth). Additionally, the researchers measured reports of vicarious or indirect discrimination – such as hearing jokes or disparaging remarks about one’s ethnic group – which they used a different adapted scale to capture. More than three-quarters of the cohort reported such experiences.

The experiences of discrimination likely bore on the mental health of both parents and youth. Using a series of instruments designed to measure overall psychological well-being as well as symptoms of depression, anxiety, and certain emotional and behavioral outcomes, Dr. Cheah and colleagues reported significant negative associations between direct online or in-person discrimination and psychological health. For parents and children alike, anxiety and depressive symptoms were positively associated with all varieties of discrimination experiences measured in the study.

About a fifth of the youth in the study were deemed, based on the symptom scales used in the study, to have an elevated risk of clinically significant mental health problems, higher than the 10%-15% that would be expected for these age groups in the United States.

“This study revealed that a high percentage of Chinese American parents and their children personally experienced or witnessed anti-Chinese or anti–Asian American racial discrimination both online and in person due to the COVID-19 pandemic,” the investigators wrote. “Most respondents reported directly experiencing or witnessing racial discrimination against other Chinese or Asian American individuals due to COVID-19 at least once.”

Dr. Cheah and colleagues noted that their cross-sectional study did not lend itself to causal interpretations and was vulnerable to certain types of reporting bias. Nonetheless, they argued, as the pandemic continues, “pediatricians should be sensitive to the potential mental health needs of Chinese American youth and their parents related to various forms of racism, in addition to other stressors, as the foundations of perceptions of racial-ethnic discrimination and their consequences may be set during this period.”
 

COVID-19 didn’t only bring infection

In an accompanying editorial, Tina L. Cheng, MD, of Johns Hopkins University, Baltimore, and her daughter Alison M. Conca-Cheng, a medical student at Brown University, Providence, R.I., remarked that the study’s findings were consistent with recent research that found “4 in 10 Americans reported that it has become more common since COVID-19 for people to express racist views about Asian Americans,” and also described an increase in complaints of discriminatory experiences by Asian Americans.

In this context, a link to poor mental health “should be no surprise,” Dr. Cheng and Ms. Conca-Cheng argued, and urged pediatricians to consult the American Academy of Pediatrics’ 2019 policy statement on racism and on child and adolescent health. “It calls for us to optimize clinical practice, improve workforce development and professional education, strengthen research, and deploy systems through community engagement, advocacy, and public policy.”

David Rettew, MD, a child and adolescent psychiatrist and associate professor of psychiatry and pediatrics at the University of Vermont, Burlington, called the study’s main points “clear and disturbing.”

“While it is difficult to find much in the way here of a silver lining, these alarming reports have helped people working in health care and mental health to understand racism as another form of trauma and abuse which, like other types, can have real negative effects on health,” Dr. Rettew said in an interview. “The more we as mental health professions ask about racism and offer resources for people who have experienced it, just as we would people who have endured other types of trauma, the more we can help people heal. That said, it would be better just to stop this from happening in the first place.”

Dr. Cheah and colleagues’ study was supported by a National Science Foundation grant. The investigators disclosed no conflicts of interest. Dr. Cheng and Ms. Conca-Cheng disclosed no financial conflicts of interest related to their editorial. Dr. Rettew said he had no relevant financial disclosures.

SOURCE: Cheah CSL et al. Pediatrics. 2020;146(5):e2020021816.

Half of Chinese American parents and their children report having experienced an in-person episode of racial discrimination related to the COVID-19 pandemic, according to results from a survey study.

In the United States, where public officials continue to refer to SARS-CoV-2 as the “China virus” and have often sought to draw attention to its origins in Wuhan, China, “the associations between discrimination triggered by the racialization of this acute public health crisis and mental health are unknown,” Charissa S.L. Cheah, PhD, of the University of Maryland, Baltimore County, and colleagues wrote.

For their research published Oct. 29 in Pediatrics, Dr. Cheah and colleagues recruited a cohort of 543 Chinese American parents of school-age children, and 230 of their children aged 10-18 years, to complete online surveys between mid-March and late May 2020. Parents in the cohort were largely foreign born, with all identifying as ethnically Chinese, while their children were mostly U.S. born.
 

Evidence of discrimination against Chinese Americans

Half of parents and their children (51% of parents and 50% of youth) reported experiencing at least one in-person incident of direct discrimination (assessed using questions derived from a validated scale of racial aggression) related to the pandemic. Dr. Cheah and colleagues also reported a high incidence of direct discrimination online (32% of parents and 46% of youth). Additionally, the researchers measured reports of vicarious or indirect discrimination – such as hearing jokes or disparaging remarks about one’s ethnic group – which they used a different adapted scale to capture. More than three-quarters of the cohort reported such experiences.

The experiences of discrimination likely bore on the mental health of both parents and youth. Using a series of instruments designed to measure overall psychological well-being as well as symptoms of depression, anxiety, and certain emotional and behavioral outcomes, Dr. Cheah and colleagues reported significant negative associations between direct online or in-person discrimination and psychological health. For parents and children alike, anxiety and depressive symptoms were positively associated with all varieties of discrimination experiences measured in the study.

About a fifth of the youth in the study were deemed, based on the symptom scales used in the study, to have an elevated risk of clinically significant mental health problems, higher than the 10%-15% that would be expected for these age groups in the United States.

“This study revealed that a high percentage of Chinese American parents and their children personally experienced or witnessed anti-Chinese or anti–Asian American racial discrimination both online and in person due to the COVID-19 pandemic,” the investigators wrote. “Most respondents reported directly experiencing or witnessing racial discrimination against other Chinese or Asian American individuals due to COVID-19 at least once.”

Dr. Cheah and colleagues noted that their cross-sectional study did not lend itself to causal interpretations and was vulnerable to certain types of reporting bias. Nonetheless, they argued, as the pandemic continues, “pediatricians should be sensitive to the potential mental health needs of Chinese American youth and their parents related to various forms of racism, in addition to other stressors, as the foundations of perceptions of racial-ethnic discrimination and their consequences may be set during this period.”
 

COVID-19 didn’t only bring infection

In an accompanying editorial, Tina L. Cheng, MD, of Johns Hopkins University, Baltimore, and her daughter Alison M. Conca-Cheng, a medical student at Brown University, Providence, R.I., remarked that the study’s findings were consistent with recent research that found “4 in 10 Americans reported that it has become more common since COVID-19 for people to express racist views about Asian Americans,” and also described an increase in complaints of discriminatory experiences by Asian Americans.

In this context, a link to poor mental health “should be no surprise,” Dr. Cheng and Ms. Conca-Cheng argued, and urged pediatricians to consult the American Academy of Pediatrics’ 2019 policy statement on racism and on child and adolescent health. “It calls for us to optimize clinical practice, improve workforce development and professional education, strengthen research, and deploy systems through community engagement, advocacy, and public policy.”

David Rettew, MD, a child and adolescent psychiatrist and associate professor of psychiatry and pediatrics at the University of Vermont, Burlington, called the study’s main points “clear and disturbing.”

“While it is difficult to find much in the way here of a silver lining, these alarming reports have helped people working in health care and mental health to understand racism as another form of trauma and abuse which, like other types, can have real negative effects on health,” Dr. Rettew said in an interview. “The more we as mental health professions ask about racism and offer resources for people who have experienced it, just as we would people who have endured other types of trauma, the more we can help people heal. That said, it would be better just to stop this from happening in the first place.”

Dr. Cheah and colleagues’ study was supported by a National Science Foundation grant. The investigators disclosed no conflicts of interest. Dr. Cheng and Ms. Conca-Cheng disclosed no financial conflicts of interest related to their editorial. Dr. Rettew said he had no relevant financial disclosures.

SOURCE: Cheah CSL et al. Pediatrics. 2020;146(5):e2020021816.

Half of Chinese American parents and their children report having experienced an in-person episode of racial discrimination related to the COVID-19 pandemic, according to results from a survey study.

In the United States, where public officials continue to refer to SARS-CoV-2 as the “China virus” and have often sought to draw attention to its origins in Wuhan, China, “the associations between discrimination triggered by the racialization of this acute public health crisis and mental health are unknown,” Charissa S.L. Cheah, PhD, of the University of Maryland, Baltimore County, and colleagues wrote.

For their research published Oct. 29 in Pediatrics, Dr. Cheah and colleagues recruited a cohort of 543 Chinese American parents of school-age children, and 230 of their children aged 10-18 years, to complete online surveys between mid-March and late May 2020. Parents in the cohort were largely foreign born, with all identifying as ethnically Chinese, while their children were mostly U.S. born.
 

Evidence of discrimination against Chinese Americans

Half of parents and their children (51% of parents and 50% of youth) reported experiencing at least one in-person incident of direct discrimination (assessed using questions derived from a validated scale of racial aggression) related to the pandemic. Dr. Cheah and colleagues also reported a high incidence of direct discrimination online (32% of parents and 46% of youth). Additionally, the researchers measured reports of vicarious or indirect discrimination – such as hearing jokes or disparaging remarks about one’s ethnic group – which they used a different adapted scale to capture. More than three-quarters of the cohort reported such experiences.

The experiences of discrimination likely bore on the mental health of both parents and youth. Using a series of instruments designed to measure overall psychological well-being as well as symptoms of depression, anxiety, and certain emotional and behavioral outcomes, Dr. Cheah and colleagues reported significant negative associations between direct online or in-person discrimination and psychological health. For parents and children alike, anxiety and depressive symptoms were positively associated with all varieties of discrimination experiences measured in the study.

About a fifth of the youth in the study were deemed, based on the symptom scales used in the study, to have an elevated risk of clinically significant mental health problems, higher than the 10%-15% that would be expected for these age groups in the United States.

“This study revealed that a high percentage of Chinese American parents and their children personally experienced or witnessed anti-Chinese or anti–Asian American racial discrimination both online and in person due to the COVID-19 pandemic,” the investigators wrote. “Most respondents reported directly experiencing or witnessing racial discrimination against other Chinese or Asian American individuals due to COVID-19 at least once.”

Dr. Cheah and colleagues noted that their cross-sectional study did not lend itself to causal interpretations and was vulnerable to certain types of reporting bias. Nonetheless, they argued, as the pandemic continues, “pediatricians should be sensitive to the potential mental health needs of Chinese American youth and their parents related to various forms of racism, in addition to other stressors, as the foundations of perceptions of racial-ethnic discrimination and their consequences may be set during this period.”
 

COVID-19 didn’t only bring infection

In an accompanying editorial, Tina L. Cheng, MD, of Johns Hopkins University, Baltimore, and her daughter Alison M. Conca-Cheng, a medical student at Brown University, Providence, R.I., remarked that the study’s findings were consistent with recent research that found “4 in 10 Americans reported that it has become more common since COVID-19 for people to express racist views about Asian Americans,” and also described an increase in complaints of discriminatory experiences by Asian Americans.

In this context, a link to poor mental health “should be no surprise,” Dr. Cheng and Ms. Conca-Cheng argued, and urged pediatricians to consult the American Academy of Pediatrics’ 2019 policy statement on racism and on child and adolescent health. “It calls for us to optimize clinical practice, improve workforce development and professional education, strengthen research, and deploy systems through community engagement, advocacy, and public policy.”

David Rettew, MD, a child and adolescent psychiatrist and associate professor of psychiatry and pediatrics at the University of Vermont, Burlington, called the study’s main points “clear and disturbing.”

“While it is difficult to find much in the way here of a silver lining, these alarming reports have helped people working in health care and mental health to understand racism as another form of trauma and abuse which, like other types, can have real negative effects on health,” Dr. Rettew said in an interview. “The more we as mental health professions ask about racism and offer resources for people who have experienced it, just as we would people who have endured other types of trauma, the more we can help people heal. That said, it would be better just to stop this from happening in the first place.”

Dr. Cheah and colleagues’ study was supported by a National Science Foundation grant. The investigators disclosed no conflicts of interest. Dr. Cheng and Ms. Conca-Cheng disclosed no financial conflicts of interest related to their editorial. Dr. Rettew said he had no relevant financial disclosures.

SOURCE: Cheah CSL et al. Pediatrics. 2020;146(5):e2020021816.

Sugary and artificially sweetened drinks are each associated with an increased risk of developing cardiovascular disease, according to results from a large prospective cohort study.

© Irochka/Fotolia.com

However, the design of that study fails to take into account other sources of dietary sugar, according to one expert.

In a research letter published online Oct. 26 in the Journal of the American College of Cardiology, Eloi Chazelas, a PhD candidate at Sorbonne Paris Nord University in Paris, and colleagues, shared results from nearly 105,000 subjects (79% women, mean age 43 at baseline, median follow up 6.6 years) enrolled in the NutriNet-Santé cohort study.

In this observational study, which began recruiting in 2009, dietary patterns are self-reported by subjects, while health outcomes are validated by investigators.

Mr. Chazelas and his colleagues identified 1,379 first incident cases of stroke, transient ischemic attack, myocardial infarction, acute coronary syndrome, and angioplasty in the cohort during 2009-2019. Cases that occurred during the first 3 years’ follow up were excluded from the analysis, to avoid potential reverse causality bias.

After adjustment for a wide range of dietary, demographic and health confounders, the investigators found that high consumers of sugary drinks or artificially sweetened drinks saw 20% and 32% higher risk of such events, respectively, compared with people who reported drinking neither beverage type (hazard ratio: 1.20; 95% confidence interval 1.04-1.40, P for trend < .0009 and HR: 1.32; 95% CI, 1.00-1.73, P for trend < .03).

Sugary drinks were defined as containing 5% or more of sugars, including natural fruit juices. The high consumers in the study had a median intake of 185 mL per day of sugary drinks, or 176 mL per day for artificially sweetened drinks. Natural noncaloric sweeteners such as Stevia were included in the artificially sweetened group.

The findings, Mr. Chazelas and colleagues wrote in their analysis, add to evidence that artificially sweetened beverages “might not be a healthy substitute for sugary drinks.” While research has suggested that artificial sweeteners induce glucose intolerance by disturbing gut microbiota, they noted, more and bigger studies are needed to understand the mechanisms by which they might bear on cardiovascular disease risk.

Robert A. Vogel, MD, of the University of Colorado Denver, urged caution in interpreting the researchers’ results. In an interview, Dr. Vogel, a preventive cardiologist, said that it is “notoriously difficult” to evaluate what a food or food group does to the body outside of a carefully controlled trial. What little randomized trial evidence exists comparing the health effects of artificially sweetened and sugary drinks includes a 2012 trial in children that found diet drinks associated with reductions in body fat – if anything a positive indication for heart health.

SOURCE: Chazelas et al. JACC 2020;76(18):2175-80.

Sugary and artificially sweetened drinks are each associated with an increased risk of developing cardiovascular disease, according to results from a large prospective cohort study.

© Irochka/Fotolia.com

However, the design of that study fails to take into account other sources of dietary sugar, according to one expert.

In a research letter published online Oct. 26 in the Journal of the American College of Cardiology, Eloi Chazelas, a PhD candidate at Sorbonne Paris Nord University in Paris, and colleagues, shared results from nearly 105,000 subjects (79% women, mean age 43 at baseline, median follow up 6.6 years) enrolled in the NutriNet-Santé cohort study.

In this observational study, which began recruiting in 2009, dietary patterns are self-reported by subjects, while health outcomes are validated by investigators.

Mr. Chazelas and his colleagues identified 1,379 first incident cases of stroke, transient ischemic attack, myocardial infarction, acute coronary syndrome, and angioplasty in the cohort during 2009-2019. Cases that occurred during the first 3 years’ follow up were excluded from the analysis, to avoid potential reverse causality bias.

After adjustment for a wide range of dietary, demographic and health confounders, the investigators found that high consumers of sugary drinks or artificially sweetened drinks saw 20% and 32% higher risk of such events, respectively, compared with people who reported drinking neither beverage type (hazard ratio: 1.20; 95% confidence interval 1.04-1.40, P for trend < .0009 and HR: 1.32; 95% CI, 1.00-1.73, P for trend < .03).

Sugary drinks were defined as containing 5% or more of sugars, including natural fruit juices. The high consumers in the study had a median intake of 185 mL per day of sugary drinks, or 176 mL per day for artificially sweetened drinks. Natural noncaloric sweeteners such as Stevia were included in the artificially sweetened group.

The findings, Mr. Chazelas and colleagues wrote in their analysis, add to evidence that artificially sweetened beverages “might not be a healthy substitute for sugary drinks.” While research has suggested that artificial sweeteners induce glucose intolerance by disturbing gut microbiota, they noted, more and bigger studies are needed to understand the mechanisms by which they might bear on cardiovascular disease risk.

Robert A. Vogel, MD, of the University of Colorado Denver, urged caution in interpreting the researchers’ results. In an interview, Dr. Vogel, a preventive cardiologist, said that it is “notoriously difficult” to evaluate what a food or food group does to the body outside of a carefully controlled trial. What little randomized trial evidence exists comparing the health effects of artificially sweetened and sugary drinks includes a 2012 trial in children that found diet drinks associated with reductions in body fat – if anything a positive indication for heart health.

SOURCE: Chazelas et al. JACC 2020;76(18):2175-80.

Sugary and artificially sweetened drinks are each associated with an increased risk of developing cardiovascular disease, according to results from a large prospective cohort study.

© Irochka/Fotolia.com

However, the design of that study fails to take into account other sources of dietary sugar, according to one expert.

In a research letter published online Oct. 26 in the Journal of the American College of Cardiology, Eloi Chazelas, a PhD candidate at Sorbonne Paris Nord University in Paris, and colleagues, shared results from nearly 105,000 subjects (79% women, mean age 43 at baseline, median follow up 6.6 years) enrolled in the NutriNet-Santé cohort study.

In this observational study, which began recruiting in 2009, dietary patterns are self-reported by subjects, while health outcomes are validated by investigators.

Mr. Chazelas and his colleagues identified 1,379 first incident cases of stroke, transient ischemic attack, myocardial infarction, acute coronary syndrome, and angioplasty in the cohort during 2009-2019. Cases that occurred during the first 3 years’ follow up were excluded from the analysis, to avoid potential reverse causality bias.

After adjustment for a wide range of dietary, demographic and health confounders, the investigators found that high consumers of sugary drinks or artificially sweetened drinks saw 20% and 32% higher risk of such events, respectively, compared with people who reported drinking neither beverage type (hazard ratio: 1.20; 95% confidence interval 1.04-1.40, P for trend < .0009 and HR: 1.32; 95% CI, 1.00-1.73, P for trend < .03).

Sugary drinks were defined as containing 5% or more of sugars, including natural fruit juices. The high consumers in the study had a median intake of 185 mL per day of sugary drinks, or 176 mL per day for artificially sweetened drinks. Natural noncaloric sweeteners such as Stevia were included in the artificially sweetened group.

The findings, Mr. Chazelas and colleagues wrote in their analysis, add to evidence that artificially sweetened beverages “might not be a healthy substitute for sugary drinks.” While research has suggested that artificial sweeteners induce glucose intolerance by disturbing gut microbiota, they noted, more and bigger studies are needed to understand the mechanisms by which they might bear on cardiovascular disease risk.

Robert A. Vogel, MD, of the University of Colorado Denver, urged caution in interpreting the researchers’ results. In an interview, Dr. Vogel, a preventive cardiologist, said that it is “notoriously difficult” to evaluate what a food or food group does to the body outside of a carefully controlled trial. What little randomized trial evidence exists comparing the health effects of artificially sweetened and sugary drinks includes a 2012 trial in children that found diet drinks associated with reductions in body fat – if anything a positive indication for heart health.

SOURCE: Chazelas et al. JACC 2020;76(18):2175-80.

Cardiac stress testing before hip and knee replacements has dropped steadily since 2006, according to results from a new study that also showed major cardiac complications to be low in the absence of stress testing – even among people with established risk factors.

Routine stress testing before noncardiac surgeries has come under fire in recent decades as an overuse of resources and a burden on patients. Practice guidelines issued in 2007 and 2014 by the American College of Cardiology and the American Heart Association sought to limit the use of preoperative testing to patients with specific cardiovascular risk factors who might have their management changed by the test results.

For their study, published online in JAMA Cardiology, Daniel S. Rubin, MD, of the University of Chicago and colleagues looked at employee-based insurance data, which included Medicare Advantage claims, for more than 800,000 total hip or knee arthroplasties (28% hip and 72% knee replacements) conducted between 2004 and 2017.

While some 10% of the cohort (mean age 62, 58% women) received a stress test in the 2 months before surgery, the investigators found that the frequency of preoperative stress testing dropped annually starting in late 2006, when it peaked at about 14%, to about 7% in 2017. Older age, male sex and a Revised Cardiac Risk Index score of 1 or greater were all associated with a higher likelihood of being tested.

The overall frequency of myocardial infarction or cardiac arrest was 0.24%, occurring in 1,677 of 686,067 patients. While the rate was higher in patients with at least one RCRI condition, this did not differ significantly between those who received a preoperative stress test and those who did not (0.60%; 221 of 36,554 vs. 0.57%; 694 of 122,466 patients.

The 2007 and 2014 ACC/AHA guidelines make clear that patients with zero RCRI conditions – which comprise a history of ischemic heart disease, heart failure, insulin therapy for diabetes, cerebrovascular disease, or chronic kidney disease – should not receive a stress test before an intermediate-risk surgery such as a hip or knee replacement. But in this study, Dr. Rubin and his colleagues found that almost half of patients who had no RCRI risk factors were stress tested anyway. This means, Dr. Rubin said in an interview, that “there’s still room for improvement” in reducing testing.

“I never want to question how a physician chooses to practice, but I have to applaud physicians for reining in the use of this test. We’re using less of this test and yet the incidence of myocardial infarction and cardiac arrest is also going down, which also calls into question whether we’re getting better at choosing the right patients for the test; or the test doesn’t impact outcomes; or overall health of these patients is improving,” he said.

One surprise finding in the study, Dr. Rubin noted, was a higher rate of complications among people without RCRI conditions who were stress tested, compared with those who were not, with a mean complication rate of 0.27%, compared with 0.14% among those who did not receive a test (P < .001). “The RCRI doesn’t capture certain things,” Dr. Rubin said. “And we know that no risk stratification tool is going to capture everything.”

The RCRI, he noted, is based on a clinical history. “If you haven’t been diagnosed yet, it won’t appear as a risk factor, even if you’re clearly at risk. The question then becomes for a physician, do you do the test or not? On a day-to-day basis it’s hard to make that decision because you want what’s best for the individual patient – and it’s hard to generalize from a study of 800,000 people what’s right for that one patient. That said, it doesn’t appear that stress testing improves outcomes and a decrease in testing appears appropriate.”

Dr. Rubin and his colleagues described as a weakness of their study that it did not capture the full scope of preoperative stress testing among Medicare patients, who are older and therefore more likely to be tested.

That the 2007 and 2014 practice guidelines bore on the drop in testing was not demonstrated by Dr. Rubin and colleagues’ study, which saw declines begin even before the guidelines were published. Nonetheless, the results appear to validate the approach advocated in the guidelines, said guideline coauthor Joshua Beckman, MD, of Vanderbilt University, whose recent research has focused on identifying risk factors for MI after noncardiac surgery.

“I hope that the guidelines have helped in changing the culture for the use of preoperative stress testing as a regular thing,” Dr. Beckman said in an interview. “In fact, the guidelines say you shouldn’t do anything before an operation that you wouldn’t do anyway. So these findings are certainly in agreement with what we’re suggesting and support the idea that unless you have something that is unstable or active, stress testing isn’t likely to help.”

Annemarie Thompson, MD, of Duke University in Durham, N.C., another coauthor on the 2014 guidelines, commented in an interview that Dr. Rubin and colleagues’ findings of a doubled rate of complications among people without RCRI conditions who were stress tested, compared with those who were not might mean something “other than just sheer overuse or overordering of tests inappropriately.”

Rather, she said, physicians might be seeing something in the clinic that cannot be captured by a screening tool reliant on existing diagnoses. “Maybe when they’re sitting in front of you in a clinic, they’re so immobile that you’re left wondering. Or maybe they haven’t been seen by a doctor in a long time,” Dr. Thompson said. “So they don’t have diagnoses if they haven’t been followed. I think what [this finding] shows is that clinicians are detecting something. They may not know what it is. But we have to give a little wiggle room to the clinician who is sitting there looking at a patient who looks like they may not make it through surgery.”

Dr. Thompson said it would be helpful, after a big-data study like this one, to go through the clinical histories of those patients – in this study fewer than 100 – who had no RCRI risk factors and yet were stress tested and ended up having complications. “Until then we’re not going to solve the mystery,” she said. “But it’s a very, very interesting study.”

Dr. Rubin is the president of DRDR Mobile Health, a company that creates mobile applications for health care and from which he has not received compensation. One of his coauthors on the study, Dr. Peter Nagele, reported fee income from Roche Diagnostics. Dr. Beckman disclosed personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and other pharmaceutical manufacturers. Dr. Thompson has no disclosures.

SOURCE: Rubin et al. JAMA Cardiol. 2020 Sep 30. doi: 10.1001/jamacardio.2020.4311.

Cardiac stress testing before hip and knee replacements has dropped steadily since 2006, according to results from a new study that also showed major cardiac complications to be low in the absence of stress testing – even among people with established risk factors.

Routine stress testing before noncardiac surgeries has come under fire in recent decades as an overuse of resources and a burden on patients. Practice guidelines issued in 2007 and 2014 by the American College of Cardiology and the American Heart Association sought to limit the use of preoperative testing to patients with specific cardiovascular risk factors who might have their management changed by the test results.

For their study, published online in JAMA Cardiology, Daniel S. Rubin, MD, of the University of Chicago and colleagues looked at employee-based insurance data, which included Medicare Advantage claims, for more than 800,000 total hip or knee arthroplasties (28% hip and 72% knee replacements) conducted between 2004 and 2017.

While some 10% of the cohort (mean age 62, 58% women) received a stress test in the 2 months before surgery, the investigators found that the frequency of preoperative stress testing dropped annually starting in late 2006, when it peaked at about 14%, to about 7% in 2017. Older age, male sex and a Revised Cardiac Risk Index score of 1 or greater were all associated with a higher likelihood of being tested.

The overall frequency of myocardial infarction or cardiac arrest was 0.24%, occurring in 1,677 of 686,067 patients. While the rate was higher in patients with at least one RCRI condition, this did not differ significantly between those who received a preoperative stress test and those who did not (0.60%; 221 of 36,554 vs. 0.57%; 694 of 122,466 patients.

The 2007 and 2014 ACC/AHA guidelines make clear that patients with zero RCRI conditions – which comprise a history of ischemic heart disease, heart failure, insulin therapy for diabetes, cerebrovascular disease, or chronic kidney disease – should not receive a stress test before an intermediate-risk surgery such as a hip or knee replacement. But in this study, Dr. Rubin and his colleagues found that almost half of patients who had no RCRI risk factors were stress tested anyway. This means, Dr. Rubin said in an interview, that “there’s still room for improvement” in reducing testing.

“I never want to question how a physician chooses to practice, but I have to applaud physicians for reining in the use of this test. We’re using less of this test and yet the incidence of myocardial infarction and cardiac arrest is also going down, which also calls into question whether we’re getting better at choosing the right patients for the test; or the test doesn’t impact outcomes; or overall health of these patients is improving,” he said.

One surprise finding in the study, Dr. Rubin noted, was a higher rate of complications among people without RCRI conditions who were stress tested, compared with those who were not, with a mean complication rate of 0.27%, compared with 0.14% among those who did not receive a test (P < .001). “The RCRI doesn’t capture certain things,” Dr. Rubin said. “And we know that no risk stratification tool is going to capture everything.”

The RCRI, he noted, is based on a clinical history. “If you haven’t been diagnosed yet, it won’t appear as a risk factor, even if you’re clearly at risk. The question then becomes for a physician, do you do the test or not? On a day-to-day basis it’s hard to make that decision because you want what’s best for the individual patient – and it’s hard to generalize from a study of 800,000 people what’s right for that one patient. That said, it doesn’t appear that stress testing improves outcomes and a decrease in testing appears appropriate.”

Dr. Rubin and his colleagues described as a weakness of their study that it did not capture the full scope of preoperative stress testing among Medicare patients, who are older and therefore more likely to be tested.

That the 2007 and 2014 practice guidelines bore on the drop in testing was not demonstrated by Dr. Rubin and colleagues’ study, which saw declines begin even before the guidelines were published. Nonetheless, the results appear to validate the approach advocated in the guidelines, said guideline coauthor Joshua Beckman, MD, of Vanderbilt University, whose recent research has focused on identifying risk factors for MI after noncardiac surgery.

“I hope that the guidelines have helped in changing the culture for the use of preoperative stress testing as a regular thing,” Dr. Beckman said in an interview. “In fact, the guidelines say you shouldn’t do anything before an operation that you wouldn’t do anyway. So these findings are certainly in agreement with what we’re suggesting and support the idea that unless you have something that is unstable or active, stress testing isn’t likely to help.”

Annemarie Thompson, MD, of Duke University in Durham, N.C., another coauthor on the 2014 guidelines, commented in an interview that Dr. Rubin and colleagues’ findings of a doubled rate of complications among people without RCRI conditions who were stress tested, compared with those who were not might mean something “other than just sheer overuse or overordering of tests inappropriately.”

Rather, she said, physicians might be seeing something in the clinic that cannot be captured by a screening tool reliant on existing diagnoses. “Maybe when they’re sitting in front of you in a clinic, they’re so immobile that you’re left wondering. Or maybe they haven’t been seen by a doctor in a long time,” Dr. Thompson said. “So they don’t have diagnoses if they haven’t been followed. I think what [this finding] shows is that clinicians are detecting something. They may not know what it is. But we have to give a little wiggle room to the clinician who is sitting there looking at a patient who looks like they may not make it through surgery.”

Dr. Thompson said it would be helpful, after a big-data study like this one, to go through the clinical histories of those patients – in this study fewer than 100 – who had no RCRI risk factors and yet were stress tested and ended up having complications. “Until then we’re not going to solve the mystery,” she said. “But it’s a very, very interesting study.”

Dr. Rubin is the president of DRDR Mobile Health, a company that creates mobile applications for health care and from which he has not received compensation. One of his coauthors on the study, Dr. Peter Nagele, reported fee income from Roche Diagnostics. Dr. Beckman disclosed personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and other pharmaceutical manufacturers. Dr. Thompson has no disclosures.

SOURCE: Rubin et al. JAMA Cardiol. 2020 Sep 30. doi: 10.1001/jamacardio.2020.4311.

Cardiac stress testing before hip and knee replacements has dropped steadily since 2006, according to results from a new study that also showed major cardiac complications to be low in the absence of stress testing – even among people with established risk factors.

Routine stress testing before noncardiac surgeries has come under fire in recent decades as an overuse of resources and a burden on patients. Practice guidelines issued in 2007 and 2014 by the American College of Cardiology and the American Heart Association sought to limit the use of preoperative testing to patients with specific cardiovascular risk factors who might have their management changed by the test results.

For their study, published online in JAMA Cardiology, Daniel S. Rubin, MD, of the University of Chicago and colleagues looked at employee-based insurance data, which included Medicare Advantage claims, for more than 800,000 total hip or knee arthroplasties (28% hip and 72% knee replacements) conducted between 2004 and 2017.

While some 10% of the cohort (mean age 62, 58% women) received a stress test in the 2 months before surgery, the investigators found that the frequency of preoperative stress testing dropped annually starting in late 2006, when it peaked at about 14%, to about 7% in 2017. Older age, male sex and a Revised Cardiac Risk Index score of 1 or greater were all associated with a higher likelihood of being tested.

The overall frequency of myocardial infarction or cardiac arrest was 0.24%, occurring in 1,677 of 686,067 patients. While the rate was higher in patients with at least one RCRI condition, this did not differ significantly between those who received a preoperative stress test and those who did not (0.60%; 221 of 36,554 vs. 0.57%; 694 of 122,466 patients.

The 2007 and 2014 ACC/AHA guidelines make clear that patients with zero RCRI conditions – which comprise a history of ischemic heart disease, heart failure, insulin therapy for diabetes, cerebrovascular disease, or chronic kidney disease – should not receive a stress test before an intermediate-risk surgery such as a hip or knee replacement. But in this study, Dr. Rubin and his colleagues found that almost half of patients who had no RCRI risk factors were stress tested anyway. This means, Dr. Rubin said in an interview, that “there’s still room for improvement” in reducing testing.

“I never want to question how a physician chooses to practice, but I have to applaud physicians for reining in the use of this test. We’re using less of this test and yet the incidence of myocardial infarction and cardiac arrest is also going down, which also calls into question whether we’re getting better at choosing the right patients for the test; or the test doesn’t impact outcomes; or overall health of these patients is improving,” he said.

One surprise finding in the study, Dr. Rubin noted, was a higher rate of complications among people without RCRI conditions who were stress tested, compared with those who were not, with a mean complication rate of 0.27%, compared with 0.14% among those who did not receive a test (P < .001). “The RCRI doesn’t capture certain things,” Dr. Rubin said. “And we know that no risk stratification tool is going to capture everything.”

The RCRI, he noted, is based on a clinical history. “If you haven’t been diagnosed yet, it won’t appear as a risk factor, even if you’re clearly at risk. The question then becomes for a physician, do you do the test or not? On a day-to-day basis it’s hard to make that decision because you want what’s best for the individual patient – and it’s hard to generalize from a study of 800,000 people what’s right for that one patient. That said, it doesn’t appear that stress testing improves outcomes and a decrease in testing appears appropriate.”

Dr. Rubin and his colleagues described as a weakness of their study that it did not capture the full scope of preoperative stress testing among Medicare patients, who are older and therefore more likely to be tested.

That the 2007 and 2014 practice guidelines bore on the drop in testing was not demonstrated by Dr. Rubin and colleagues’ study, which saw declines begin even before the guidelines were published. Nonetheless, the results appear to validate the approach advocated in the guidelines, said guideline coauthor Joshua Beckman, MD, of Vanderbilt University, whose recent research has focused on identifying risk factors for MI after noncardiac surgery.

“I hope that the guidelines have helped in changing the culture for the use of preoperative stress testing as a regular thing,” Dr. Beckman said in an interview. “In fact, the guidelines say you shouldn’t do anything before an operation that you wouldn’t do anyway. So these findings are certainly in agreement with what we’re suggesting and support the idea that unless you have something that is unstable or active, stress testing isn’t likely to help.”

Annemarie Thompson, MD, of Duke University in Durham, N.C., another coauthor on the 2014 guidelines, commented in an interview that Dr. Rubin and colleagues’ findings of a doubled rate of complications among people without RCRI conditions who were stress tested, compared with those who were not might mean something “other than just sheer overuse or overordering of tests inappropriately.”

Rather, she said, physicians might be seeing something in the clinic that cannot be captured by a screening tool reliant on existing diagnoses. “Maybe when they’re sitting in front of you in a clinic, they’re so immobile that you’re left wondering. Or maybe they haven’t been seen by a doctor in a long time,” Dr. Thompson said. “So they don’t have diagnoses if they haven’t been followed. I think what [this finding] shows is that clinicians are detecting something. They may not know what it is. But we have to give a little wiggle room to the clinician who is sitting there looking at a patient who looks like they may not make it through surgery.”

Dr. Thompson said it would be helpful, after a big-data study like this one, to go through the clinical histories of those patients – in this study fewer than 100 – who had no RCRI risk factors and yet were stress tested and ended up having complications. “Until then we’re not going to solve the mystery,” she said. “But it’s a very, very interesting study.”

Dr. Rubin is the president of DRDR Mobile Health, a company that creates mobile applications for health care and from which he has not received compensation. One of his coauthors on the study, Dr. Peter Nagele, reported fee income from Roche Diagnostics. Dr. Beckman disclosed personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and other pharmaceutical manufacturers. Dr. Thompson has no disclosures.

SOURCE: Rubin et al. JAMA Cardiol. 2020 Sep 30. doi: 10.1001/jamacardio.2020.4311.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

While guidelines for bronchiolitis aim to reduce gratuitous tests and treatments, one-third of infants presenting at EDs with bronchiolitis receive an unnecessary intervention, according to a new global study.

For infants with symptoms of bronchiolitis, viral testing, blood tests, and chest x-rays are discouraged in most cases. Antibiotics are not recommended as treatment.

In a study published in Pediatrics, Amy Zipursky, MD, of the Hospital for Sick Children and the University of Toronto, and colleagues, reviewed records for 2,359 infants aged 2-11 months diagnosed with bronchiolitis during the year 2013. The data came from a network of 38 EDs in the Australia, Canada, Ireland, New Zealand, Portugal, Spain, the United Kingdom, and the United States.

Dr. Zipursky and colleagues found that, while 8% of infants in the cohort had been treated with antibiotics, 33% had received at least one nonrecommended test, with rates ranging widely across regions. In the United Kingdom and Ireland, for example, only 15% received such a test, compared with 50% in Spain and Portugal.

Of the children given antibiotics, two-thirds had suspected bacterial infections, the researchers found. Antibiotic use was highest in the United States, at 11% of infants seen for bronchiolitis, and lowest in the United Kingdom and Ireland at 4%. Administration of chest x-rays – which occurred in nearly a quarter of the cohort – increased the likelihood of antibiotics being administered (odds ratio, 2.29; 95% confidence interval, 1.62-3.24) independent of fever or severe symptoms.

The most common nonrecommended tests performed in the study were:

• Nasopharyngeal viral testing without admission to hospital (n = 591).
• Chest x-ray without ICU admission (n = 507).
• Complete blood counts (n = 222).
• Blood cultures (n = 129).
• Urinalysis in the absence of fever (n = 86).
• Febrile infants 3 months of age or less had blood cultures (n = 49).

In some treatment centers the rate of nonrecommended tests performed was 6%, while others saw rates of 74%.

“Despite the evidence that laboratory testing rarely impacts bronchiolitis management and that bacterial infections in bronchiolitis are uncommon, our study reveals that these tests continue to be performed frequently in many parts of the world,” Dr. Zipursky and colleagues wrote in their analysis.

“Plausible reasons may include ‘automatic’ blood draws with intravenous placement, uncertainty about institutional policies, perceived need for reassurance about the diagnosis, perception of ‘doing something,’ and parental desire for a viral label,” the authors surmised. “Because parental pressure to provide interventions may be a driver of care in infants with bronchiolitis in some countries, ED clinicians need to have higher confidence in the evidence-based bronchiolitis care and convey this trust to families.”

The researchers listed among the weaknesses of their study its retrospective design, and that results from x-rays and lab tests performed were not available.

In an editorial comment accompanying the study, Joseph J. Zorc, MD, of Children’s Hospital of Philadelphia and the University of Pennsylvania in Philadelphia, noted that some of the regional differences seen in the study may be attributable to different clinical criteria used to diagnose bronchiolitis. In the United Kingdom, for example, national guidelines include the presence of crackles, while in North America guidelines focus on wheeze. “Perhaps clinicians in the United Kingdom accept the presence of crackles as an expected finding in infant with bronchiolitis and are less likely to order imaging,” Dr. Zorc said (Pediatrics. 2020 Jul 13;146[2]:e20193684).

He also pointed out that the coronavirus pandemic caused by SARS-CoV-2 (COVID- 19) could have an impact on global testing and treatment practices for bronchiolitis, as coronaviruses are a known cause of bronchiolitis. The Pediatric Emergency Research Network, comprising the 38 EDs from which Dr. Zipursky and colleagues drew their data, is conducting a prospective study looking at pediatric disease caused by SARS-CoV-2.

The “collaboration of international networks of pediatric emergency providers is an encouraging sign of potential opportunities to come ... [providing] an opportunity to evaluate variation that can lead to innovation,” Dr. Zorc concluded.

Dr. Zipursky and colleagues reported no external funding or relevant financial disclosures. Dr. Zorc reported no relevant conflicts of interest.

SOURCE: Zipursky A et al. Pediatrics. 2020 Jul 13;146(2):e2020002311.

While guidelines for bronchiolitis aim to reduce gratuitous tests and treatments, one-third of infants presenting at EDs with bronchiolitis receive an unnecessary intervention, according to a new global study.

For infants with symptoms of bronchiolitis, viral testing, blood tests, and chest x-rays are discouraged in most cases. Antibiotics are not recommended as treatment.

In a study published in Pediatrics, Amy Zipursky, MD, of the Hospital for Sick Children and the University of Toronto, and colleagues, reviewed records for 2,359 infants aged 2-11 months diagnosed with bronchiolitis during the year 2013. The data came from a network of 38 EDs in the Australia, Canada, Ireland, New Zealand, Portugal, Spain, the United Kingdom, and the United States.

Dr. Zipursky and colleagues found that, while 8% of infants in the cohort had been treated with antibiotics, 33% had received at least one nonrecommended test, with rates ranging widely across regions. In the United Kingdom and Ireland, for example, only 15% received such a test, compared with 50% in Spain and Portugal.

Of the children given antibiotics, two-thirds had suspected bacterial infections, the researchers found. Antibiotic use was highest in the United States, at 11% of infants seen for bronchiolitis, and lowest in the United Kingdom and Ireland at 4%. Administration of chest x-rays – which occurred in nearly a quarter of the cohort – increased the likelihood of antibiotics being administered (odds ratio, 2.29; 95% confidence interval, 1.62-3.24) independent of fever or severe symptoms.

The most common nonrecommended tests performed in the study were:

• Nasopharyngeal viral testing without admission to hospital (n = 591).
• Chest x-ray without ICU admission (n = 507).
• Complete blood counts (n = 222).
• Blood cultures (n = 129).
• Urinalysis in the absence of fever (n = 86).
• Febrile infants 3 months of age or less had blood cultures (n = 49).

In some treatment centers the rate of nonrecommended tests performed was 6%, while others saw rates of 74%.

“Despite the evidence that laboratory testing rarely impacts bronchiolitis management and that bacterial infections in bronchiolitis are uncommon, our study reveals that these tests continue to be performed frequently in many parts of the world,” Dr. Zipursky and colleagues wrote in their analysis.

“Plausible reasons may include ‘automatic’ blood draws with intravenous placement, uncertainty about institutional policies, perceived need for reassurance about the diagnosis, perception of ‘doing something,’ and parental desire for a viral label,” the authors surmised. “Because parental pressure to provide interventions may be a driver of care in infants with bronchiolitis in some countries, ED clinicians need to have higher confidence in the evidence-based bronchiolitis care and convey this trust to families.”

The researchers listed among the weaknesses of their study its retrospective design, and that results from x-rays and lab tests performed were not available.

In an editorial comment accompanying the study, Joseph J. Zorc, MD, of Children’s Hospital of Philadelphia and the University of Pennsylvania in Philadelphia, noted that some of the regional differences seen in the study may be attributable to different clinical criteria used to diagnose bronchiolitis. In the United Kingdom, for example, national guidelines include the presence of crackles, while in North America guidelines focus on wheeze. “Perhaps clinicians in the United Kingdom accept the presence of crackles as an expected finding in infant with bronchiolitis and are less likely to order imaging,” Dr. Zorc said (Pediatrics. 2020 Jul 13;146[2]:e20193684).

He also pointed out that the coronavirus pandemic caused by SARS-CoV-2 (COVID- 19) could have an impact on global testing and treatment practices for bronchiolitis, as coronaviruses are a known cause of bronchiolitis. The Pediatric Emergency Research Network, comprising the 38 EDs from which Dr. Zipursky and colleagues drew their data, is conducting a prospective study looking at pediatric disease caused by SARS-CoV-2.

The “collaboration of international networks of pediatric emergency providers is an encouraging sign of potential opportunities to come ... [providing] an opportunity to evaluate variation that can lead to innovation,” Dr. Zorc concluded.

Dr. Zipursky and colleagues reported no external funding or relevant financial disclosures. Dr. Zorc reported no relevant conflicts of interest.

SOURCE: Zipursky A et al. Pediatrics. 2020 Jul 13;146(2):e2020002311.

While guidelines for bronchiolitis aim to reduce gratuitous tests and treatments, one-third of infants presenting at EDs with bronchiolitis receive an unnecessary intervention, according to a new global study.

For infants with symptoms of bronchiolitis, viral testing, blood tests, and chest x-rays are discouraged in most cases. Antibiotics are not recommended as treatment.

In a study published in Pediatrics, Amy Zipursky, MD, of the Hospital for Sick Children and the University of Toronto, and colleagues, reviewed records for 2,359 infants aged 2-11 months diagnosed with bronchiolitis during the year 2013. The data came from a network of 38 EDs in the Australia, Canada, Ireland, New Zealand, Portugal, Spain, the United Kingdom, and the United States.

Dr. Zipursky and colleagues found that, while 8% of infants in the cohort had been treated with antibiotics, 33% had received at least one nonrecommended test, with rates ranging widely across regions. In the United Kingdom and Ireland, for example, only 15% received such a test, compared with 50% in Spain and Portugal.

Of the children given antibiotics, two-thirds had suspected bacterial infections, the researchers found. Antibiotic use was highest in the United States, at 11% of infants seen for bronchiolitis, and lowest in the United Kingdom and Ireland at 4%. Administration of chest x-rays – which occurred in nearly a quarter of the cohort – increased the likelihood of antibiotics being administered (odds ratio, 2.29; 95% confidence interval, 1.62-3.24) independent of fever or severe symptoms.

The most common nonrecommended tests performed in the study were:

• Nasopharyngeal viral testing without admission to hospital (n = 591).
• Chest x-ray without ICU admission (n = 507).
• Complete blood counts (n = 222).
• Blood cultures (n = 129).
• Urinalysis in the absence of fever (n = 86).
• Febrile infants 3 months of age or less had blood cultures (n = 49).

In some treatment centers the rate of nonrecommended tests performed was 6%, while others saw rates of 74%.

“Despite the evidence that laboratory testing rarely impacts bronchiolitis management and that bacterial infections in bronchiolitis are uncommon, our study reveals that these tests continue to be performed frequently in many parts of the world,” Dr. Zipursky and colleagues wrote in their analysis.

“Plausible reasons may include ‘automatic’ blood draws with intravenous placement, uncertainty about institutional policies, perceived need for reassurance about the diagnosis, perception of ‘doing something,’ and parental desire for a viral label,” the authors surmised. “Because parental pressure to provide interventions may be a driver of care in infants with bronchiolitis in some countries, ED clinicians need to have higher confidence in the evidence-based bronchiolitis care and convey this trust to families.”

The researchers listed among the weaknesses of their study its retrospective design, and that results from x-rays and lab tests performed were not available.

In an editorial comment accompanying the study, Joseph J. Zorc, MD, of Children’s Hospital of Philadelphia and the University of Pennsylvania in Philadelphia, noted that some of the regional differences seen in the study may be attributable to different clinical criteria used to diagnose bronchiolitis. In the United Kingdom, for example, national guidelines include the presence of crackles, while in North America guidelines focus on wheeze. “Perhaps clinicians in the United Kingdom accept the presence of crackles as an expected finding in infant with bronchiolitis and are less likely to order imaging,” Dr. Zorc said (Pediatrics. 2020 Jul 13;146[2]:e20193684).

He also pointed out that the coronavirus pandemic caused by SARS-CoV-2 (COVID- 19) could have an impact on global testing and treatment practices for bronchiolitis, as coronaviruses are a known cause of bronchiolitis. The Pediatric Emergency Research Network, comprising the 38 EDs from which Dr. Zipursky and colleagues drew their data, is conducting a prospective study looking at pediatric disease caused by SARS-CoV-2.

The “collaboration of international networks of pediatric emergency providers is an encouraging sign of potential opportunities to come ... [providing] an opportunity to evaluate variation that can lead to innovation,” Dr. Zorc concluded.

Dr. Zipursky and colleagues reported no external funding or relevant financial disclosures. Dr. Zorc reported no relevant conflicts of interest.

SOURCE: Zipursky A et al. Pediatrics. 2020 Jul 13;146(2):e2020002311.