MADRID – Consistent with previous evidence of higher relative rates of drug delivery, mesh nebulizers offer several advantages over jet nebulizers for treatment of acute asthma in children presenting to an emergency department, according to results of a randomized trial presented at the annual congress of the European Respiratory Society.

For the primary outcome of hospital admission, the advantage of the mesh over the jet nebulizer only reached significance when used with a mask, rather than a valve, but trial results overall support the conclusion that the mesh device delivers drug more efficiently, according to Gerald Moody, RRT-NPS, clinical research coordinator at Children’s Medical Center, Dallas.

In this multicenter, single-blinded trial, 217 children presenting to an ED with acute asthma of moderate or greater severity were randomized to receive bronchodilator treatment delivered with a mesh device or a jet device. For drug delivery, aerosol masks or mouthpiece valves were permitted and selected at the discretion of the clinician administrating treatment. Masks were used in 80% of cases.

Patients remained in the study until either symptom control was achieved or a decision was reached to advise hospital admission. Patients with complex comorbidities or who had received oral corticosteroids within the previous 24 hours were excluded.

For the primary outcome of hospital discharge, the 31% reduction (P = .22) in hospitalization in favor of the mesh nebulizer failed to reach statistical significance. Although the study is likely to have been underpowered, Mr. Moody also pointed out an uneven distribution in severity of disease at baseline. In addition to a significantly higher median asthma score (9.0 vs. 8.0; P = .042) in the mesh nebulizer group, there was also a significantly higher percentage with severe disease (57% vs. 42%; P = .025).

“There were no significant differences in any of the other variables we evaluated, such as age, gender, race, or body mass index,” Mr. Moody reported.

Despite the higher disease burden in the mesh nebulizer group, there was a 48% reduction (P = .03) in hospital admissions among those randomized to the mesh nebulizer when both groups received treatment through a mask.

In addition, those treated with the mask required on average only two treatments before achieving symptom control whether they met criteria for moderate or severe asthma at baseline. The median numbers of treatments in the jet nebulizer group for moderate and severe asthma were 3 and 3.5, respectively.

In previous experimental studies, which ultimately provided the rationale for this trial, the estimated amount of drug reaching the airways with a mesh nebulizer was approximately twice as great as that estimated in the model when delivery was performed with a jet device, according to Mr. Moody.

This study appeared to corroborate that advantage. Both the median doses of albuterol (10 mg vs. 15 mg) and ipratropium (1,000 mcg vs. 1,500 mcg) were significantly lower (P less than .001 for both) among the patients randomized to the mesh nebulizer.

Although the jet nebulizers are widely employed “for their ease of use and low cost,” Mr. Moody characterized mesh nebulizers as an advance in technology. In this study, which Mr. Moody said is the first to evaluate whether the experimental evidence of greater drug delivery efficiency translates into a clinical advantage, the primary endpoint was missed, but Mr. Moody indicated that the overall findings support the potential for a difference.

The ERS-invited discussant on this study, Celeste Michala Porsbjerg, MD, Bispebjerg Hospital, Copenhagen University, expressed a concern that might deserve attention in a larger trial. Based on the premise that more efficient delivery increases drug exposure, she questioned whether it might not also increase risks.

There were no significant treatment-related adverse events reported in either arm of this study, Mr. Moody responded, but he conceded that this is an appropriate focus of attention for future studies.

Mr. Moody reported a financial relationship with Aerogen, which produces the mesh device tested in this trial.

MADRID – Consistent with previous evidence of higher relative rates of drug delivery, mesh nebulizers offer several advantages over jet nebulizers for treatment of acute asthma in children presenting to an emergency department, according to results of a randomized trial presented at the annual congress of the European Respiratory Society.

For the primary outcome of hospital admission, the advantage of the mesh over the jet nebulizer only reached significance when used with a mask, rather than a valve, but trial results overall support the conclusion that the mesh device delivers drug more efficiently, according to Gerald Moody, RRT-NPS, clinical research coordinator at Children’s Medical Center, Dallas.

In this multicenter, single-blinded trial, 217 children presenting to an ED with acute asthma of moderate or greater severity were randomized to receive bronchodilator treatment delivered with a mesh device or a jet device. For drug delivery, aerosol masks or mouthpiece valves were permitted and selected at the discretion of the clinician administrating treatment. Masks were used in 80% of cases.

Patients remained in the study until either symptom control was achieved or a decision was reached to advise hospital admission. Patients with complex comorbidities or who had received oral corticosteroids within the previous 24 hours were excluded.

For the primary outcome of hospital discharge, the 31% reduction (P = .22) in hospitalization in favor of the mesh nebulizer failed to reach statistical significance. Although the study is likely to have been underpowered, Mr. Moody also pointed out an uneven distribution in severity of disease at baseline. In addition to a significantly higher median asthma score (9.0 vs. 8.0; P = .042) in the mesh nebulizer group, there was also a significantly higher percentage with severe disease (57% vs. 42%; P = .025).

“There were no significant differences in any of the other variables we evaluated, such as age, gender, race, or body mass index,” Mr. Moody reported.

Despite the higher disease burden in the mesh nebulizer group, there was a 48% reduction (P = .03) in hospital admissions among those randomized to the mesh nebulizer when both groups received treatment through a mask.

In addition, those treated with the mask required on average only two treatments before achieving symptom control whether they met criteria for moderate or severe asthma at baseline. The median numbers of treatments in the jet nebulizer group for moderate and severe asthma were 3 and 3.5, respectively.

In previous experimental studies, which ultimately provided the rationale for this trial, the estimated amount of drug reaching the airways with a mesh nebulizer was approximately twice as great as that estimated in the model when delivery was performed with a jet device, according to Mr. Moody.

This study appeared to corroborate that advantage. Both the median doses of albuterol (10 mg vs. 15 mg) and ipratropium (1,000 mcg vs. 1,500 mcg) were significantly lower (P less than .001 for both) among the patients randomized to the mesh nebulizer.

Although the jet nebulizers are widely employed “for their ease of use and low cost,” Mr. Moody characterized mesh nebulizers as an advance in technology. In this study, which Mr. Moody said is the first to evaluate whether the experimental evidence of greater drug delivery efficiency translates into a clinical advantage, the primary endpoint was missed, but Mr. Moody indicated that the overall findings support the potential for a difference.

The ERS-invited discussant on this study, Celeste Michala Porsbjerg, MD, Bispebjerg Hospital, Copenhagen University, expressed a concern that might deserve attention in a larger trial. Based on the premise that more efficient delivery increases drug exposure, she questioned whether it might not also increase risks.

There were no significant treatment-related adverse events reported in either arm of this study, Mr. Moody responded, but he conceded that this is an appropriate focus of attention for future studies.

Mr. Moody reported a financial relationship with Aerogen, which produces the mesh device tested in this trial.

MADRID – Consistent with previous evidence of higher relative rates of drug delivery, mesh nebulizers offer several advantages over jet nebulizers for treatment of acute asthma in children presenting to an emergency department, according to results of a randomized trial presented at the annual congress of the European Respiratory Society.

For the primary outcome of hospital admission, the advantage of the mesh over the jet nebulizer only reached significance when used with a mask, rather than a valve, but trial results overall support the conclusion that the mesh device delivers drug more efficiently, according to Gerald Moody, RRT-NPS, clinical research coordinator at Children’s Medical Center, Dallas.

In this multicenter, single-blinded trial, 217 children presenting to an ED with acute asthma of moderate or greater severity were randomized to receive bronchodilator treatment delivered with a mesh device or a jet device. For drug delivery, aerosol masks or mouthpiece valves were permitted and selected at the discretion of the clinician administrating treatment. Masks were used in 80% of cases.

Patients remained in the study until either symptom control was achieved or a decision was reached to advise hospital admission. Patients with complex comorbidities or who had received oral corticosteroids within the previous 24 hours were excluded.

For the primary outcome of hospital discharge, the 31% reduction (P = .22) in hospitalization in favor of the mesh nebulizer failed to reach statistical significance. Although the study is likely to have been underpowered, Mr. Moody also pointed out an uneven distribution in severity of disease at baseline. In addition to a significantly higher median asthma score (9.0 vs. 8.0; P = .042) in the mesh nebulizer group, there was also a significantly higher percentage with severe disease (57% vs. 42%; P = .025).

“There were no significant differences in any of the other variables we evaluated, such as age, gender, race, or body mass index,” Mr. Moody reported.

Despite the higher disease burden in the mesh nebulizer group, there was a 48% reduction (P = .03) in hospital admissions among those randomized to the mesh nebulizer when both groups received treatment through a mask.

In addition, those treated with the mask required on average only two treatments before achieving symptom control whether they met criteria for moderate or severe asthma at baseline. The median numbers of treatments in the jet nebulizer group for moderate and severe asthma were 3 and 3.5, respectively.

In previous experimental studies, which ultimately provided the rationale for this trial, the estimated amount of drug reaching the airways with a mesh nebulizer was approximately twice as great as that estimated in the model when delivery was performed with a jet device, according to Mr. Moody.

This study appeared to corroborate that advantage. Both the median doses of albuterol (10 mg vs. 15 mg) and ipratropium (1,000 mcg vs. 1,500 mcg) were significantly lower (P less than .001 for both) among the patients randomized to the mesh nebulizer.

Although the jet nebulizers are widely employed “for their ease of use and low cost,” Mr. Moody characterized mesh nebulizers as an advance in technology. In this study, which Mr. Moody said is the first to evaluate whether the experimental evidence of greater drug delivery efficiency translates into a clinical advantage, the primary endpoint was missed, but Mr. Moody indicated that the overall findings support the potential for a difference.

The ERS-invited discussant on this study, Celeste Michala Porsbjerg, MD, Bispebjerg Hospital, Copenhagen University, expressed a concern that might deserve attention in a larger trial. Based on the premise that more efficient delivery increases drug exposure, she questioned whether it might not also increase risks.

There were no significant treatment-related adverse events reported in either arm of this study, Mr. Moody responded, but he conceded that this is an appropriate focus of attention for future studies.

Mr. Moody reported a financial relationship with Aerogen, which produces the mesh device tested in this trial.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Patients with bipolar disorder who had undergone multiple manic episodes had significantly lower regional activation in the prefrontal‐striatal‐amygdala networks than single-episode patients, according to Logan Borgelt of the department of psychiatry and behavioral neuroscience at the University of Cincinnati and associates.

For the study, the investigators collected functional MRI data from 57 first‐episode manic patients (mean age, 19 years; mean Young Mania Rating Scale [YMRS] score, 26) and 50 multiepisode patients (mean age, 32 years; mean YMRS score, 21) who performed a continuous task with emotional distractions, as well as MR spectroscopy from 52 first-episode patients (mean age, 19 years; mean YMRS score, 26) and 54 multiepisode patients (mean age, 32 years; mean YMRS, 22). The study was published in Bipolar Disorders.

The investigation found that activation of the bilateral ventrolateral prefrontal cortex (P = .0122 for left; P = .0007 for right), anterior cingulate cortex (P less than .0001), orbitofrontal cortex (P = .0133), putamen (P = .0032), caudate (P = .0008), and amygdala (P = .0215) was significantly lower in multiepisode patients than in single-episode patients. Glutamate and N‐acetylaspartate concentration in the anterior cingulate cortex was also lower in multiepisode patients.

The age of multiepisode patients was, in general, not heavily associated with worse activation; only the right putamen (r = 0.30) and right thalamus (r = 0.30) reached a moderate effect size.

“Our findings are consistent with a hypothesized vicious cycle in which progressive atrophic changes in the prefrontal cortex are associated with functional decrements in affective networks, which in turn contribute to both further neuronal loss and clinical observations of accelerating symptomatic recurrence. Particularly striking is the widespread and unidirectional nature of the observed differences in activity, inviting speculation that these findings support suggestions of mitochondrial impairment or other metabolic inefficiency,” the investigators wrote.

Mr. Borgelt reported no conflicts. Three coauthors reported consulting with, receiving support and honoraria from, or serving on the speaker’s bureaus for numerous sources. The remaining coauthors did not report any conflicts of interest.

[email protected]

SOURCE: Borgelt L et al. Bipolar Disord. 2019 Apr 26. doi: 10.1111/bdi.12782.

Patients with bipolar disorder who had undergone multiple manic episodes had significantly lower regional activation in the prefrontal‐striatal‐amygdala networks than single-episode patients, according to Logan Borgelt of the department of psychiatry and behavioral neuroscience at the University of Cincinnati and associates.

For the study, the investigators collected functional MRI data from 57 first‐episode manic patients (mean age, 19 years; mean Young Mania Rating Scale [YMRS] score, 26) and 50 multiepisode patients (mean age, 32 years; mean YMRS score, 21) who performed a continuous task with emotional distractions, as well as MR spectroscopy from 52 first-episode patients (mean age, 19 years; mean YMRS score, 26) and 54 multiepisode patients (mean age, 32 years; mean YMRS, 22). The study was published in Bipolar Disorders.

The investigation found that activation of the bilateral ventrolateral prefrontal cortex (P = .0122 for left; P = .0007 for right), anterior cingulate cortex (P less than .0001), orbitofrontal cortex (P = .0133), putamen (P = .0032), caudate (P = .0008), and amygdala (P = .0215) was significantly lower in multiepisode patients than in single-episode patients. Glutamate and N‐acetylaspartate concentration in the anterior cingulate cortex was also lower in multiepisode patients.

The age of multiepisode patients was, in general, not heavily associated with worse activation; only the right putamen (r = 0.30) and right thalamus (r = 0.30) reached a moderate effect size.

“Our findings are consistent with a hypothesized vicious cycle in which progressive atrophic changes in the prefrontal cortex are associated with functional decrements in affective networks, which in turn contribute to both further neuronal loss and clinical observations of accelerating symptomatic recurrence. Particularly striking is the widespread and unidirectional nature of the observed differences in activity, inviting speculation that these findings support suggestions of mitochondrial impairment or other metabolic inefficiency,” the investigators wrote.

Mr. Borgelt reported no conflicts. Three coauthors reported consulting with, receiving support and honoraria from, or serving on the speaker’s bureaus for numerous sources. The remaining coauthors did not report any conflicts of interest.

[email protected]

SOURCE: Borgelt L et al. Bipolar Disord. 2019 Apr 26. doi: 10.1111/bdi.12782.

Patients with bipolar disorder who had undergone multiple manic episodes had significantly lower regional activation in the prefrontal‐striatal‐amygdala networks than single-episode patients, according to Logan Borgelt of the department of psychiatry and behavioral neuroscience at the University of Cincinnati and associates.

For the study, the investigators collected functional MRI data from 57 first‐episode manic patients (mean age, 19 years; mean Young Mania Rating Scale [YMRS] score, 26) and 50 multiepisode patients (mean age, 32 years; mean YMRS score, 21) who performed a continuous task with emotional distractions, as well as MR spectroscopy from 52 first-episode patients (mean age, 19 years; mean YMRS score, 26) and 54 multiepisode patients (mean age, 32 years; mean YMRS, 22). The study was published in Bipolar Disorders.

The investigation found that activation of the bilateral ventrolateral prefrontal cortex (P = .0122 for left; P = .0007 for right), anterior cingulate cortex (P less than .0001), orbitofrontal cortex (P = .0133), putamen (P = .0032), caudate (P = .0008), and amygdala (P = .0215) was significantly lower in multiepisode patients than in single-episode patients. Glutamate and N‐acetylaspartate concentration in the anterior cingulate cortex was also lower in multiepisode patients.

The age of multiepisode patients was, in general, not heavily associated with worse activation; only the right putamen (r = 0.30) and right thalamus (r = 0.30) reached a moderate effect size.

“Our findings are consistent with a hypothesized vicious cycle in which progressive atrophic changes in the prefrontal cortex are associated with functional decrements in affective networks, which in turn contribute to both further neuronal loss and clinical observations of accelerating symptomatic recurrence. Particularly striking is the widespread and unidirectional nature of the observed differences in activity, inviting speculation that these findings support suggestions of mitochondrial impairment or other metabolic inefficiency,” the investigators wrote.

Mr. Borgelt reported no conflicts. Three coauthors reported consulting with, receiving support and honoraria from, or serving on the speaker’s bureaus for numerous sources. The remaining coauthors did not report any conflicts of interest.

[email protected]

SOURCE: Borgelt L et al. Bipolar Disord. 2019 Apr 26. doi: 10.1111/bdi.12782.

Patients with sickle cell disease are 2.5 times more likely to be readmitted within 30 days of a hospital stay than those without SCD, according to the Agency for Healthcare Research and Quality.

The 30-day all-cause readmission rate for index stays with a principal diagnosis of SCD was 33.5% in 2016, compared with 12.5% for non-SCD hospital stays. Patients with a secondary diagnosis of SCD had readmission rates of 32.9% with a pain crisis and 21.0% without one, and the overall readmission rate for an index stay with any SCD diagnosis was 31.1%, Kathryn R. Fingar, PhD, MPH, of IBM Watson Health, Sacramento, Calif., and associates wrote in an AHRQ statistical brief.

When age is factored in, the readmission gap between a principal SCD diagnosis and non-SCD becomes even greater – and smaller. The difference was greatest for patients aged 18-34 years – 39.4% with a principal diagnosis of SCD versus 7.8% without any SCD – and then narrowed as patients got older. For those aged 65 years and older, the rates were 22.6% with a principal diagnosis of SCD and 15.9% without, the investigators reported.

The approximately 100,000 Americans with SCD accounted for 134,000 admissions in 2016, and more than three-quarters of those stays involved a pain crisis. A principal diagnosis of SCD was recorded for almost 96,000 of those visits, and nearly all (96%) of those stays involved a pain crisis. For those with a secondary diagnosis of SCD, the most common reasons for hospitalization were diseases of the respiratory system (14.3% of those stays) and infectious and parasitic diseases (13.2%).

Patients with SCD were more likely than non-SCD patients to be admitted from the ED (79.6% vs. 51.3%), and they were more likely to discharged against medical advice (4.1% vs. 1.2%). Among those who left the hospital against medical advice, patients with SCD were much more likely to be readmitted than those without SCD (46.6% vs. 26.5%), based on data from the AHRQ’s Nationwide Readmissions Database.

Improved treatment of complications has “reduced mortality rates so that nearly 95% of individuals born with SCD in the United States reach 18 years of age [but] limited knowledge of SCD treatment guidelines among healthcare professionals continues to pose a barrier to effective patient-provider relationships, and this barrier contributes to lower quality of life,” Dr. Fingar and associates wrote.

[email protected]

Patients with sickle cell disease are 2.5 times more likely to be readmitted within 30 days of a hospital stay than those without SCD, according to the Agency for Healthcare Research and Quality.

The 30-day all-cause readmission rate for index stays with a principal diagnosis of SCD was 33.5% in 2016, compared with 12.5% for non-SCD hospital stays. Patients with a secondary diagnosis of SCD had readmission rates of 32.9% with a pain crisis and 21.0% without one, and the overall readmission rate for an index stay with any SCD diagnosis was 31.1%, Kathryn R. Fingar, PhD, MPH, of IBM Watson Health, Sacramento, Calif., and associates wrote in an AHRQ statistical brief.

When age is factored in, the readmission gap between a principal SCD diagnosis and non-SCD becomes even greater – and smaller. The difference was greatest for patients aged 18-34 years – 39.4% with a principal diagnosis of SCD versus 7.8% without any SCD – and then narrowed as patients got older. For those aged 65 years and older, the rates were 22.6% with a principal diagnosis of SCD and 15.9% without, the investigators reported.

The approximately 100,000 Americans with SCD accounted for 134,000 admissions in 2016, and more than three-quarters of those stays involved a pain crisis. A principal diagnosis of SCD was recorded for almost 96,000 of those visits, and nearly all (96%) of those stays involved a pain crisis. For those with a secondary diagnosis of SCD, the most common reasons for hospitalization were diseases of the respiratory system (14.3% of those stays) and infectious and parasitic diseases (13.2%).

Patients with SCD were more likely than non-SCD patients to be admitted from the ED (79.6% vs. 51.3%), and they were more likely to discharged against medical advice (4.1% vs. 1.2%). Among those who left the hospital against medical advice, patients with SCD were much more likely to be readmitted than those without SCD (46.6% vs. 26.5%), based on data from the AHRQ’s Nationwide Readmissions Database.

Improved treatment of complications has “reduced mortality rates so that nearly 95% of individuals born with SCD in the United States reach 18 years of age [but] limited knowledge of SCD treatment guidelines among healthcare professionals continues to pose a barrier to effective patient-provider relationships, and this barrier contributes to lower quality of life,” Dr. Fingar and associates wrote.

[email protected]

Patients with sickle cell disease are 2.5 times more likely to be readmitted within 30 days of a hospital stay than those without SCD, according to the Agency for Healthcare Research and Quality.

The 30-day all-cause readmission rate for index stays with a principal diagnosis of SCD was 33.5% in 2016, compared with 12.5% for non-SCD hospital stays. Patients with a secondary diagnosis of SCD had readmission rates of 32.9% with a pain crisis and 21.0% without one, and the overall readmission rate for an index stay with any SCD diagnosis was 31.1%, Kathryn R. Fingar, PhD, MPH, of IBM Watson Health, Sacramento, Calif., and associates wrote in an AHRQ statistical brief.

When age is factored in, the readmission gap between a principal SCD diagnosis and non-SCD becomes even greater – and smaller. The difference was greatest for patients aged 18-34 years – 39.4% with a principal diagnosis of SCD versus 7.8% without any SCD – and then narrowed as patients got older. For those aged 65 years and older, the rates were 22.6% with a principal diagnosis of SCD and 15.9% without, the investigators reported.

The approximately 100,000 Americans with SCD accounted for 134,000 admissions in 2016, and more than three-quarters of those stays involved a pain crisis. A principal diagnosis of SCD was recorded for almost 96,000 of those visits, and nearly all (96%) of those stays involved a pain crisis. For those with a secondary diagnosis of SCD, the most common reasons for hospitalization were diseases of the respiratory system (14.3% of those stays) and infectious and parasitic diseases (13.2%).

Patients with SCD were more likely than non-SCD patients to be admitted from the ED (79.6% vs. 51.3%), and they were more likely to discharged against medical advice (4.1% vs. 1.2%). Among those who left the hospital against medical advice, patients with SCD were much more likely to be readmitted than those without SCD (46.6% vs. 26.5%), based on data from the AHRQ’s Nationwide Readmissions Database.

Improved treatment of complications has “reduced mortality rates so that nearly 95% of individuals born with SCD in the United States reach 18 years of age [but] limited knowledge of SCD treatment guidelines among healthcare professionals continues to pose a barrier to effective patient-provider relationships, and this barrier contributes to lower quality of life,” Dr. Fingar and associates wrote.

[email protected]

A diet low in fermentable carbohydrates can reduce gut symptoms related to inflammatory bowel disease (IBD), according to a study by U.K. researchers.

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) occur in a number of common foods, including certain fruits, vegetables, and dairy products. They can draw increased water to the gut, and through microbial fermentation increase hydrogen in the colon.

While previous research has shown that a low-FODMAP diet can relieve gut symptoms such as swelling and flatulence in people with irritable bowel syndrome, the diet has been little studied in IBD patients, for whom gut symptoms often persist even in the absence of gastrointestinal inflammation. In a study published in Gastroenterology, Selina Cox, MD, of King’s College, London, and colleagues randomized 52 people with ulcerative colitis or Crohn’s disease with persistent gut symptoms but without active inflammation to 4 weeks on a low-FODMAP diet (n = 27) or a control diet comprising sham dietary advice (n = 25). Investigators were not blinded to treatment allocation.

At 4 weeks, Dr. Cox and her colleagues reported more patients on the low-FODMAP diet reported “adequate” relief of gut symptoms (52% vs. 16%, P = .007), and saw slight improvements in health-related quality of life scores, compared with the control group. Patient-reported flatulence and bloating were significantly lower in the treatment group, while few other symptom-specific differences were seen between groups.

Stool samples collected at baseline and at the study’s endpoint showed significantly reduced abundance of three types of gut bacteria thought to have a role in immune response – Bifidobacterium adolescentis, B longum, and Faecalibacterium prausnitzii – compared with control subjects. But there were no significant between-group differences in bacterial diversity or in biomarkers of inflammation.

“A major strength of this trial is that low-FODMAP dietary advice was compared to sham dietary advice, providing the first placebo-controlled evidence of effectiveness in IBD,” the researchers wrote in their analysis. Weaknesses of the study include its single-blinded design and inability to control for nutritional alterations related to the low-FODMAP diet.

Ms. Cox and her colleagues recommended a 4-week low-FODMAP diet along with “expert advice and intensive follow-up” for the management of gut symptoms in IBD, but cautioned that longer-term use may not be appropriate.

The study was funded by the U.S.-based Kenneth Rainin Foundation. Two of Dr. Cox’s coauthors declared financial conflicts of interest from a patent on a mobile application to support the low-FODMAP diet; the study’s corresponding author, Kevin Whelan, PhD, additionally reported receiving fees or research support from food and nutrition firms.

SOURCE: Cox S et al. Gastroenterology 2019. doi: 10.1053/j.gastro.2019.09.024.

A diet low in fermentable carbohydrates can reduce gut symptoms related to inflammatory bowel disease (IBD), according to a study by U.K. researchers.

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) occur in a number of common foods, including certain fruits, vegetables, and dairy products. They can draw increased water to the gut, and through microbial fermentation increase hydrogen in the colon.

While previous research has shown that a low-FODMAP diet can relieve gut symptoms such as swelling and flatulence in people with irritable bowel syndrome, the diet has been little studied in IBD patients, for whom gut symptoms often persist even in the absence of gastrointestinal inflammation. In a study published in Gastroenterology, Selina Cox, MD, of King’s College, London, and colleagues randomized 52 people with ulcerative colitis or Crohn’s disease with persistent gut symptoms but without active inflammation to 4 weeks on a low-FODMAP diet (n = 27) or a control diet comprising sham dietary advice (n = 25). Investigators were not blinded to treatment allocation.

At 4 weeks, Dr. Cox and her colleagues reported more patients on the low-FODMAP diet reported “adequate” relief of gut symptoms (52% vs. 16%, P = .007), and saw slight improvements in health-related quality of life scores, compared with the control group. Patient-reported flatulence and bloating were significantly lower in the treatment group, while few other symptom-specific differences were seen between groups.

Stool samples collected at baseline and at the study’s endpoint showed significantly reduced abundance of three types of gut bacteria thought to have a role in immune response – Bifidobacterium adolescentis, B longum, and Faecalibacterium prausnitzii – compared with control subjects. But there were no significant between-group differences in bacterial diversity or in biomarkers of inflammation.

“A major strength of this trial is that low-FODMAP dietary advice was compared to sham dietary advice, providing the first placebo-controlled evidence of effectiveness in IBD,” the researchers wrote in their analysis. Weaknesses of the study include its single-blinded design and inability to control for nutritional alterations related to the low-FODMAP diet.

Ms. Cox and her colleagues recommended a 4-week low-FODMAP diet along with “expert advice and intensive follow-up” for the management of gut symptoms in IBD, but cautioned that longer-term use may not be appropriate.

The study was funded by the U.S.-based Kenneth Rainin Foundation. Two of Dr. Cox’s coauthors declared financial conflicts of interest from a patent on a mobile application to support the low-FODMAP diet; the study’s corresponding author, Kevin Whelan, PhD, additionally reported receiving fees or research support from food and nutrition firms.

SOURCE: Cox S et al. Gastroenterology 2019. doi: 10.1053/j.gastro.2019.09.024.

A diet low in fermentable carbohydrates can reduce gut symptoms related to inflammatory bowel disease (IBD), according to a study by U.K. researchers.

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) occur in a number of common foods, including certain fruits, vegetables, and dairy products. They can draw increased water to the gut, and through microbial fermentation increase hydrogen in the colon.

While previous research has shown that a low-FODMAP diet can relieve gut symptoms such as swelling and flatulence in people with irritable bowel syndrome, the diet has been little studied in IBD patients, for whom gut symptoms often persist even in the absence of gastrointestinal inflammation. In a study published in Gastroenterology, Selina Cox, MD, of King’s College, London, and colleagues randomized 52 people with ulcerative colitis or Crohn’s disease with persistent gut symptoms but without active inflammation to 4 weeks on a low-FODMAP diet (n = 27) or a control diet comprising sham dietary advice (n = 25). Investigators were not blinded to treatment allocation.

At 4 weeks, Dr. Cox and her colleagues reported more patients on the low-FODMAP diet reported “adequate” relief of gut symptoms (52% vs. 16%, P = .007), and saw slight improvements in health-related quality of life scores, compared with the control group. Patient-reported flatulence and bloating were significantly lower in the treatment group, while few other symptom-specific differences were seen between groups.

Stool samples collected at baseline and at the study’s endpoint showed significantly reduced abundance of three types of gut bacteria thought to have a role in immune response – Bifidobacterium adolescentis, B longum, and Faecalibacterium prausnitzii – compared with control subjects. But there were no significant between-group differences in bacterial diversity or in biomarkers of inflammation.

“A major strength of this trial is that low-FODMAP dietary advice was compared to sham dietary advice, providing the first placebo-controlled evidence of effectiveness in IBD,” the researchers wrote in their analysis. Weaknesses of the study include its single-blinded design and inability to control for nutritional alterations related to the low-FODMAP diet.

Ms. Cox and her colleagues recommended a 4-week low-FODMAP diet along with “expert advice and intensive follow-up” for the management of gut symptoms in IBD, but cautioned that longer-term use may not be appropriate.

The study was funded by the U.S.-based Kenneth Rainin Foundation. Two of Dr. Cox’s coauthors declared financial conflicts of interest from a patent on a mobile application to support the low-FODMAP diet; the study’s corresponding author, Kevin Whelan, PhD, additionally reported receiving fees or research support from food and nutrition firms.

SOURCE: Cox S et al. Gastroenterology 2019. doi: 10.1053/j.gastro.2019.09.024.

Federal health officials are seeking to update provisions of the Stark Physician Self-Referral law and the federal Anti-Kickback Statute in an effort to encourage more physicians to enter into value-based care arrangements.

The long-awaited reforms would create permanent exemptions and safe harbors to protect doctors participating in legitimate value-based arrangements. If finalized, the proposals also would offer flexibility for innovation and improved care coordination, while easing the compliance burden for health care professionals and maintaining safeguards against actual fraud and abuse, according to the U.S. Department of Health & Human Services.

The proposals acknowledge that the Stark Law has been an unintentional roadblock to value-based programs in part because it circumscribed parties’ exchanges of rewards for good behavior, said Donna K. Thiel, a Washington-based health law attorney.

“This should be helpful to doctors in that it removes some of the risk in such arrangements under the existing law,” she said in an interview. “If finalized, the new regulations will alleviate some roadblocks created by the Stark Law with respect to hospital-physician and other arrangements designed to enhance care coordination, improve quality, and reduce waste. Likewise, the changes to the [Anti-Kickback Statute] and Beneficiary Inducement laws loosen the reins on compensation arrangements that might be technical violations of those laws where the arrangement fosters [value-based payments] or efficiency, transparency, or innovation in the provision of health care.”

“These proposed rules would be a historic reform of how healthcare is regulated in America,” HHS Deputy Secretary Eric Hargan said in a statement. “They are part of a much broader effort to update, reform, and cut back our regulations to allow innovation toward a more affordable, higher quality, value-based health care system, while maintaining the important protections patients need.”

The two proposed measures – one rule by the Centers for Medicare and Medicaid Services and the other rule by the Office of Inspector General – include safe harbors for certain remuneration exchanged among participants in a value-based arrangement that fosters better coordinated and managed patient care. This includes care arrangements that improve quality, health outcomes, and efficiency, value-based arrangements with substantial downside financial risk, and value-based arrangements with full financial risk.

In addition, the proposals would protect certain tools and supports shared or delivered under patient engagement and support arrangements to improve quality, health outcomes, and efficiency. For example, a specialty physician practice could share data analytics services with a primary care physician practice in an effort to coordinate care and better manage shared patients, according to the HHS.

If finalized, the changes would modify existing safe harbor for personal services and management contracts to add flexibility with respect to outcomes-based payments and part-time arrangements, according to a fact sheet by the OIG. The rule would also modify existing safe harbors for local transportation to expand and modify mileage limits for rural areas and for transportation for discharged patients.

The proposals include guidance on several requirements that must be met for physicians and health care providers to comply with the Stark Law. For example, compensation provided to a doctor by another health care provider generally must be at fair-market value. As part of the proposals, the HHS offers guidance on how to determine if compensation meets this requirement and provides clarity on a range of other technical compliance requirements.

If the rules are approved, more physicians may be encouraged to become part of value-based arrangements, according to Anjali N.C. Downs, a health law attorney based in Washington.

[email protected]

Federal health officials are seeking to update provisions of the Stark Physician Self-Referral law and the federal Anti-Kickback Statute in an effort to encourage more physicians to enter into value-based care arrangements.

The long-awaited reforms would create permanent exemptions and safe harbors to protect doctors participating in legitimate value-based arrangements. If finalized, the proposals also would offer flexibility for innovation and improved care coordination, while easing the compliance burden for health care professionals and maintaining safeguards against actual fraud and abuse, according to the U.S. Department of Health & Human Services.

The proposals acknowledge that the Stark Law has been an unintentional roadblock to value-based programs in part because it circumscribed parties’ exchanges of rewards for good behavior, said Donna K. Thiel, a Washington-based health law attorney.

“This should be helpful to doctors in that it removes some of the risk in such arrangements under the existing law,” she said in an interview. “If finalized, the new regulations will alleviate some roadblocks created by the Stark Law with respect to hospital-physician and other arrangements designed to enhance care coordination, improve quality, and reduce waste. Likewise, the changes to the [Anti-Kickback Statute] and Beneficiary Inducement laws loosen the reins on compensation arrangements that might be technical violations of those laws where the arrangement fosters [value-based payments] or efficiency, transparency, or innovation in the provision of health care.”

“These proposed rules would be a historic reform of how healthcare is regulated in America,” HHS Deputy Secretary Eric Hargan said in a statement. “They are part of a much broader effort to update, reform, and cut back our regulations to allow innovation toward a more affordable, higher quality, value-based health care system, while maintaining the important protections patients need.”

The two proposed measures – one rule by the Centers for Medicare and Medicaid Services and the other rule by the Office of Inspector General – include safe harbors for certain remuneration exchanged among participants in a value-based arrangement that fosters better coordinated and managed patient care. This includes care arrangements that improve quality, health outcomes, and efficiency, value-based arrangements with substantial downside financial risk, and value-based arrangements with full financial risk.

In addition, the proposals would protect certain tools and supports shared or delivered under patient engagement and support arrangements to improve quality, health outcomes, and efficiency. For example, a specialty physician practice could share data analytics services with a primary care physician practice in an effort to coordinate care and better manage shared patients, according to the HHS.

If finalized, the changes would modify existing safe harbor for personal services and management contracts to add flexibility with respect to outcomes-based payments and part-time arrangements, according to a fact sheet by the OIG. The rule would also modify existing safe harbors for local transportation to expand and modify mileage limits for rural areas and for transportation for discharged patients.

The proposals include guidance on several requirements that must be met for physicians and health care providers to comply with the Stark Law. For example, compensation provided to a doctor by another health care provider generally must be at fair-market value. As part of the proposals, the HHS offers guidance on how to determine if compensation meets this requirement and provides clarity on a range of other technical compliance requirements.

If the rules are approved, more physicians may be encouraged to become part of value-based arrangements, according to Anjali N.C. Downs, a health law attorney based in Washington.

[email protected]

Federal health officials are seeking to update provisions of the Stark Physician Self-Referral law and the federal Anti-Kickback Statute in an effort to encourage more physicians to enter into value-based care arrangements.

The long-awaited reforms would create permanent exemptions and safe harbors to protect doctors participating in legitimate value-based arrangements. If finalized, the proposals also would offer flexibility for innovation and improved care coordination, while easing the compliance burden for health care professionals and maintaining safeguards against actual fraud and abuse, according to the U.S. Department of Health & Human Services.

The proposals acknowledge that the Stark Law has been an unintentional roadblock to value-based programs in part because it circumscribed parties’ exchanges of rewards for good behavior, said Donna K. Thiel, a Washington-based health law attorney.

“This should be helpful to doctors in that it removes some of the risk in such arrangements under the existing law,” she said in an interview. “If finalized, the new regulations will alleviate some roadblocks created by the Stark Law with respect to hospital-physician and other arrangements designed to enhance care coordination, improve quality, and reduce waste. Likewise, the changes to the [Anti-Kickback Statute] and Beneficiary Inducement laws loosen the reins on compensation arrangements that might be technical violations of those laws where the arrangement fosters [value-based payments] or efficiency, transparency, or innovation in the provision of health care.”

“These proposed rules would be a historic reform of how healthcare is regulated in America,” HHS Deputy Secretary Eric Hargan said in a statement. “They are part of a much broader effort to update, reform, and cut back our regulations to allow innovation toward a more affordable, higher quality, value-based health care system, while maintaining the important protections patients need.”

The two proposed measures – one rule by the Centers for Medicare and Medicaid Services and the other rule by the Office of Inspector General – include safe harbors for certain remuneration exchanged among participants in a value-based arrangement that fosters better coordinated and managed patient care. This includes care arrangements that improve quality, health outcomes, and efficiency, value-based arrangements with substantial downside financial risk, and value-based arrangements with full financial risk.

In addition, the proposals would protect certain tools and supports shared or delivered under patient engagement and support arrangements to improve quality, health outcomes, and efficiency. For example, a specialty physician practice could share data analytics services with a primary care physician practice in an effort to coordinate care and better manage shared patients, according to the HHS.

If finalized, the changes would modify existing safe harbor for personal services and management contracts to add flexibility with respect to outcomes-based payments and part-time arrangements, according to a fact sheet by the OIG. The rule would also modify existing safe harbors for local transportation to expand and modify mileage limits for rural areas and for transportation for discharged patients.

The proposals include guidance on several requirements that must be met for physicians and health care providers to comply with the Stark Law. For example, compensation provided to a doctor by another health care provider generally must be at fair-market value. As part of the proposals, the HHS offers guidance on how to determine if compensation meets this requirement and provides clarity on a range of other technical compliance requirements.

If the rules are approved, more physicians may be encouraged to become part of value-based arrangements, according to Anjali N.C. Downs, a health law attorney based in Washington.

[email protected]

Patients with stress urinary incontinence treated with synthetic mesh midurethral sling surgery had low reoperation rates at up to 9 years after surgery, according to a study published in Obstetrics & Gynecology.

Alexander A. Berger, MD, MPH, of the division of female pelvic medicine and reconstructive surgery at Kaiser Permanente in San Diego, and colleagues performed a retrospective cohort study of 17,030 patients with stress urinary incontinence (SUI) who underwent midurethral sling surgery between 2005 and 2016, examining the reoperation rate at 1 year, 5 years, and 9 years after the procedure, as well as secondary outcomes of mesh revision, mesh removal, and recurrence of SUI.

Overall, the rate of reoperation at 1 year was 2.1% (95% confidence interval, 1.9%-2.4%), was 4.5% at 5 years (95% CI, 4.1%-4.8%) and 6.0% at 9 years (95% CI, 5.5%-6.5%). Compared with white patients, there was a lower rate of reoperation among Asian or Pacific Islander patients.

The rate of reoperation involving mesh removal was 0.7% at 1 year (95% CI, 0.6%-0.8%), 1.0% at 5 years (95% CI, 0.8%-1.1%) and 1.1% at 9 years (95% CI, 0.9%-1.3%).

The rate of recurrent SUI leading to operation was 1.6% at 1 year (95% CI, 1.4%-1.8%), 3.9% at 5 years (95% CI, 3.5%-4.2%) and 5.2% at 9 years (95% CI, 4.7%-5.7%), with more reoperations occurring for patients who received a single-incision sling, rather than a retropubic sling (adjusted hazard ratio, 1.5; 95% CI, 1.06-2.11; P = .03), Dr. Berger and associates wrote.

Urogynecologists, ob.gyns., and urologists who use mesh for slings and reconstructive surgery have struggled to recommend synthetic mesh slings to their patients with SUI, said Patrick J. Woodman, DO, MS, program director of obstetrics and gynecology residency at Providence Health Ascension Macomb-Oakland, Warren (Mich.) Campus, said in an interview. In 2008, the Food and Drug Administration issued a public health notification for transvaginal placement of surgical mesh in patients with pelvic organ prolapse and SUI.

“Although some of the recommendations first made by the FDA were reasoned and reasonable, such as the need for direct, premarket, patient studies instead of the mostly administrative 510(k) ‘similar-to’ process that had been used previously, physicians and patients had been eagerly awaiting the outcomes of some of these clinical studies that would help answer some of the safety and efficacy questions that had been dogging the transvaginal use of mesh material for years,” he said.

“But, to everyone’s surprise, in April [2019] they called for a recall of all vaginal mesh products, even before the study data could be analyzed, written up and released,” added Dr. Woodman. “Companies were forced to halt production, pull stocks from the shelves, and halt and reverse shipments.”

One reason the results by Berger et al. show midurethral slings have had a good safety record is because of a small incision size and low amount of mesh, noted Dr. Woodman, who was not involved with the study. “This article seems to underline and highlight the fact that reoperation is rare for midurethral slings (for all reasons), but particularly for mesh erosion or exposure. This is well within the experience of most female pelvic medicine and reconstructive surgery and urologic surgeons, and incredibly less than the 8%-24% of mesh exposures reported in the variety of mesh exposure literature on vaginal mesh procedures.”

Despite this safety record, some women may still experience adverse events with midurethral slings, admitted Dr. Woodman. “The fact remains, if a surgeon drags a large piece of synthetic fabric through a ‘clean-contaminated’ vaginal environment, and buries this mesh under the skin of the vagina, and then rests this mesh against a long incision, some women’s immune systems will not be able to handle the resultant inflammation and bacterial load, despite antibiotics, vaginal prepping, and any number of coatings or soakings of the mesh.”

The researchers noted the study’s retrospective nature is one potential limitation, and the data has not been compiled by surgeon type or skill, or considered patients with complications that did not choose reoperations.

“But, the flip side is also true,” said Dr. Woodman, an Ob.Gyn News editorial advisor. “There may have been a number of individuals who had a surgical removal who did not need or warrant it due to the societal, family, or legal ‘suggestion’ that the mesh is now ‘dangerous’ and must be removed at all costs.”

Berger et al. “hit the nail on the head” with the study, including a large amount of patients that demonstrates the safety of midurethral slings, he said. “We need a solid body of unquestioned evidence of safety and effectiveness from which to base solid, evidence-based medical decisions. If there is a way to effectively use mesh to reinforce a vaginal repair in a high-risk woman (for example, with previous failed surgeries), then we have to take the stigma away from its use: because no one wants to use it now, even if it could help.

“The best we can hope for, as physicians, is a rehabilitation of reputation for vaginal mesh,” he concluded.

The study was supported by a grant from the Regional Research Committee of Kaiser Permanente Southern California. One coauthor reported receiving royalties from UptoDate and the American Urogynecologic Society Board Member for travel for board meetings. The other authors reported no relevant conflicts of interest. Dr. Woodman said he had no relevant financial disclosures.*

SOURCE: Berger AA et al. Obstet Gynecol. 2019 Oct 10. doi:10.1097/AOG.0000000000003526.

* Updated 10/14/2019

Patients with stress urinary incontinence treated with synthetic mesh midurethral sling surgery had low reoperation rates at up to 9 years after surgery, according to a study published in Obstetrics & Gynecology.

Alexander A. Berger, MD, MPH, of the division of female pelvic medicine and reconstructive surgery at Kaiser Permanente in San Diego, and colleagues performed a retrospective cohort study of 17,030 patients with stress urinary incontinence (SUI) who underwent midurethral sling surgery between 2005 and 2016, examining the reoperation rate at 1 year, 5 years, and 9 years after the procedure, as well as secondary outcomes of mesh revision, mesh removal, and recurrence of SUI.

Overall, the rate of reoperation at 1 year was 2.1% (95% confidence interval, 1.9%-2.4%), was 4.5% at 5 years (95% CI, 4.1%-4.8%) and 6.0% at 9 years (95% CI, 5.5%-6.5%). Compared with white patients, there was a lower rate of reoperation among Asian or Pacific Islander patients.

The rate of reoperation involving mesh removal was 0.7% at 1 year (95% CI, 0.6%-0.8%), 1.0% at 5 years (95% CI, 0.8%-1.1%) and 1.1% at 9 years (95% CI, 0.9%-1.3%).

The rate of recurrent SUI leading to operation was 1.6% at 1 year (95% CI, 1.4%-1.8%), 3.9% at 5 years (95% CI, 3.5%-4.2%) and 5.2% at 9 years (95% CI, 4.7%-5.7%), with more reoperations occurring for patients who received a single-incision sling, rather than a retropubic sling (adjusted hazard ratio, 1.5; 95% CI, 1.06-2.11; P = .03), Dr. Berger and associates wrote.

Urogynecologists, ob.gyns., and urologists who use mesh for slings and reconstructive surgery have struggled to recommend synthetic mesh slings to their patients with SUI, said Patrick J. Woodman, DO, MS, program director of obstetrics and gynecology residency at Providence Health Ascension Macomb-Oakland, Warren (Mich.) Campus, said in an interview. In 2008, the Food and Drug Administration issued a public health notification for transvaginal placement of surgical mesh in patients with pelvic organ prolapse and SUI.

“Although some of the recommendations first made by the FDA were reasoned and reasonable, such as the need for direct, premarket, patient studies instead of the mostly administrative 510(k) ‘similar-to’ process that had been used previously, physicians and patients had been eagerly awaiting the outcomes of some of these clinical studies that would help answer some of the safety and efficacy questions that had been dogging the transvaginal use of mesh material for years,” he said.

“But, to everyone’s surprise, in April [2019] they called for a recall of all vaginal mesh products, even before the study data could be analyzed, written up and released,” added Dr. Woodman. “Companies were forced to halt production, pull stocks from the shelves, and halt and reverse shipments.”

One reason the results by Berger et al. show midurethral slings have had a good safety record is because of a small incision size and low amount of mesh, noted Dr. Woodman, who was not involved with the study. “This article seems to underline and highlight the fact that reoperation is rare for midurethral slings (for all reasons), but particularly for mesh erosion or exposure. This is well within the experience of most female pelvic medicine and reconstructive surgery and urologic surgeons, and incredibly less than the 8%-24% of mesh exposures reported in the variety of mesh exposure literature on vaginal mesh procedures.”

Despite this safety record, some women may still experience adverse events with midurethral slings, admitted Dr. Woodman. “The fact remains, if a surgeon drags a large piece of synthetic fabric through a ‘clean-contaminated’ vaginal environment, and buries this mesh under the skin of the vagina, and then rests this mesh against a long incision, some women’s immune systems will not be able to handle the resultant inflammation and bacterial load, despite antibiotics, vaginal prepping, and any number of coatings or soakings of the mesh.”

The researchers noted the study’s retrospective nature is one potential limitation, and the data has not been compiled by surgeon type or skill, or considered patients with complications that did not choose reoperations.

“But, the flip side is also true,” said Dr. Woodman, an Ob.Gyn News editorial advisor. “There may have been a number of individuals who had a surgical removal who did not need or warrant it due to the societal, family, or legal ‘suggestion’ that the mesh is now ‘dangerous’ and must be removed at all costs.”

Berger et al. “hit the nail on the head” with the study, including a large amount of patients that demonstrates the safety of midurethral slings, he said. “We need a solid body of unquestioned evidence of safety and effectiveness from which to base solid, evidence-based medical decisions. If there is a way to effectively use mesh to reinforce a vaginal repair in a high-risk woman (for example, with previous failed surgeries), then we have to take the stigma away from its use: because no one wants to use it now, even if it could help.

“The best we can hope for, as physicians, is a rehabilitation of reputation for vaginal mesh,” he concluded.

The study was supported by a grant from the Regional Research Committee of Kaiser Permanente Southern California. One coauthor reported receiving royalties from UptoDate and the American Urogynecologic Society Board Member for travel for board meetings. The other authors reported no relevant conflicts of interest. Dr. Woodman said he had no relevant financial disclosures.*

SOURCE: Berger AA et al. Obstet Gynecol. 2019 Oct 10. doi:10.1097/AOG.0000000000003526.

* Updated 10/14/2019

Patients with stress urinary incontinence treated with synthetic mesh midurethral sling surgery had low reoperation rates at up to 9 years after surgery, according to a study published in Obstetrics & Gynecology.

Alexander A. Berger, MD, MPH, of the division of female pelvic medicine and reconstructive surgery at Kaiser Permanente in San Diego, and colleagues performed a retrospective cohort study of 17,030 patients with stress urinary incontinence (SUI) who underwent midurethral sling surgery between 2005 and 2016, examining the reoperation rate at 1 year, 5 years, and 9 years after the procedure, as well as secondary outcomes of mesh revision, mesh removal, and recurrence of SUI.

Overall, the rate of reoperation at 1 year was 2.1% (95% confidence interval, 1.9%-2.4%), was 4.5% at 5 years (95% CI, 4.1%-4.8%) and 6.0% at 9 years (95% CI, 5.5%-6.5%). Compared with white patients, there was a lower rate of reoperation among Asian or Pacific Islander patients.

The rate of reoperation involving mesh removal was 0.7% at 1 year (95% CI, 0.6%-0.8%), 1.0% at 5 years (95% CI, 0.8%-1.1%) and 1.1% at 9 years (95% CI, 0.9%-1.3%).

The rate of recurrent SUI leading to operation was 1.6% at 1 year (95% CI, 1.4%-1.8%), 3.9% at 5 years (95% CI, 3.5%-4.2%) and 5.2% at 9 years (95% CI, 4.7%-5.7%), with more reoperations occurring for patients who received a single-incision sling, rather than a retropubic sling (adjusted hazard ratio, 1.5; 95% CI, 1.06-2.11; P = .03), Dr. Berger and associates wrote.

Urogynecologists, ob.gyns., and urologists who use mesh for slings and reconstructive surgery have struggled to recommend synthetic mesh slings to their patients with SUI, said Patrick J. Woodman, DO, MS, program director of obstetrics and gynecology residency at Providence Health Ascension Macomb-Oakland, Warren (Mich.) Campus, said in an interview. In 2008, the Food and Drug Administration issued a public health notification for transvaginal placement of surgical mesh in patients with pelvic organ prolapse and SUI.

“Although some of the recommendations first made by the FDA were reasoned and reasonable, such as the need for direct, premarket, patient studies instead of the mostly administrative 510(k) ‘similar-to’ process that had been used previously, physicians and patients had been eagerly awaiting the outcomes of some of these clinical studies that would help answer some of the safety and efficacy questions that had been dogging the transvaginal use of mesh material for years,” he said.

“But, to everyone’s surprise, in April [2019] they called for a recall of all vaginal mesh products, even before the study data could be analyzed, written up and released,” added Dr. Woodman. “Companies were forced to halt production, pull stocks from the shelves, and halt and reverse shipments.”

One reason the results by Berger et al. show midurethral slings have had a good safety record is because of a small incision size and low amount of mesh, noted Dr. Woodman, who was not involved with the study. “This article seems to underline and highlight the fact that reoperation is rare for midurethral slings (for all reasons), but particularly for mesh erosion or exposure. This is well within the experience of most female pelvic medicine and reconstructive surgery and urologic surgeons, and incredibly less than the 8%-24% of mesh exposures reported in the variety of mesh exposure literature on vaginal mesh procedures.”

Despite this safety record, some women may still experience adverse events with midurethral slings, admitted Dr. Woodman. “The fact remains, if a surgeon drags a large piece of synthetic fabric through a ‘clean-contaminated’ vaginal environment, and buries this mesh under the skin of the vagina, and then rests this mesh against a long incision, some women’s immune systems will not be able to handle the resultant inflammation and bacterial load, despite antibiotics, vaginal prepping, and any number of coatings or soakings of the mesh.”

The researchers noted the study’s retrospective nature is one potential limitation, and the data has not been compiled by surgeon type or skill, or considered patients with complications that did not choose reoperations.

“But, the flip side is also true,” said Dr. Woodman, an Ob.Gyn News editorial advisor. “There may have been a number of individuals who had a surgical removal who did not need or warrant it due to the societal, family, or legal ‘suggestion’ that the mesh is now ‘dangerous’ and must be removed at all costs.”

Berger et al. “hit the nail on the head” with the study, including a large amount of patients that demonstrates the safety of midurethral slings, he said. “We need a solid body of unquestioned evidence of safety and effectiveness from which to base solid, evidence-based medical decisions. If there is a way to effectively use mesh to reinforce a vaginal repair in a high-risk woman (for example, with previous failed surgeries), then we have to take the stigma away from its use: because no one wants to use it now, even if it could help.

“The best we can hope for, as physicians, is a rehabilitation of reputation for vaginal mesh,” he concluded.

The study was supported by a grant from the Regional Research Committee of Kaiser Permanente Southern California. One coauthor reported receiving royalties from UptoDate and the American Urogynecologic Society Board Member for travel for board meetings. The other authors reported no relevant conflicts of interest. Dr. Woodman said he had no relevant financial disclosures.*

SOURCE: Berger AA et al. Obstet Gynecol. 2019 Oct 10. doi:10.1097/AOG.0000000000003526.

* Updated 10/14/2019

SAN FRANCISCO – Reducing the dual antiplatelet therapy period to 3 months after implantation of Ultimaster sirolimus-eluting stent was noninferior to a longer duration of DAPT in a historical cohort, results from a prospective study showed.

Doug Brunk/MDedge News

In addition, P2Y12 inhibitor monotherapy was almost equivalent to aspirin monotherapy after 3 months in terms of both bleeding and thrombotic events.

“Recent guidelines recommend short DAPT up to 3 months, only in high bleeding risk patients,” lead investigator Ken Kozuma, MD, said during a media briefing at the Transcatheter Cardiovascular Therapeutics annual meeting. “However, short-term DAPT may be beneficial for any patients. Aspirin may be more associated with bleeding complication than P2Y12 receptor inhibitors.”

In a single-arm registry trial known as MODEL U-SES, Dr. Kozuma, of Teikyo University Hospital in Tokyo, and colleagues at 65 sites in Japan prospectively evaluated the safety of 3-month DAPT after implantation of the Ultimaster bioresorbable polymer sirolimus-eluting stent (BP-SES). The secondary objective was to investigate the appropriateness of P2Y12 receptor inhibitor monotherapy compared with aspirin monotherapy after 3 months. The researchers enrolled 1,695 patients with a mean age of 70 years who were treated with U-SES and considered appropriate for 3-month DAPT after implantation.

The primary endpoint was a composite endpoint of all-cause death, myocardial infarction, stroke (ischemic and hemorrhagic), Academic Research Consortium (ARC) definite/probable stent thrombosis, and serious bleeding (Bleeding Academic Research Consortium [BARC] 3 or 5) during the 12 months after stent implantation. Major secondary endpoints included a comparison of the incidence of each event for each continued antiplatelet drug.

Of the 1,695 patients enrolled, 1,686 completed 3-month clinical follow-up while 1,616 completed 1-year clinical follow-up. Patient-level adjusted historical data from 542 subjects in the CENTURY II cohort was used as the control group. Patients in that trial received the same stent but took DAPT for 1 year.

Dr. Kozuma reported that the primary endpoint occurred in 4.3% of patients in the MODEL U-SES group, compared with 5.7% of patients in the CENTURY II BP-SES group, a difference of –3.17%, which demonstrated noninferiority of the trial (P less than .001). At 3 months, P2Y12 inhibitor monotherapy was equivalent to aspirin monotherapy in terms of both bleeding and thrombotic events (2.5% in each modality; hazard ratio, 1.14; P = 0.71).

Dr. Kozuma acknowledged certain limitations of the trial, including the fact that propensity score adjusted analysis “may not compensate the selection bias of this study sufficiently, since considerable baseline difference was observed. Also, comparison between aspirin and P2Y12 receptor inhibitors was not randomized so that the safety and efficacy of each antiplatelet monotherapy cannot be conclusive.”

Despite these limitations, he concluded that the trial “demonstrated that 3-month DAPT was noninferior to an adjusted cohort of longer DAPT after BP-SES implantation in net adverse clinical events. Direct comparison between P2Y12 inhibitor and aspirin would be necessary to confirm the efficacy and safety of P2Y12 inhibitor monotherapy in a randomized fashion.”

The meeting was sponsored by the Cardiovascular Research Foundation.

Terumo sponsored the trial. Dr. Kozuma disclosed that he serves on the scientific advisory boards for and has received honoraria from Terumo, Abbott Vascular Japan, Boston Scientific Japan, Daiichi-Sankyo, Sanofi, Bayer, Boehringer Ingelheim and Bristol-Meyers Squibb.

[email protected]

SOURCE: Kozuma K et al. TCT 2019, late-breaking presentation.

SAN FRANCISCO – Reducing the dual antiplatelet therapy period to 3 months after implantation of Ultimaster sirolimus-eluting stent was noninferior to a longer duration of DAPT in a historical cohort, results from a prospective study showed.

Doug Brunk/MDedge News

In addition, P2Y12 inhibitor monotherapy was almost equivalent to aspirin monotherapy after 3 months in terms of both bleeding and thrombotic events.

“Recent guidelines recommend short DAPT up to 3 months, only in high bleeding risk patients,” lead investigator Ken Kozuma, MD, said during a media briefing at the Transcatheter Cardiovascular Therapeutics annual meeting. “However, short-term DAPT may be beneficial for any patients. Aspirin may be more associated with bleeding complication than P2Y12 receptor inhibitors.”

In a single-arm registry trial known as MODEL U-SES, Dr. Kozuma, of Teikyo University Hospital in Tokyo, and colleagues at 65 sites in Japan prospectively evaluated the safety of 3-month DAPT after implantation of the Ultimaster bioresorbable polymer sirolimus-eluting stent (BP-SES). The secondary objective was to investigate the appropriateness of P2Y12 receptor inhibitor monotherapy compared with aspirin monotherapy after 3 months. The researchers enrolled 1,695 patients with a mean age of 70 years who were treated with U-SES and considered appropriate for 3-month DAPT after implantation.

The primary endpoint was a composite endpoint of all-cause death, myocardial infarction, stroke (ischemic and hemorrhagic), Academic Research Consortium (ARC) definite/probable stent thrombosis, and serious bleeding (Bleeding Academic Research Consortium [BARC] 3 or 5) during the 12 months after stent implantation. Major secondary endpoints included a comparison of the incidence of each event for each continued antiplatelet drug.

Of the 1,695 patients enrolled, 1,686 completed 3-month clinical follow-up while 1,616 completed 1-year clinical follow-up. Patient-level adjusted historical data from 542 subjects in the CENTURY II cohort was used as the control group. Patients in that trial received the same stent but took DAPT for 1 year.

Dr. Kozuma reported that the primary endpoint occurred in 4.3% of patients in the MODEL U-SES group, compared with 5.7% of patients in the CENTURY II BP-SES group, a difference of –3.17%, which demonstrated noninferiority of the trial (P less than .001). At 3 months, P2Y12 inhibitor monotherapy was equivalent to aspirin monotherapy in terms of both bleeding and thrombotic events (2.5% in each modality; hazard ratio, 1.14; P = 0.71).

Dr. Kozuma acknowledged certain limitations of the trial, including the fact that propensity score adjusted analysis “may not compensate the selection bias of this study sufficiently, since considerable baseline difference was observed. Also, comparison between aspirin and P2Y12 receptor inhibitors was not randomized so that the safety and efficacy of each antiplatelet monotherapy cannot be conclusive.”

Despite these limitations, he concluded that the trial “demonstrated that 3-month DAPT was noninferior to an adjusted cohort of longer DAPT after BP-SES implantation in net adverse clinical events. Direct comparison between P2Y12 inhibitor and aspirin would be necessary to confirm the efficacy and safety of P2Y12 inhibitor monotherapy in a randomized fashion.”

The meeting was sponsored by the Cardiovascular Research Foundation.

Terumo sponsored the trial. Dr. Kozuma disclosed that he serves on the scientific advisory boards for and has received honoraria from Terumo, Abbott Vascular Japan, Boston Scientific Japan, Daiichi-Sankyo, Sanofi, Bayer, Boehringer Ingelheim and Bristol-Meyers Squibb.

[email protected]

SOURCE: Kozuma K et al. TCT 2019, late-breaking presentation.

SAN FRANCISCO – Reducing the dual antiplatelet therapy period to 3 months after implantation of Ultimaster sirolimus-eluting stent was noninferior to a longer duration of DAPT in a historical cohort, results from a prospective study showed.

Doug Brunk/MDedge News

In addition, P2Y12 inhibitor monotherapy was almost equivalent to aspirin monotherapy after 3 months in terms of both bleeding and thrombotic events.

“Recent guidelines recommend short DAPT up to 3 months, only in high bleeding risk patients,” lead investigator Ken Kozuma, MD, said during a media briefing at the Transcatheter Cardiovascular Therapeutics annual meeting. “However, short-term DAPT may be beneficial for any patients. Aspirin may be more associated with bleeding complication than P2Y12 receptor inhibitors.”

In a single-arm registry trial known as MODEL U-SES, Dr. Kozuma, of Teikyo University Hospital in Tokyo, and colleagues at 65 sites in Japan prospectively evaluated the safety of 3-month DAPT after implantation of the Ultimaster bioresorbable polymer sirolimus-eluting stent (BP-SES). The secondary objective was to investigate the appropriateness of P2Y12 receptor inhibitor monotherapy compared with aspirin monotherapy after 3 months. The researchers enrolled 1,695 patients with a mean age of 70 years who were treated with U-SES and considered appropriate for 3-month DAPT after implantation.

The primary endpoint was a composite endpoint of all-cause death, myocardial infarction, stroke (ischemic and hemorrhagic), Academic Research Consortium (ARC) definite/probable stent thrombosis, and serious bleeding (Bleeding Academic Research Consortium [BARC] 3 or 5) during the 12 months after stent implantation. Major secondary endpoints included a comparison of the incidence of each event for each continued antiplatelet drug.

Of the 1,695 patients enrolled, 1,686 completed 3-month clinical follow-up while 1,616 completed 1-year clinical follow-up. Patient-level adjusted historical data from 542 subjects in the CENTURY II cohort was used as the control group. Patients in that trial received the same stent but took DAPT for 1 year.

Dr. Kozuma reported that the primary endpoint occurred in 4.3% of patients in the MODEL U-SES group, compared with 5.7% of patients in the CENTURY II BP-SES group, a difference of –3.17%, which demonstrated noninferiority of the trial (P less than .001). At 3 months, P2Y12 inhibitor monotherapy was equivalent to aspirin monotherapy in terms of both bleeding and thrombotic events (2.5% in each modality; hazard ratio, 1.14; P = 0.71).

Dr. Kozuma acknowledged certain limitations of the trial, including the fact that propensity score adjusted analysis “may not compensate the selection bias of this study sufficiently, since considerable baseline difference was observed. Also, comparison between aspirin and P2Y12 receptor inhibitors was not randomized so that the safety and efficacy of each antiplatelet monotherapy cannot be conclusive.”

Despite these limitations, he concluded that the trial “demonstrated that 3-month DAPT was noninferior to an adjusted cohort of longer DAPT after BP-SES implantation in net adverse clinical events. Direct comparison between P2Y12 inhibitor and aspirin would be necessary to confirm the efficacy and safety of P2Y12 inhibitor monotherapy in a randomized fashion.”

The meeting was sponsored by the Cardiovascular Research Foundation.

Terumo sponsored the trial. Dr. Kozuma disclosed that he serves on the scientific advisory boards for and has received honoraria from Terumo, Abbott Vascular Japan, Boston Scientific Japan, Daiichi-Sankyo, Sanofi, Bayer, Boehringer Ingelheim and Bristol-Meyers Squibb.

[email protected]

SOURCE: Kozuma K et al. TCT 2019, late-breaking presentation.

Almost all of Medicare’s 58 million enrollees had a blood pressure screening in 2017, and just under 90% saw a physician during the year, according to new data released by the Centers for Medicare & Medicaid Services.

The latest edition of Medicare Beneficiaries at a Glance takes a look at some of the services provided in 2017, and BP checks were high on the list, with 96% of enrollees getting screened. BP was also prominent on another list featured in the Medicare snapshot for 2017, as hypertension was the most common chronic condition among beneficiaries with a prevalence of 58%, the CMS said.

A second glance at the report shows that 41% of enrollees had high cholesterol that year, making it the next-most common chronic condition, with arthritis third at 33%, the CMS said. Diabetes was fourth and heart disease was fifth, but rounding gives them the same prevalence of 27%.

[email protected]

Almost all of Medicare’s 58 million enrollees had a blood pressure screening in 2017, and just under 90% saw a physician during the year, according to new data released by the Centers for Medicare & Medicaid Services.

The latest edition of Medicare Beneficiaries at a Glance takes a look at some of the services provided in 2017, and BP checks were high on the list, with 96% of enrollees getting screened. BP was also prominent on another list featured in the Medicare snapshot for 2017, as hypertension was the most common chronic condition among beneficiaries with a prevalence of 58%, the CMS said.

A second glance at the report shows that 41% of enrollees had high cholesterol that year, making it the next-most common chronic condition, with arthritis third at 33%, the CMS said. Diabetes was fourth and heart disease was fifth, but rounding gives them the same prevalence of 27%.

[email protected]

Almost all of Medicare’s 58 million enrollees had a blood pressure screening in 2017, and just under 90% saw a physician during the year, according to new data released by the Centers for Medicare & Medicaid Services.

The latest edition of Medicare Beneficiaries at a Glance takes a look at some of the services provided in 2017, and BP checks were high on the list, with 96% of enrollees getting screened. BP was also prominent on another list featured in the Medicare snapshot for 2017, as hypertension was the most common chronic condition among beneficiaries with a prevalence of 58%, the CMS said.

A second glance at the report shows that 41% of enrollees had high cholesterol that year, making it the next-most common chronic condition, with arthritis third at 33%, the CMS said. Diabetes was fourth and heart disease was fifth, but rounding gives them the same prevalence of 27%.

[email protected]

It is rare in this modern era for medicine to confront an infectious disease for which there is no cure. Today, there are comparatively few infectious diseases (in the developed world and in places where money is no object) for which medicine cannot offer at least a glimmer of hope to infected patients. Even at its most futile, modern medicine has achieved vast improvements in the efficacy of palliative care. But it wasn’t that long ago that HIV infection was a nearly inevitable death sentence from the complications of AIDS, with no available treatments. And however monstrous that suffering and death, which still continues in many areas of the developing world, it was decades rather than centuries before modern medicine came up with effective treatments. Recently, there is even significant hope on the Ebola virus front that curative treatments may soon become available.

Wellcome Library, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

Medicine has always been in the business of hope, even when true cures were not available. Today that hope is less often misplaced. But in previous centuries, the need to offer hope to – and perhaps to make money from – desperate patients was a hallmark of the doctor’s trade.

It was this need to give patients hope and for doctors to feel that they were being effective that led to some highly dubious and desperate efforts to cure syphilis throughout history. These efforts meant centuries of fruitless torture for countless patients until the rise of modern antibiotics.

For the most part, what we now look upon as horrors and insanity in treatment were the result of misguided scientific theories, half-baked folk wisdom, and the generally well-intentioned efforts of medical practitioners at a cure. There were the charlatans as well, seeking a quick buck from the truly hopeless.

However, the social stigma of syphilis as a venereal disease played a role in the courses of treatment.

By the 15th century, syphilis was recognized as being spread by sexual intercourse, and in a situation analogous with the early AIDS epidemic, “16th- and 17th-century writers and physicians were divided on the moral aspects of syphilis. Some thought it was a divine punishment for sin – and as such only harsh treatments would cure it – or that people with syphilis shouldn’t be treated at all.”
 

Mercury rising

In its earliest manifestations, syphilis was considered untreatable. In 1496, Sebastian Brandt, wrote a poem entitled “De pestilentiali Scorra sive mala de Franzos” detailing the disease’s early spread across Europe and how doctors had no remedy for it.

Science Museum, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

However, it wasn’t long before desperate physicians turned their quest for a cure to a reliable old standby treatment of the period – mercury, which had a history of being used for skin diseases. Mercury salves had been in use in the Arab world for leprosy and eczema, among other skin afflictions, and had been brought to Europe with the return of the medieval crusaders. Another way elemental mercury was administered was through the use of heated cinnabar (HgS), which gave off mercury vapors that could be absorbed by breathing and through the skin. In the 16th century, doctors would place a syphilis-infected individual inside an ovenlike chamber over pans of cinnabar, which were then heated at the person’s feet.

Oral mercury treatments were promoted by Paracelsus (1493?-1541), an alchemist and physician who prescribed calomel (HgCl), or mercury chloride, pills. Mercury treatment, administered at almost inevitably toxic doses, led to ulcerations of the lips, tongue, palate, and jaw; tooth loss; and fetid breath and excessive salivation. This last symptom was, in fact, considered the endpoint in mercury therapy for syphilis, which was “originally judged to be a copious secretion of saliva – ‘some few liters per diem.’ ” Even as recent as the late 19th century and early 20th century, syphilitic patients such as Oscar Wilde (whose teeth were blackened by the treatment), were prescribed calomel.

Looking to the “holy wood”

By 1519, an alternative treatment to mercury was available. In that year, Ulrich von Hutton, a German scholar who suffered from the “great pox,” described its treatment with guaiacum sanctum, or holy wood, in “De Morbo Gallico.” Four years later, despite such treatment, he was dead from the disease himself. But the lack of efficacy did not stop the faith that doctors placed in this botanical cure.

Wellcome Library, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

Holy wood was an herbal treatment derived from the bark of trees from the Guaiacum family. It was brought back on trading ships from the Caribbean and South America, the origin of syphilis’s foothold in Europe and the rest of the world. The use of holy wood matched a then-current theory that the cure to a disease could be found in the area from which it came. Other botanicals from around the world were also tried, but never came into routine use.

Guaiacum was the first treatment given to sufferers of syphilis in the Blatterhaus (pox hospital) in Augsburg after 1522, according to information from the archives at the Edward Worth Library in Dublin. The botanical therapy was given as a hot drink and followed by a sweating cure. Guaiacum extract acted as a sudorific, a compound which induces sweating when ingested. Even though the use of Guaiacum was initially popular, it was replaced almost exclusively by the use of mercury.

“Give me fever”

In the late 1800s, Julius Wagner von Jauregg (1857-1940), a Viennese neurologist, observed that Austrian army officers with neurosyphilis did not become partially paralyzed if they had also contracted malaria or relapsing fever. He initiated clinical trials in which he induced fever in syphilitics with tuberculin (1-10 mg) and observed in many the remissions their neuropsychiatric symptoms and signs. He also injected neurosyphilitic patients with a mild form of malaria to induce fever, which could then be suppressed with quinine treatment.

“Other physicians soon began using malariotherapy in uncontrolled studies of neurosyphilitics and reported clinical success rates of 33%-51% and only a 5% mortality. Persons with tabes dorsalis (the “wasting” paralysis of neurosyphilis) were hospitalized for 3 weeks of alternate-day fever therapy involving 5-hour long hot baths and extended periods wrapped in heavy blankets,” according to C.T. Ambrose, MD, of the University of Kentucky, Lexington.

A 1931 medical text summarizes in 35 studies involving 2,356 cases of general paresis treated with malaria and reported a 27.5% “full remission,” he added. A bacterial treatment developed in this period used a course of 18-23 injections of killed typhoid cells administered every 2-3 days in order to produce a fever of 103°–104^°F. Animal studies of rabbits infected with syphilis showed that high temperatures could be curative.

Dr. Ambrose suggests that 16th-century syphilitics who had been subjected to mercury fumigation in ovenlike chambers endured severe sweating conditions and – for those who survived – the prolonged elevated body temperature (not the mercury) may have proved curative. Fever “was the common therapeutic denominator in the cinnabar-oven treatment, botanical sudorifics (guaiacum, China root), malarial infections (natural and iatrogenic), and bacterial (tuberculin) vaccine therapy.”

Prelude to modern antibiotics

German bacteriologist/immunologist Paul Ehrlich, MD, (1854-1915) investigated the use of atoxyl (sodium arsanilate) in syphilis, but the metallic drug had severe side effects, injuring the optic nerve and causing blindness. To overcome this problem, Ehrlich and his coworkers synthesized and tested related organic arsenicals. The antisyphilitic activity of arsphenamine (compound 606) was discovered by Sahachiro Hata, MD, (1879-1938) in 1909. This compound, known as Salvarsan, became “Dr. Ehrlich’s Magic Bullet,” for the treatment of syphilis in the 1910s, and it, and later, the less-toxic compound neoarsphenamine (compound 914) became mainstays of successful clinical treatment until the development and use of penicillin in the 1940s.

[email protected]
 

Selected sources

Ambrose, CT. Pre-antibiotic therapy of syphilis. NESSA J Infect Dis Immunology. 2016. 1(1);1-20.

Frith J. Syphilis: Its early history and treatment until penicillin and the debate on its origins. J Mil Veterans Health. 2012;20(4):49-58.

Tognotti B. The rise and fall of syphilis in Renaissance Italy. J Med Humanit. 2009 Jun;30(2):99-113.

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.

It is rare in this modern era for medicine to confront an infectious disease for which there is no cure. Today, there are comparatively few infectious diseases (in the developed world and in places where money is no object) for which medicine cannot offer at least a glimmer of hope to infected patients. Even at its most futile, modern medicine has achieved vast improvements in the efficacy of palliative care. But it wasn’t that long ago that HIV infection was a nearly inevitable death sentence from the complications of AIDS, with no available treatments. And however monstrous that suffering and death, which still continues in many areas of the developing world, it was decades rather than centuries before modern medicine came up with effective treatments. Recently, there is even significant hope on the Ebola virus front that curative treatments may soon become available.

Wellcome Library, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

Medicine has always been in the business of hope, even when true cures were not available. Today that hope is less often misplaced. But in previous centuries, the need to offer hope to – and perhaps to make money from – desperate patients was a hallmark of the doctor’s trade.

It was this need to give patients hope and for doctors to feel that they were being effective that led to some highly dubious and desperate efforts to cure syphilis throughout history. These efforts meant centuries of fruitless torture for countless patients until the rise of modern antibiotics.

For the most part, what we now look upon as horrors and insanity in treatment were the result of misguided scientific theories, half-baked folk wisdom, and the generally well-intentioned efforts of medical practitioners at a cure. There were the charlatans as well, seeking a quick buck from the truly hopeless.

However, the social stigma of syphilis as a venereal disease played a role in the courses of treatment.

By the 15th century, syphilis was recognized as being spread by sexual intercourse, and in a situation analogous with the early AIDS epidemic, “16th- and 17th-century writers and physicians were divided on the moral aspects of syphilis. Some thought it was a divine punishment for sin – and as such only harsh treatments would cure it – or that people with syphilis shouldn’t be treated at all.”
 

Mercury rising

In its earliest manifestations, syphilis was considered untreatable. In 1496, Sebastian Brandt, wrote a poem entitled “De pestilentiali Scorra sive mala de Franzos” detailing the disease’s early spread across Europe and how doctors had no remedy for it.

Science Museum, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

However, it wasn’t long before desperate physicians turned their quest for a cure to a reliable old standby treatment of the period – mercury, which had a history of being used for skin diseases. Mercury salves had been in use in the Arab world for leprosy and eczema, among other skin afflictions, and had been brought to Europe with the return of the medieval crusaders. Another way elemental mercury was administered was through the use of heated cinnabar (HgS), which gave off mercury vapors that could be absorbed by breathing and through the skin. In the 16th century, doctors would place a syphilis-infected individual inside an ovenlike chamber over pans of cinnabar, which were then heated at the person’s feet.

Oral mercury treatments were promoted by Paracelsus (1493?-1541), an alchemist and physician who prescribed calomel (HgCl), or mercury chloride, pills. Mercury treatment, administered at almost inevitably toxic doses, led to ulcerations of the lips, tongue, palate, and jaw; tooth loss; and fetid breath and excessive salivation. This last symptom was, in fact, considered the endpoint in mercury therapy for syphilis, which was “originally judged to be a copious secretion of saliva – ‘some few liters per diem.’ ” Even as recent as the late 19th century and early 20th century, syphilitic patients such as Oscar Wilde (whose teeth were blackened by the treatment), were prescribed calomel.

Looking to the “holy wood”

By 1519, an alternative treatment to mercury was available. In that year, Ulrich von Hutton, a German scholar who suffered from the “great pox,” described its treatment with guaiacum sanctum, or holy wood, in “De Morbo Gallico.” Four years later, despite such treatment, he was dead from the disease himself. But the lack of efficacy did not stop the faith that doctors placed in this botanical cure.

Wellcome Library, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

Holy wood was an herbal treatment derived from the bark of trees from the Guaiacum family. It was brought back on trading ships from the Caribbean and South America, the origin of syphilis’s foothold in Europe and the rest of the world. The use of holy wood matched a then-current theory that the cure to a disease could be found in the area from which it came. Other botanicals from around the world were also tried, but never came into routine use.

Guaiacum was the first treatment given to sufferers of syphilis in the Blatterhaus (pox hospital) in Augsburg after 1522, according to information from the archives at the Edward Worth Library in Dublin. The botanical therapy was given as a hot drink and followed by a sweating cure. Guaiacum extract acted as a sudorific, a compound which induces sweating when ingested. Even though the use of Guaiacum was initially popular, it was replaced almost exclusively by the use of mercury.

“Give me fever”

In the late 1800s, Julius Wagner von Jauregg (1857-1940), a Viennese neurologist, observed that Austrian army officers with neurosyphilis did not become partially paralyzed if they had also contracted malaria or relapsing fever. He initiated clinical trials in which he induced fever in syphilitics with tuberculin (1-10 mg) and observed in many the remissions their neuropsychiatric symptoms and signs. He also injected neurosyphilitic patients with a mild form of malaria to induce fever, which could then be suppressed with quinine treatment.

“Other physicians soon began using malariotherapy in uncontrolled studies of neurosyphilitics and reported clinical success rates of 33%-51% and only a 5% mortality. Persons with tabes dorsalis (the “wasting” paralysis of neurosyphilis) were hospitalized for 3 weeks of alternate-day fever therapy involving 5-hour long hot baths and extended periods wrapped in heavy blankets,” according to C.T. Ambrose, MD, of the University of Kentucky, Lexington.

A 1931 medical text summarizes in 35 studies involving 2,356 cases of general paresis treated with malaria and reported a 27.5% “full remission,” he added. A bacterial treatment developed in this period used a course of 18-23 injections of killed typhoid cells administered every 2-3 days in order to produce a fever of 103°–104^°F. Animal studies of rabbits infected with syphilis showed that high temperatures could be curative.

Dr. Ambrose suggests that 16th-century syphilitics who had been subjected to mercury fumigation in ovenlike chambers endured severe sweating conditions and – for those who survived – the prolonged elevated body temperature (not the mercury) may have proved curative. Fever “was the common therapeutic denominator in the cinnabar-oven treatment, botanical sudorifics (guaiacum, China root), malarial infections (natural and iatrogenic), and bacterial (tuberculin) vaccine therapy.”

Prelude to modern antibiotics

German bacteriologist/immunologist Paul Ehrlich, MD, (1854-1915) investigated the use of atoxyl (sodium arsanilate) in syphilis, but the metallic drug had severe side effects, injuring the optic nerve and causing blindness. To overcome this problem, Ehrlich and his coworkers synthesized and tested related organic arsenicals. The antisyphilitic activity of arsphenamine (compound 606) was discovered by Sahachiro Hata, MD, (1879-1938) in 1909. This compound, known as Salvarsan, became “Dr. Ehrlich’s Magic Bullet,” for the treatment of syphilis in the 1910s, and it, and later, the less-toxic compound neoarsphenamine (compound 914) became mainstays of successful clinical treatment until the development and use of penicillin in the 1940s.

[email protected]
 

Selected sources

Ambrose, CT. Pre-antibiotic therapy of syphilis. NESSA J Infect Dis Immunology. 2016. 1(1);1-20.

Frith J. Syphilis: Its early history and treatment until penicillin and the debate on its origins. J Mil Veterans Health. 2012;20(4):49-58.

Tognotti B. The rise and fall of syphilis in Renaissance Italy. J Med Humanit. 2009 Jun;30(2):99-113.

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.

It is rare in this modern era for medicine to confront an infectious disease for which there is no cure. Today, there are comparatively few infectious diseases (in the developed world and in places where money is no object) for which medicine cannot offer at least a glimmer of hope to infected patients. Even at its most futile, modern medicine has achieved vast improvements in the efficacy of palliative care. But it wasn’t that long ago that HIV infection was a nearly inevitable death sentence from the complications of AIDS, with no available treatments. And however monstrous that suffering and death, which still continues in many areas of the developing world, it was decades rather than centuries before modern medicine came up with effective treatments. Recently, there is even significant hope on the Ebola virus front that curative treatments may soon become available.

Wellcome Library, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

Medicine has always been in the business of hope, even when true cures were not available. Today that hope is less often misplaced. But in previous centuries, the need to offer hope to – and perhaps to make money from – desperate patients was a hallmark of the doctor’s trade.

It was this need to give patients hope and for doctors to feel that they were being effective that led to some highly dubious and desperate efforts to cure syphilis throughout history. These efforts meant centuries of fruitless torture for countless patients until the rise of modern antibiotics.

For the most part, what we now look upon as horrors and insanity in treatment were the result of misguided scientific theories, half-baked folk wisdom, and the generally well-intentioned efforts of medical practitioners at a cure. There were the charlatans as well, seeking a quick buck from the truly hopeless.

However, the social stigma of syphilis as a venereal disease played a role in the courses of treatment.

By the 15th century, syphilis was recognized as being spread by sexual intercourse, and in a situation analogous with the early AIDS epidemic, “16th- and 17th-century writers and physicians were divided on the moral aspects of syphilis. Some thought it was a divine punishment for sin – and as such only harsh treatments would cure it – or that people with syphilis shouldn’t be treated at all.”
 

Mercury rising

In its earliest manifestations, syphilis was considered untreatable. In 1496, Sebastian Brandt, wrote a poem entitled “De pestilentiali Scorra sive mala de Franzos” detailing the disease’s early spread across Europe and how doctors had no remedy for it.

Science Museum, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

However, it wasn’t long before desperate physicians turned their quest for a cure to a reliable old standby treatment of the period – mercury, which had a history of being used for skin diseases. Mercury salves had been in use in the Arab world for leprosy and eczema, among other skin afflictions, and had been brought to Europe with the return of the medieval crusaders. Another way elemental mercury was administered was through the use of heated cinnabar (HgS), which gave off mercury vapors that could be absorbed by breathing and through the skin. In the 16th century, doctors would place a syphilis-infected individual inside an ovenlike chamber over pans of cinnabar, which were then heated at the person’s feet.

Oral mercury treatments were promoted by Paracelsus (1493?-1541), an alchemist and physician who prescribed calomel (HgCl), or mercury chloride, pills. Mercury treatment, administered at almost inevitably toxic doses, led to ulcerations of the lips, tongue, palate, and jaw; tooth loss; and fetid breath and excessive salivation. This last symptom was, in fact, considered the endpoint in mercury therapy for syphilis, which was “originally judged to be a copious secretion of saliva – ‘some few liters per diem.’ ” Even as recent as the late 19th century and early 20th century, syphilitic patients such as Oscar Wilde (whose teeth were blackened by the treatment), were prescribed calomel.

Looking to the “holy wood”

By 1519, an alternative treatment to mercury was available. In that year, Ulrich von Hutton, a German scholar who suffered from the “great pox,” described its treatment with guaiacum sanctum, or holy wood, in “De Morbo Gallico.” Four years later, despite such treatment, he was dead from the disease himself. But the lack of efficacy did not stop the faith that doctors placed in this botanical cure.

Wellcome Library, London. Wellcome Images/Wikimedia Commons/CCA-4.0 International

Holy wood was an herbal treatment derived from the bark of trees from the Guaiacum family. It was brought back on trading ships from the Caribbean and South America, the origin of syphilis’s foothold in Europe and the rest of the world. The use of holy wood matched a then-current theory that the cure to a disease could be found in the area from which it came. Other botanicals from around the world were also tried, but never came into routine use.

Guaiacum was the first treatment given to sufferers of syphilis in the Blatterhaus (pox hospital) in Augsburg after 1522, according to information from the archives at the Edward Worth Library in Dublin. The botanical therapy was given as a hot drink and followed by a sweating cure. Guaiacum extract acted as a sudorific, a compound which induces sweating when ingested. Even though the use of Guaiacum was initially popular, it was replaced almost exclusively by the use of mercury.

“Give me fever”

In the late 1800s, Julius Wagner von Jauregg (1857-1940), a Viennese neurologist, observed that Austrian army officers with neurosyphilis did not become partially paralyzed if they had also contracted malaria or relapsing fever. He initiated clinical trials in which he induced fever in syphilitics with tuberculin (1-10 mg) and observed in many the remissions their neuropsychiatric symptoms and signs. He also injected neurosyphilitic patients with a mild form of malaria to induce fever, which could then be suppressed with quinine treatment.

“Other physicians soon began using malariotherapy in uncontrolled studies of neurosyphilitics and reported clinical success rates of 33%-51% and only a 5% mortality. Persons with tabes dorsalis (the “wasting” paralysis of neurosyphilis) were hospitalized for 3 weeks of alternate-day fever therapy involving 5-hour long hot baths and extended periods wrapped in heavy blankets,” according to C.T. Ambrose, MD, of the University of Kentucky, Lexington.

A 1931 medical text summarizes in 35 studies involving 2,356 cases of general paresis treated with malaria and reported a 27.5% “full remission,” he added. A bacterial treatment developed in this period used a course of 18-23 injections of killed typhoid cells administered every 2-3 days in order to produce a fever of 103°–104^°F. Animal studies of rabbits infected with syphilis showed that high temperatures could be curative.

Dr. Ambrose suggests that 16th-century syphilitics who had been subjected to mercury fumigation in ovenlike chambers endured severe sweating conditions and – for those who survived – the prolonged elevated body temperature (not the mercury) may have proved curative. Fever “was the common therapeutic denominator in the cinnabar-oven treatment, botanical sudorifics (guaiacum, China root), malarial infections (natural and iatrogenic), and bacterial (tuberculin) vaccine therapy.”

Prelude to modern antibiotics

German bacteriologist/immunologist Paul Ehrlich, MD, (1854-1915) investigated the use of atoxyl (sodium arsanilate) in syphilis, but the metallic drug had severe side effects, injuring the optic nerve and causing blindness. To overcome this problem, Ehrlich and his coworkers synthesized and tested related organic arsenicals. The antisyphilitic activity of arsphenamine (compound 606) was discovered by Sahachiro Hata, MD, (1879-1938) in 1909. This compound, known as Salvarsan, became “Dr. Ehrlich’s Magic Bullet,” for the treatment of syphilis in the 1910s, and it, and later, the less-toxic compound neoarsphenamine (compound 914) became mainstays of successful clinical treatment until the development and use of penicillin in the 1940s.

[email protected]
 

Selected sources

Ambrose, CT. Pre-antibiotic therapy of syphilis. NESSA J Infect Dis Immunology. 2016. 1(1);1-20.

Frith J. Syphilis: Its early history and treatment until penicillin and the debate on its origins. J Mil Veterans Health. 2012;20(4):49-58.

Tognotti B. The rise and fall of syphilis in Renaissance Italy. J Med Humanit. 2009 Jun;30(2):99-113.

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor in the department of biochemistry and molecular & cellular biology at Georgetown University, Washington.