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COVID-19 Pandemic stress affected ovulation, not menstruation
ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.
Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.
The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.
Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.
“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.
It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.
Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”
Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”
But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
‘Experiment of nature’ revealed invisible effect of pandemic stress
The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.
Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.
Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.
There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m2 (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.
More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).
The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).
Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.
The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.
And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).
Employment changes, caring responsibilities, and worry likely causes
The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.
“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.
Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.
“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.
Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.
“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.
Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”
Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.
Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.
The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.
Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.
“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.
It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.
Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”
Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”
But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
‘Experiment of nature’ revealed invisible effect of pandemic stress
The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.
Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.
Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.
There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m2 (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.
More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).
The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).
Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.
The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.
And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).
Employment changes, caring responsibilities, and worry likely causes
The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.
“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.
Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.
“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.
Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.
“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.
Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”
Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA – Disturbances in ovulation that didn’t produce any actual changes in the menstrual cycle of women were extremely common during the first year of the COVID-19 pandemic and were linked to emotional stress, according to the findings of an “experiment of nature” that allowed for comparison with women a decade earlier.
Findings from two studies of reproductive-age women, one conducted in 2006-2008 and the other in 2020-2021, were presented by Jerilynn C. Prior, MD, at the annual meeting of the Endocrine Society.
The comparison of the two time periods yielded several novel findings. “I was taught in medical school that when women don’t eat enough they lose their period. But what we now understand is there’s a graded response to various stressors, acting through the hypothalamus in a common pathway. There is a gradation of disturbances, some of which are subclinical or not obvious,” said Dr. Prior, professor of endocrinology and metabolism at the University of British Columbia, Vancouver.
Moreover, women’s menstrual cycle lengths didn’t differ across the two time periods, despite a dramatic 63% decrement in normal ovulatory function related to increased depression, anxiety, and outside stresses that the women reported in diaries.
“Assuming that regular cycles need normal ovulation is something we should just get out of our minds. It changes our concept about what’s normal if we only know about the cycle length,” she observed.
It will be critical going forward to see whether the ovulatory disturbances have resolved as the pandemic has shifted “because there’s strong evidence that ovulatory disturbances, even with normal cycle length, are related to bone loss and some evidence it’s related to early heart attacks, breast and endometrial cancers,” Dr. Prior said during a press conference.
Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told this news organization: “I think what we can take away is that stress itself is a modifier of the way the brain and the gonads communicate with each other, and that then has an impact on ovulatory function.”
Dr. Neal-Perry noted that the association of stress and ovulatory disruption has been reported in various ways previously, but “clearly it doesn’t affect everyone. What we don’t know is who is most susceptible. There have been some studies showing a genetic predisposition and a genetic anomaly that actually makes them more susceptible to the impact of stress on the reproductive system.”
But the lack of data on weight change in the study cohorts is a limitation. “To me one of the more important questions was what was going on with weight. Just looking at a static number doesn’t tell you whether there were changes. We know that weight gain or weight loss can stress the reproductive axis,” noted Dr. Neal-Parry of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
‘Experiment of nature’ revealed invisible effect of pandemic stress
The women in both cohorts of the Menstruation Ovulation Study (MOS) were healthy volunteers aged 19-35 years recruited from the metropolitan Vancouver region. All were menstruating monthly and none were taking hormonal birth control. Recruitment for the second cohort had begun just prior to the March 2020 COVID-19 pandemic lockdown.
Interviewer-administered questionnaires (CaMos) covering demographics, socioeconomic status, and reproductive history, and daily diaries kept by the women (menstrual cycle diary) were identical for both cohorts.
Assessments of ovulation differed for the two studies but were cross-validated. For the earlier time period, ovulation was assessed by a threefold increase in follicular-to-luteal urinary progesterone (PdG). For the pandemic-era study, the validated quantitative basal temperature (QBT) method was used.
There were 301 women in the earlier cohort and 125 during the pandemic. Both were an average age of about 29 years and had a body mass index of about 24.3 kg/m2 (within the normal range). The pandemic cohort was more racially/ethnically diverse than the earlier one and more in-line with recent census data.
More of the women were nulliparous during the pandemic than earlier (92.7% vs. 80.4%; P = .002).
The distribution of menstrual cycle lengths didn’t differ, with both cohorts averaging about 30 days (P = .893). However, while 90% of the women in the earlier cohort ovulated normally, only 37% did during the pandemic, a highly significant difference (P < .0001).
Thus, during the pandemic, 63% of women had “silent ovulatory disturbances,” either with short luteal phases after ovulation or no ovulation, compared with just 10% in the earlier cohort, “which is remarkable, unbelievable actually,” Dr. Prior remarked.
The difference wasn’t explained by any of the demographic information collected either, including socioeconomic status, lifestyle, or reproductive history variables.
And it wasn’t because of COVID-19 vaccination, as the vaccine wasn’t available when most of the women were recruited, and of the 79 who were recruited during vaccine availability, only two received a COVID-19 vaccine during the study (and both had normal ovulation).
Employment changes, caring responsibilities, and worry likely causes
The information from the diaries was more revealing. Several diary components were far more common during the pandemic, including negative mood (feeling depressed or anxious, sleep problems, and outside stresses), self-worth, interest in sex, energy level, and appetite. All were significantly different between the two cohorts (P < .001) and between those with and without ovulatory disturbances.
“So menstrual cycle lengths and long cycles didn’t differ, but there was a much higher prevalence of silent or subclinical ovulatory disturbances, and these were related to the increased stresses that women recorded in their diaries. This means that the estrogen levels were pretty close to normal but the progesterone levels were remarkably decreased,” Dr. Prior said.
Interestingly, reported menstrual cramps were also significantly more common during the pandemic and associated with ovulatory disruption.
“That is a new observation because previously we’ve always thought that you needed to ovulate in order to even have cramps,” she commented.
Asked whether COVID-19 itself might have played a role, Dr. Prior said no woman in the study tested positive for the virus or had long COVID.
“As far as I’m aware, it was the changes in employment … and caring for elders and worry about illness in somebody you loved that was related,” she said.
Asked what she thinks the result would be if the study were conducted now, she said: “I don’t know. We’re still in a stressful time with inflation and not complete recovery, so probably the issue is still very present.”
Dr. Prior and Dr. Neal-Perry have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ENDO 2022
HPV vaccination with Cervarix ‘unmasks’ cervical lesions from non-vax strains
Vaccines against human papillomavirus have been hailed as a success: they have been shown to decrease the incidence of cervical lesions associated with the HPV types that are in the vaccine.
However,
An expert not involved in the research said the new data “tell us to be a little bit careful.” Although the HPV types not included in the vaccine are rarer and less aggressive, they can still cause cancer.
The data come from the Costa Rica HPV Vaccine Trial, which involved more than 10,000 women aged 18-25 years. The HPV vaccine used in the trial was Cervarix, from GlaxoSmithKline. It covers the two leading causes of cervical cancer, HPV-16 and -18, and provides partial protection against three other genotypes.
After a follow-up of 11 years, among vaccinated women, there was an excess of precancerous cervical lesions caused by genotypes not included in the vaccine, resulting in negative vaccine efficacy for those HPV variants.
The increase wasn’t enough to offset the overall benefit of vaccination when all genotypes were considered, said the researchers, led by Jaimie Shing, PhD, a postdoctoral research fellow at the National Cancer Institute in Bethesda, Md.
Vaccinated women “still had long-term absolute reductions in high-grade lesions,” they pointed out.
The net protection “remained considerable, emphasizing the importance of HPV vaccination for cervical cancer prevention,” the team concluded.
The findings were published online in The Lancet Oncology.
The results are likely the first evidence to date of “clinical unmasking” with HPV vaccination, meaning that protection against the strains covered by the vaccine leaves women more prone to attack from other carcinogenic HPV variants.
This phenomenon “could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programs,” the investigators commented.
Highlighting a need for caution
The take-home message from the trial is that “we have to be careful,” said Marc Steben, MD, co-President of HPV Global Action and a professor at the University of Montreal.
He noted that the Cervarix HPV vaccine used in the trial is not the vaccine that is used now in developed nations.
The current standard HPV vaccine is Gardasil 9 (Merck), which offers broader coverage against nine HPV types (types 6, 11, 16, 18, 31, 33, 45, 52, and 58).
There are 12 main carcinogenic HPV genotypes, so unmasking of other strains is still possible with Gardasil 9, he said.
There is another issue, Dr. Steben added. The success of HPV vaccinations - a nearly 90% reduction in invasive cervical cancer in women who are vaccinated at a young age – has led to questions about the future role of routine cervical cancer screening.
“Some people are saying that if we achieve 90% coverage, we might” eliminate community transmission and no longer need to screen, he said.
These trial results “tell us to be a little bit careful,” Dr. Steben continued. Those HPV types that are less aggressive and rarer than HPV-16 and -18 “can still cause cancer and might be there and surprise us. It could take more time than we thought” to get to the point where screening can be eliminated.
“There might be a little problem if we stop too early,” he said.
Study details
During the period 2004-2005, the investigators randomly assigned 3,727 women aged 18-25 years to receive Cervarix and 3,739 to a control group that received the hepatitis A vaccine; after 4 years, the control group also received Cervarix and exited the study. They were replaced by an unvaccinated control group of 2,836 women. The new control group and the original HPV vaccine group were followed for an additional 7 years.
In years 7-11 of the trial, the investigators found 9.2 additional cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) from HPV types not covered by Cervarix per 1,000 vaccinated women in comparison with unvaccinated participants. This corresponds to –71.2% negative vaccine efficacy against CIN2+ lesions of HPV types not covered by the vaccine.
There were 8.3 additional CIN3+ lesions from nontargeted HPV strains per 1,000 vaccinated women in comparison with unvaccinated participants, which corresponds to –135% negative vaccine efficacy.
Overall, however, there was a net benefit of vaccination, with 27 fewer CIN2+ lesions when all HPV genotypes – vaccine covered or not – were considered per 1,000 vaccinated women over the entire 11 years of follow-up.
There were also 8.7 fewer CIN3+ lesions across all genotypes per 1,000 vaccinated women, but the benefit was not statistically significant.
Among the study limits, the team was unable to evaluate the effect of clinical unmasking on cervical cancer, because women were treated for high-grade cervical lesions before cases could progress to cervical cancer.
The trial was funded by the National Cancer Institute and the National Institutes of Health Office of Research on Women’s Health. GlaxoSmithKline provided the Cervarix vaccine and supported aspects of the trial. Two authors are named inventors on U.S. government–owned HPV vaccine patents with expired licenses to GlaxoSmithKline and Merck. Dr. Steben is an adviser/speaker for many companies, including GlaxoSmithKline and Merck.
A version of this article first appeared on Medscape.com.
Vaccines against human papillomavirus have been hailed as a success: they have been shown to decrease the incidence of cervical lesions associated with the HPV types that are in the vaccine.
However,
An expert not involved in the research said the new data “tell us to be a little bit careful.” Although the HPV types not included in the vaccine are rarer and less aggressive, they can still cause cancer.
The data come from the Costa Rica HPV Vaccine Trial, which involved more than 10,000 women aged 18-25 years. The HPV vaccine used in the trial was Cervarix, from GlaxoSmithKline. It covers the two leading causes of cervical cancer, HPV-16 and -18, and provides partial protection against three other genotypes.
After a follow-up of 11 years, among vaccinated women, there was an excess of precancerous cervical lesions caused by genotypes not included in the vaccine, resulting in negative vaccine efficacy for those HPV variants.
The increase wasn’t enough to offset the overall benefit of vaccination when all genotypes were considered, said the researchers, led by Jaimie Shing, PhD, a postdoctoral research fellow at the National Cancer Institute in Bethesda, Md.
Vaccinated women “still had long-term absolute reductions in high-grade lesions,” they pointed out.
The net protection “remained considerable, emphasizing the importance of HPV vaccination for cervical cancer prevention,” the team concluded.
The findings were published online in The Lancet Oncology.
The results are likely the first evidence to date of “clinical unmasking” with HPV vaccination, meaning that protection against the strains covered by the vaccine leaves women more prone to attack from other carcinogenic HPV variants.
This phenomenon “could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programs,” the investigators commented.
Highlighting a need for caution
The take-home message from the trial is that “we have to be careful,” said Marc Steben, MD, co-President of HPV Global Action and a professor at the University of Montreal.
He noted that the Cervarix HPV vaccine used in the trial is not the vaccine that is used now in developed nations.
The current standard HPV vaccine is Gardasil 9 (Merck), which offers broader coverage against nine HPV types (types 6, 11, 16, 18, 31, 33, 45, 52, and 58).
There are 12 main carcinogenic HPV genotypes, so unmasking of other strains is still possible with Gardasil 9, he said.
There is another issue, Dr. Steben added. The success of HPV vaccinations - a nearly 90% reduction in invasive cervical cancer in women who are vaccinated at a young age – has led to questions about the future role of routine cervical cancer screening.
“Some people are saying that if we achieve 90% coverage, we might” eliminate community transmission and no longer need to screen, he said.
These trial results “tell us to be a little bit careful,” Dr. Steben continued. Those HPV types that are less aggressive and rarer than HPV-16 and -18 “can still cause cancer and might be there and surprise us. It could take more time than we thought” to get to the point where screening can be eliminated.
“There might be a little problem if we stop too early,” he said.
Study details
During the period 2004-2005, the investigators randomly assigned 3,727 women aged 18-25 years to receive Cervarix and 3,739 to a control group that received the hepatitis A vaccine; after 4 years, the control group also received Cervarix and exited the study. They were replaced by an unvaccinated control group of 2,836 women. The new control group and the original HPV vaccine group were followed for an additional 7 years.
In years 7-11 of the trial, the investigators found 9.2 additional cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) from HPV types not covered by Cervarix per 1,000 vaccinated women in comparison with unvaccinated participants. This corresponds to –71.2% negative vaccine efficacy against CIN2+ lesions of HPV types not covered by the vaccine.
There were 8.3 additional CIN3+ lesions from nontargeted HPV strains per 1,000 vaccinated women in comparison with unvaccinated participants, which corresponds to –135% negative vaccine efficacy.
Overall, however, there was a net benefit of vaccination, with 27 fewer CIN2+ lesions when all HPV genotypes – vaccine covered or not – were considered per 1,000 vaccinated women over the entire 11 years of follow-up.
There were also 8.7 fewer CIN3+ lesions across all genotypes per 1,000 vaccinated women, but the benefit was not statistically significant.
Among the study limits, the team was unable to evaluate the effect of clinical unmasking on cervical cancer, because women were treated for high-grade cervical lesions before cases could progress to cervical cancer.
The trial was funded by the National Cancer Institute and the National Institutes of Health Office of Research on Women’s Health. GlaxoSmithKline provided the Cervarix vaccine and supported aspects of the trial. Two authors are named inventors on U.S. government–owned HPV vaccine patents with expired licenses to GlaxoSmithKline and Merck. Dr. Steben is an adviser/speaker for many companies, including GlaxoSmithKline and Merck.
A version of this article first appeared on Medscape.com.
Vaccines against human papillomavirus have been hailed as a success: they have been shown to decrease the incidence of cervical lesions associated with the HPV types that are in the vaccine.
However,
An expert not involved in the research said the new data “tell us to be a little bit careful.” Although the HPV types not included in the vaccine are rarer and less aggressive, they can still cause cancer.
The data come from the Costa Rica HPV Vaccine Trial, which involved more than 10,000 women aged 18-25 years. The HPV vaccine used in the trial was Cervarix, from GlaxoSmithKline. It covers the two leading causes of cervical cancer, HPV-16 and -18, and provides partial protection against three other genotypes.
After a follow-up of 11 years, among vaccinated women, there was an excess of precancerous cervical lesions caused by genotypes not included in the vaccine, resulting in negative vaccine efficacy for those HPV variants.
The increase wasn’t enough to offset the overall benefit of vaccination when all genotypes were considered, said the researchers, led by Jaimie Shing, PhD, a postdoctoral research fellow at the National Cancer Institute in Bethesda, Md.
Vaccinated women “still had long-term absolute reductions in high-grade lesions,” they pointed out.
The net protection “remained considerable, emphasizing the importance of HPV vaccination for cervical cancer prevention,” the team concluded.
The findings were published online in The Lancet Oncology.
The results are likely the first evidence to date of “clinical unmasking” with HPV vaccination, meaning that protection against the strains covered by the vaccine leaves women more prone to attack from other carcinogenic HPV variants.
This phenomenon “could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programs,” the investigators commented.
Highlighting a need for caution
The take-home message from the trial is that “we have to be careful,” said Marc Steben, MD, co-President of HPV Global Action and a professor at the University of Montreal.
He noted that the Cervarix HPV vaccine used in the trial is not the vaccine that is used now in developed nations.
The current standard HPV vaccine is Gardasil 9 (Merck), which offers broader coverage against nine HPV types (types 6, 11, 16, 18, 31, 33, 45, 52, and 58).
There are 12 main carcinogenic HPV genotypes, so unmasking of other strains is still possible with Gardasil 9, he said.
There is another issue, Dr. Steben added. The success of HPV vaccinations - a nearly 90% reduction in invasive cervical cancer in women who are vaccinated at a young age – has led to questions about the future role of routine cervical cancer screening.
“Some people are saying that if we achieve 90% coverage, we might” eliminate community transmission and no longer need to screen, he said.
These trial results “tell us to be a little bit careful,” Dr. Steben continued. Those HPV types that are less aggressive and rarer than HPV-16 and -18 “can still cause cancer and might be there and surprise us. It could take more time than we thought” to get to the point where screening can be eliminated.
“There might be a little problem if we stop too early,” he said.
Study details
During the period 2004-2005, the investigators randomly assigned 3,727 women aged 18-25 years to receive Cervarix and 3,739 to a control group that received the hepatitis A vaccine; after 4 years, the control group also received Cervarix and exited the study. They were replaced by an unvaccinated control group of 2,836 women. The new control group and the original HPV vaccine group were followed for an additional 7 years.
In years 7-11 of the trial, the investigators found 9.2 additional cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) from HPV types not covered by Cervarix per 1,000 vaccinated women in comparison with unvaccinated participants. This corresponds to –71.2% negative vaccine efficacy against CIN2+ lesions of HPV types not covered by the vaccine.
There were 8.3 additional CIN3+ lesions from nontargeted HPV strains per 1,000 vaccinated women in comparison with unvaccinated participants, which corresponds to –135% negative vaccine efficacy.
Overall, however, there was a net benefit of vaccination, with 27 fewer CIN2+ lesions when all HPV genotypes – vaccine covered or not – were considered per 1,000 vaccinated women over the entire 11 years of follow-up.
There were also 8.7 fewer CIN3+ lesions across all genotypes per 1,000 vaccinated women, but the benefit was not statistically significant.
Among the study limits, the team was unable to evaluate the effect of clinical unmasking on cervical cancer, because women were treated for high-grade cervical lesions before cases could progress to cervical cancer.
The trial was funded by the National Cancer Institute and the National Institutes of Health Office of Research on Women’s Health. GlaxoSmithKline provided the Cervarix vaccine and supported aspects of the trial. Two authors are named inventors on U.S. government–owned HPV vaccine patents with expired licenses to GlaxoSmithKline and Merck. Dr. Steben is an adviser/speaker for many companies, including GlaxoSmithKline and Merck.
A version of this article first appeared on Medscape.com.
FROM THE LANCET ONCOLOGY
What’s the best time of day to exercise? It depends on your goals
For most of us, the “best” time of day to work out is simple: When we can.
Maybe that’s before or after work. Or when the gym offers free daycare. Or when our favorite instructor teaches our favorite class.
That’s why we call it a “routine.” And if the results are the same, it’s hard to imagine changing it up.
But what if the results aren’t the same?
They may not be, according to a new study from a research team at Skidmore College in Saratoga Springs, N.Y.
Women who worked out in the morning lost more fat, while those who trained in the evening gained more upper-body strength and power. As for men, the performance improvements were similar no matter when they exercised. But those who did so in the evening had a significant drop in blood pressure, among other benefits.
The study is part of a growing body of research showing different results for different times of day among different populations. As it turns out, when you exercise can ultimately have a big effect, not just on strength and fat loss, but also heart health, mood, and quality of sleep.
An accidental discovery
The original goal of the Skidmore study was to test a unique fitness program with a group of healthy, fit, and extremely active adults in early middle age.
The program includes four workouts a week, each with a different focus: strength, steady-pace endurance, high-intensity intervals, and flexibility (traditional stretching combined with yoga and Pilates exercises).
But because the group was so large – 27 women and 20 men completed the 3-month program – they had to split them into morning and evening workout groups.
It wasn’t until researchers looked at the results that they saw the differences between morning and evening exercise, says lead author Paul Arciero, PhD.
Dr. Arciero stressed that participants in every group got leaner and stronger. But the women who worked out in the morning got much bigger reductions in body fat and body-fat percentage than the evening group. Meanwhile, women in the evening group got much bigger gains in upper-body strength, power, and muscular endurance than their morning counterparts.
Among the men, the evening group had significantly larger improvements in blood pressure, cholesterol levels, and the percentage of fat they burned for energy, along with a bigger drop in feelings of fatigue.
Strategic timing for powerful results
Some of these findings are consistent with previous research. For example, a study published in 2021 showed that the ability to exert high effort and express strength and power peaks in the late afternoon, about the same time that your core body temperature is at its highest point.
On the other hand, you’ll probably perform better in the morning when the activity requires a lot of skill and coordination or depends on strategic decision-making.
The findings apply to both men and women.
Performance aside, exercise timing might offer strong health benefits for men with type 2 diabetes, or at high risk for it.
A study showed that men who exercised between 3 p.m. and 6 p.m. saw dramatic improvements in blood sugar management and insulin sensitivity, compared to a group that worked out between 8 a.m. and 10 a.m.
They also lost more fat during the 12-week program, even though they were doing the exact same workouts.
Train consistently, sleep well
When you exercise can affect your sleep quality in many ways, said neuroscientist Jennifer Heisz, PhD, of McMaster University, Hamilton, Ont.
First, she said, “exercise helps you fall asleep faster and sleep deeper at night.” (The only exception is if you exercise so intensely or so close to bedtime that your heart rate is still elevated.)
Second, “exercising at a consistent time every day helps regulate the body’s circadian rhythms.” It doesn’t matter if the exercise is in the morning, evening, or anywhere in between. As long as it’s predictable, it will help you fall asleep and wake up at the same times.
Outdoor exercise is even better, she said. The sun is the most powerful regulator of the circadian clock and works in tandem with physical activity.
Third, exercising at specific times can help you overcome jet lag or adjust to an earlier or later shift at work.
“Exercising at 7 a.m. or between 1 and 4 p.m. helps your circadian clock to ‘fall back’ in time, making it easier to wake up earlier,” Dr. Heisz said. If you need to train your body to wake up later in the morning, try working out between 7 p.m. and 10 p.m.
All exercise is good, but the right timing can make it even better
“The best time to exercise is when you can fit it in,” Dr. Arciero said. “You’ve got to choose the time that fits your lifestyle best.”
But context matters, he noted.
“For someone needing to achieve an improvement in their risk for cardiometabolic disease,” his study shows an advantage to working out later in the day, especially for men. If you’re more focused on building upper-body strength and power, you’ll probably get better results from training in the afternoon or evening.
And for fat loss, the Skidmore study shows better results for women who did morning workouts.
And if you’re still not sure? Try sleeping on it – preferably after your workout.
A version of this article first appeared on WebMD.com.
For most of us, the “best” time of day to work out is simple: When we can.
Maybe that’s before or after work. Or when the gym offers free daycare. Or when our favorite instructor teaches our favorite class.
That’s why we call it a “routine.” And if the results are the same, it’s hard to imagine changing it up.
But what if the results aren’t the same?
They may not be, according to a new study from a research team at Skidmore College in Saratoga Springs, N.Y.
Women who worked out in the morning lost more fat, while those who trained in the evening gained more upper-body strength and power. As for men, the performance improvements were similar no matter when they exercised. But those who did so in the evening had a significant drop in blood pressure, among other benefits.
The study is part of a growing body of research showing different results for different times of day among different populations. As it turns out, when you exercise can ultimately have a big effect, not just on strength and fat loss, but also heart health, mood, and quality of sleep.
An accidental discovery
The original goal of the Skidmore study was to test a unique fitness program with a group of healthy, fit, and extremely active adults in early middle age.
The program includes four workouts a week, each with a different focus: strength, steady-pace endurance, high-intensity intervals, and flexibility (traditional stretching combined with yoga and Pilates exercises).
But because the group was so large – 27 women and 20 men completed the 3-month program – they had to split them into morning and evening workout groups.
It wasn’t until researchers looked at the results that they saw the differences between morning and evening exercise, says lead author Paul Arciero, PhD.
Dr. Arciero stressed that participants in every group got leaner and stronger. But the women who worked out in the morning got much bigger reductions in body fat and body-fat percentage than the evening group. Meanwhile, women in the evening group got much bigger gains in upper-body strength, power, and muscular endurance than their morning counterparts.
Among the men, the evening group had significantly larger improvements in blood pressure, cholesterol levels, and the percentage of fat they burned for energy, along with a bigger drop in feelings of fatigue.
Strategic timing for powerful results
Some of these findings are consistent with previous research. For example, a study published in 2021 showed that the ability to exert high effort and express strength and power peaks in the late afternoon, about the same time that your core body temperature is at its highest point.
On the other hand, you’ll probably perform better in the morning when the activity requires a lot of skill and coordination or depends on strategic decision-making.
The findings apply to both men and women.
Performance aside, exercise timing might offer strong health benefits for men with type 2 diabetes, or at high risk for it.
A study showed that men who exercised between 3 p.m. and 6 p.m. saw dramatic improvements in blood sugar management and insulin sensitivity, compared to a group that worked out between 8 a.m. and 10 a.m.
They also lost more fat during the 12-week program, even though they were doing the exact same workouts.
Train consistently, sleep well
When you exercise can affect your sleep quality in many ways, said neuroscientist Jennifer Heisz, PhD, of McMaster University, Hamilton, Ont.
First, she said, “exercise helps you fall asleep faster and sleep deeper at night.” (The only exception is if you exercise so intensely or so close to bedtime that your heart rate is still elevated.)
Second, “exercising at a consistent time every day helps regulate the body’s circadian rhythms.” It doesn’t matter if the exercise is in the morning, evening, or anywhere in between. As long as it’s predictable, it will help you fall asleep and wake up at the same times.
Outdoor exercise is even better, she said. The sun is the most powerful regulator of the circadian clock and works in tandem with physical activity.
Third, exercising at specific times can help you overcome jet lag or adjust to an earlier or later shift at work.
“Exercising at 7 a.m. or between 1 and 4 p.m. helps your circadian clock to ‘fall back’ in time, making it easier to wake up earlier,” Dr. Heisz said. If you need to train your body to wake up later in the morning, try working out between 7 p.m. and 10 p.m.
All exercise is good, but the right timing can make it even better
“The best time to exercise is when you can fit it in,” Dr. Arciero said. “You’ve got to choose the time that fits your lifestyle best.”
But context matters, he noted.
“For someone needing to achieve an improvement in their risk for cardiometabolic disease,” his study shows an advantage to working out later in the day, especially for men. If you’re more focused on building upper-body strength and power, you’ll probably get better results from training in the afternoon or evening.
And for fat loss, the Skidmore study shows better results for women who did morning workouts.
And if you’re still not sure? Try sleeping on it – preferably after your workout.
A version of this article first appeared on WebMD.com.
For most of us, the “best” time of day to work out is simple: When we can.
Maybe that’s before or after work. Or when the gym offers free daycare. Or when our favorite instructor teaches our favorite class.
That’s why we call it a “routine.” And if the results are the same, it’s hard to imagine changing it up.
But what if the results aren’t the same?
They may not be, according to a new study from a research team at Skidmore College in Saratoga Springs, N.Y.
Women who worked out in the morning lost more fat, while those who trained in the evening gained more upper-body strength and power. As for men, the performance improvements were similar no matter when they exercised. But those who did so in the evening had a significant drop in blood pressure, among other benefits.
The study is part of a growing body of research showing different results for different times of day among different populations. As it turns out, when you exercise can ultimately have a big effect, not just on strength and fat loss, but also heart health, mood, and quality of sleep.
An accidental discovery
The original goal of the Skidmore study was to test a unique fitness program with a group of healthy, fit, and extremely active adults in early middle age.
The program includes four workouts a week, each with a different focus: strength, steady-pace endurance, high-intensity intervals, and flexibility (traditional stretching combined with yoga and Pilates exercises).
But because the group was so large – 27 women and 20 men completed the 3-month program – they had to split them into morning and evening workout groups.
It wasn’t until researchers looked at the results that they saw the differences between morning and evening exercise, says lead author Paul Arciero, PhD.
Dr. Arciero stressed that participants in every group got leaner and stronger. But the women who worked out in the morning got much bigger reductions in body fat and body-fat percentage than the evening group. Meanwhile, women in the evening group got much bigger gains in upper-body strength, power, and muscular endurance than their morning counterparts.
Among the men, the evening group had significantly larger improvements in blood pressure, cholesterol levels, and the percentage of fat they burned for energy, along with a bigger drop in feelings of fatigue.
Strategic timing for powerful results
Some of these findings are consistent with previous research. For example, a study published in 2021 showed that the ability to exert high effort and express strength and power peaks in the late afternoon, about the same time that your core body temperature is at its highest point.
On the other hand, you’ll probably perform better in the morning when the activity requires a lot of skill and coordination or depends on strategic decision-making.
The findings apply to both men and women.
Performance aside, exercise timing might offer strong health benefits for men with type 2 diabetes, or at high risk for it.
A study showed that men who exercised between 3 p.m. and 6 p.m. saw dramatic improvements in blood sugar management and insulin sensitivity, compared to a group that worked out between 8 a.m. and 10 a.m.
They also lost more fat during the 12-week program, even though they were doing the exact same workouts.
Train consistently, sleep well
When you exercise can affect your sleep quality in many ways, said neuroscientist Jennifer Heisz, PhD, of McMaster University, Hamilton, Ont.
First, she said, “exercise helps you fall asleep faster and sleep deeper at night.” (The only exception is if you exercise so intensely or so close to bedtime that your heart rate is still elevated.)
Second, “exercising at a consistent time every day helps regulate the body’s circadian rhythms.” It doesn’t matter if the exercise is in the morning, evening, or anywhere in between. As long as it’s predictable, it will help you fall asleep and wake up at the same times.
Outdoor exercise is even better, she said. The sun is the most powerful regulator of the circadian clock and works in tandem with physical activity.
Third, exercising at specific times can help you overcome jet lag or adjust to an earlier or later shift at work.
“Exercising at 7 a.m. or between 1 and 4 p.m. helps your circadian clock to ‘fall back’ in time, making it easier to wake up earlier,” Dr. Heisz said. If you need to train your body to wake up later in the morning, try working out between 7 p.m. and 10 p.m.
All exercise is good, but the right timing can make it even better
“The best time to exercise is when you can fit it in,” Dr. Arciero said. “You’ve got to choose the time that fits your lifestyle best.”
But context matters, he noted.
“For someone needing to achieve an improvement in their risk for cardiometabolic disease,” his study shows an advantage to working out later in the day, especially for men. If you’re more focused on building upper-body strength and power, you’ll probably get better results from training in the afternoon or evening.
And for fat loss, the Skidmore study shows better results for women who did morning workouts.
And if you’re still not sure? Try sleeping on it – preferably after your workout.
A version of this article first appeared on WebMD.com.
FROM FRONTIERS IN PHYSIOLOGY
To predict mortality, you need a leg to stand on
Storks everywhere, rejoice.
According to the findings, people in middle age and older who couldn’t perform the 10-second standing test were nearly four times as likely to die of any cause – heart attacks, strokes, cancer, and more – in the coming years than those who could, well, stand the test of time.
Claudio Gil Araújo, MD, PhD, research director of the Exercise Medicine Clinic-CLINIMEX in Rio de Janeiro, who led the study, called the results “awesome!”
“As a physician who has worked with cardiac patients for over 4 decades, I was very impressed in finding out that, for those between 51 and 75 years of age, it is riskier for survival to not complete the 10-second one-leg standing test than to have been diagnosed as having coronary artery disease or in being hypertensive” or having abnormal cholesterol, Dr. Araújo said in an interview.
The findings appeared in the British Journal of Sports Medicine.
Researchers have known for at least a half century that balance and mortality are connected. One reason is falls: Worldwide, nearly 700,000 people each year die as a result of a fall, according to the World Health Organization, and more than 37 million falls annually require medical attention. But as the new study indicates, falls aren’t the only problem.
Dr. Araújo and colleagues have been working on ways to improve balance and strength as people age. In addition to the one-legged standing test, they have previously shown that the ability to rise from a sitting position on the floor is also a strong predictor of longevity.
For the new study, the researchers assessed 1,702 people in Brazil (68% men) aged 51-75 years who had been participating in an ongoing exercise study that began there in 1994.
Three tries to succeed
Starting in 2008, the team introduced the standing test, which involves balancing on one leg and placing the other foot at the back weight-bearing limb for support. People get three tries to maintain that posture for at least 10 seconds.
Not surprisingly, the ability to perform the test dropped with age. Although 20% of people in the study overall were unable to stand on one leg for 10 seconds, that figure rose to about 70% for those aged 76-80 years, and nearly 90% for those aged 81-85, according to the researchers. Of the two dozen 85-year-olds in the study, only two were able to complete the standing test, Dr. Araújo told this news organization.
At roughly age 70, half of people could not complete the 10-second test.
Over an average of 7 years of follow-up, 17.5% of people who could not manage the 10-second stand had died, compared with 4.5% of those who could last that long, the study found.
After accounting for age and many other risk factors, such as diabetes, body mass index, and a history of heart disease, people who were unable to complete the standing test were 84% more likely to die from any cause over the study period than their peers with better one-legged static balance (95% confidence interval, 1.23-2.78; P < .001).
The researchers said their study was limited by its lack of diversity – all the participants were relatively affluent Brazilians – and the inability to control for a history of falls and physical activity. But they said the size of the cohort, the long follow-up period, and their use of sophistical statistical methods helped mitigate the shortcomings.
Although low aerobic fitness is a marker of poor health, much less attention has been paid to nonaerobic fitness – things like balance, flexibility, and muscle strength and power, Dr. Araújo said.
“We are accumulating evidence that these three components of nonaerobic physical fitness are potentially relevant for good health and even more relevant for survival in older subjects,” Dr. Araújo said. Poor nonaerobic fitness, which is normally but not always associated with a sedentary lifestyle, “is the background of most cases of frailty, and being frail is strongly associated with a poor quality of life, less physical activity and exercise, and so on. It’s a bad circle.”
Dr. Araújo’s group has been using the standing test in their clinic for more than a dozen years and have seen gains in their patients. “Patients are often unaware that they are unable to sustain 10 seconds standing one legged. After this simple evaluation, they are much more prone to engage in balance training,” he said.
For now, the researchers don’t have data to show that improving static balance or performance on the standing test can affect survival, a “quite attractive” possibility, he added. But balance can be substantially improved through training.
“After only a few sessions, an improvement can be perceived, and this influences quality of life,” Dr. Araújo said. “And this is exactly what we do with the patients that we evaluated and for those that are attending our medically supervised exercise program.”
George A. Kuchel, MD, CM, FRCP, professor and Travelers Chair in Geriatrics and Gerontology at the University of Connecticut, Farmington, called the research “well done” and said the results “make perfect sense, since we have known for a long time that muscle strength is an important determinant of health, independence, and survival.”
Identifying frail patients quickly, simply, and reliably in the clinical setting is a pressing need, Dr. Kuchel, director of the UConn Center on Aging, said in an interview. The 10-second test “has considerable appeal” for this purpose.
“This could be, or rather should be, of great interest to all busy clinicians who see older adults in primary care or consultative capacities,” Dr. Kuchel added. “I hate to be nihilistic as regards what is possible in the context of really busy clinical practices, but even the minute or so that this takes to do may very well be too much for busy clinicians to do.”
Dr. Araújo and Dr. Kuchel reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Storks everywhere, rejoice.
According to the findings, people in middle age and older who couldn’t perform the 10-second standing test were nearly four times as likely to die of any cause – heart attacks, strokes, cancer, and more – in the coming years than those who could, well, stand the test of time.
Claudio Gil Araújo, MD, PhD, research director of the Exercise Medicine Clinic-CLINIMEX in Rio de Janeiro, who led the study, called the results “awesome!”
“As a physician who has worked with cardiac patients for over 4 decades, I was very impressed in finding out that, for those between 51 and 75 years of age, it is riskier for survival to not complete the 10-second one-leg standing test than to have been diagnosed as having coronary artery disease or in being hypertensive” or having abnormal cholesterol, Dr. Araújo said in an interview.
The findings appeared in the British Journal of Sports Medicine.
Researchers have known for at least a half century that balance and mortality are connected. One reason is falls: Worldwide, nearly 700,000 people each year die as a result of a fall, according to the World Health Organization, and more than 37 million falls annually require medical attention. But as the new study indicates, falls aren’t the only problem.
Dr. Araújo and colleagues have been working on ways to improve balance and strength as people age. In addition to the one-legged standing test, they have previously shown that the ability to rise from a sitting position on the floor is also a strong predictor of longevity.
For the new study, the researchers assessed 1,702 people in Brazil (68% men) aged 51-75 years who had been participating in an ongoing exercise study that began there in 1994.
Three tries to succeed
Starting in 2008, the team introduced the standing test, which involves balancing on one leg and placing the other foot at the back weight-bearing limb for support. People get three tries to maintain that posture for at least 10 seconds.
Not surprisingly, the ability to perform the test dropped with age. Although 20% of people in the study overall were unable to stand on one leg for 10 seconds, that figure rose to about 70% for those aged 76-80 years, and nearly 90% for those aged 81-85, according to the researchers. Of the two dozen 85-year-olds in the study, only two were able to complete the standing test, Dr. Araújo told this news organization.
At roughly age 70, half of people could not complete the 10-second test.
Over an average of 7 years of follow-up, 17.5% of people who could not manage the 10-second stand had died, compared with 4.5% of those who could last that long, the study found.
After accounting for age and many other risk factors, such as diabetes, body mass index, and a history of heart disease, people who were unable to complete the standing test were 84% more likely to die from any cause over the study period than their peers with better one-legged static balance (95% confidence interval, 1.23-2.78; P < .001).
The researchers said their study was limited by its lack of diversity – all the participants were relatively affluent Brazilians – and the inability to control for a history of falls and physical activity. But they said the size of the cohort, the long follow-up period, and their use of sophistical statistical methods helped mitigate the shortcomings.
Although low aerobic fitness is a marker of poor health, much less attention has been paid to nonaerobic fitness – things like balance, flexibility, and muscle strength and power, Dr. Araújo said.
“We are accumulating evidence that these three components of nonaerobic physical fitness are potentially relevant for good health and even more relevant for survival in older subjects,” Dr. Araújo said. Poor nonaerobic fitness, which is normally but not always associated with a sedentary lifestyle, “is the background of most cases of frailty, and being frail is strongly associated with a poor quality of life, less physical activity and exercise, and so on. It’s a bad circle.”
Dr. Araújo’s group has been using the standing test in their clinic for more than a dozen years and have seen gains in their patients. “Patients are often unaware that they are unable to sustain 10 seconds standing one legged. After this simple evaluation, they are much more prone to engage in balance training,” he said.
For now, the researchers don’t have data to show that improving static balance or performance on the standing test can affect survival, a “quite attractive” possibility, he added. But balance can be substantially improved through training.
“After only a few sessions, an improvement can be perceived, and this influences quality of life,” Dr. Araújo said. “And this is exactly what we do with the patients that we evaluated and for those that are attending our medically supervised exercise program.”
George A. Kuchel, MD, CM, FRCP, professor and Travelers Chair in Geriatrics and Gerontology at the University of Connecticut, Farmington, called the research “well done” and said the results “make perfect sense, since we have known for a long time that muscle strength is an important determinant of health, independence, and survival.”
Identifying frail patients quickly, simply, and reliably in the clinical setting is a pressing need, Dr. Kuchel, director of the UConn Center on Aging, said in an interview. The 10-second test “has considerable appeal” for this purpose.
“This could be, or rather should be, of great interest to all busy clinicians who see older adults in primary care or consultative capacities,” Dr. Kuchel added. “I hate to be nihilistic as regards what is possible in the context of really busy clinical practices, but even the minute or so that this takes to do may very well be too much for busy clinicians to do.”
Dr. Araújo and Dr. Kuchel reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Storks everywhere, rejoice.
According to the findings, people in middle age and older who couldn’t perform the 10-second standing test were nearly four times as likely to die of any cause – heart attacks, strokes, cancer, and more – in the coming years than those who could, well, stand the test of time.
Claudio Gil Araújo, MD, PhD, research director of the Exercise Medicine Clinic-CLINIMEX in Rio de Janeiro, who led the study, called the results “awesome!”
“As a physician who has worked with cardiac patients for over 4 decades, I was very impressed in finding out that, for those between 51 and 75 years of age, it is riskier for survival to not complete the 10-second one-leg standing test than to have been diagnosed as having coronary artery disease or in being hypertensive” or having abnormal cholesterol, Dr. Araújo said in an interview.
The findings appeared in the British Journal of Sports Medicine.
Researchers have known for at least a half century that balance and mortality are connected. One reason is falls: Worldwide, nearly 700,000 people each year die as a result of a fall, according to the World Health Organization, and more than 37 million falls annually require medical attention. But as the new study indicates, falls aren’t the only problem.
Dr. Araújo and colleagues have been working on ways to improve balance and strength as people age. In addition to the one-legged standing test, they have previously shown that the ability to rise from a sitting position on the floor is also a strong predictor of longevity.
For the new study, the researchers assessed 1,702 people in Brazil (68% men) aged 51-75 years who had been participating in an ongoing exercise study that began there in 1994.
Three tries to succeed
Starting in 2008, the team introduced the standing test, which involves balancing on one leg and placing the other foot at the back weight-bearing limb for support. People get three tries to maintain that posture for at least 10 seconds.
Not surprisingly, the ability to perform the test dropped with age. Although 20% of people in the study overall were unable to stand on one leg for 10 seconds, that figure rose to about 70% for those aged 76-80 years, and nearly 90% for those aged 81-85, according to the researchers. Of the two dozen 85-year-olds in the study, only two were able to complete the standing test, Dr. Araújo told this news organization.
At roughly age 70, half of people could not complete the 10-second test.
Over an average of 7 years of follow-up, 17.5% of people who could not manage the 10-second stand had died, compared with 4.5% of those who could last that long, the study found.
After accounting for age and many other risk factors, such as diabetes, body mass index, and a history of heart disease, people who were unable to complete the standing test were 84% more likely to die from any cause over the study period than their peers with better one-legged static balance (95% confidence interval, 1.23-2.78; P < .001).
The researchers said their study was limited by its lack of diversity – all the participants were relatively affluent Brazilians – and the inability to control for a history of falls and physical activity. But they said the size of the cohort, the long follow-up period, and their use of sophistical statistical methods helped mitigate the shortcomings.
Although low aerobic fitness is a marker of poor health, much less attention has been paid to nonaerobic fitness – things like balance, flexibility, and muscle strength and power, Dr. Araújo said.
“We are accumulating evidence that these three components of nonaerobic physical fitness are potentially relevant for good health and even more relevant for survival in older subjects,” Dr. Araújo said. Poor nonaerobic fitness, which is normally but not always associated with a sedentary lifestyle, “is the background of most cases of frailty, and being frail is strongly associated with a poor quality of life, less physical activity and exercise, and so on. It’s a bad circle.”
Dr. Araújo’s group has been using the standing test in their clinic for more than a dozen years and have seen gains in their patients. “Patients are often unaware that they are unable to sustain 10 seconds standing one legged. After this simple evaluation, they are much more prone to engage in balance training,” he said.
For now, the researchers don’t have data to show that improving static balance or performance on the standing test can affect survival, a “quite attractive” possibility, he added. But balance can be substantially improved through training.
“After only a few sessions, an improvement can be perceived, and this influences quality of life,” Dr. Araújo said. “And this is exactly what we do with the patients that we evaluated and for those that are attending our medically supervised exercise program.”
George A. Kuchel, MD, CM, FRCP, professor and Travelers Chair in Geriatrics and Gerontology at the University of Connecticut, Farmington, called the research “well done” and said the results “make perfect sense, since we have known for a long time that muscle strength is an important determinant of health, independence, and survival.”
Identifying frail patients quickly, simply, and reliably in the clinical setting is a pressing need, Dr. Kuchel, director of the UConn Center on Aging, said in an interview. The 10-second test “has considerable appeal” for this purpose.
“This could be, or rather should be, of great interest to all busy clinicians who see older adults in primary care or consultative capacities,” Dr. Kuchel added. “I hate to be nihilistic as regards what is possible in the context of really busy clinical practices, but even the minute or so that this takes to do may very well be too much for busy clinicians to do.”
Dr. Araújo and Dr. Kuchel reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE BRITISH JOURNAL OF SPORTS MEDICINE
Updates in aspirin use, aducanumab, and CKD diagnostic criteria in geriatric medicine
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
It’s hot outside – and that’s bad news for children’s health
Heat waves are getting hotter and becoming more frequent because of rising rates of air pollution, putting children’s health at risk, a wide-ranging new report finds.
An article in the New England Journal of Medicine reviews current research to take a sweeping inventory of how air pollution and climate change interact to adversely affect people’s health, especially that of kids. It examined the link between fossil fuel emissions and a variety of consequences of climate change – including extreme weather events; wildfires; vector-borne illnesses such as malaria, Zika, and Lyme disease; and heat waves, a topic at the forefront of many people’s minds.
This month, for example, record-high temperatures have been reported across the United States, affecting more than 100 million people and touching locations from the Gulf Coast to the Great Lakes, the Southwest, the mid-Atlantic, and the Midwest.
In Texas, Austin has already experienced an 8-day streak of temperatures above the 100° F mark in June, according to the Austin American-Statesman.
These patterns are an important reality to note, said Frederica Perera, DrPH, PhD, the article’s lead author. “My concern is that the threats are rising as temperature is rising,” Dr. Perera, a professor at Columbia University’s Mailman School of Public Health, New York, told KHN. “Temperatures are rising because greenhouse gas emissions are rising, and that’s a great concern for everyone’s health – but especially the most vulnerable.”
Children fit into this category, wrote Dr. Perera and her coauthor, Kari Nadeau, MD, PhD, Naddisy Foundation Endowed Professor of Medicine and Pediatrics at Stanford (Calif.) University, because their ability to regulate temperature, known as thermoregulation, is not fully developed.
They are also more susceptible to heat-related stress because they’re smaller and need to drink and eat more frequently to stay healthy, said Dr. Perera. But because “young children are dependent on parents to provide, sometimes their needs go ignored,” she said.
The authors noted that heat-related illness is “a leading and increasing cause of death and illness among student athletes” in the United States. In addition, they cited studies suggesting that “the heat associated with climate change” takes a toll on the mental health of children and adolescents, as well as their ability to learn.
The review article pointed to previous research. that associated in utero exposure to heat waves with “increased risks of preterm birth or low birth weight; hyperthermia and death among infants; and heat stress, kidney disease, and other illnesses” among kids.
“Being pregnant is very physiologically demanding in itself, and then heat places additional stress on a pregnant woman,” said Dr. Robert Dubrow, a professor of epidemiology at Yale’s School of Public Health, New Haven, Conn., who was not associated with either study. “And the fetus can experience heat stress as well, which could result in adverse birth outcomes.”
And these heat-related risks are across-the-board greater for “low-income communities and communities of color,” wrote the authors of the new article.
Carbon dioxide emissions from burning fossil fuels have risen sharply in the past 70 years, according to the article. “Modeling indicates that some heat waves would be extraordinarily unlikely to occur in the absence of climate change,” it says.
The authors briefly outline solutions that they describe as “climate and environmental strategies” that “should also be seen as essential public health policy.” Beyond big-picture efforts to mitigate fossil fuel and greenhouse gas emissions, they offered various ways to protect children – steps they term “adaptation measures” – which included providing clean water to children and families facing drought or water contamination and creating shaded areas where children play, live, and go to school.
Separately, Austin-based research highlighted why this step could be meaningful.
Researchers tracked the physical activity levels and location of students ages 8 to 10 during recess at three elementary schools in 2019. They compared children’s activity at recess during two weeks in September, the hottest full month during the school year, to a cooler week in November. “We wanted to understand the impact of outdoor temperatures on children’s play in schoolyard environments,” said Dr. Kevin Lanza, the study’s lead investigator, to inform the design of “future school-based interventions for physical activity in the face of climate change.”
During the hotter periods, he said, “children engaged in less physical activity and sought shade.”
As temperatures continue to rise, he said, schools must be flexible in making sure students are getting the daily exercise they need. “Schools should consider adding shade, either by planting trees or installing artificial structures that cover spaces intended for physical activity,” said Dr. Lanza, an assistant professor at UTHealth School of Public Health, Austin, Tex. He also noted that school policies could be updated so that recesses are scheduled during cooler times of the day and moved inside during periods of extreme heat.
But the overall need to protect kids from scorching weather patterns requires action beyond such steps, Dr. Perera said, and more climate and clean air policies must be enacted.
“Governments have the responsibility to protect the population and especially those most vulnerable, which especially includes children,” Dr. Perera said. “Action must be done immediately because we’re absolutely heading in the wrong direction.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Heat waves are getting hotter and becoming more frequent because of rising rates of air pollution, putting children’s health at risk, a wide-ranging new report finds.
An article in the New England Journal of Medicine reviews current research to take a sweeping inventory of how air pollution and climate change interact to adversely affect people’s health, especially that of kids. It examined the link between fossil fuel emissions and a variety of consequences of climate change – including extreme weather events; wildfires; vector-borne illnesses such as malaria, Zika, and Lyme disease; and heat waves, a topic at the forefront of many people’s minds.
This month, for example, record-high temperatures have been reported across the United States, affecting more than 100 million people and touching locations from the Gulf Coast to the Great Lakes, the Southwest, the mid-Atlantic, and the Midwest.
In Texas, Austin has already experienced an 8-day streak of temperatures above the 100° F mark in June, according to the Austin American-Statesman.
These patterns are an important reality to note, said Frederica Perera, DrPH, PhD, the article’s lead author. “My concern is that the threats are rising as temperature is rising,” Dr. Perera, a professor at Columbia University’s Mailman School of Public Health, New York, told KHN. “Temperatures are rising because greenhouse gas emissions are rising, and that’s a great concern for everyone’s health – but especially the most vulnerable.”
Children fit into this category, wrote Dr. Perera and her coauthor, Kari Nadeau, MD, PhD, Naddisy Foundation Endowed Professor of Medicine and Pediatrics at Stanford (Calif.) University, because their ability to regulate temperature, known as thermoregulation, is not fully developed.
They are also more susceptible to heat-related stress because they’re smaller and need to drink and eat more frequently to stay healthy, said Dr. Perera. But because “young children are dependent on parents to provide, sometimes their needs go ignored,” she said.
The authors noted that heat-related illness is “a leading and increasing cause of death and illness among student athletes” in the United States. In addition, they cited studies suggesting that “the heat associated with climate change” takes a toll on the mental health of children and adolescents, as well as their ability to learn.
The review article pointed to previous research. that associated in utero exposure to heat waves with “increased risks of preterm birth or low birth weight; hyperthermia and death among infants; and heat stress, kidney disease, and other illnesses” among kids.
“Being pregnant is very physiologically demanding in itself, and then heat places additional stress on a pregnant woman,” said Dr. Robert Dubrow, a professor of epidemiology at Yale’s School of Public Health, New Haven, Conn., who was not associated with either study. “And the fetus can experience heat stress as well, which could result in adverse birth outcomes.”
And these heat-related risks are across-the-board greater for “low-income communities and communities of color,” wrote the authors of the new article.
Carbon dioxide emissions from burning fossil fuels have risen sharply in the past 70 years, according to the article. “Modeling indicates that some heat waves would be extraordinarily unlikely to occur in the absence of climate change,” it says.
The authors briefly outline solutions that they describe as “climate and environmental strategies” that “should also be seen as essential public health policy.” Beyond big-picture efforts to mitigate fossil fuel and greenhouse gas emissions, they offered various ways to protect children – steps they term “adaptation measures” – which included providing clean water to children and families facing drought or water contamination and creating shaded areas where children play, live, and go to school.
Separately, Austin-based research highlighted why this step could be meaningful.
Researchers tracked the physical activity levels and location of students ages 8 to 10 during recess at three elementary schools in 2019. They compared children’s activity at recess during two weeks in September, the hottest full month during the school year, to a cooler week in November. “We wanted to understand the impact of outdoor temperatures on children’s play in schoolyard environments,” said Dr. Kevin Lanza, the study’s lead investigator, to inform the design of “future school-based interventions for physical activity in the face of climate change.”
During the hotter periods, he said, “children engaged in less physical activity and sought shade.”
As temperatures continue to rise, he said, schools must be flexible in making sure students are getting the daily exercise they need. “Schools should consider adding shade, either by planting trees or installing artificial structures that cover spaces intended for physical activity,” said Dr. Lanza, an assistant professor at UTHealth School of Public Health, Austin, Tex. He also noted that school policies could be updated so that recesses are scheduled during cooler times of the day and moved inside during periods of extreme heat.
But the overall need to protect kids from scorching weather patterns requires action beyond such steps, Dr. Perera said, and more climate and clean air policies must be enacted.
“Governments have the responsibility to protect the population and especially those most vulnerable, which especially includes children,” Dr. Perera said. “Action must be done immediately because we’re absolutely heading in the wrong direction.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Heat waves are getting hotter and becoming more frequent because of rising rates of air pollution, putting children’s health at risk, a wide-ranging new report finds.
An article in the New England Journal of Medicine reviews current research to take a sweeping inventory of how air pollution and climate change interact to adversely affect people’s health, especially that of kids. It examined the link between fossil fuel emissions and a variety of consequences of climate change – including extreme weather events; wildfires; vector-borne illnesses such as malaria, Zika, and Lyme disease; and heat waves, a topic at the forefront of many people’s minds.
This month, for example, record-high temperatures have been reported across the United States, affecting more than 100 million people and touching locations from the Gulf Coast to the Great Lakes, the Southwest, the mid-Atlantic, and the Midwest.
In Texas, Austin has already experienced an 8-day streak of temperatures above the 100° F mark in June, according to the Austin American-Statesman.
These patterns are an important reality to note, said Frederica Perera, DrPH, PhD, the article’s lead author. “My concern is that the threats are rising as temperature is rising,” Dr. Perera, a professor at Columbia University’s Mailman School of Public Health, New York, told KHN. “Temperatures are rising because greenhouse gas emissions are rising, and that’s a great concern for everyone’s health – but especially the most vulnerable.”
Children fit into this category, wrote Dr. Perera and her coauthor, Kari Nadeau, MD, PhD, Naddisy Foundation Endowed Professor of Medicine and Pediatrics at Stanford (Calif.) University, because their ability to regulate temperature, known as thermoregulation, is not fully developed.
They are also more susceptible to heat-related stress because they’re smaller and need to drink and eat more frequently to stay healthy, said Dr. Perera. But because “young children are dependent on parents to provide, sometimes their needs go ignored,” she said.
The authors noted that heat-related illness is “a leading and increasing cause of death and illness among student athletes” in the United States. In addition, they cited studies suggesting that “the heat associated with climate change” takes a toll on the mental health of children and adolescents, as well as their ability to learn.
The review article pointed to previous research. that associated in utero exposure to heat waves with “increased risks of preterm birth or low birth weight; hyperthermia and death among infants; and heat stress, kidney disease, and other illnesses” among kids.
“Being pregnant is very physiologically demanding in itself, and then heat places additional stress on a pregnant woman,” said Dr. Robert Dubrow, a professor of epidemiology at Yale’s School of Public Health, New Haven, Conn., who was not associated with either study. “And the fetus can experience heat stress as well, which could result in adverse birth outcomes.”
And these heat-related risks are across-the-board greater for “low-income communities and communities of color,” wrote the authors of the new article.
Carbon dioxide emissions from burning fossil fuels have risen sharply in the past 70 years, according to the article. “Modeling indicates that some heat waves would be extraordinarily unlikely to occur in the absence of climate change,” it says.
The authors briefly outline solutions that they describe as “climate and environmental strategies” that “should also be seen as essential public health policy.” Beyond big-picture efforts to mitigate fossil fuel and greenhouse gas emissions, they offered various ways to protect children – steps they term “adaptation measures” – which included providing clean water to children and families facing drought or water contamination and creating shaded areas where children play, live, and go to school.
Separately, Austin-based research highlighted why this step could be meaningful.
Researchers tracked the physical activity levels and location of students ages 8 to 10 during recess at three elementary schools in 2019. They compared children’s activity at recess during two weeks in September, the hottest full month during the school year, to a cooler week in November. “We wanted to understand the impact of outdoor temperatures on children’s play in schoolyard environments,” said Dr. Kevin Lanza, the study’s lead investigator, to inform the design of “future school-based interventions for physical activity in the face of climate change.”
During the hotter periods, he said, “children engaged in less physical activity and sought shade.”
As temperatures continue to rise, he said, schools must be flexible in making sure students are getting the daily exercise they need. “Schools should consider adding shade, either by planting trees or installing artificial structures that cover spaces intended for physical activity,” said Dr. Lanza, an assistant professor at UTHealth School of Public Health, Austin, Tex. He also noted that school policies could be updated so that recesses are scheduled during cooler times of the day and moved inside during periods of extreme heat.
But the overall need to protect kids from scorching weather patterns requires action beyond such steps, Dr. Perera said, and more climate and clean air policies must be enacted.
“Governments have the responsibility to protect the population and especially those most vulnerable, which especially includes children,” Dr. Perera said. “Action must be done immediately because we’re absolutely heading in the wrong direction.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Rheumatologic Perspective on Persistent Right-Hand Tenosynovitis Secondary to Mycobacterium marinum Infection
Rheumatologic conditions and infections may imitate each other, often making diagnosis challenging. Therefore, it is imperative to obtain adequate histories and have a keen eye for these potentially confounding differential diagnoses. Immunosuppressants used in managing rheumatologic etiologies have detrimental consequences in undiagnosed underlying infections. Consequently, worsening symptoms with standard therapy should raise awareness to a different diagnosis.
Nontuberculous mycobacteria (NTM) are slow-growing organisms difficult to yield in culture. Initial negative synovial fluid stains and cultures when suspecting NTM infectious arthritis or tenosynovitis should not exclude the diagnosis if there is a strong clinical scenario. The identification of Mycobacterium marinum (M marinum) infection in the hand is of utmost importance given that delayed treatment may cause significant and even permanent disability.
We present the case of a 73-year-old male patient with progressively worsening right-hand tenosynovitis who was evaluated for crystal-induced and sarcoid arthropathies in the setting of negative synovial biopsy cultures but was subsequently diagnosed with M marinum infectious tenosynovitis after a second surgical debridement.
Case Presentation
A 73-year-old male patient with history of type 2 diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism, bilateral knee osteoarthritis, obstructive sleep apnea, and posttraumatic stress disorder presented to the emergency department (ED) with right wrist swelling and pain for 4 days. The patient reported that he was working in his garden when symptoms started. He did not recall any skin abrasions or wounds, insect bites, thorn punctures, trauma, or exposure to swimming pools or fish tanks. Patient was afebrile, and vital signs were within normal range. On physical examination, there was erythema, swelling, and tenderness in the dorsum of the right hand and over the dorsal aspect of the fourth metacarpophalangeal joint (Figure 1). The skin was intact.
Symptoms had not responded to 7 days of cefalexin nor to a short course of oral steroids. Leukocytosis of 14.35 × 109/L (reference range, 3.90-9.90 × 109/L) with neutrophilia at 11.10 × 109/L (reference range, 1.73-6.37 × 109/L) was noted. Sedimentation rate and C-reactive protein levels were normal. Right-hand X-ray was remarkable for chondrocalcinosis in the triangular fibrocartilage. Right upper extremity magnetic resonance imaging (MRI) revealed diffuse inflammation in the right wrist and hand (Figure 2). There was no evidence of septic arthritis or osteomyelitis. Consequently, orthopedic service recommended no surgical intervention. Additionally, the patient had preserved range of motion that further indicated tenosynovitis, which could be medically managed with antibiotics, rather than a septic joint.
One dose of IV piperacillin/tazobactam was given at the ED, and he was admitted to the internal medicine ward with right hand and wrist cellulitis and indolent suppurative tenosynovitis. Empiric IV ceftriaxone and vancomycin were started as per infectious disease (ID) service with adequate response defined as a reduction of the swelling, erythema, and tenderness of the right hand and wrist. Differential diagnosis included sporotrichosis, nocardia vs NTM infection.
Interventional radiology was consulted for right wrist drainage. However, only 1 mL of fluid was obtained. Synovial fluid was sent for cell count and differential, crystal analysis, bacterial cultures, fungal cultures, and acid-fast bacilli (AFB) stains and culture. Neutrophils were 43% and lymphocytes were 57%. Crystal analysis was negative. Bacterial culture and mycology were negative. AFB stain and culture results were negative after 6 weeks. Based on gardening history and risk of thorn exposure and low suspicion for common bacterial pathogens, ID service switched antibiotics to moxifloxacin, minocycline, and linezolid for broad coverage to complete 3 weeks as outpatient. The patient reported significantly improved pain and handgrip with notable decrease in swelling. Nonetheless, 3 weeks after completing antibiotics, the right-hand pain recurred, raising concern for complex regional syndrome vs crystalline arthropathy.
The patient was referred to rheumatology service for evaluation of crystal-induced arthropathy given chondrocalcinosis. Physical examination revealed right third proximal interphalangeal joint swelling and tenderness with overimposed tophilike nodule. No erythema or palpable effusions were appreciated. Range of motion was preserved. Laboratory workup showed resolved leukocytosis and neutrophilia, and normal sedimentation rate or C-reactive protein levels. Antinuclear antibody panel, rheumatoid factor, and anti–cyclic citrullinated peptide levels were normal. Serum uric acid levels were 5.9 mg/dL. Chlamydia, gonorrhea, and HIV tests were negative. Short course of low-dose oral prednisone starting at 15 mg daily with tapering by 5 mg every 3 days was given for presumptive calcium pyrophosphate deposition vs gout. Nevertheless, right-hand swelling and pain worsened after steroids. Repeat right upper extremity MRI showed persistent soft tissue edema and inflammation along the dorsum of the hand extending to the digits, tenosynovitis, and fluid in the third metacarpophalangeal that could represent a superficial abscess. The patient was hospitalized given concerns of infection.
The relapse of tenosynovitis raised concerns for a persistent infection secondary to a fastidious organism, such as NTM. Thus, inquiries specifically pertaining to any contact with bodies of water were entertained. The patient remembered that he had gone scuba diving in the ocean weeks before symptom onset. This meant scuba diving could then be the inciting event rather than gardening, which placed NTM higher in the differential. ID service did not recommend antibiotics until new cultures were available. Orthopedic service was consulted for surgical debridement. The right dorsal hand, wrist, and distal forearm tendon sheaths were surgically opened to obtain a synovial biopsy.
Synovial fluid was sent for fungal, bacterial, and AFB cultures, and synovial biopsy for AFB stains, PCR amplification/sequencing assay, and cultures. Results showed nonnecrotizing granulomas and all cultures were negative (Figures 3, 4). Rheumatology was again consulted for evaluation for sarcoidosis given negative cultures and noncaseating granulomas. Review of systems was completely negative for sarcoidosis. Computed tomography (CT) of the thorax did not show any pulmonary abnormalities, lymphadenopathy, and hilar adenopathy. Serum calcium and angiotensin-converting enzyme levels were normal. ID service recommended against empiric antibiotics given negative culture. Given persistent pain, and reported cases of isolated sarcoid tenosynovitis, low-dose oral prednisone 20 mg daily was given after clearance by ID service. Nonetheless, the right wrist and hand swelling, erythema, and tenderness relapsed with 1 dose of prednisone, leading to a repeat right upper extremity synovial biopsy due to high suspicion for persistent infection with a fastidious organism. New synovial tissue biopsy revealed fibro-adipose tissue with prominent vessels and fibrosis, nonnecrotizing, sarcoidlike granuloma with giant cell granulomatous reaction. The AFB and Grocott methenamine silver stains were negative. PCR was negative for AFB. No crystals were reported. After 5 weeks, the synovial biopsy culture was positive for M marinum. Patient was started on oral azithromycin 500 mg daily, rifabutin 300 mg daily, and ethambutol 15 mg/kg daily. At the time of this report, the patient was still completing antibiotic therapy with adequate response and undergoing occupational therapy rehabilitation (Figure 5).
Discussion
M marinum is an NTM found in bodies of water and marine settings. Infection arises after direct contact of lacerated skin with contaminated water. In a review article of 5 cases of M marinum tenosynovitis, they found that all individuals had wounds with exposure to fish or shrimp while in the water or while handling seafood.1 The incidence of this infection is infrequent, estimated to be 0.04 cases per 100,000, with only about 25% of these cases presenting as tenosynovitis.2 The incubation period ranges from 2 to 4 weeks.3 Late identification of this organism is common because of its slow development. For example, presentation from first exposure to symptom onset may take as long as 32 days.1 In addition, in the same review, surgical intervention occurred in 63 days.1 It has been reported that AFB stains are positive in just 9% of cases, which confounds diagnosis even more.4 After synovial tissue culture is obtained, it takes approximately 6 weeks for the organism to grow. Moreover, diagnosis may take longer if it is not suspected.5
Four types of M marinum infections have been described.5 The status of the immune system plays a role in how the manifestations present. The first type is limited, which is seen in immunocompetent persons, characterized by skin involvement, such as erythematous nodular lesions, that may improve on their own in months or years.4 Conversely, in immunosuppressed patients, the second type of infection may cause sporotrichoid spreading described as following lymphangitic pattern. The third type presents with musculoskeletal findings, such as arthritis, tenosynovitis, bursitis, or osteomyelitis, as seen in our patient. The fourth type consists of systemic manifestations.5 Medications that lower the immune system, such as corticosteroids, chemotherapy, and biologic disease modifying agents, may increase the risk for developing this entity.4 Specifically, antitumor necrosis factor inhibitors have been historically associated with mycobacterium infections.6
Patients are frequently diagnosed with soft tissue infection, such as abscesses or cellulitis, as in our case. They may at times be found to have other musculoskeletal conditions such as trigger finger.1 Other similar presenting entities are psoriatic arthritis, rheumatoid arthritis, and remitting seronegative arthritis.4 These clinical resemblances complicate the scenario, especially when initial cultures are negative, as the treatment for these rheumatic diseases is immunosuppression, which adversely impact the fastidious infection. In our case, the improved swelling and range of motion after the 3-week course of empiric antibiotics for suppurative tenosynovitis was initially reassuring that the previous infection had been successfully treated. Subsequently, the presence of chondrocalcinosis in the triangular fibrocartilage in the right-hand X-rays, persistent pain, and the tophi-like appearance of the right third proximal interphalangeal nodule raised concerns for crystalline arthropathies, such as calcium pyrophosphate deposition vs gout. Nonetheless, given the lack of response to low-dose steroids, an ongoing infectious process was strongly considered.
Sarcoidosis was a concern after the first synovial biopsy revealed noncaseating granulomas and negative stains and cultures. Sarcoid tenosynovitis is rare with only 22 cases described as per a 2015 report.7 Musculoskeletal involvement in sarcoidosis has been reported in 1 to 13% of sarcoid patients.7 Once again, unresponsiveness to steroids led to another synovial biopsy for culture due to potential infection. Akin to other cases, more than one surgical debridement was required to diagnose our patient.
Conclusions
Our case reinforces the vital role of history gathering in establishing diagnoses. It underscores the value of clinical suspicion especially in patients unresponsive to standard treatment for inflammatory arthritis, namely corticosteroids. Tissue biopsy with culture for AFB is crucial for accurate diagnosis in NTM infection, which may imitate rheumatic inflammatory arthritis. Clinicians should be keenly aware of this fastidious, indolent organism in the setting of persistent localized tenosynovitis.
1. Pang HN, Lee JY, Puhaindran ME, Tan SH, Tan AB, Yong FC. Mycobacterium marinum as a cause of chronic granulomatous tenosynovitis in the hand. J Infect. 2007;54(6):584-588. doi:10.1016/j.jinf.2006.11.014
2. Wongworawat MD, Holtom P, Learch TJ, Fedenko A, Stevanovic MV. A prolonged case of Mycobacterium marinum flexor tenosynovitis: radiographic and histological correlation, and review of the literature. Skeletal Radiol. 2003;32(9):542-545. doi:10.1007/s00256-003-0636-y
3. Schubert N, Schill T, Plüß M, Korsten P. Flare or foe? - Mycobacterium marinum infection mimicking rheumatoid arthritis tenosynovitis: case report and literature review. BMC Rheumatol. 2020;4:11. Published 2020 Mar 16. doi:10.1186/s41927-020-0114-3
4. Lam A, Toma W, Schlesinger N. Mycobacterium marinum arthritis mimicking rheumatoid arthritis. J Rheumatol. 2006;33(4):817-819.
5. Hashish E, Merwad A, Elgaml S, et al. Mycobacterium marinum infection in fish and man: epidemiology, pathophysiology and management; a review. Vet Q. 2018;38(1):35-46. doi:10.1080/01652176.2018.1447171
6. Thanou-Stavraki A, Sawalha AH, Crowson AN, Harley JB. Noodling and Mycobacterium marinum infection mimicking seronegative rheumatoid arthritis complicated by anti-tumor necrosis factor α therapy. Arthritis Care Res (Hoboken). 2011;63(1):160-164. doi:10.1002/acr.20303
7. Al-Ani Z, Oh TC, Macphie E, Woodruff MJ. Sarcoid tenosynovitis, rare presentation of a common disease. Case report and literature review. J Radiol Case Rep. 2015;9(8):16-23. Published 2015 Aug 31. doi:10.3941/jrcr.v9i8.2311
Rheumatologic conditions and infections may imitate each other, often making diagnosis challenging. Therefore, it is imperative to obtain adequate histories and have a keen eye for these potentially confounding differential diagnoses. Immunosuppressants used in managing rheumatologic etiologies have detrimental consequences in undiagnosed underlying infections. Consequently, worsening symptoms with standard therapy should raise awareness to a different diagnosis.
Nontuberculous mycobacteria (NTM) are slow-growing organisms difficult to yield in culture. Initial negative synovial fluid stains and cultures when suspecting NTM infectious arthritis or tenosynovitis should not exclude the diagnosis if there is a strong clinical scenario. The identification of Mycobacterium marinum (M marinum) infection in the hand is of utmost importance given that delayed treatment may cause significant and even permanent disability.
We present the case of a 73-year-old male patient with progressively worsening right-hand tenosynovitis who was evaluated for crystal-induced and sarcoid arthropathies in the setting of negative synovial biopsy cultures but was subsequently diagnosed with M marinum infectious tenosynovitis after a second surgical debridement.
Case Presentation
A 73-year-old male patient with history of type 2 diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism, bilateral knee osteoarthritis, obstructive sleep apnea, and posttraumatic stress disorder presented to the emergency department (ED) with right wrist swelling and pain for 4 days. The patient reported that he was working in his garden when symptoms started. He did not recall any skin abrasions or wounds, insect bites, thorn punctures, trauma, or exposure to swimming pools or fish tanks. Patient was afebrile, and vital signs were within normal range. On physical examination, there was erythema, swelling, and tenderness in the dorsum of the right hand and over the dorsal aspect of the fourth metacarpophalangeal joint (Figure 1). The skin was intact.
Symptoms had not responded to 7 days of cefalexin nor to a short course of oral steroids. Leukocytosis of 14.35 × 109/L (reference range, 3.90-9.90 × 109/L) with neutrophilia at 11.10 × 109/L (reference range, 1.73-6.37 × 109/L) was noted. Sedimentation rate and C-reactive protein levels were normal. Right-hand X-ray was remarkable for chondrocalcinosis in the triangular fibrocartilage. Right upper extremity magnetic resonance imaging (MRI) revealed diffuse inflammation in the right wrist and hand (Figure 2). There was no evidence of septic arthritis or osteomyelitis. Consequently, orthopedic service recommended no surgical intervention. Additionally, the patient had preserved range of motion that further indicated tenosynovitis, which could be medically managed with antibiotics, rather than a septic joint.
One dose of IV piperacillin/tazobactam was given at the ED, and he was admitted to the internal medicine ward with right hand and wrist cellulitis and indolent suppurative tenosynovitis. Empiric IV ceftriaxone and vancomycin were started as per infectious disease (ID) service with adequate response defined as a reduction of the swelling, erythema, and tenderness of the right hand and wrist. Differential diagnosis included sporotrichosis, nocardia vs NTM infection.
Interventional radiology was consulted for right wrist drainage. However, only 1 mL of fluid was obtained. Synovial fluid was sent for cell count and differential, crystal analysis, bacterial cultures, fungal cultures, and acid-fast bacilli (AFB) stains and culture. Neutrophils were 43% and lymphocytes were 57%. Crystal analysis was negative. Bacterial culture and mycology were negative. AFB stain and culture results were negative after 6 weeks. Based on gardening history and risk of thorn exposure and low suspicion for common bacterial pathogens, ID service switched antibiotics to moxifloxacin, minocycline, and linezolid for broad coverage to complete 3 weeks as outpatient. The patient reported significantly improved pain and handgrip with notable decrease in swelling. Nonetheless, 3 weeks after completing antibiotics, the right-hand pain recurred, raising concern for complex regional syndrome vs crystalline arthropathy.
The patient was referred to rheumatology service for evaluation of crystal-induced arthropathy given chondrocalcinosis. Physical examination revealed right third proximal interphalangeal joint swelling and tenderness with overimposed tophilike nodule. No erythema or palpable effusions were appreciated. Range of motion was preserved. Laboratory workup showed resolved leukocytosis and neutrophilia, and normal sedimentation rate or C-reactive protein levels. Antinuclear antibody panel, rheumatoid factor, and anti–cyclic citrullinated peptide levels were normal. Serum uric acid levels were 5.9 mg/dL. Chlamydia, gonorrhea, and HIV tests were negative. Short course of low-dose oral prednisone starting at 15 mg daily with tapering by 5 mg every 3 days was given for presumptive calcium pyrophosphate deposition vs gout. Nevertheless, right-hand swelling and pain worsened after steroids. Repeat right upper extremity MRI showed persistent soft tissue edema and inflammation along the dorsum of the hand extending to the digits, tenosynovitis, and fluid in the third metacarpophalangeal that could represent a superficial abscess. The patient was hospitalized given concerns of infection.
The relapse of tenosynovitis raised concerns for a persistent infection secondary to a fastidious organism, such as NTM. Thus, inquiries specifically pertaining to any contact with bodies of water were entertained. The patient remembered that he had gone scuba diving in the ocean weeks before symptom onset. This meant scuba diving could then be the inciting event rather than gardening, which placed NTM higher in the differential. ID service did not recommend antibiotics until new cultures were available. Orthopedic service was consulted for surgical debridement. The right dorsal hand, wrist, and distal forearm tendon sheaths were surgically opened to obtain a synovial biopsy.
Synovial fluid was sent for fungal, bacterial, and AFB cultures, and synovial biopsy for AFB stains, PCR amplification/sequencing assay, and cultures. Results showed nonnecrotizing granulomas and all cultures were negative (Figures 3, 4). Rheumatology was again consulted for evaluation for sarcoidosis given negative cultures and noncaseating granulomas. Review of systems was completely negative for sarcoidosis. Computed tomography (CT) of the thorax did not show any pulmonary abnormalities, lymphadenopathy, and hilar adenopathy. Serum calcium and angiotensin-converting enzyme levels were normal. ID service recommended against empiric antibiotics given negative culture. Given persistent pain, and reported cases of isolated sarcoid tenosynovitis, low-dose oral prednisone 20 mg daily was given after clearance by ID service. Nonetheless, the right wrist and hand swelling, erythema, and tenderness relapsed with 1 dose of prednisone, leading to a repeat right upper extremity synovial biopsy due to high suspicion for persistent infection with a fastidious organism. New synovial tissue biopsy revealed fibro-adipose tissue with prominent vessels and fibrosis, nonnecrotizing, sarcoidlike granuloma with giant cell granulomatous reaction. The AFB and Grocott methenamine silver stains were negative. PCR was negative for AFB. No crystals were reported. After 5 weeks, the synovial biopsy culture was positive for M marinum. Patient was started on oral azithromycin 500 mg daily, rifabutin 300 mg daily, and ethambutol 15 mg/kg daily. At the time of this report, the patient was still completing antibiotic therapy with adequate response and undergoing occupational therapy rehabilitation (Figure 5).
Discussion
M marinum is an NTM found in bodies of water and marine settings. Infection arises after direct contact of lacerated skin with contaminated water. In a review article of 5 cases of M marinum tenosynovitis, they found that all individuals had wounds with exposure to fish or shrimp while in the water or while handling seafood.1 The incidence of this infection is infrequent, estimated to be 0.04 cases per 100,000, with only about 25% of these cases presenting as tenosynovitis.2 The incubation period ranges from 2 to 4 weeks.3 Late identification of this organism is common because of its slow development. For example, presentation from first exposure to symptom onset may take as long as 32 days.1 In addition, in the same review, surgical intervention occurred in 63 days.1 It has been reported that AFB stains are positive in just 9% of cases, which confounds diagnosis even more.4 After synovial tissue culture is obtained, it takes approximately 6 weeks for the organism to grow. Moreover, diagnosis may take longer if it is not suspected.5
Four types of M marinum infections have been described.5 The status of the immune system plays a role in how the manifestations present. The first type is limited, which is seen in immunocompetent persons, characterized by skin involvement, such as erythematous nodular lesions, that may improve on their own in months or years.4 Conversely, in immunosuppressed patients, the second type of infection may cause sporotrichoid spreading described as following lymphangitic pattern. The third type presents with musculoskeletal findings, such as arthritis, tenosynovitis, bursitis, or osteomyelitis, as seen in our patient. The fourth type consists of systemic manifestations.5 Medications that lower the immune system, such as corticosteroids, chemotherapy, and biologic disease modifying agents, may increase the risk for developing this entity.4 Specifically, antitumor necrosis factor inhibitors have been historically associated with mycobacterium infections.6
Patients are frequently diagnosed with soft tissue infection, such as abscesses or cellulitis, as in our case. They may at times be found to have other musculoskeletal conditions such as trigger finger.1 Other similar presenting entities are psoriatic arthritis, rheumatoid arthritis, and remitting seronegative arthritis.4 These clinical resemblances complicate the scenario, especially when initial cultures are negative, as the treatment for these rheumatic diseases is immunosuppression, which adversely impact the fastidious infection. In our case, the improved swelling and range of motion after the 3-week course of empiric antibiotics for suppurative tenosynovitis was initially reassuring that the previous infection had been successfully treated. Subsequently, the presence of chondrocalcinosis in the triangular fibrocartilage in the right-hand X-rays, persistent pain, and the tophi-like appearance of the right third proximal interphalangeal nodule raised concerns for crystalline arthropathies, such as calcium pyrophosphate deposition vs gout. Nonetheless, given the lack of response to low-dose steroids, an ongoing infectious process was strongly considered.
Sarcoidosis was a concern after the first synovial biopsy revealed noncaseating granulomas and negative stains and cultures. Sarcoid tenosynovitis is rare with only 22 cases described as per a 2015 report.7 Musculoskeletal involvement in sarcoidosis has been reported in 1 to 13% of sarcoid patients.7 Once again, unresponsiveness to steroids led to another synovial biopsy for culture due to potential infection. Akin to other cases, more than one surgical debridement was required to diagnose our patient.
Conclusions
Our case reinforces the vital role of history gathering in establishing diagnoses. It underscores the value of clinical suspicion especially in patients unresponsive to standard treatment for inflammatory arthritis, namely corticosteroids. Tissue biopsy with culture for AFB is crucial for accurate diagnosis in NTM infection, which may imitate rheumatic inflammatory arthritis. Clinicians should be keenly aware of this fastidious, indolent organism in the setting of persistent localized tenosynovitis.
Rheumatologic conditions and infections may imitate each other, often making diagnosis challenging. Therefore, it is imperative to obtain adequate histories and have a keen eye for these potentially confounding differential diagnoses. Immunosuppressants used in managing rheumatologic etiologies have detrimental consequences in undiagnosed underlying infections. Consequently, worsening symptoms with standard therapy should raise awareness to a different diagnosis.
Nontuberculous mycobacteria (NTM) are slow-growing organisms difficult to yield in culture. Initial negative synovial fluid stains and cultures when suspecting NTM infectious arthritis or tenosynovitis should not exclude the diagnosis if there is a strong clinical scenario. The identification of Mycobacterium marinum (M marinum) infection in the hand is of utmost importance given that delayed treatment may cause significant and even permanent disability.
We present the case of a 73-year-old male patient with progressively worsening right-hand tenosynovitis who was evaluated for crystal-induced and sarcoid arthropathies in the setting of negative synovial biopsy cultures but was subsequently diagnosed with M marinum infectious tenosynovitis after a second surgical debridement.
Case Presentation
A 73-year-old male patient with history of type 2 diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism, bilateral knee osteoarthritis, obstructive sleep apnea, and posttraumatic stress disorder presented to the emergency department (ED) with right wrist swelling and pain for 4 days. The patient reported that he was working in his garden when symptoms started. He did not recall any skin abrasions or wounds, insect bites, thorn punctures, trauma, or exposure to swimming pools or fish tanks. Patient was afebrile, and vital signs were within normal range. On physical examination, there was erythema, swelling, and tenderness in the dorsum of the right hand and over the dorsal aspect of the fourth metacarpophalangeal joint (Figure 1). The skin was intact.
Symptoms had not responded to 7 days of cefalexin nor to a short course of oral steroids. Leukocytosis of 14.35 × 109/L (reference range, 3.90-9.90 × 109/L) with neutrophilia at 11.10 × 109/L (reference range, 1.73-6.37 × 109/L) was noted. Sedimentation rate and C-reactive protein levels were normal. Right-hand X-ray was remarkable for chondrocalcinosis in the triangular fibrocartilage. Right upper extremity magnetic resonance imaging (MRI) revealed diffuse inflammation in the right wrist and hand (Figure 2). There was no evidence of septic arthritis or osteomyelitis. Consequently, orthopedic service recommended no surgical intervention. Additionally, the patient had preserved range of motion that further indicated tenosynovitis, which could be medically managed with antibiotics, rather than a septic joint.
One dose of IV piperacillin/tazobactam was given at the ED, and he was admitted to the internal medicine ward with right hand and wrist cellulitis and indolent suppurative tenosynovitis. Empiric IV ceftriaxone and vancomycin were started as per infectious disease (ID) service with adequate response defined as a reduction of the swelling, erythema, and tenderness of the right hand and wrist. Differential diagnosis included sporotrichosis, nocardia vs NTM infection.
Interventional radiology was consulted for right wrist drainage. However, only 1 mL of fluid was obtained. Synovial fluid was sent for cell count and differential, crystal analysis, bacterial cultures, fungal cultures, and acid-fast bacilli (AFB) stains and culture. Neutrophils were 43% and lymphocytes were 57%. Crystal analysis was negative. Bacterial culture and mycology were negative. AFB stain and culture results were negative after 6 weeks. Based on gardening history and risk of thorn exposure and low suspicion for common bacterial pathogens, ID service switched antibiotics to moxifloxacin, minocycline, and linezolid for broad coverage to complete 3 weeks as outpatient. The patient reported significantly improved pain and handgrip with notable decrease in swelling. Nonetheless, 3 weeks after completing antibiotics, the right-hand pain recurred, raising concern for complex regional syndrome vs crystalline arthropathy.
The patient was referred to rheumatology service for evaluation of crystal-induced arthropathy given chondrocalcinosis. Physical examination revealed right third proximal interphalangeal joint swelling and tenderness with overimposed tophilike nodule. No erythema or palpable effusions were appreciated. Range of motion was preserved. Laboratory workup showed resolved leukocytosis and neutrophilia, and normal sedimentation rate or C-reactive protein levels. Antinuclear antibody panel, rheumatoid factor, and anti–cyclic citrullinated peptide levels were normal. Serum uric acid levels were 5.9 mg/dL. Chlamydia, gonorrhea, and HIV tests were negative. Short course of low-dose oral prednisone starting at 15 mg daily with tapering by 5 mg every 3 days was given for presumptive calcium pyrophosphate deposition vs gout. Nevertheless, right-hand swelling and pain worsened after steroids. Repeat right upper extremity MRI showed persistent soft tissue edema and inflammation along the dorsum of the hand extending to the digits, tenosynovitis, and fluid in the third metacarpophalangeal that could represent a superficial abscess. The patient was hospitalized given concerns of infection.
The relapse of tenosynovitis raised concerns for a persistent infection secondary to a fastidious organism, such as NTM. Thus, inquiries specifically pertaining to any contact with bodies of water were entertained. The patient remembered that he had gone scuba diving in the ocean weeks before symptom onset. This meant scuba diving could then be the inciting event rather than gardening, which placed NTM higher in the differential. ID service did not recommend antibiotics until new cultures were available. Orthopedic service was consulted for surgical debridement. The right dorsal hand, wrist, and distal forearm tendon sheaths were surgically opened to obtain a synovial biopsy.
Synovial fluid was sent for fungal, bacterial, and AFB cultures, and synovial biopsy for AFB stains, PCR amplification/sequencing assay, and cultures. Results showed nonnecrotizing granulomas and all cultures were negative (Figures 3, 4). Rheumatology was again consulted for evaluation for sarcoidosis given negative cultures and noncaseating granulomas. Review of systems was completely negative for sarcoidosis. Computed tomography (CT) of the thorax did not show any pulmonary abnormalities, lymphadenopathy, and hilar adenopathy. Serum calcium and angiotensin-converting enzyme levels were normal. ID service recommended against empiric antibiotics given negative culture. Given persistent pain, and reported cases of isolated sarcoid tenosynovitis, low-dose oral prednisone 20 mg daily was given after clearance by ID service. Nonetheless, the right wrist and hand swelling, erythema, and tenderness relapsed with 1 dose of prednisone, leading to a repeat right upper extremity synovial biopsy due to high suspicion for persistent infection with a fastidious organism. New synovial tissue biopsy revealed fibro-adipose tissue with prominent vessels and fibrosis, nonnecrotizing, sarcoidlike granuloma with giant cell granulomatous reaction. The AFB and Grocott methenamine silver stains were negative. PCR was negative for AFB. No crystals were reported. After 5 weeks, the synovial biopsy culture was positive for M marinum. Patient was started on oral azithromycin 500 mg daily, rifabutin 300 mg daily, and ethambutol 15 mg/kg daily. At the time of this report, the patient was still completing antibiotic therapy with adequate response and undergoing occupational therapy rehabilitation (Figure 5).
Discussion
M marinum is an NTM found in bodies of water and marine settings. Infection arises after direct contact of lacerated skin with contaminated water. In a review article of 5 cases of M marinum tenosynovitis, they found that all individuals had wounds with exposure to fish or shrimp while in the water or while handling seafood.1 The incidence of this infection is infrequent, estimated to be 0.04 cases per 100,000, with only about 25% of these cases presenting as tenosynovitis.2 The incubation period ranges from 2 to 4 weeks.3 Late identification of this organism is common because of its slow development. For example, presentation from first exposure to symptom onset may take as long as 32 days.1 In addition, in the same review, surgical intervention occurred in 63 days.1 It has been reported that AFB stains are positive in just 9% of cases, which confounds diagnosis even more.4 After synovial tissue culture is obtained, it takes approximately 6 weeks for the organism to grow. Moreover, diagnosis may take longer if it is not suspected.5
Four types of M marinum infections have been described.5 The status of the immune system plays a role in how the manifestations present. The first type is limited, which is seen in immunocompetent persons, characterized by skin involvement, such as erythematous nodular lesions, that may improve on their own in months or years.4 Conversely, in immunosuppressed patients, the second type of infection may cause sporotrichoid spreading described as following lymphangitic pattern. The third type presents with musculoskeletal findings, such as arthritis, tenosynovitis, bursitis, or osteomyelitis, as seen in our patient. The fourth type consists of systemic manifestations.5 Medications that lower the immune system, such as corticosteroids, chemotherapy, and biologic disease modifying agents, may increase the risk for developing this entity.4 Specifically, antitumor necrosis factor inhibitors have been historically associated with mycobacterium infections.6
Patients are frequently diagnosed with soft tissue infection, such as abscesses or cellulitis, as in our case. They may at times be found to have other musculoskeletal conditions such as trigger finger.1 Other similar presenting entities are psoriatic arthritis, rheumatoid arthritis, and remitting seronegative arthritis.4 These clinical resemblances complicate the scenario, especially when initial cultures are negative, as the treatment for these rheumatic diseases is immunosuppression, which adversely impact the fastidious infection. In our case, the improved swelling and range of motion after the 3-week course of empiric antibiotics for suppurative tenosynovitis was initially reassuring that the previous infection had been successfully treated. Subsequently, the presence of chondrocalcinosis in the triangular fibrocartilage in the right-hand X-rays, persistent pain, and the tophi-like appearance of the right third proximal interphalangeal nodule raised concerns for crystalline arthropathies, such as calcium pyrophosphate deposition vs gout. Nonetheless, given the lack of response to low-dose steroids, an ongoing infectious process was strongly considered.
Sarcoidosis was a concern after the first synovial biopsy revealed noncaseating granulomas and negative stains and cultures. Sarcoid tenosynovitis is rare with only 22 cases described as per a 2015 report.7 Musculoskeletal involvement in sarcoidosis has been reported in 1 to 13% of sarcoid patients.7 Once again, unresponsiveness to steroids led to another synovial biopsy for culture due to potential infection. Akin to other cases, more than one surgical debridement was required to diagnose our patient.
Conclusions
Our case reinforces the vital role of history gathering in establishing diagnoses. It underscores the value of clinical suspicion especially in patients unresponsive to standard treatment for inflammatory arthritis, namely corticosteroids. Tissue biopsy with culture for AFB is crucial for accurate diagnosis in NTM infection, which may imitate rheumatic inflammatory arthritis. Clinicians should be keenly aware of this fastidious, indolent organism in the setting of persistent localized tenosynovitis.
1. Pang HN, Lee JY, Puhaindran ME, Tan SH, Tan AB, Yong FC. Mycobacterium marinum as a cause of chronic granulomatous tenosynovitis in the hand. J Infect. 2007;54(6):584-588. doi:10.1016/j.jinf.2006.11.014
2. Wongworawat MD, Holtom P, Learch TJ, Fedenko A, Stevanovic MV. A prolonged case of Mycobacterium marinum flexor tenosynovitis: radiographic and histological correlation, and review of the literature. Skeletal Radiol. 2003;32(9):542-545. doi:10.1007/s00256-003-0636-y
3. Schubert N, Schill T, Plüß M, Korsten P. Flare or foe? - Mycobacterium marinum infection mimicking rheumatoid arthritis tenosynovitis: case report and literature review. BMC Rheumatol. 2020;4:11. Published 2020 Mar 16. doi:10.1186/s41927-020-0114-3
4. Lam A, Toma W, Schlesinger N. Mycobacterium marinum arthritis mimicking rheumatoid arthritis. J Rheumatol. 2006;33(4):817-819.
5. Hashish E, Merwad A, Elgaml S, et al. Mycobacterium marinum infection in fish and man: epidemiology, pathophysiology and management; a review. Vet Q. 2018;38(1):35-46. doi:10.1080/01652176.2018.1447171
6. Thanou-Stavraki A, Sawalha AH, Crowson AN, Harley JB. Noodling and Mycobacterium marinum infection mimicking seronegative rheumatoid arthritis complicated by anti-tumor necrosis factor α therapy. Arthritis Care Res (Hoboken). 2011;63(1):160-164. doi:10.1002/acr.20303
7. Al-Ani Z, Oh TC, Macphie E, Woodruff MJ. Sarcoid tenosynovitis, rare presentation of a common disease. Case report and literature review. J Radiol Case Rep. 2015;9(8):16-23. Published 2015 Aug 31. doi:10.3941/jrcr.v9i8.2311
1. Pang HN, Lee JY, Puhaindran ME, Tan SH, Tan AB, Yong FC. Mycobacterium marinum as a cause of chronic granulomatous tenosynovitis in the hand. J Infect. 2007;54(6):584-588. doi:10.1016/j.jinf.2006.11.014
2. Wongworawat MD, Holtom P, Learch TJ, Fedenko A, Stevanovic MV. A prolonged case of Mycobacterium marinum flexor tenosynovitis: radiographic and histological correlation, and review of the literature. Skeletal Radiol. 2003;32(9):542-545. doi:10.1007/s00256-003-0636-y
3. Schubert N, Schill T, Plüß M, Korsten P. Flare or foe? - Mycobacterium marinum infection mimicking rheumatoid arthritis tenosynovitis: case report and literature review. BMC Rheumatol. 2020;4:11. Published 2020 Mar 16. doi:10.1186/s41927-020-0114-3
4. Lam A, Toma W, Schlesinger N. Mycobacterium marinum arthritis mimicking rheumatoid arthritis. J Rheumatol. 2006;33(4):817-819.
5. Hashish E, Merwad A, Elgaml S, et al. Mycobacterium marinum infection in fish and man: epidemiology, pathophysiology and management; a review. Vet Q. 2018;38(1):35-46. doi:10.1080/01652176.2018.1447171
6. Thanou-Stavraki A, Sawalha AH, Crowson AN, Harley JB. Noodling and Mycobacterium marinum infection mimicking seronegative rheumatoid arthritis complicated by anti-tumor necrosis factor α therapy. Arthritis Care Res (Hoboken). 2011;63(1):160-164. doi:10.1002/acr.20303
7. Al-Ani Z, Oh TC, Macphie E, Woodruff MJ. Sarcoid tenosynovitis, rare presentation of a common disease. Case report and literature review. J Radiol Case Rep. 2015;9(8):16-23. Published 2015 Aug 31. doi:10.3941/jrcr.v9i8.2311
Why do we treat menopause as a disease?
Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.
Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.
It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.
“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.
Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.
“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
The ‘untold misery of oestrogen-starved women’
These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken
homes caused by these unstable, oestrogen-starved women.’ ”
Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.
“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”
The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
Promoting exercise, stopping smoking among positive messages
An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.
The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).
The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.
While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
Menopause blamed in a difficult time of life
Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.
It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.
People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.
The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”
Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.
Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.
Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”
She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.
The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.
Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.
Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.
It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.
“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.
Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.
“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
The ‘untold misery of oestrogen-starved women’
These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken
homes caused by these unstable, oestrogen-starved women.’ ”
Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.
“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”
The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
Promoting exercise, stopping smoking among positive messages
An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.
The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).
The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.
While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
Menopause blamed in a difficult time of life
Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.
It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.
People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.
The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”
Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.
Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.
Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”
She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.
The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.
Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.
Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.
It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.
“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.
Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.
“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
The ‘untold misery of oestrogen-starved women’
These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken
homes caused by these unstable, oestrogen-starved women.’ ”
Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.
“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”
The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
Promoting exercise, stopping smoking among positive messages
An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.
The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).
The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.
While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
Menopause blamed in a difficult time of life
Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.
It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.
People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.
The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”
Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.
Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.
Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”
She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.
The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.
FROM BMJ
Ancient human teeth revise the history of microbial evolution
The cupboard in Dr. Nicolás Rascovan’s microbial paleogenomics lab at Institut Pasteur in Paris is filled up with cardboard boxes that look as if they were shipped from an office supply store. Yet, instead of pencils and Post-it notes, the boxes are filled with ancient human remains from South America – several-thousand-year-old vertebrae, petrus bones (which protect inner ear structures), and teeth – all neatly packed in plastic bags. It could even, perhaps, rewrite history. “It’s a story of a continent in a closet,” Dr. Rascovan says.
Over the past decade, technologic advances in DNA recovery and sequencing have made it possible for scientists such as Dr. Rascovan, an Argentinian molecular biologist, to analyze ancient specimens relatively quickly and affordably. They’ve been hunting for – and finding – DNA of centuries-old microbes in various archeological samples: from smallpox variola virus and Mycobacterium tuberculosis in mummified tissues, to the Black Death bacteria, Yesinia pestis, in neolithic teeth, to Plasmodium falciparum preserved in historical blood stains.
The ultramodern Parisian offices of the microbial paleogenomics group, a team of five scientists led by Dr. Rascovan, clash with the logo they half-jokingly chose for themselves and plastered all over the lab’s walls: a Jurassic Park–inspired dinosaur baring its giant, ancient teeth, made to look like an image seen under a microscope. Ancient teeth are certainly central to the group’s work, because it’s there where ancient pathogens’ DNA is most likely to be preserved – after death, teeth act like tiny, sealed-up boxes for microbes. “If you have a pathogen that is circulating in the blood, it will sometimes get into the teeth, and when you die, the DNA will stay there,” Dr. Rascovan says.
To process ancient teeth, Dr. Rascovan enters a lab clad head to toe in protective gear. That’s not so much to save himself from potentially deadly disease as to save the samples from contamination, he says. According to Sebastian Duchene Garzon, a microbiologist at the University of Melbourne, “the likelihood of ancient pathogen DNA leading to infections at present is remote, although certainly not impossible, because of how degraded the DNA usually is and because it would still need all the molecular machinery to infect a modern host.”
To process ancient teeth in his lab, Dr. Rascovan starts with a thorough cleaning that involves bleach to remove any modern DNA contamination. Next, he cuts the tooth with a Dremel rotary tool to open it up and get into its pulp – which is not only very durable but also naturally sterile – a perfect place to find ancient pathogens. He then scrapes the pulp into a powder that can be poured into a tube for DNA extraction.
So far, Dr. Rascovan’s biggest breakthrough didn’t come from the teeth he cut up himself, though. It came from analyzing publicly available DNA data from studies of ancient human genomes. When such genomes are sequenced from fossil teeth or bones, scientists pick out the material they need for study of our ancestors’ evolutionary history. However, among the double helixes coding hominid genetic instructions often hide scraps of microbial DNA, which in the past were frequently simply discarded.
Dr. Rascovan downloaded data from published articles on ancient human DNA that had been found in teeth and reanalyzed them, searching for bacteria. One night, when he was alone in his office going through lines and lines of data, he spotted it: DNA of the plague-causing bacteria, Y. pestis. When Dr. Rascovan cross-checked to determine in which samples the bacteria’s DNA was found, his heart raced. “It was not supposed to be there,” he says. He had just discovered the most ancient case of plague in humans – which occurred 4,900 years ago in Sweden.
Scientists used to believe that plague pandemics came to Europe from the Eurasian Steppe. Yet here was the DNA of Y. pestis lodged in the teeth of two farmers, a woman and a man, who died in Scandinavia before the plague’s supposed arrival from the East. Their bodies were buried in an unusually large common grave – of itself a possible indication of an epidemic.
When Dr. Rascovan and his colleagues applied molecular-clock analyses of the phylogenetic tree of the plague bacteria and compared various strains to see which one was the most ancestral, they confirmed that the Swedish strain of Y. pestis, named Gok2, was indeed the oldest – the origin of the Steppe strains rather than its distant cousin. Plague, it seemed, wasn’t brought to Europe during mass migrations from the East. Instead, it might have originated there.
Such work is not simply about rewriting history. By updating our knowledge of ancient pandemics, we can learn how different factors influence each other in fostering outbreaks. For Dr. Rascovan, the Swedish plague story underscores the importance of our lifestyle and environment for the emergence and spread of dangerous pathogens. The Gok2 strain didn’t contain a gene that makes plague particularly virulent, called ymt, yet it might have played an important role in Bronze Age Europe. At that time, mega-settlements of 10,000 to 20,000 people existed in what is now Ukraine, Romania, and Moldova, yet those settlements were frequently burned to the ground and abandoned. According to Dr. Rascovan and his colleagues, that could fit with the plague pandemic story (although this remains very much a hypothesis).
In Mexico, environmental factors might have played an important role in the severity of the 16th century “cocoliztli” epidemic (the word means “pestilence” in a local language), considered one of the most devastating epidemics in New World history. The disease, which caused vomiting, red spots on the skin, and bleeding from various body orifices, didn’t have a known cause. Some hypothesized the bug might have been smallpox, judging by the severity of the outbreak. A 2018 study of a victim’s DNA showed it contained the genome of Salmonella enterica, a bacterium that causes enteric fever – a microbe generally milder than smallpox. The study’s authors argued that specific conditions may have been necessary at the onset of the epidemic for the S. enterica microbe to cause such devastating outcomes. A mix of severe draught, forced relocations of the local population by their Spanish rulers, and new subsistence farming practices all negatively affected hygienic conditions in the local settlements. According to Dr. Rascovan, such research can “place pandemics into their broader context” – with potential lessons for the future.
One of the microbes Dr. Rascovan and his team are hoping to find in the ancient teeth stocked in their lab’s closet is tuberculosis – a pathogen that kills 1.5 million people a year, yet whose evolutionary history remains largely a mystery. The focus of Dr. Rascovan and his colleagues remains on fossils shipped from South America, since we still know very little about microbes that were associated with pre-Columbian populations. South Americans have been isolated from the rest of the world for 20,000 years, making them particularly interesting candidates for the study of emergence, evolution, and spread of pathogens.
Dr. Rascovan believes that ancient microbial genomic data can help scientists better understand antibiotic resistance through comparisons of bacterial evolution before and after the discovery of antibiotics. In general, he says, by studying only current pathogens and the modern outbreaks they cause, we see only a narrow sample of something that is much more diverse and much larger. “We are missing an important part of information. Ancient samples can bring us a perspective,” he says.
A version of this article first appeared on Medscape.com.
The cupboard in Dr. Nicolás Rascovan’s microbial paleogenomics lab at Institut Pasteur in Paris is filled up with cardboard boxes that look as if they were shipped from an office supply store. Yet, instead of pencils and Post-it notes, the boxes are filled with ancient human remains from South America – several-thousand-year-old vertebrae, petrus bones (which protect inner ear structures), and teeth – all neatly packed in plastic bags. It could even, perhaps, rewrite history. “It’s a story of a continent in a closet,” Dr. Rascovan says.
Over the past decade, technologic advances in DNA recovery and sequencing have made it possible for scientists such as Dr. Rascovan, an Argentinian molecular biologist, to analyze ancient specimens relatively quickly and affordably. They’ve been hunting for – and finding – DNA of centuries-old microbes in various archeological samples: from smallpox variola virus and Mycobacterium tuberculosis in mummified tissues, to the Black Death bacteria, Yesinia pestis, in neolithic teeth, to Plasmodium falciparum preserved in historical blood stains.
The ultramodern Parisian offices of the microbial paleogenomics group, a team of five scientists led by Dr. Rascovan, clash with the logo they half-jokingly chose for themselves and plastered all over the lab’s walls: a Jurassic Park–inspired dinosaur baring its giant, ancient teeth, made to look like an image seen under a microscope. Ancient teeth are certainly central to the group’s work, because it’s there where ancient pathogens’ DNA is most likely to be preserved – after death, teeth act like tiny, sealed-up boxes for microbes. “If you have a pathogen that is circulating in the blood, it will sometimes get into the teeth, and when you die, the DNA will stay there,” Dr. Rascovan says.
To process ancient teeth, Dr. Rascovan enters a lab clad head to toe in protective gear. That’s not so much to save himself from potentially deadly disease as to save the samples from contamination, he says. According to Sebastian Duchene Garzon, a microbiologist at the University of Melbourne, “the likelihood of ancient pathogen DNA leading to infections at present is remote, although certainly not impossible, because of how degraded the DNA usually is and because it would still need all the molecular machinery to infect a modern host.”
To process ancient teeth in his lab, Dr. Rascovan starts with a thorough cleaning that involves bleach to remove any modern DNA contamination. Next, he cuts the tooth with a Dremel rotary tool to open it up and get into its pulp – which is not only very durable but also naturally sterile – a perfect place to find ancient pathogens. He then scrapes the pulp into a powder that can be poured into a tube for DNA extraction.
So far, Dr. Rascovan’s biggest breakthrough didn’t come from the teeth he cut up himself, though. It came from analyzing publicly available DNA data from studies of ancient human genomes. When such genomes are sequenced from fossil teeth or bones, scientists pick out the material they need for study of our ancestors’ evolutionary history. However, among the double helixes coding hominid genetic instructions often hide scraps of microbial DNA, which in the past were frequently simply discarded.
Dr. Rascovan downloaded data from published articles on ancient human DNA that had been found in teeth and reanalyzed them, searching for bacteria. One night, when he was alone in his office going through lines and lines of data, he spotted it: DNA of the plague-causing bacteria, Y. pestis. When Dr. Rascovan cross-checked to determine in which samples the bacteria’s DNA was found, his heart raced. “It was not supposed to be there,” he says. He had just discovered the most ancient case of plague in humans – which occurred 4,900 years ago in Sweden.
Scientists used to believe that plague pandemics came to Europe from the Eurasian Steppe. Yet here was the DNA of Y. pestis lodged in the teeth of two farmers, a woman and a man, who died in Scandinavia before the plague’s supposed arrival from the East. Their bodies were buried in an unusually large common grave – of itself a possible indication of an epidemic.
When Dr. Rascovan and his colleagues applied molecular-clock analyses of the phylogenetic tree of the plague bacteria and compared various strains to see which one was the most ancestral, they confirmed that the Swedish strain of Y. pestis, named Gok2, was indeed the oldest – the origin of the Steppe strains rather than its distant cousin. Plague, it seemed, wasn’t brought to Europe during mass migrations from the East. Instead, it might have originated there.
Such work is not simply about rewriting history. By updating our knowledge of ancient pandemics, we can learn how different factors influence each other in fostering outbreaks. For Dr. Rascovan, the Swedish plague story underscores the importance of our lifestyle and environment for the emergence and spread of dangerous pathogens. The Gok2 strain didn’t contain a gene that makes plague particularly virulent, called ymt, yet it might have played an important role in Bronze Age Europe. At that time, mega-settlements of 10,000 to 20,000 people existed in what is now Ukraine, Romania, and Moldova, yet those settlements were frequently burned to the ground and abandoned. According to Dr. Rascovan and his colleagues, that could fit with the plague pandemic story (although this remains very much a hypothesis).
In Mexico, environmental factors might have played an important role in the severity of the 16th century “cocoliztli” epidemic (the word means “pestilence” in a local language), considered one of the most devastating epidemics in New World history. The disease, which caused vomiting, red spots on the skin, and bleeding from various body orifices, didn’t have a known cause. Some hypothesized the bug might have been smallpox, judging by the severity of the outbreak. A 2018 study of a victim’s DNA showed it contained the genome of Salmonella enterica, a bacterium that causes enteric fever – a microbe generally milder than smallpox. The study’s authors argued that specific conditions may have been necessary at the onset of the epidemic for the S. enterica microbe to cause such devastating outcomes. A mix of severe draught, forced relocations of the local population by their Spanish rulers, and new subsistence farming practices all negatively affected hygienic conditions in the local settlements. According to Dr. Rascovan, such research can “place pandemics into their broader context” – with potential lessons for the future.
One of the microbes Dr. Rascovan and his team are hoping to find in the ancient teeth stocked in their lab’s closet is tuberculosis – a pathogen that kills 1.5 million people a year, yet whose evolutionary history remains largely a mystery. The focus of Dr. Rascovan and his colleagues remains on fossils shipped from South America, since we still know very little about microbes that were associated with pre-Columbian populations. South Americans have been isolated from the rest of the world for 20,000 years, making them particularly interesting candidates for the study of emergence, evolution, and spread of pathogens.
Dr. Rascovan believes that ancient microbial genomic data can help scientists better understand antibiotic resistance through comparisons of bacterial evolution before and after the discovery of antibiotics. In general, he says, by studying only current pathogens and the modern outbreaks they cause, we see only a narrow sample of something that is much more diverse and much larger. “We are missing an important part of information. Ancient samples can bring us a perspective,” he says.
A version of this article first appeared on Medscape.com.
The cupboard in Dr. Nicolás Rascovan’s microbial paleogenomics lab at Institut Pasteur in Paris is filled up with cardboard boxes that look as if they were shipped from an office supply store. Yet, instead of pencils and Post-it notes, the boxes are filled with ancient human remains from South America – several-thousand-year-old vertebrae, petrus bones (which protect inner ear structures), and teeth – all neatly packed in plastic bags. It could even, perhaps, rewrite history. “It’s a story of a continent in a closet,” Dr. Rascovan says.
Over the past decade, technologic advances in DNA recovery and sequencing have made it possible for scientists such as Dr. Rascovan, an Argentinian molecular biologist, to analyze ancient specimens relatively quickly and affordably. They’ve been hunting for – and finding – DNA of centuries-old microbes in various archeological samples: from smallpox variola virus and Mycobacterium tuberculosis in mummified tissues, to the Black Death bacteria, Yesinia pestis, in neolithic teeth, to Plasmodium falciparum preserved in historical blood stains.
The ultramodern Parisian offices of the microbial paleogenomics group, a team of five scientists led by Dr. Rascovan, clash with the logo they half-jokingly chose for themselves and plastered all over the lab’s walls: a Jurassic Park–inspired dinosaur baring its giant, ancient teeth, made to look like an image seen under a microscope. Ancient teeth are certainly central to the group’s work, because it’s there where ancient pathogens’ DNA is most likely to be preserved – after death, teeth act like tiny, sealed-up boxes for microbes. “If you have a pathogen that is circulating in the blood, it will sometimes get into the teeth, and when you die, the DNA will stay there,” Dr. Rascovan says.
To process ancient teeth, Dr. Rascovan enters a lab clad head to toe in protective gear. That’s not so much to save himself from potentially deadly disease as to save the samples from contamination, he says. According to Sebastian Duchene Garzon, a microbiologist at the University of Melbourne, “the likelihood of ancient pathogen DNA leading to infections at present is remote, although certainly not impossible, because of how degraded the DNA usually is and because it would still need all the molecular machinery to infect a modern host.”
To process ancient teeth in his lab, Dr. Rascovan starts with a thorough cleaning that involves bleach to remove any modern DNA contamination. Next, he cuts the tooth with a Dremel rotary tool to open it up and get into its pulp – which is not only very durable but also naturally sterile – a perfect place to find ancient pathogens. He then scrapes the pulp into a powder that can be poured into a tube for DNA extraction.
So far, Dr. Rascovan’s biggest breakthrough didn’t come from the teeth he cut up himself, though. It came from analyzing publicly available DNA data from studies of ancient human genomes. When such genomes are sequenced from fossil teeth or bones, scientists pick out the material they need for study of our ancestors’ evolutionary history. However, among the double helixes coding hominid genetic instructions often hide scraps of microbial DNA, which in the past were frequently simply discarded.
Dr. Rascovan downloaded data from published articles on ancient human DNA that had been found in teeth and reanalyzed them, searching for bacteria. One night, when he was alone in his office going through lines and lines of data, he spotted it: DNA of the plague-causing bacteria, Y. pestis. When Dr. Rascovan cross-checked to determine in which samples the bacteria’s DNA was found, his heart raced. “It was not supposed to be there,” he says. He had just discovered the most ancient case of plague in humans – which occurred 4,900 years ago in Sweden.
Scientists used to believe that plague pandemics came to Europe from the Eurasian Steppe. Yet here was the DNA of Y. pestis lodged in the teeth of two farmers, a woman and a man, who died in Scandinavia before the plague’s supposed arrival from the East. Their bodies were buried in an unusually large common grave – of itself a possible indication of an epidemic.
When Dr. Rascovan and his colleagues applied molecular-clock analyses of the phylogenetic tree of the plague bacteria and compared various strains to see which one was the most ancestral, they confirmed that the Swedish strain of Y. pestis, named Gok2, was indeed the oldest – the origin of the Steppe strains rather than its distant cousin. Plague, it seemed, wasn’t brought to Europe during mass migrations from the East. Instead, it might have originated there.
Such work is not simply about rewriting history. By updating our knowledge of ancient pandemics, we can learn how different factors influence each other in fostering outbreaks. For Dr. Rascovan, the Swedish plague story underscores the importance of our lifestyle and environment for the emergence and spread of dangerous pathogens. The Gok2 strain didn’t contain a gene that makes plague particularly virulent, called ymt, yet it might have played an important role in Bronze Age Europe. At that time, mega-settlements of 10,000 to 20,000 people existed in what is now Ukraine, Romania, and Moldova, yet those settlements were frequently burned to the ground and abandoned. According to Dr. Rascovan and his colleagues, that could fit with the plague pandemic story (although this remains very much a hypothesis).
In Mexico, environmental factors might have played an important role in the severity of the 16th century “cocoliztli” epidemic (the word means “pestilence” in a local language), considered one of the most devastating epidemics in New World history. The disease, which caused vomiting, red spots on the skin, and bleeding from various body orifices, didn’t have a known cause. Some hypothesized the bug might have been smallpox, judging by the severity of the outbreak. A 2018 study of a victim’s DNA showed it contained the genome of Salmonella enterica, a bacterium that causes enteric fever – a microbe generally milder than smallpox. The study’s authors argued that specific conditions may have been necessary at the onset of the epidemic for the S. enterica microbe to cause such devastating outcomes. A mix of severe draught, forced relocations of the local population by their Spanish rulers, and new subsistence farming practices all negatively affected hygienic conditions in the local settlements. According to Dr. Rascovan, such research can “place pandemics into their broader context” – with potential lessons for the future.
One of the microbes Dr. Rascovan and his team are hoping to find in the ancient teeth stocked in their lab’s closet is tuberculosis – a pathogen that kills 1.5 million people a year, yet whose evolutionary history remains largely a mystery. The focus of Dr. Rascovan and his colleagues remains on fossils shipped from South America, since we still know very little about microbes that were associated with pre-Columbian populations. South Americans have been isolated from the rest of the world for 20,000 years, making them particularly interesting candidates for the study of emergence, evolution, and spread of pathogens.
Dr. Rascovan believes that ancient microbial genomic data can help scientists better understand antibiotic resistance through comparisons of bacterial evolution before and after the discovery of antibiotics. In general, he says, by studying only current pathogens and the modern outbreaks they cause, we see only a narrow sample of something that is much more diverse and much larger. “We are missing an important part of information. Ancient samples can bring us a perspective,” he says.
A version of this article first appeared on Medscape.com.
Back at the American Psychiatric Association annual meeting again, in person
It was wonderful to see long-term friends and colleagues again in New Orleans! Warmed me from the bottom of my COVID-scarred heart.
I had trepidation and anxiety about further COVID exposure, as I am sure many of you all did. I have carefully resumed traveling, although the rules on masking continue to change and confuse us all.
But I did it. I went to the American Psychiatric Association meeting in New Orleans and am so glad I did.
There was of course a lot of discussion about the pandemic, which separated us physically for 3 years – too many virtual meetings. And quiet discussions of grief and loss, both before and during the APA.
I just learned that Joe Napoli, MD, died. He was one of the hearts of the APA Disaster Psychiatry Committee. Others were lost as well, and I am processing those losses.
I do not want this column to be just a promotion for the APA, although it has been my home organization for decades. So, let me define further the cons and pros of going to the meeting. (Yes, I am deliberately reversing the order of these words.) I warn all the readers in advance that this is a soapbox.
Cons
The convention center in New Orleans is ridiculously long. Our convention was in Hall G down at end of its telescoping length. Only a couple of doors were open – clearly quite a challenge for folks with disabilities, or those aging into possible disability, like myself. I helped a psychiatrist with impaired vision down the endless hall and of course, felt good about it. (My motto: “Perform acts of kindness, and you will feel better yourself.”)
Another con: Too much going on at the same time. That’s a perpetual problem.
And the noise at the parties was way too loud. We could not hear each other.
Pros
Seeing people I have known for 40 years – with masks, without masks. Hugs or bows (on my part, I bow I do not yet hug in COVID times).
The receptions. Great networking. Mid-level psychiatrists who I had forgotten I had mentored. The “young ones” – the psychiatry residents. They seem to be a great and ambitious group.
I did several talks, including one on female veterans, and another on clinical management of the homeless population. The audiences were large and engaged. I am wondering how to make these topics an APA priority, especially engagement with strategies to take care of the unhoused/homeless folks.
Let me give you a brief synopsis of both of those talks, as they represent some of my passions. The first on female veterans. We tend to focus on PTSD and military sexual trauma. I am also concerned about reproductive and musculoskeletal concerns. Too many female service members get pregnant, then quit the military as they cannot manage being a Service member and a mother. They think they can make it (go to school, get a job) but they cannot manage it all.
Veterans services usually focus on single older men. There are not enough rooms and services for female veterans with children. In fairness to the Department of Veterans Affairs, they are trying to remedy this lack.
Transitioning to the homeless population in general, this is an incredible problem which is not easily solved. The VA has done an incredible job here, but the whole country should be mobilized.
My focus at the talk was the importance of assessing and treating medical problems. Again, homeless women are at high risk for barriers to contraception, sexual assault, pregnancy, and the corresponding difficulties of finding housing that will accept infants and small children.
Then there are the numerous medical issues in the unhoused population. Diabetes, hypertension, ulcers on the feet leading to cellulitis and amputation. I am advocating that we psychiatrists behave as medical doctors and think of the whole person, not just of the mind.
Another pro of the APA meeting: such desire to share what we know with the world. I found a few more potential authors for book chapters, specifically Dr. Anne Hansen to write a chapter in my capacity volume. And getting recruited myself, by Maria Llorente, MD, for one on centenarians (people who aged over 100.) Not sure if I know very much now, but I will try.
But another con: We have plenty of business for all, in this never-ending anxiety tide of COVID.
Another con: I tested positive for COVID after my return, as did several of my friends.
I am sure our readers have many more takes on returning to the APA. These are a few of my thoughts.
Dr. Ritchie is chair of psychiatry at Medstar Washington (D.C.) Hospital Center. She is a member of the Clinical Psychiatry News editorial advisory board, and has no conflicts of interest.
It was wonderful to see long-term friends and colleagues again in New Orleans! Warmed me from the bottom of my COVID-scarred heart.
I had trepidation and anxiety about further COVID exposure, as I am sure many of you all did. I have carefully resumed traveling, although the rules on masking continue to change and confuse us all.
But I did it. I went to the American Psychiatric Association meeting in New Orleans and am so glad I did.
There was of course a lot of discussion about the pandemic, which separated us physically for 3 years – too many virtual meetings. And quiet discussions of grief and loss, both before and during the APA.
I just learned that Joe Napoli, MD, died. He was one of the hearts of the APA Disaster Psychiatry Committee. Others were lost as well, and I am processing those losses.
I do not want this column to be just a promotion for the APA, although it has been my home organization for decades. So, let me define further the cons and pros of going to the meeting. (Yes, I am deliberately reversing the order of these words.) I warn all the readers in advance that this is a soapbox.
Cons
The convention center in New Orleans is ridiculously long. Our convention was in Hall G down at end of its telescoping length. Only a couple of doors were open – clearly quite a challenge for folks with disabilities, or those aging into possible disability, like myself. I helped a psychiatrist with impaired vision down the endless hall and of course, felt good about it. (My motto: “Perform acts of kindness, and you will feel better yourself.”)
Another con: Too much going on at the same time. That’s a perpetual problem.
And the noise at the parties was way too loud. We could not hear each other.
Pros
Seeing people I have known for 40 years – with masks, without masks. Hugs or bows (on my part, I bow I do not yet hug in COVID times).
The receptions. Great networking. Mid-level psychiatrists who I had forgotten I had mentored. The “young ones” – the psychiatry residents. They seem to be a great and ambitious group.
I did several talks, including one on female veterans, and another on clinical management of the homeless population. The audiences were large and engaged. I am wondering how to make these topics an APA priority, especially engagement with strategies to take care of the unhoused/homeless folks.
Let me give you a brief synopsis of both of those talks, as they represent some of my passions. The first on female veterans. We tend to focus on PTSD and military sexual trauma. I am also concerned about reproductive and musculoskeletal concerns. Too many female service members get pregnant, then quit the military as they cannot manage being a Service member and a mother. They think they can make it (go to school, get a job) but they cannot manage it all.
Veterans services usually focus on single older men. There are not enough rooms and services for female veterans with children. In fairness to the Department of Veterans Affairs, they are trying to remedy this lack.
Transitioning to the homeless population in general, this is an incredible problem which is not easily solved. The VA has done an incredible job here, but the whole country should be mobilized.
My focus at the talk was the importance of assessing and treating medical problems. Again, homeless women are at high risk for barriers to contraception, sexual assault, pregnancy, and the corresponding difficulties of finding housing that will accept infants and small children.
Then there are the numerous medical issues in the unhoused population. Diabetes, hypertension, ulcers on the feet leading to cellulitis and amputation. I am advocating that we psychiatrists behave as medical doctors and think of the whole person, not just of the mind.
Another pro of the APA meeting: such desire to share what we know with the world. I found a few more potential authors for book chapters, specifically Dr. Anne Hansen to write a chapter in my capacity volume. And getting recruited myself, by Maria Llorente, MD, for one on centenarians (people who aged over 100.) Not sure if I know very much now, but I will try.
But another con: We have plenty of business for all, in this never-ending anxiety tide of COVID.
Another con: I tested positive for COVID after my return, as did several of my friends.
I am sure our readers have many more takes on returning to the APA. These are a few of my thoughts.
Dr. Ritchie is chair of psychiatry at Medstar Washington (D.C.) Hospital Center. She is a member of the Clinical Psychiatry News editorial advisory board, and has no conflicts of interest.
It was wonderful to see long-term friends and colleagues again in New Orleans! Warmed me from the bottom of my COVID-scarred heart.
I had trepidation and anxiety about further COVID exposure, as I am sure many of you all did. I have carefully resumed traveling, although the rules on masking continue to change and confuse us all.
But I did it. I went to the American Psychiatric Association meeting in New Orleans and am so glad I did.
There was of course a lot of discussion about the pandemic, which separated us physically for 3 years – too many virtual meetings. And quiet discussions of grief and loss, both before and during the APA.
I just learned that Joe Napoli, MD, died. He was one of the hearts of the APA Disaster Psychiatry Committee. Others were lost as well, and I am processing those losses.
I do not want this column to be just a promotion for the APA, although it has been my home organization for decades. So, let me define further the cons and pros of going to the meeting. (Yes, I am deliberately reversing the order of these words.) I warn all the readers in advance that this is a soapbox.
Cons
The convention center in New Orleans is ridiculously long. Our convention was in Hall G down at end of its telescoping length. Only a couple of doors were open – clearly quite a challenge for folks with disabilities, or those aging into possible disability, like myself. I helped a psychiatrist with impaired vision down the endless hall and of course, felt good about it. (My motto: “Perform acts of kindness, and you will feel better yourself.”)
Another con: Too much going on at the same time. That’s a perpetual problem.
And the noise at the parties was way too loud. We could not hear each other.
Pros
Seeing people I have known for 40 years – with masks, without masks. Hugs or bows (on my part, I bow I do not yet hug in COVID times).
The receptions. Great networking. Mid-level psychiatrists who I had forgotten I had mentored. The “young ones” – the psychiatry residents. They seem to be a great and ambitious group.
I did several talks, including one on female veterans, and another on clinical management of the homeless population. The audiences were large and engaged. I am wondering how to make these topics an APA priority, especially engagement with strategies to take care of the unhoused/homeless folks.
Let me give you a brief synopsis of both of those talks, as they represent some of my passions. The first on female veterans. We tend to focus on PTSD and military sexual trauma. I am also concerned about reproductive and musculoskeletal concerns. Too many female service members get pregnant, then quit the military as they cannot manage being a Service member and a mother. They think they can make it (go to school, get a job) but they cannot manage it all.
Veterans services usually focus on single older men. There are not enough rooms and services for female veterans with children. In fairness to the Department of Veterans Affairs, they are trying to remedy this lack.
Transitioning to the homeless population in general, this is an incredible problem which is not easily solved. The VA has done an incredible job here, but the whole country should be mobilized.
My focus at the talk was the importance of assessing and treating medical problems. Again, homeless women are at high risk for barriers to contraception, sexual assault, pregnancy, and the corresponding difficulties of finding housing that will accept infants and small children.
Then there are the numerous medical issues in the unhoused population. Diabetes, hypertension, ulcers on the feet leading to cellulitis and amputation. I am advocating that we psychiatrists behave as medical doctors and think of the whole person, not just of the mind.
Another pro of the APA meeting: such desire to share what we know with the world. I found a few more potential authors for book chapters, specifically Dr. Anne Hansen to write a chapter in my capacity volume. And getting recruited myself, by Maria Llorente, MD, for one on centenarians (people who aged over 100.) Not sure if I know very much now, but I will try.
But another con: We have plenty of business for all, in this never-ending anxiety tide of COVID.
Another con: I tested positive for COVID after my return, as did several of my friends.
I am sure our readers have many more takes on returning to the APA. These are a few of my thoughts.
Dr. Ritchie is chair of psychiatry at Medstar Washington (D.C.) Hospital Center. She is a member of the Clinical Psychiatry News editorial advisory board, and has no conflicts of interest.