Mixed Topics

What tests are best for the diagnosis of COVID-19 infection?

Continue to the answer...

The 2 key diagnostic tests for COVID-19 infection are detecting antigen in nasopharyngeal washings or saliva by nucleic acid amplification tests and identifying ground-glass opacities on computed tomography imaging of the chest. (Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383:2451-2460.)

What tests are best for the diagnosis of COVID-19 infection?

Continue to the answer...

The 2 key diagnostic tests for COVID-19 infection are detecting antigen in nasopharyngeal washings or saliva by nucleic acid amplification tests and identifying ground-glass opacities on computed tomography imaging of the chest. (Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383:2451-2460.)

What tests are best for the diagnosis of COVID-19 infection?

Continue to the answer...

The 2 key diagnostic tests for COVID-19 infection are detecting antigen in nasopharyngeal washings or saliva by nucleic acid amplification tests and identifying ground-glass opacities on computed tomography imaging of the chest. (Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383:2451-2460.)

The Endocrine Society is among several organizations and individuals petitioning the Food and Drug Administration to remove its approvals of bisphenol A (BPA), citing recent evidence that exposure to it is unsafe.

The chemical is used to make plastics in items such as food containers, pitchers, and inner linings of metal products. Small amounts of BPA can leak into food and beverages.

tezzstock/Thinkstock

The petition points to a December 2021 report by the European Food Safety Authority titled: “Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs,” which summarizes evidence gathered since 2013.

It concludes that “there is a health concern from BPA exposure for all age groups.” Specific concerns include harm to the immune system and male and female reproductive systems.
 

Average American exposed to 5,000 times the safe level of BPA

The EFSA established a new “tolerable daily intake” of BPA of 0.04 ng/kg of body weight per day. By contrast, in 2014 the FDA estimated that the mean BPA intake for the U.S. population older than 2 years was 200 ng/kg bw/day and that the 90th percentile for BPA intake was 500 ng/kg of body weight per day.

“Using FDA’s own exposure estimates, the average American is exposed to more than 5000 times the safe level of 0.04 ng BPA/kg [body weight per day] set by the EFSA expert panel. Without a doubt, these values constitute a high health risk and support the conclusion that uses of BPA are not safe ... Given the magnitude of the overexposure, we request an expedited review by FDA,” the petition reads.

In addition to the Endocrine Society, which has long warned about the dangers of endocrine-disrupting chemicals, other signatories to the petition include the Environmental Defense Fund, Breast Cancer Prevention Partners, Clean Water Action/Clean Water Fund, Consumer Reports, Environmental Working Group, Healthy Babies Bright Futures, and the former director of the National Institute of Environmental Health Sciences and National Toxicology Program.

In a statement, Endocrine Society BPA expert Heather Patisaul, PhD, of North Carolina University, Raleigh, said the report’s findings “are extremely concerning and prove the point that even very low levels of BPA exposure can be harmful and lead to issues with reproductive health, breast cancer risk, behavior, and metabolism.”

“The FDA needs to acknowledge the science behind endocrine-disrupting chemicals and act accordingly to protect public health,” she urged.

The FDA is expected to decide within the next few days whether to open a docket to accept comments.

A final decision could take 6 months or longer, an Endocrine Society spokesperson told this news organization.

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

The Endocrine Society is among several organizations and individuals petitioning the Food and Drug Administration to remove its approvals of bisphenol A (BPA), citing recent evidence that exposure to it is unsafe.

The chemical is used to make plastics in items such as food containers, pitchers, and inner linings of metal products. Small amounts of BPA can leak into food and beverages.

tezzstock/Thinkstock

The petition points to a December 2021 report by the European Food Safety Authority titled: “Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs,” which summarizes evidence gathered since 2013.

It concludes that “there is a health concern from BPA exposure for all age groups.” Specific concerns include harm to the immune system and male and female reproductive systems.
 

Average American exposed to 5,000 times the safe level of BPA

The EFSA established a new “tolerable daily intake” of BPA of 0.04 ng/kg of body weight per day. By contrast, in 2014 the FDA estimated that the mean BPA intake for the U.S. population older than 2 years was 200 ng/kg bw/day and that the 90th percentile for BPA intake was 500 ng/kg of body weight per day.

“Using FDA’s own exposure estimates, the average American is exposed to more than 5000 times the safe level of 0.04 ng BPA/kg [body weight per day] set by the EFSA expert panel. Without a doubt, these values constitute a high health risk and support the conclusion that uses of BPA are not safe ... Given the magnitude of the overexposure, we request an expedited review by FDA,” the petition reads.

In addition to the Endocrine Society, which has long warned about the dangers of endocrine-disrupting chemicals, other signatories to the petition include the Environmental Defense Fund, Breast Cancer Prevention Partners, Clean Water Action/Clean Water Fund, Consumer Reports, Environmental Working Group, Healthy Babies Bright Futures, and the former director of the National Institute of Environmental Health Sciences and National Toxicology Program.

In a statement, Endocrine Society BPA expert Heather Patisaul, PhD, of North Carolina University, Raleigh, said the report’s findings “are extremely concerning and prove the point that even very low levels of BPA exposure can be harmful and lead to issues with reproductive health, breast cancer risk, behavior, and metabolism.”

“The FDA needs to acknowledge the science behind endocrine-disrupting chemicals and act accordingly to protect public health,” she urged.

The FDA is expected to decide within the next few days whether to open a docket to accept comments.

A final decision could take 6 months or longer, an Endocrine Society spokesperson told this news organization.

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

The Endocrine Society is among several organizations and individuals petitioning the Food and Drug Administration to remove its approvals of bisphenol A (BPA), citing recent evidence that exposure to it is unsafe.

The chemical is used to make plastics in items such as food containers, pitchers, and inner linings of metal products. Small amounts of BPA can leak into food and beverages.

tezzstock/Thinkstock

The petition points to a December 2021 report by the European Food Safety Authority titled: “Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs,” which summarizes evidence gathered since 2013.

It concludes that “there is a health concern from BPA exposure for all age groups.” Specific concerns include harm to the immune system and male and female reproductive systems.
 

Average American exposed to 5,000 times the safe level of BPA

The EFSA established a new “tolerable daily intake” of BPA of 0.04 ng/kg of body weight per day. By contrast, in 2014 the FDA estimated that the mean BPA intake for the U.S. population older than 2 years was 200 ng/kg bw/day and that the 90th percentile for BPA intake was 500 ng/kg of body weight per day.

“Using FDA’s own exposure estimates, the average American is exposed to more than 5000 times the safe level of 0.04 ng BPA/kg [body weight per day] set by the EFSA expert panel. Without a doubt, these values constitute a high health risk and support the conclusion that uses of BPA are not safe ... Given the magnitude of the overexposure, we request an expedited review by FDA,” the petition reads.

In addition to the Endocrine Society, which has long warned about the dangers of endocrine-disrupting chemicals, other signatories to the petition include the Environmental Defense Fund, Breast Cancer Prevention Partners, Clean Water Action/Clean Water Fund, Consumer Reports, Environmental Working Group, Healthy Babies Bright Futures, and the former director of the National Institute of Environmental Health Sciences and National Toxicology Program.

In a statement, Endocrine Society BPA expert Heather Patisaul, PhD, of North Carolina University, Raleigh, said the report’s findings “are extremely concerning and prove the point that even very low levels of BPA exposure can be harmful and lead to issues with reproductive health, breast cancer risk, behavior, and metabolism.”

“The FDA needs to acknowledge the science behind endocrine-disrupting chemicals and act accordingly to protect public health,” she urged.

The FDA is expected to decide within the next few days whether to open a docket to accept comments.

A final decision could take 6 months or longer, an Endocrine Society spokesperson told this news organization.

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

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

To the Editor:

With a steady increase in dermatology publications over recent decades, there is an expanding pool of evidence to address clinical questions.¹ Residency training is the time when appraising the medical literature and practicing evidence-based medicine is most honed. Evidence-based medicine is an essential component of Practice-based Learning and Improvement, a required core competency of the Accreditation Council for Graduate Medical Education.² Assimilation of new research evidence is traditionally taught through didactics and journal club discussions in residency.

However, at a time when the demand for information overwhelms safeguards that exist to evaluate its quality, it is more important than ever to be equipped with the proper tools to critically appraise novel literature. Beyond accepting a scientific article at face value, physicians must learn to ask targeted questions of the study design, results, and clinical relevance. These questions change based on the type of study, and organizations such as the Oxford Centre for Evidence-Based Medicine provide guidance through critical appraisal worksheets.³

To investigate the utility of using guided questions to evaluate the reliability, significance, and applicability of clinical evidence, we beta tested a novel web-based application in an academic dermatology setting to design and run a journal club for residents. Six dermatology residents participated in this institutional review board–approved study comprised of 3 phases: (1) independent article appraisal through the web-based application, (2) group discussion, and (3) anonymous postsurvey.

Using this platform, we uploaded a recent article into the interactive reader, which contained an integrated tool for appraisal based on specific questions. Because the article described the results of a randomized clinical trial, we used questions from the Centre for Evidence-Based Medicine’s Randomised Controlled Trials Critical Appraisal Worksheet, which has a series of questions to evaluate internal validity, results, and external validity and applicability.³

Residents used the platform to independently read the article, highlight areas of the text that corresponded to 8 critical appraisal questions, and answer yes or no to these questions. Based on residents’ answers, a final appraisal score (on a scale of 1% to 100%) was generated. Simultaneously, the attending dermatologist leading the journal club (C.W.) also completed the assignment to establish an expert score.

Scores from the residents’ independent appraisal ranged from 75% to 100% (mean, 85.4%). Upon discussing the article in a group setting, the residents established a consensus score of 75%. This consensus score matched the expert score, which suggested to us that both independently reviewing the article using guided questions and conducting a group debriefing were necessary to match the expert level of critical appraisal.

Of note, the residents’ average independent appraisal score was higher than both the consensus and expert scores, indicating that the residents evaluated the article less critically on their own. With more practice using this method, it is possible that the precision and accuracy of the residents’ critical appraisal of scientific articles will improve.

In the postsurvey, we asked residents about the critical appraisal of the medical literature. All residents agreed that evaluating the quality of evidence when reading a scientific article was somewhat important or very important to them; however, only 2 of 6 evaluated the quality of evidence all the time, and the other 4 did so half of the time or less than half of the time.

When critically appraising articles, 2 of 6 residents used specific rubrics half of the time; 4 of 6 less than half of the time. Most important, 5 of 6 residents agreed that the quality of evidence affected their management decisions more than half of the time or all of the time. Although it is clear that residents value evidence-based medicine and understand the importance of evaluating the quality of evidence, doing so currently might not be simple or practical.

An organized framework for appraising articles would streamline the process. Five of 6 residents agreed that the use of specific questions as a guide made it easier to appraise an article for the quality of its evidence. Four of 6 residents found that juxtaposing specific questions with the interactive reader was helpful; 5 of 6 agreed that they would use a web-based journal club platform if given the option.

Lastly, 5 of 6 residents agreed that if such a tool were available, a platform containing all major dermatology publications in an interactive reader format, along with relevant appraisal questions on the side, would be useful.

This pilot study augmented the typical journal club experience by emphasizing goal-directed reading and the importance of analyzing the quality of evidence. The combination of independent appraisal of an article using targeted questions and a group debrief led to better understanding of the evidence and its clinical applicability. The COVID-19 pandemic may be a better time than ever to explore innovative ways to teach evidence-based medicine in residency training.

To the Editor:

With a steady increase in dermatology publications over recent decades, there is an expanding pool of evidence to address clinical questions.¹ Residency training is the time when appraising the medical literature and practicing evidence-based medicine is most honed. Evidence-based medicine is an essential component of Practice-based Learning and Improvement, a required core competency of the Accreditation Council for Graduate Medical Education.² Assimilation of new research evidence is traditionally taught through didactics and journal club discussions in residency.

However, at a time when the demand for information overwhelms safeguards that exist to evaluate its quality, it is more important than ever to be equipped with the proper tools to critically appraise novel literature. Beyond accepting a scientific article at face value, physicians must learn to ask targeted questions of the study design, results, and clinical relevance. These questions change based on the type of study, and organizations such as the Oxford Centre for Evidence-Based Medicine provide guidance through critical appraisal worksheets.³

To investigate the utility of using guided questions to evaluate the reliability, significance, and applicability of clinical evidence, we beta tested a novel web-based application in an academic dermatology setting to design and run a journal club for residents. Six dermatology residents participated in this institutional review board–approved study comprised of 3 phases: (1) independent article appraisal through the web-based application, (2) group discussion, and (3) anonymous postsurvey.

Using this platform, we uploaded a recent article into the interactive reader, which contained an integrated tool for appraisal based on specific questions. Because the article described the results of a randomized clinical trial, we used questions from the Centre for Evidence-Based Medicine’s Randomised Controlled Trials Critical Appraisal Worksheet, which has a series of questions to evaluate internal validity, results, and external validity and applicability.³

Residents used the platform to independently read the article, highlight areas of the text that corresponded to 8 critical appraisal questions, and answer yes or no to these questions. Based on residents’ answers, a final appraisal score (on a scale of 1% to 100%) was generated. Simultaneously, the attending dermatologist leading the journal club (C.W.) also completed the assignment to establish an expert score.

Scores from the residents’ independent appraisal ranged from 75% to 100% (mean, 85.4%). Upon discussing the article in a group setting, the residents established a consensus score of 75%. This consensus score matched the expert score, which suggested to us that both independently reviewing the article using guided questions and conducting a group debriefing were necessary to match the expert level of critical appraisal.

Of note, the residents’ average independent appraisal score was higher than both the consensus and expert scores, indicating that the residents evaluated the article less critically on their own. With more practice using this method, it is possible that the precision and accuracy of the residents’ critical appraisal of scientific articles will improve.

In the postsurvey, we asked residents about the critical appraisal of the medical literature. All residents agreed that evaluating the quality of evidence when reading a scientific article was somewhat important or very important to them; however, only 2 of 6 evaluated the quality of evidence all the time, and the other 4 did so half of the time or less than half of the time.

When critically appraising articles, 2 of 6 residents used specific rubrics half of the time; 4 of 6 less than half of the time. Most important, 5 of 6 residents agreed that the quality of evidence affected their management decisions more than half of the time or all of the time. Although it is clear that residents value evidence-based medicine and understand the importance of evaluating the quality of evidence, doing so currently might not be simple or practical.

An organized framework for appraising articles would streamline the process. Five of 6 residents agreed that the use of specific questions as a guide made it easier to appraise an article for the quality of its evidence. Four of 6 residents found that juxtaposing specific questions with the interactive reader was helpful; 5 of 6 agreed that they would use a web-based journal club platform if given the option.

Lastly, 5 of 6 residents agreed that if such a tool were available, a platform containing all major dermatology publications in an interactive reader format, along with relevant appraisal questions on the side, would be useful.

This pilot study augmented the typical journal club experience by emphasizing goal-directed reading and the importance of analyzing the quality of evidence. The combination of independent appraisal of an article using targeted questions and a group debrief led to better understanding of the evidence and its clinical applicability. The COVID-19 pandemic may be a better time than ever to explore innovative ways to teach evidence-based medicine in residency training.

To the Editor:

With a steady increase in dermatology publications over recent decades, there is an expanding pool of evidence to address clinical questions.¹ Residency training is the time when appraising the medical literature and practicing evidence-based medicine is most honed. Evidence-based medicine is an essential component of Practice-based Learning and Improvement, a required core competency of the Accreditation Council for Graduate Medical Education.² Assimilation of new research evidence is traditionally taught through didactics and journal club discussions in residency.

However, at a time when the demand for information overwhelms safeguards that exist to evaluate its quality, it is more important than ever to be equipped with the proper tools to critically appraise novel literature. Beyond accepting a scientific article at face value, physicians must learn to ask targeted questions of the study design, results, and clinical relevance. These questions change based on the type of study, and organizations such as the Oxford Centre for Evidence-Based Medicine provide guidance through critical appraisal worksheets.³

To investigate the utility of using guided questions to evaluate the reliability, significance, and applicability of clinical evidence, we beta tested a novel web-based application in an academic dermatology setting to design and run a journal club for residents. Six dermatology residents participated in this institutional review board–approved study comprised of 3 phases: (1) independent article appraisal through the web-based application, (2) group discussion, and (3) anonymous postsurvey.

Using this platform, we uploaded a recent article into the interactive reader, which contained an integrated tool for appraisal based on specific questions. Because the article described the results of a randomized clinical trial, we used questions from the Centre for Evidence-Based Medicine’s Randomised Controlled Trials Critical Appraisal Worksheet, which has a series of questions to evaluate internal validity, results, and external validity and applicability.³

Residents used the platform to independently read the article, highlight areas of the text that corresponded to 8 critical appraisal questions, and answer yes or no to these questions. Based on residents’ answers, a final appraisal score (on a scale of 1% to 100%) was generated. Simultaneously, the attending dermatologist leading the journal club (C.W.) also completed the assignment to establish an expert score.

Scores from the residents’ independent appraisal ranged from 75% to 100% (mean, 85.4%). Upon discussing the article in a group setting, the residents established a consensus score of 75%. This consensus score matched the expert score, which suggested to us that both independently reviewing the article using guided questions and conducting a group debriefing were necessary to match the expert level of critical appraisal.

Of note, the residents’ average independent appraisal score was higher than both the consensus and expert scores, indicating that the residents evaluated the article less critically on their own. With more practice using this method, it is possible that the precision and accuracy of the residents’ critical appraisal of scientific articles will improve.

In the postsurvey, we asked residents about the critical appraisal of the medical literature. All residents agreed that evaluating the quality of evidence when reading a scientific article was somewhat important or very important to them; however, only 2 of 6 evaluated the quality of evidence all the time, and the other 4 did so half of the time or less than half of the time.

When critically appraising articles, 2 of 6 residents used specific rubrics half of the time; 4 of 6 less than half of the time. Most important, 5 of 6 residents agreed that the quality of evidence affected their management decisions more than half of the time or all of the time. Although it is clear that residents value evidence-based medicine and understand the importance of evaluating the quality of evidence, doing so currently might not be simple or practical.

An organized framework for appraising articles would streamline the process. Five of 6 residents agreed that the use of specific questions as a guide made it easier to appraise an article for the quality of its evidence. Four of 6 residents found that juxtaposing specific questions with the interactive reader was helpful; 5 of 6 agreed that they would use a web-based journal club platform if given the option.

Lastly, 5 of 6 residents agreed that if such a tool were available, a platform containing all major dermatology publications in an interactive reader format, along with relevant appraisal questions on the side, would be useful.

This pilot study augmented the typical journal club experience by emphasizing goal-directed reading and the importance of analyzing the quality of evidence. The combination of independent appraisal of an article using targeted questions and a group debrief led to better understanding of the evidence and its clinical applicability. The COVID-19 pandemic may be a better time than ever to explore innovative ways to teach evidence-based medicine in residency training.

A breakthrough neuromodulation system rapidly restores motor function in patients with a severe spinal cord injury (SCI), new research shows.

The study demonstrated that an epidural electrical stimulation (EES) system developed specifically for spinal cord injuries enabled three men with complete paralysis to stand, walk, cycle, swim, and move their torso within 1 day.

“Thanks to this technology, we have been able to target individuals with the most serious spinal cord injury, meaning those with clinically complete spinal cord injury, with no sensation and no movement in the legs,” Grégoire Courtine, PhD, professor of neuroscience and neurotechnology at the Swiss Federal Institute of Technology, University Hospital Lausanne (Switzerland), and the University of Lausanne, told reporters attending a press briefing.

The study was published online Feb. 7, 2022, in Nature Medicine.
 

More rapid, precise, effective

SCIs involve severed connections between the brain and extremities. To compensate for these lost connections, researchers have investigated stem cell therapy, brain-machine interfaces, and powered exoskeletons.

However, these approaches aren’t yet ready for prime time.

In the meantime, researchers discovered even patients with a “complete” injury may have low-functioning connections and started investigating epidural stimulators designed to treat chronic pain. Recent studies – including three published in 2018 – showed promise for these pain-related stimulators in patients with incomplete SCI.

But using such “repurposed” technology meant the electrode array was relatively narrow and short, “so we could not target all the regions of the spinal cord involving control of leg and trunk movements,” said Dr. Courtine. With the newer technology “we are much more precise, effective, and more rapid in delivering therapy.”

To develop this new approach, the researchers designed a paddle lead with an arrangement of electrodes that targets sacral, lumbar, and low-thoracic dorsal roots involved in leg and trunk movements. They also established a personalized computational framework that allows for optimal surgical placement of this paddle lead.

In addition, they developed software that renders the configuration of individualized activity–dependent stimulation programs rapid, simple, and predictable.

They tested these neurotechnologies in three men with complete sensorimotor paralysis as part of an ongoing clinical trial. The participants, aged 29, 32, and 41 years, suffered an SCI from a motor bike accident 3, 9, and 1 year before enrollment.

All three patients exhibited complete sensorimotor paralysis. They were unable to take any step, and muscles remained quiescent during these attempts.

A neurosurgeon implanted electrodes along the spinal cord of study subjects. Wires from these electrodes were connected to a neurostimulator implanted under the skin in the abdomen.

The men can select different activity-based programs from a tablet that sends signals to the implanted device.
 

Personalized approach

Within a single day of the surgery, the participants were able to stand, walk, cycle, swim, and control trunk movements.

“It was not perfect at the very beginning, but they could train very early on to have a more fluid gait,” said study investigator neurosurgeon Joceylyne Bloch, MD, associate professor, University of Lausanne and University Hospital Lausanne.

At this stage, not all paralyzed patients are eligible for the procedure. Dr. Bloch explained that at least 6 cm of healthy spinal cord under the lesion is needed to implant the electrodes.

“There’s a huge variability of spinal cord anatomy between individuals. That’s why it’s important to study each person individually and to have individual models in order to be precise.”

Researchers envision having “a library of electrode arrays,” added Dr. Courtine. With preoperative imaging of the individual’s spinal cord, “the neurosurgeon can select the more appropriate electrode array for that specific patient.”

Dr. Courtine noted recovery of sensation with the system differs from one individual to another. One study participant, Michel Roccati, now 30, told the briefing he feels a contraction in his muscle during the stimulation.

Currently, only individuals whose injury is more than a year old are included in the study to ensure patients have “a stable lesion” and reached “a plateau of recovery,” said Dr. Bloch. However, animal models show intervening earlier might boost the benefits.

A patient’s age can influence the outcome, as younger patients are likely in better condition and more motivated than older patients, said Dr. Bloch. However, she noted patients closing in on 50 years have responded well to the therapy.

Such stimulation systems may prove useful in treating conditions typically associated with SCI, such as hypertension and bladder control, and perhaps also in patients with Parkinson’s disease, said Dr. Courtine.

The researchers plan to conduct another study that will include a next-generation pulse generator with features that make the stimulation even more effective and user friendly. A voice recognition system could eventually be connected to the system.

“The next step is a minicomputer that you implant in the body that communicates in real time with an external iPhone,” said Dr. Courtine.

ONWARD Medical, which developed the technology, has received a breakthrough device designation from the Food and Drug Administration. The company is in discussions with the FDA to carry out a clinical trial of the device in the United States.
 

A ‘huge step forward’

Peter J. Grahn, PhD, assistant professor, department of physical medicine and rehabilitation and department of neurologic surgery, Mayo Clinic, Rochester, Minn., an author of one of the 2018 studies, said this technology “is a huge step forward” and “really pushes the field.”

Compared with the device used in his study that’s designed to treat neuropathic pain, this new system “is much more capable of dynamic stimulation,” said Dr. Grahn. “You can tailor the stimulation based on which area of the spinal cord you want to target during a specific function.”

There has been “a lot of hope and hype” recently around stem cells and biological molecules that were supposed to be “magic pills” to cure spinal cord dysfunction, said Dr. Grahn. “I don’t think this is one of those.”

However, he questioned the researchers’ use of the word “walking.”

“They say independent stepping or walking is restored on day 1, but the graphs show day 1 function is having over 60% of their body weight supported when they’re taking these steps,” he said.

In addition, the “big question” is how this technology can “be distilled down” into an approach “applicable across rehabilitation centers,” said Dr. Grahn.

The study was supported by numerous organizations, including ONWARD Medical. Dr. Courtine and Dr. Bloch hold various patents in relation with the present work. Dr. Courtine is a consultant with ONWARD Medical, and he and Dr. Bloch are shareholders of ONWARD Medical, a company with direct relationships with the presented work. Dr. Grahn reported no relevant financial relationships.

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

A breakthrough neuromodulation system rapidly restores motor function in patients with a severe spinal cord injury (SCI), new research shows.

The study demonstrated that an epidural electrical stimulation (EES) system developed specifically for spinal cord injuries enabled three men with complete paralysis to stand, walk, cycle, swim, and move their torso within 1 day.

“Thanks to this technology, we have been able to target individuals with the most serious spinal cord injury, meaning those with clinically complete spinal cord injury, with no sensation and no movement in the legs,” Grégoire Courtine, PhD, professor of neuroscience and neurotechnology at the Swiss Federal Institute of Technology, University Hospital Lausanne (Switzerland), and the University of Lausanne, told reporters attending a press briefing.

The study was published online Feb. 7, 2022, in Nature Medicine.
 

More rapid, precise, effective

SCIs involve severed connections between the brain and extremities. To compensate for these lost connections, researchers have investigated stem cell therapy, brain-machine interfaces, and powered exoskeletons.

However, these approaches aren’t yet ready for prime time.

In the meantime, researchers discovered even patients with a “complete” injury may have low-functioning connections and started investigating epidural stimulators designed to treat chronic pain. Recent studies – including three published in 2018 – showed promise for these pain-related stimulators in patients with incomplete SCI.

But using such “repurposed” technology meant the electrode array was relatively narrow and short, “so we could not target all the regions of the spinal cord involving control of leg and trunk movements,” said Dr. Courtine. With the newer technology “we are much more precise, effective, and more rapid in delivering therapy.”

To develop this new approach, the researchers designed a paddle lead with an arrangement of electrodes that targets sacral, lumbar, and low-thoracic dorsal roots involved in leg and trunk movements. They also established a personalized computational framework that allows for optimal surgical placement of this paddle lead.

In addition, they developed software that renders the configuration of individualized activity–dependent stimulation programs rapid, simple, and predictable.

They tested these neurotechnologies in three men with complete sensorimotor paralysis as part of an ongoing clinical trial. The participants, aged 29, 32, and 41 years, suffered an SCI from a motor bike accident 3, 9, and 1 year before enrollment.

All three patients exhibited complete sensorimotor paralysis. They were unable to take any step, and muscles remained quiescent during these attempts.

A neurosurgeon implanted electrodes along the spinal cord of study subjects. Wires from these electrodes were connected to a neurostimulator implanted under the skin in the abdomen.

The men can select different activity-based programs from a tablet that sends signals to the implanted device.
 

Personalized approach

Within a single day of the surgery, the participants were able to stand, walk, cycle, swim, and control trunk movements.

“It was not perfect at the very beginning, but they could train very early on to have a more fluid gait,” said study investigator neurosurgeon Joceylyne Bloch, MD, associate professor, University of Lausanne and University Hospital Lausanne.

At this stage, not all paralyzed patients are eligible for the procedure. Dr. Bloch explained that at least 6 cm of healthy spinal cord under the lesion is needed to implant the electrodes.

“There’s a huge variability of spinal cord anatomy between individuals. That’s why it’s important to study each person individually and to have individual models in order to be precise.”

Researchers envision having “a library of electrode arrays,” added Dr. Courtine. With preoperative imaging of the individual’s spinal cord, “the neurosurgeon can select the more appropriate electrode array for that specific patient.”

Dr. Courtine noted recovery of sensation with the system differs from one individual to another. One study participant, Michel Roccati, now 30, told the briefing he feels a contraction in his muscle during the stimulation.

Currently, only individuals whose injury is more than a year old are included in the study to ensure patients have “a stable lesion” and reached “a plateau of recovery,” said Dr. Bloch. However, animal models show intervening earlier might boost the benefits.

A patient’s age can influence the outcome, as younger patients are likely in better condition and more motivated than older patients, said Dr. Bloch. However, she noted patients closing in on 50 years have responded well to the therapy.

Such stimulation systems may prove useful in treating conditions typically associated with SCI, such as hypertension and bladder control, and perhaps also in patients with Parkinson’s disease, said Dr. Courtine.

The researchers plan to conduct another study that will include a next-generation pulse generator with features that make the stimulation even more effective and user friendly. A voice recognition system could eventually be connected to the system.

“The next step is a minicomputer that you implant in the body that communicates in real time with an external iPhone,” said Dr. Courtine.

ONWARD Medical, which developed the technology, has received a breakthrough device designation from the Food and Drug Administration. The company is in discussions with the FDA to carry out a clinical trial of the device in the United States.
 

A ‘huge step forward’

Peter J. Grahn, PhD, assistant professor, department of physical medicine and rehabilitation and department of neurologic surgery, Mayo Clinic, Rochester, Minn., an author of one of the 2018 studies, said this technology “is a huge step forward” and “really pushes the field.”

Compared with the device used in his study that’s designed to treat neuropathic pain, this new system “is much more capable of dynamic stimulation,” said Dr. Grahn. “You can tailor the stimulation based on which area of the spinal cord you want to target during a specific function.”

There has been “a lot of hope and hype” recently around stem cells and biological molecules that were supposed to be “magic pills” to cure spinal cord dysfunction, said Dr. Grahn. “I don’t think this is one of those.”

However, he questioned the researchers’ use of the word “walking.”

“They say independent stepping or walking is restored on day 1, but the graphs show day 1 function is having over 60% of their body weight supported when they’re taking these steps,” he said.

In addition, the “big question” is how this technology can “be distilled down” into an approach “applicable across rehabilitation centers,” said Dr. Grahn.

The study was supported by numerous organizations, including ONWARD Medical. Dr. Courtine and Dr. Bloch hold various patents in relation with the present work. Dr. Courtine is a consultant with ONWARD Medical, and he and Dr. Bloch are shareholders of ONWARD Medical, a company with direct relationships with the presented work. Dr. Grahn reported no relevant financial relationships.

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

A breakthrough neuromodulation system rapidly restores motor function in patients with a severe spinal cord injury (SCI), new research shows.

The study demonstrated that an epidural electrical stimulation (EES) system developed specifically for spinal cord injuries enabled three men with complete paralysis to stand, walk, cycle, swim, and move their torso within 1 day.

“Thanks to this technology, we have been able to target individuals with the most serious spinal cord injury, meaning those with clinically complete spinal cord injury, with no sensation and no movement in the legs,” Grégoire Courtine, PhD, professor of neuroscience and neurotechnology at the Swiss Federal Institute of Technology, University Hospital Lausanne (Switzerland), and the University of Lausanne, told reporters attending a press briefing.

The study was published online Feb. 7, 2022, in Nature Medicine.
 

More rapid, precise, effective

SCIs involve severed connections between the brain and extremities. To compensate for these lost connections, researchers have investigated stem cell therapy, brain-machine interfaces, and powered exoskeletons.

However, these approaches aren’t yet ready for prime time.

In the meantime, researchers discovered even patients with a “complete” injury may have low-functioning connections and started investigating epidural stimulators designed to treat chronic pain. Recent studies – including three published in 2018 – showed promise for these pain-related stimulators in patients with incomplete SCI.

But using such “repurposed” technology meant the electrode array was relatively narrow and short, “so we could not target all the regions of the spinal cord involving control of leg and trunk movements,” said Dr. Courtine. With the newer technology “we are much more precise, effective, and more rapid in delivering therapy.”

To develop this new approach, the researchers designed a paddle lead with an arrangement of electrodes that targets sacral, lumbar, and low-thoracic dorsal roots involved in leg and trunk movements. They also established a personalized computational framework that allows for optimal surgical placement of this paddle lead.

In addition, they developed software that renders the configuration of individualized activity–dependent stimulation programs rapid, simple, and predictable.

They tested these neurotechnologies in three men with complete sensorimotor paralysis as part of an ongoing clinical trial. The participants, aged 29, 32, and 41 years, suffered an SCI from a motor bike accident 3, 9, and 1 year before enrollment.

All three patients exhibited complete sensorimotor paralysis. They were unable to take any step, and muscles remained quiescent during these attempts.

A neurosurgeon implanted electrodes along the spinal cord of study subjects. Wires from these electrodes were connected to a neurostimulator implanted under the skin in the abdomen.

The men can select different activity-based programs from a tablet that sends signals to the implanted device.
 

Personalized approach

Within a single day of the surgery, the participants were able to stand, walk, cycle, swim, and control trunk movements.

“It was not perfect at the very beginning, but they could train very early on to have a more fluid gait,” said study investigator neurosurgeon Joceylyne Bloch, MD, associate professor, University of Lausanne and University Hospital Lausanne.

At this stage, not all paralyzed patients are eligible for the procedure. Dr. Bloch explained that at least 6 cm of healthy spinal cord under the lesion is needed to implant the electrodes.

“There’s a huge variability of spinal cord anatomy between individuals. That’s why it’s important to study each person individually and to have individual models in order to be precise.”

Researchers envision having “a library of electrode arrays,” added Dr. Courtine. With preoperative imaging of the individual’s spinal cord, “the neurosurgeon can select the more appropriate electrode array for that specific patient.”

Dr. Courtine noted recovery of sensation with the system differs from one individual to another. One study participant, Michel Roccati, now 30, told the briefing he feels a contraction in his muscle during the stimulation.

Currently, only individuals whose injury is more than a year old are included in the study to ensure patients have “a stable lesion” and reached “a plateau of recovery,” said Dr. Bloch. However, animal models show intervening earlier might boost the benefits.

A patient’s age can influence the outcome, as younger patients are likely in better condition and more motivated than older patients, said Dr. Bloch. However, she noted patients closing in on 50 years have responded well to the therapy.

Such stimulation systems may prove useful in treating conditions typically associated with SCI, such as hypertension and bladder control, and perhaps also in patients with Parkinson’s disease, said Dr. Courtine.

The researchers plan to conduct another study that will include a next-generation pulse generator with features that make the stimulation even more effective and user friendly. A voice recognition system could eventually be connected to the system.

“The next step is a minicomputer that you implant in the body that communicates in real time with an external iPhone,” said Dr. Courtine.

ONWARD Medical, which developed the technology, has received a breakthrough device designation from the Food and Drug Administration. The company is in discussions with the FDA to carry out a clinical trial of the device in the United States.
 

A ‘huge step forward’

Peter J. Grahn, PhD, assistant professor, department of physical medicine and rehabilitation and department of neurologic surgery, Mayo Clinic, Rochester, Minn., an author of one of the 2018 studies, said this technology “is a huge step forward” and “really pushes the field.”

Compared with the device used in his study that’s designed to treat neuropathic pain, this new system “is much more capable of dynamic stimulation,” said Dr. Grahn. “You can tailor the stimulation based on which area of the spinal cord you want to target during a specific function.”

There has been “a lot of hope and hype” recently around stem cells and biological molecules that were supposed to be “magic pills” to cure spinal cord dysfunction, said Dr. Grahn. “I don’t think this is one of those.”

However, he questioned the researchers’ use of the word “walking.”

“They say independent stepping or walking is restored on day 1, but the graphs show day 1 function is having over 60% of their body weight supported when they’re taking these steps,” he said.

In addition, the “big question” is how this technology can “be distilled down” into an approach “applicable across rehabilitation centers,” said Dr. Grahn.

The study was supported by numerous organizations, including ONWARD Medical. Dr. Courtine and Dr. Bloch hold various patents in relation with the present work. Dr. Courtine is a consultant with ONWARD Medical, and he and Dr. Bloch are shareholders of ONWARD Medical, a company with direct relationships with the presented work. Dr. Grahn reported no relevant financial relationships.

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

Cerebral palsy (CP) embodies a collection of disorders involving permanent but nonprogressive motor dysfunction secondary to one of a variety of abnormal disturbances that can occur in the developing fetal or infantile brain.¹ The motor impairment of CP classically leads to irregularities in muscle tone, posture, and/or movement, resulting in limitations of functional abilities that vary in severity.^1,2 Patients with CP commonly experience dysphagia, gastroesophageal reflux disease, impaired airway clearance, chest wall and spine deformities, restrictive lung disease, and/or recurrent aspiration.¹ Consequently, pulmonary disease is the leading cause of morbidity and mortality in patients with severe CP, characterized by recurrent bacterial infections.^3,4

Frequent antibiotic use increases the risk of multidrug-resistant pathogen formation and hypersensitivity to antibiotics. Life-threatening allergic reactions in a patient population with impaired lung function significantly complicates patient management, often leading to suboptimal treatment with second-line agents.⁵ This case study describes a previously penicillin-tolerant patient with CP who developed a type I hypersensitivity reaction to ceftazidime/avibactam and was treated successfully with the antibiotic after rapid induction of temporary tolerance.

Case Presentation

A 34-year-old male with a complex medical history of severe spastic CP and atonic seizures was recently diagnosed with adenocarcinoma of the colon and admitted for ileostomy and sigmoidectomy. The surgery was complicated by spillage of intestinal contents into the peritoneal cavity 3 days postoperation. The patient was urgently taken to the operating room for exploratory laparotomy, culminating in remaining colectomy, complete abdominal washout, and wound vacuum placement. He continued to deteriorate clinically over the next few weeks, beginning with the development of feculent peritonitis and septic shock. Respiratory distress ensued, and the patient required a tracheostomy with mechanical ventilation. A computed tomography of the chest was consistent with multifocal pneumonia, and a respiratory culture of bronchioalveolar lavage fluid cultivated Klebsiella pneumoniae, a carbapenem-resistant Enterobacteriaceae.

The infectious disease service was consulted and recommended ceftazidime/avibactam as the only acceptable antibiotic to treat this organism. The patient had no history of drug hypersensitivities. However, he developed diffuse, generalized urticaria and predominately right-sided flushing immediately following the onset of the antibiotic infusion. The urticaria was pruritic. The patient did not have angioedema, and he did not experience any adverse respiratory, cardiac, gastrointestinal, or neurologic symptoms. The infusion was ceased immediately, and the patient was treated with a combination of diphenhydramine 50 mg IV and ranitidine 50 mg IV. Resolution of his hypersensitivity symptoms occurred within an hour of treatment, and vital signs remained stable with no resurgence of symptoms. At the time of his reaction, the patient also was taking pantoprazole, valproate, metoprolol, risperidone, and oxycodone as needed for pain. A tryptase level was not measured.

Discussion

This is the first reported case in the literature to describe a type I hypersensitivity reaction with rapid IV induction of tolerance to ceftazidime/avibactam. We describe his reaction as type I hypersensitivity because the patient developed immediate generalized urticaria and flushing. Use of a safe desensitization protocol, demonstrated in this case report, is paramount to optimal management of infections in patient populations with severely decreased lung function, such as CP.^5-7 It provides a safe and effective technique to maintain patients on first line, preferred therapy, despite their increased risk of potentially life-threatening allergic reactions.

Interestingly, this patient previously tolerated penicillins and cephalosporins without adverse reactions, suggesting the possibility of a non–IgE-mediated vs an IgE-mediated mechanism to the hypersensitivity reaction. The patient also was receiving oxycodone at the time of his reaction, and oxycodone can cause nonspecific mast cell degranulation. Additional information from skin testing to ceftazidime/avibactam could help determine whether the patient had an IgE-mediated hypersensitivity reaction. This information could help clarify the culprit agent and guide further avoidance recommendations.

Unfortunately, because the patient was critically ill, skin testing was not performed, and he underwent an urgent antibiotic desensitization with success. It was recommended that the patient follow up in the allergy and immunology clinic for further evaluation with skin testing to ceftazidime/avibactam as well as other β-lactams to determine his future risk of reaction. Unfortunately, he was lost to follow-up.

Frequent IV antibiotic use is a risk factor for the development of antibiotic allergies.^8,9 This patient had received many prior courses of IV antibiotics, and this factor most likely contributed to his immediate hypersensitivity reaction to ceftazidime/avibactam. Fortunately, he tolerated a rapid induction of tolerance.

As life expectancies for patients with chronic medical conditions that involve recurrent infections increase, the associated emergence of multidrug-resistant pathogens and necessity for use of novel combination antibiotics should prompt further investigation of nonirritating doses of these drugs for skin testing in the case of drug hypersensitivities. This information would be essential for skin prick testing and determination of whether patients have a true IgE-mediated reaction to these antibiotics.

Conclusions

This is the first case report demonstrating a successful rapid induction of tolerance for the antibiotic ceftazidime/avibactam. Fortunately, the patient tolerated the desensitization procedure without further adverse reactions, and he had a resolution of his infection.

Cerebral palsy (CP) embodies a collection of disorders involving permanent but nonprogressive motor dysfunction secondary to one of a variety of abnormal disturbances that can occur in the developing fetal or infantile brain.¹ The motor impairment of CP classically leads to irregularities in muscle tone, posture, and/or movement, resulting in limitations of functional abilities that vary in severity.^1,2 Patients with CP commonly experience dysphagia, gastroesophageal reflux disease, impaired airway clearance, chest wall and spine deformities, restrictive lung disease, and/or recurrent aspiration.¹ Consequently, pulmonary disease is the leading cause of morbidity and mortality in patients with severe CP, characterized by recurrent bacterial infections.^3,4

Frequent antibiotic use increases the risk of multidrug-resistant pathogen formation and hypersensitivity to antibiotics. Life-threatening allergic reactions in a patient population with impaired lung function significantly complicates patient management, often leading to suboptimal treatment with second-line agents.⁵ This case study describes a previously penicillin-tolerant patient with CP who developed a type I hypersensitivity reaction to ceftazidime/avibactam and was treated successfully with the antibiotic after rapid induction of temporary tolerance.

Case Presentation

A 34-year-old male with a complex medical history of severe spastic CP and atonic seizures was recently diagnosed with adenocarcinoma of the colon and admitted for ileostomy and sigmoidectomy. The surgery was complicated by spillage of intestinal contents into the peritoneal cavity 3 days postoperation. The patient was urgently taken to the operating room for exploratory laparotomy, culminating in remaining colectomy, complete abdominal washout, and wound vacuum placement. He continued to deteriorate clinically over the next few weeks, beginning with the development of feculent peritonitis and septic shock. Respiratory distress ensued, and the patient required a tracheostomy with mechanical ventilation. A computed tomography of the chest was consistent with multifocal pneumonia, and a respiratory culture of bronchioalveolar lavage fluid cultivated Klebsiella pneumoniae, a carbapenem-resistant Enterobacteriaceae.

The infectious disease service was consulted and recommended ceftazidime/avibactam as the only acceptable antibiotic to treat this organism. The patient had no history of drug hypersensitivities. However, he developed diffuse, generalized urticaria and predominately right-sided flushing immediately following the onset of the antibiotic infusion. The urticaria was pruritic. The patient did not have angioedema, and he did not experience any adverse respiratory, cardiac, gastrointestinal, or neurologic symptoms. The infusion was ceased immediately, and the patient was treated with a combination of diphenhydramine 50 mg IV and ranitidine 50 mg IV. Resolution of his hypersensitivity symptoms occurred within an hour of treatment, and vital signs remained stable with no resurgence of symptoms. At the time of his reaction, the patient also was taking pantoprazole, valproate, metoprolol, risperidone, and oxycodone as needed for pain. A tryptase level was not measured.

Discussion

This is the first reported case in the literature to describe a type I hypersensitivity reaction with rapid IV induction of tolerance to ceftazidime/avibactam. We describe his reaction as type I hypersensitivity because the patient developed immediate generalized urticaria and flushing. Use of a safe desensitization protocol, demonstrated in this case report, is paramount to optimal management of infections in patient populations with severely decreased lung function, such as CP.^5-7 It provides a safe and effective technique to maintain patients on first line, preferred therapy, despite their increased risk of potentially life-threatening allergic reactions.

Interestingly, this patient previously tolerated penicillins and cephalosporins without adverse reactions, suggesting the possibility of a non–IgE-mediated vs an IgE-mediated mechanism to the hypersensitivity reaction. The patient also was receiving oxycodone at the time of his reaction, and oxycodone can cause nonspecific mast cell degranulation. Additional information from skin testing to ceftazidime/avibactam could help determine whether the patient had an IgE-mediated hypersensitivity reaction. This information could help clarify the culprit agent and guide further avoidance recommendations.

Unfortunately, because the patient was critically ill, skin testing was not performed, and he underwent an urgent antibiotic desensitization with success. It was recommended that the patient follow up in the allergy and immunology clinic for further evaluation with skin testing to ceftazidime/avibactam as well as other β-lactams to determine his future risk of reaction. Unfortunately, he was lost to follow-up.

Frequent IV antibiotic use is a risk factor for the development of antibiotic allergies.^8,9 This patient had received many prior courses of IV antibiotics, and this factor most likely contributed to his immediate hypersensitivity reaction to ceftazidime/avibactam. Fortunately, he tolerated a rapid induction of tolerance.

As life expectancies for patients with chronic medical conditions that involve recurrent infections increase, the associated emergence of multidrug-resistant pathogens and necessity for use of novel combination antibiotics should prompt further investigation of nonirritating doses of these drugs for skin testing in the case of drug hypersensitivities. This information would be essential for skin prick testing and determination of whether patients have a true IgE-mediated reaction to these antibiotics.

Conclusions

This is the first case report demonstrating a successful rapid induction of tolerance for the antibiotic ceftazidime/avibactam. Fortunately, the patient tolerated the desensitization procedure without further adverse reactions, and he had a resolution of his infection.

Cerebral palsy (CP) embodies a collection of disorders involving permanent but nonprogressive motor dysfunction secondary to one of a variety of abnormal disturbances that can occur in the developing fetal or infantile brain.¹ The motor impairment of CP classically leads to irregularities in muscle tone, posture, and/or movement, resulting in limitations of functional abilities that vary in severity.^1,2 Patients with CP commonly experience dysphagia, gastroesophageal reflux disease, impaired airway clearance, chest wall and spine deformities, restrictive lung disease, and/or recurrent aspiration.¹ Consequently, pulmonary disease is the leading cause of morbidity and mortality in patients with severe CP, characterized by recurrent bacterial infections.^3,4

Frequent antibiotic use increases the risk of multidrug-resistant pathogen formation and hypersensitivity to antibiotics. Life-threatening allergic reactions in a patient population with impaired lung function significantly complicates patient management, often leading to suboptimal treatment with second-line agents.⁵ This case study describes a previously penicillin-tolerant patient with CP who developed a type I hypersensitivity reaction to ceftazidime/avibactam and was treated successfully with the antibiotic after rapid induction of temporary tolerance.

Case Presentation

A 34-year-old male with a complex medical history of severe spastic CP and atonic seizures was recently diagnosed with adenocarcinoma of the colon and admitted for ileostomy and sigmoidectomy. The surgery was complicated by spillage of intestinal contents into the peritoneal cavity 3 days postoperation. The patient was urgently taken to the operating room for exploratory laparotomy, culminating in remaining colectomy, complete abdominal washout, and wound vacuum placement. He continued to deteriorate clinically over the next few weeks, beginning with the development of feculent peritonitis and septic shock. Respiratory distress ensued, and the patient required a tracheostomy with mechanical ventilation. A computed tomography of the chest was consistent with multifocal pneumonia, and a respiratory culture of bronchioalveolar lavage fluid cultivated Klebsiella pneumoniae, a carbapenem-resistant Enterobacteriaceae.

The infectious disease service was consulted and recommended ceftazidime/avibactam as the only acceptable antibiotic to treat this organism. The patient had no history of drug hypersensitivities. However, he developed diffuse, generalized urticaria and predominately right-sided flushing immediately following the onset of the antibiotic infusion. The urticaria was pruritic. The patient did not have angioedema, and he did not experience any adverse respiratory, cardiac, gastrointestinal, or neurologic symptoms. The infusion was ceased immediately, and the patient was treated with a combination of diphenhydramine 50 mg IV and ranitidine 50 mg IV. Resolution of his hypersensitivity symptoms occurred within an hour of treatment, and vital signs remained stable with no resurgence of symptoms. At the time of his reaction, the patient also was taking pantoprazole, valproate, metoprolol, risperidone, and oxycodone as needed for pain. A tryptase level was not measured.

Discussion

This is the first reported case in the literature to describe a type I hypersensitivity reaction with rapid IV induction of tolerance to ceftazidime/avibactam. We describe his reaction as type I hypersensitivity because the patient developed immediate generalized urticaria and flushing. Use of a safe desensitization protocol, demonstrated in this case report, is paramount to optimal management of infections in patient populations with severely decreased lung function, such as CP.^5-7 It provides a safe and effective technique to maintain patients on first line, preferred therapy, despite their increased risk of potentially life-threatening allergic reactions.

Interestingly, this patient previously tolerated penicillins and cephalosporins without adverse reactions, suggesting the possibility of a non–IgE-mediated vs an IgE-mediated mechanism to the hypersensitivity reaction. The patient also was receiving oxycodone at the time of his reaction, and oxycodone can cause nonspecific mast cell degranulation. Additional information from skin testing to ceftazidime/avibactam could help determine whether the patient had an IgE-mediated hypersensitivity reaction. This information could help clarify the culprit agent and guide further avoidance recommendations.

Unfortunately, because the patient was critically ill, skin testing was not performed, and he underwent an urgent antibiotic desensitization with success. It was recommended that the patient follow up in the allergy and immunology clinic for further evaluation with skin testing to ceftazidime/avibactam as well as other β-lactams to determine his future risk of reaction. Unfortunately, he was lost to follow-up.

Frequent IV antibiotic use is a risk factor for the development of antibiotic allergies.^8,9 This patient had received many prior courses of IV antibiotics, and this factor most likely contributed to his immediate hypersensitivity reaction to ceftazidime/avibactam. Fortunately, he tolerated a rapid induction of tolerance.

As life expectancies for patients with chronic medical conditions that involve recurrent infections increase, the associated emergence of multidrug-resistant pathogens and necessity for use of novel combination antibiotics should prompt further investigation of nonirritating doses of these drugs for skin testing in the case of drug hypersensitivities. This information would be essential for skin prick testing and determination of whether patients have a true IgE-mediated reaction to these antibiotics.

Conclusions

This is the first case report demonstrating a successful rapid induction of tolerance for the antibiotic ceftazidime/avibactam. Fortunately, the patient tolerated the desensitization procedure without further adverse reactions, and he had a resolution of his infection.

The increase in cardiovascular disease caused by chronic stress is related to biologic mechanisms (metabolic, hormonal, inflammatory) and to behavioral mechanisms (lifestyle). There is a popular saying that “stress speeds up aging,” which makes sense if we consider the age-old idea that “our age corresponds to that of our arteries.”

The study of the mechanisms of psychosocial risk factors is of major relevance to the creation of the individual and communal preventive strategies that ensure longevity and maintain quality of life.

The following hypotheses were proposed by a group of researchers from Yale University, in New Haven, Conn., in a recent study:

1. Stress is positively associated with accelerated biologic aging, and this relationship will be mediated by stress-related physiologic changes, such as insulin and hypothalamic-pituitary-adrenal (HPA) signaling.

2. Strong factors associated with psychologic resilience will be protective against the negative consequences of stress on aging. (These relationships are predictive, not causative, as this study is cross-sectional.)
 

The study

In their study, the team assessed 444 adults with no chronic medical conditions or psychiatric disorders who were 18-50 years of age and living in the greater New Haven area. Levels of obesity and alcohol consumption in the study cohort were generally in line with those in a community population, so alcohol use and body mass index were used as covariates to account for their impact on the results.

The team also used the latest “epigenetic clock,” known as GrimAge. In recent years, several methods of determining biologic age have been developed that trace chemical changes in the DNA that are natural to the aging process but occur at different moments in different people. The epigenetic clocks have proved to be better predictors of longevity and health than chronologic age, and GrimAge predicts mortality better than other epigenetic clocks.
 

Results

1. Cumulative stress was associated with the acceleration of GrimAge and stress-related physiologic measures of adrenal sensitivity (cortisol/ACTH ratio) and insulin resistance (HOMA). After the researchers controlled for demographic and behavioral factors, HOMA was correlated with GrimAge acceleration.

2. Psychologic resilience factors moderated the association between stress and aging, such that with worse regulation of emotions, there was greater stress-related age acceleration, and with stronger regulation of emotions, any significant effect of stress on GrimAge was prevented. Self-control moderated the relationship between stress and insulin resistance, with high self-control blunting this relationship.

3. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge acceleration, even when demographic, physiologic, and behavioral covariates were accounted for.
 

Implications

These results elegantly demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Even after adjustment for demographic and behavioral factors – such as smoking, body mass index, race, and income – people with high chronic stress scores showed markers of accelerated aging and physiologic changes, such as increased insulin resistance.

However, individuals with high scores on two psychologic resilience measures – emotion regulation and self-control – were more resilient to the effects of stress on aging and insulin resistance.

These results support the popular notion that stress ages (and sickens) us, and suggest a viable way of minimizing the adverse consequences of stress by strengthening the regulation of emotion and self-control.

In other words, the greater the psychologic resilience, the more likely the individual is to live a long and healthy life. “We like to feel as if we have some sovereignty over our destiny and, therefore, it is worth emphasizing to people (and healthcare providers) that it is important to invest in mental health,” said one of the study researchers.

With all the stress we face these days, it is essential to remember that there is no health without mental health. Above all, if we can achieve greater psychologic resilience, we will have a better chance of delaying aging.

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

The increase in cardiovascular disease caused by chronic stress is related to biologic mechanisms (metabolic, hormonal, inflammatory) and to behavioral mechanisms (lifestyle). There is a popular saying that “stress speeds up aging,” which makes sense if we consider the age-old idea that “our age corresponds to that of our arteries.”

The study of the mechanisms of psychosocial risk factors is of major relevance to the creation of the individual and communal preventive strategies that ensure longevity and maintain quality of life.

The following hypotheses were proposed by a group of researchers from Yale University, in New Haven, Conn., in a recent study:

1. Stress is positively associated with accelerated biologic aging, and this relationship will be mediated by stress-related physiologic changes, such as insulin and hypothalamic-pituitary-adrenal (HPA) signaling.

2. Strong factors associated with psychologic resilience will be protective against the negative consequences of stress on aging. (These relationships are predictive, not causative, as this study is cross-sectional.)
 

The study

In their study, the team assessed 444 adults with no chronic medical conditions or psychiatric disorders who were 18-50 years of age and living in the greater New Haven area. Levels of obesity and alcohol consumption in the study cohort were generally in line with those in a community population, so alcohol use and body mass index were used as covariates to account for their impact on the results.

The team also used the latest “epigenetic clock,” known as GrimAge. In recent years, several methods of determining biologic age have been developed that trace chemical changes in the DNA that are natural to the aging process but occur at different moments in different people. The epigenetic clocks have proved to be better predictors of longevity and health than chronologic age, and GrimAge predicts mortality better than other epigenetic clocks.
 

Results

1. Cumulative stress was associated with the acceleration of GrimAge and stress-related physiologic measures of adrenal sensitivity (cortisol/ACTH ratio) and insulin resistance (HOMA). After the researchers controlled for demographic and behavioral factors, HOMA was correlated with GrimAge acceleration.

2. Psychologic resilience factors moderated the association between stress and aging, such that with worse regulation of emotions, there was greater stress-related age acceleration, and with stronger regulation of emotions, any significant effect of stress on GrimAge was prevented. Self-control moderated the relationship between stress and insulin resistance, with high self-control blunting this relationship.

3. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge acceleration, even when demographic, physiologic, and behavioral covariates were accounted for.
 

Implications

These results elegantly demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Even after adjustment for demographic and behavioral factors – such as smoking, body mass index, race, and income – people with high chronic stress scores showed markers of accelerated aging and physiologic changes, such as increased insulin resistance.

However, individuals with high scores on two psychologic resilience measures – emotion regulation and self-control – were more resilient to the effects of stress on aging and insulin resistance.

These results support the popular notion that stress ages (and sickens) us, and suggest a viable way of minimizing the adverse consequences of stress by strengthening the regulation of emotion and self-control.

In other words, the greater the psychologic resilience, the more likely the individual is to live a long and healthy life. “We like to feel as if we have some sovereignty over our destiny and, therefore, it is worth emphasizing to people (and healthcare providers) that it is important to invest in mental health,” said one of the study researchers.

With all the stress we face these days, it is essential to remember that there is no health without mental health. Above all, if we can achieve greater psychologic resilience, we will have a better chance of delaying aging.

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

The increase in cardiovascular disease caused by chronic stress is related to biologic mechanisms (metabolic, hormonal, inflammatory) and to behavioral mechanisms (lifestyle). There is a popular saying that “stress speeds up aging,” which makes sense if we consider the age-old idea that “our age corresponds to that of our arteries.”

The study of the mechanisms of psychosocial risk factors is of major relevance to the creation of the individual and communal preventive strategies that ensure longevity and maintain quality of life.

The following hypotheses were proposed by a group of researchers from Yale University, in New Haven, Conn., in a recent study:

1. Stress is positively associated with accelerated biologic aging, and this relationship will be mediated by stress-related physiologic changes, such as insulin and hypothalamic-pituitary-adrenal (HPA) signaling.

2. Strong factors associated with psychologic resilience will be protective against the negative consequences of stress on aging. (These relationships are predictive, not causative, as this study is cross-sectional.)
 

The study

In their study, the team assessed 444 adults with no chronic medical conditions or psychiatric disorders who were 18-50 years of age and living in the greater New Haven area. Levels of obesity and alcohol consumption in the study cohort were generally in line with those in a community population, so alcohol use and body mass index were used as covariates to account for their impact on the results.

The team also used the latest “epigenetic clock,” known as GrimAge. In recent years, several methods of determining biologic age have been developed that trace chemical changes in the DNA that are natural to the aging process but occur at different moments in different people. The epigenetic clocks have proved to be better predictors of longevity and health than chronologic age, and GrimAge predicts mortality better than other epigenetic clocks.
 

Results

1. Cumulative stress was associated with the acceleration of GrimAge and stress-related physiologic measures of adrenal sensitivity (cortisol/ACTH ratio) and insulin resistance (HOMA). After the researchers controlled for demographic and behavioral factors, HOMA was correlated with GrimAge acceleration.

2. Psychologic resilience factors moderated the association between stress and aging, such that with worse regulation of emotions, there was greater stress-related age acceleration, and with stronger regulation of emotions, any significant effect of stress on GrimAge was prevented. Self-control moderated the relationship between stress and insulin resistance, with high self-control blunting this relationship.

3. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge acceleration, even when demographic, physiologic, and behavioral covariates were accounted for.
 

Implications

These results elegantly demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Even after adjustment for demographic and behavioral factors – such as smoking, body mass index, race, and income – people with high chronic stress scores showed markers of accelerated aging and physiologic changes, such as increased insulin resistance.

However, individuals with high scores on two psychologic resilience measures – emotion regulation and self-control – were more resilient to the effects of stress on aging and insulin resistance.

These results support the popular notion that stress ages (and sickens) us, and suggest a viable way of minimizing the adverse consequences of stress by strengthening the regulation of emotion and self-control.

In other words, the greater the psychologic resilience, the more likely the individual is to live a long and healthy life. “We like to feel as if we have some sovereignty over our destiny and, therefore, it is worth emphasizing to people (and healthcare providers) that it is important to invest in mental health,” said one of the study researchers.

With all the stress we face these days, it is essential to remember that there is no health without mental health. Above all, if we can achieve greater psychologic resilience, we will have a better chance of delaying aging.

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