The Long and Tortured History of Alpha-Synuclein and Parkinson’s Disease

By STEVEN ZECOLA

This study tracks the decades-long journey to harness alpha-synuclein as a treatment for Parkinson’s disease. Steven Zecola an activist who tracks Parkinson’s research and was on THCB last month discussing it, offers three key changes needed to overcome the underlying challenges.

A Quick Start for Alpha-Synuclein R&D

In the mid-1990’s, Parkinson’s patient advocacy groups had become impatient by the absence of any major therapeutic advances in the 25 years since L-dopa had been approved for Parkinson’s disease (PD).

The Director of National Institute of Neurological Disorders and Stroke (NINDS) set up a workshop in August 1995 that featured scientists with expertise in human genetics who might open novel avenues for PD research.

One such scientist, Robert Nussbaum, made the following remarks at the workshop:

“…finding genes responsible for familial Parkinson’s should be helpful for understanding all forms of the disease. Techniques now available should allow researchers to find the genes responsible for familial Parkinson’s disease in a relatively short time.”

Two years later in 1997, Spillantini et al. showed that alpha-synuclein (A-syn) was a major contributor of abnormal clusters of proteins in the brain, not only in patients with synuclein mutations but, more importantly, in patients with sporadic Parkinson’s disease as well.

As Nussbaum had predicted, progress had occurred rapidly. President Clinton in his 1998 State of the Union address, said:

“Think about this, the entire store of human knowledge now doubles every 5 years. In the 1980’s, scientists identified the gene causing cystic fibrosis. It took 9 years. Last year scientists located the gene that causes Parkinson’s disease in only 9 days.”

The NIH is Asked to Take a Leadership Role

Shortly after President Clinton’s call to action, a Senate Committee asked the National Institutes of Health (NIH) to develop a coordinated effort to take advantage of promising opportunities in PD research.

In response, the NIH and the National Institute of Neurological Disease and Stroke (NINDS) held a major planning meeting that included all components of the PD community. The group’s recommendations formed the basis of a five-year PD Research Agenda.

The Research Agenda was codified in a comprehensive 42-page report that covered all aspects of research from better understanding the disease, to creating new research capabilities, to developing new treatments, and to enhancing the research process.

Noting the “remarkable paradigm shift in Parkinson’s disease research” from the discovery of the effects of alpha-synuclein, the report stated that:

“New insights into the role of synucleins in the pathobiology of Parkinson’s disease would accelerate discovery of more effective therapies and provide fresh research opportunities to advance our understanding of Parkinson’s disease”.

NIH invested nearly $1 billion from FY 2000 to FY 2004 to implement the PD Research Agenda.  A-syn research would be funded out of the funds allocated to the categories of Genetics and Epidemiology, with both categories targeted to receive about 15% of the overall spending.

Overall, there were 19 broad categories with spending authorizations, including $32.7 million allocated to Program Management and Direction.

When the PD Research Agenda reached the end of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005.  It brought together an industry-wide consortium to assess the progress over the previous five years and to develop future directions for PD research.

The participants generated more than fifty specific recommendations.  NIH considered these plans and the unmet goals from previous efforts and developed a 3-year Plan.

A major focus of that Plan was to identify and intervene with the causes of PD.

As reiterated in the 2006 Plan:

“…Understanding the role of alpha-synuclein may enable strategies to selectively block the harmful effects associated with this protein as a novel approach to treatment of PD”.

NINDS noted that:

“While PD is not a rare or orphan disease, other more prevalent diseases such as stroke, obesity and diabetes offer considerably larger “markets” for drug therapies than does PD. Thus, pharmaceutical companies have primarily focused on medicinal chemistry and alterations of existing PD or other neurological drugs (e.g., dopamine agonists) rather than investing in new drugs.”

In essence, NINDS recognized the financial conundrum of drug development for A-syn and other PD therapies, but looked to academia to solve the problem through its grant program.

Lacking success from the efforts of the 2006 Plan, NINDS organized another conference in January 2014 called: Parkinson’s Disease 2014: Advancing Research, Improving Lives. The purpose of this initiative was to identify significant challenges and to highlight the highest priorities for advancing research.

Thirty-one recommendations were provided. The summary of the conference included the Top 3 priorities for clinical research, translational research, and basic research. Under basic research, priorities 1 and 2 related to alpha-synuclein.

Given that the work specified for A-syn research was still at an early stage of basic research in 2014, it is clear that a large gap existed between the previous NINDS priorities for A-syn and what was delivered.

Private Interests Finally Move Forward with Alpha-Synuclein

Recognizing the continuing lack of progress and the need for funding, the Michael J. Fox Foundation announced a $10-million “Ken Griffin Alpha-synuclein Imaging Competition” in 2019 to spur development of a critical and elusive imaging research tool for Parkinson’s disease.

In March 2023, MJFF announced that the three initial Alpha-synuclein imaging competition teams — AC Immune, Mass General Brigham and Merck— made tremendous advancements in the development of different alpha-synuclein tracer methods.

MJFF awarded Merck an additional $1.5 million to continue the work and bring its tool to life. The first-in-human clinical trial of its alpha-synuclein PET tracer began in 2023. 

Additionally, after more than two decades of basic research, five private research companies filed applications with the FDA and have initiated early-stage PD trials.

• Neuropore Therapies and UCB are collaborating on an oral small molecule, which aims to prevent the formation of alpha-synuclein clusters.
• Prothena Biosciences, in conjunction with Roche, is testing a humanized anti-alpha-synuclein antibody.
• Biogen is investigating another monoclonal antibody against alpha-synuclein.
• AFFiRiS, an Austrian biotech company, is testing an alpha-synuclein vaccine. AC Immune has recently announced the acquisition of all of AFFiRiS’ assets and underlying intellectual property related to its vaccine candidates targeting a-syn.
• Vaxxinity uses an immunotherapy candidate codenamed UB–312 to target toxic forms of aggregated α-synuclein in the brain to fight Parkinson’s. Its Chairman recently said that: “Our findings suggest UB-312 could transform Parkinson’s care, offering hope for improved outcomes with a disease-modifying treatment”.

As with all R&D projects, there are many remaining challenges in the development of A-syn therapies before reaching the market. Nevertheless, assuming that at least one of the five on-going trials will be successful, we can expect a therapy utilizing A-syn will be approved by the FDA within the next 5-8 years. The net effect is that the overall development window between A-syn’s discovery in 1997 and its application to patients would be approximately 35 years – assuming that the research goes relatively smoothly from here.

Given its performance to date, the view from NIH regarding PD research is:

“… Our failures in bringing treatments to the goal line are due to remaining large gaps in knowledge of the underlying biology that causes and drives the disease. As we fill in these gaps, the chances of success will increase. Some of the gaps we know about, others we only find out about when the science opens another door”.

Why Has This Research Taken So Long?

With the benefit of hindsight, we can point to two areas that accounted for the greatest obstacles to progress – focus and resources.

In reading the PD research plans and reports from 2000, 2006 and 2014, it appears that NINDS threw everything it knew about PD into the hopper. There were hundreds of recommendations, projects and so-called priorities. But a key factor of success in research is having a team of motivated scientists with the necessary skills, knowledge and thinking ability to solve a finely-honed question.

There simply are not enough great minds to track down all of the “to do’s” in the three NINDS PD research plans.  Also, communications and networking are important components of scientific advancement, yet the capability to network with the widespread participation in the small grants program was lacking.

The implication of using the term “focus” is that it comes with the assignment of responsibility and accountability if the priority doesn’t get done. There appears to be little outside oversight of the efficiency and effectiveness of the research dollars that were utilized on A-syn or other PD research projects. If anything, NIH seems content with the output.

Finally, NIH/NINDS knew there was a funding problem in crossing the Valley of Death from basic research to clinical trials, but these organizations fell back to their comfort zone, namely small grants to academicians. This strategy did not produce the necessary results.

A Better Approach

In 1998 and thereafter, alpha-synuclein needed a swat team of top-flight researchers along with a commitment for additional funds as the project progressed out of basic research and through the requisite clinical trials.

To address the shortcomings to date, the Department of Health and Human Services (HHS) should step in and 1) narrow the PD research priority list to the top candidates, 2) require the establishment of a robust communications network for sharing information and 3) relax the FDA regulations for PD to help level the fund-raising playing field.

In particular, HHS/NIH/NINDS must recognize that investments in new healthcare therapies such as A-syn come with very high risks and those risky investment dollars get to choose between healthcare therapies that go through 15+ years of basic research and expensive clinical trials and other opportunities that can be launched in less than a year.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious effects on fund-raising. First, the FDA overhang has dried up interest in angel and venture capital investing in potential therapies such as A-syn. The result has been a Valley of Death between basic research and drug development. Second, even if the initial Valley can be crossed through government grants or non-profit donations, the FDA regulatory scheme puts an enormous burden on companies to raise scores of millions of dollars for lengthy clinical trials that face an uncertain regulatory outcome.

NIH/NINDS have not recognized that even without any direct role in fundraising, the FDA dominates the fund-raising process. For example, approximately 90% of fundraising for R&D is based on claims tied to regulatory milestones. Investors are well-aware of the challenges of the FDA approval process and it curbs investor interest.

Even in basic research, the FDA has had a large influence on scientific progress. For the academic entrepreneur, early development of an effective regulatory plan can be the difference between success and failure. Therefore, regulatory strategy becomes a critical component of the innovation process.

HHS must also recognize that the FDA has safety-first culture and a not-invented-here syndrome when it comes to any proposed changes to its processes.

The solution to these challenges, in part, entails HHS imposing a relaxed regulatory scheme for PD. For example, the FDA should be excludedfrom Phase 1 and Phase 2 trials and from providing any guidance to researchers prior to Phase 3 clinical trials. Such a change will speed development, unleash innovation, and improve early-stage fund-raising.

Second, to improve performance of the research endeavors, NINDS should be tasked to develop and manage a formal, hub-and-spoke, communications network among all stakeholders involved in PD research. ClinicalTrials.gov does not satisfy this requirement because it contains misleading information.

Facilitating regular exchanges of information, data sharing, and collaboration should help to maximize the impact of research efforts and avoid duplication of work. For the investment community, a partition in the hub with investment-related information would help to build a bridge over the Valley of Death and bring more funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications office should generally be housed by MBAs (rather than by Ph.D.’s) who are focused on communicating high value research endeavors with the not-so-subtle intent of fomenting an interest in investments. NIH should consider hiring an investment banking firm to assist in setting up the investor-related component of this information network.

The third recommendation for change is that NIH should convene a very small group of experts working on PD research to identify the three most-likely-to-succeed paths to a cure. It should ensure that those paths have adequate personnel and sufficient research dollars for completion.  Progress should be monitored on a regular basis.

Lastly, I should mention that the Michael J. Fox Foundation has done an excellent job on a number of important issues and should be a major part of any restructure going forward. For example, HHS could outsource the communications hub to MJFF.

The bottom line is that all components of the PD industry, including the FDA, must be on the same page in terms of finding a cure for PD within a reasonable amount of time given existing resources whether it be with alpha synuclein or other therapies. Such has not been the case with A-syn to date, and similarly, we have witnessed that the entire research effort for PD has underperformed – and will continue to underperform – in the absence of corrective action.

The Long and Tortured History of Alpha-Synuclein and Parkinson’s Disease

Preface

This study tracks the decades-long journey to harness alpha-synuclein as a treatment for Parkinson’s disease. The author offers three key changes needed to overcome the underlying challenges.

A Quick Start for Alpha-Synuclein R&D

In the mid-1990’s, Parkinson’s patient advocacy groups had become impatient by the absence of any major therapeutic advances in the 25 years since L-dopa had been approved for Parkinson’s disease (PD).

The Director of National Institute of Neurological Disorders and Stroke (NINDS) set up a workshop in August 1995 that featured scientists with expertise in human genetics who might open novel avenues for PD research.

One such scientist, Robert Nussbaum, made the following remarks at the workshop:

“…finding genes responsible for familial Parkinson’s should be helpful for understanding all forms of the disease. Techniques now available should allow researchers to find the genes responsible for familial Parkinson’s disease in a relatively short time.”

Two years later in 1997, Spillantini et al. showed that alpha-synuclein (A-syn) was a major contributor of abnormal clusters of proteins in the brain, not only in patients with synuclein mutations but, more importantly, in patients with sporadic Parkinson’s disease as well.

As Nussbaum had predicted, progress had occurred rapidly. President Clinton in his 1998 State of the Union address, said:

“Think about this, the entire store of human knowledge now doubles every 5 years. In the 1980’s, scientists identified the gene causing cystic fibrosis. It took 9 years. Last year scientists located the gene that causes Parkinson’s disease in only 9 days.”

The NIH is Asked to Take a Leadership Role

Shortly after President Clinton’s call to action, a Senate Committee asked the National Institutes of Health (NIH) to develop a coordinated effort to take advantage of promising opportunities in PD research.

In response, the NIH and the National Institute of Neurological Disease and Stroke (NINDS) held a major planning meeting that included all components of the PD community. The group’s recommendations formed the basis of a five-year PD Research Agenda.

The Research Agenda was codified in a comprehensive 42-page report that covered all aspects of research from better understanding the disease, to creating new research capabilities, to developing new treatments, and to enhancing the research process.

Noting the “remarkable paradigm shift in Parkinson’s disease research” from the discovery of the effects of alpha-synuclein, the report stated that:

“New insights into the role of synucleins in the pathobiology of Parkinson’s disease would accelerate discovery of more effective therapies and provide fresh research opportunities to advance our understanding of Parkinson’s disease”.

NIH invested nearly $1 billion from FY 2000 to FY 2004 to implement the PD Research Agenda.  A-syn research would be funded out of the funds allocated to the categories of Genetics and Epidemiology, with both categories targeted to receive about 15% of the overall spending.

Overall, there were 19 broad categories with spending authorizations, including $32.7 million allocated to Program Management and Direction.

When the PD Research Agenda reached the end of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005.  It brought together an industry-wide consortium to assess the progress over the previous five years and to develop future directions for PD research.

The participants generated more than fifty specific recommendations.  NIH considered these plans and the unmet goals from previous efforts and developed a 3-year Plan.

A major focus of that Plan was to identify and intervene with the causes of PD. As reiterated in the 2006 Plan:

“…Understanding the role of alpha-synuclein may enable strategies to selectively block the harmful effects associated with this protein as a novel approach to treatment of PD”.

NINDS noted that:

“While PD is not a rare or orphan disease, other more prevalent diseases such as stroke, obesity and diabetes offer considerably larger “markets” for drug therapies than does PD. Thus, pharmaceutical companies have primarily focused on medicinal chemistry and alterations of existing PD or other neurological drugs (e.g., dopamine agonists) rather than investing in new drugs.”

In essence, NINDS recognized the financial conundrum of drug development for A-syn and other PD therapies, but looked to academia to solve the problem through its grant program.

Lacking success from the efforts of the 2006 Plan, NINDS organized another conference in January 2014 called: Parkinson’s Disease 2014: Advancing Research, Improving Lives. The purpose of this initiative was to identify significant challenges and to highlight the highest priorities for advancing research.

Thirty-one recommendations were provided. The summary of the conference included the Top 3 priorities for clinical research, translational research, and basic research. Under basic research, priorities 1 and 2 related to alpha-synuclein.

Given that the work specified for A-syn research was still at an early stage of basic research in 2014, it is clear that a large gap existed between the previous NINDS priorities for A-syn and what was delivered.

Private Interests Finally Move Forward with Alpha-Synuclein

Recognizing the continuing lack of progress and the need for funding, the Michael J. Fox Foundation announced a $10-million “Ken Griffin Alpha-synuclein Imaging Competition” in 2019 to spur development of a critical and elusive imaging research tool for Parkinson’s disease.

In March 2023, MJFF announced that the three initial Alpha-synuclein imaging competition teams — AC Immune, Mass General Brigham and Merck— made tremendous advancements in the development of different alpha-synuclein tracer methods.

MJFF awarded Merck an additional $1.5 million to continue the work and bring its tool to life. The first-in-human clinical trial of its alpha-synuclein PET tracer began in 2023. 

Additionally, after more than two decades of basic research, five private research companies filed applications with the FDA and have initiated early-stage PD trials.

• Neuropore Therapies and UCB are collaborating on an oral small molecule, which aims to prevent the formation of alpha-synuclein clusters.
• Prothena Biosciences, in conjunction with Roche, is testing a humanized anti-alpha-synuclein antibody.
• Biogen is investigating another monoclonal antibody against alpha-synuclein.
• AFFiRiS, an Austrian biotech company, is testing an alpha-synuclein vaccine. AC Immune has recently announced the acquisition of all of AFFiRiS’ assets and underlying intellectual property related to its vaccine candidates targeting a-syn.
• Vaxxinity uses an immunotherapy candidate codenamed UB–312 to target toxic forms of aggregated α-synuclein in the brain to fight Parkinson’s. Its Chairman recently said that: “Our findings suggest UB-312 could transform Parkinson’s care, offering hope for improved outcomes with a disease-modifying treatment”.

As with all R&D projects, there are many remaining challenges in the development of A-syn therapies before reaching the market. Nevertheless, assuming that at least one of the five on-going trials will be successful, we can expect a therapy utilizing A-syn will be approved by the FDA within the next 5-8 years. The net effect is that the overall development window between A-syn’s discovery in 1997 and its application to patients would be approximately 35 years – assuming that the research goes relatively smoothly from here.

Given its performance to date, the view from NIH regarding PD research is:

“… Our failures in bringing treatments to the goal line are due to remaining large gaps in knowledge of the underlying biology that causes and drives the disease. As we fill in these gaps, the chances of success will increase. Some of the gaps we know about, others we only find out about when the science opens another door”.

Why Has This Research Taken So Long?

With the benefit of hindsight, we can point to two areas that accounted for the greatest obstacles to progress – focus and resources.

In reading the PD research plans and reports from 2000, 2006 and 2014, it appears that NINDS threw everything it knew about PD into the hopper. There were hundreds of recommendations, projects and so-called priorities. But a key factor of success in research is having a team of motivated scientists with the necessary skills, knowledge and thinking ability to solve a finely-honed question.

There simply are not enough great minds to track down all of the “to do’s” in the three NINDS PD research plans.  Also, communications and networking are important components of scientific advancement, yet the capability to network with the widespread participation in the small grants program was lacking.

The implication of using the term “focus” is that it comes with the assignment of responsibility and accountability if the priority doesn’t get done. There appears to be little outside oversight of the efficiency and effectiveness of the research dollars that were utilized on A-syn or other PD research projects. If anything, NIH seems content with the output.

Finally, NIH/NINDS knew there was a funding problem in crossing the Valley of Death from basic research to clinical trials, but these organizations fell back to their comfort zone, namely small grants to academicians. This strategy did not produce the necessary results.

A Better Approach

In 1998 and thereafter, alpha-synuclein needed a swat team of top-flight researchers along with a commitment for additional funds as the project progressed out of basic research and through the requisite clinical trials.

To address the shortcomings to date, the Department of Health and Human Services (HHS) should step in and 1) narrow the PD research priority list to the top candidates, 2) require the establishment of a robust communications network for sharing information and 3) relax the FDA regulations for PD to help level the fund-raising playing field.

In particular, HHS/NIH/NINDS must recognize that investments in new healthcare therapies such as A-syn come with very high risks and those risky investment dollars get to choose between healthcare therapies that go through 15+ years of basic research and expensive clinical trials and other opportunities that can be launched in less than a year.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious effects on fund-raising. First, the FDA overhang has dried up interest in angel and venture capital investing in potential therapies such as A-syn. The result has been a Valley of Death between basic research and drug development. Second, even if the initial Valley can be crossed through government grants or non-profit donations, the FDA regulatory scheme puts an enormous burden on companies to raise scores of millions of dollars for lengthy clinical trials that face an uncertain regulatory outcome.

NIH/NINDS have not recognized that even without any direct role in fundraising, the FDA dominates the fund-raising process. For example, approximately 90% of fundraising for R&D is based on claims tied to regulatory milestones. Investors are well-aware of the challenges of the FDA approval process and it curbs investor interest.

Even in basic research, the FDA has had a large influence on scientific progress. For the academic entrepreneur, early development of an effective regulatory plan can be the difference between success and failure. Therefore, regulatory strategy becomes a critical component of the innovation process.

HHS must also recognize that the FDA has safety-first culture and a not-invented-here syndrome when it comes to any proposed changes to its processes.

The solution to these challenges, in part, entails HHS imposing a relaxed regulatory scheme for PD. For example, the FDA should be excludedfrom Phase 1 and Phase 2 trials and from providing any guidance to researchers prior to Phase 3 clinical trials. Such a change will speed development, unleash innovation, and improve early-stage fund-raising.

Second, to improve performance of the research endeavors, NINDS should be tasked to develop and manage a formal, hub-and-spoke, communications network among all stakeholders involved in PD research. ClinicalTrials.gov does not satisfy this requirement because it contains misleading information.

Facilitating regular exchanges of information, data sharing, and collaboration should help to maximize the impact of research efforts and avoid duplication of work. For the investment community, a partition in the hub with investment-related information would help to build a bridge over the Valley of Death and bring more funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications office should generally be housed by MBAs (rather than by Ph.D.’s) who are focused on communicating high value research endeavors with the not-so-subtle intent of fomenting an interest in investments. NIH should consider hiring an investment banking firm to assist in setting up the investor-related component of this information network.

The third recommendation for change is that NIH should convene a very small group of experts working on PD research to identify the three most-likely-to-succeed paths to a cure. It should ensure that those paths have adequate personnel and sufficient research dollars for completion.  Progress should be monitored on a regular basis.

Lastly, I should mention that the Michael J. Fox Foundation has done an excellent job on a number of important issues and should be a major part of any restructure going forward. For example, HHS could outsource the communications hub to MJFF.

The bottom line is that all components of the PD industry, including the FDA, must be on the same page in terms of finding a cure for PD within a reasonable amount of time given existing resources whether it be with alpha synuclein or other therapies. Such has not been the case with A-syn to date, and similarly, we have witnessed that the entire research effort for PD has underperformed – and will continue to underperform – in the absence of corrective action.

Steve Zecola sold his web application and hosting business when he was diagnosed with Parkinson’s disease twenty three years ago.  Since then, he has run a consulting practice, taught in graduate business school, and exercised extensively

from The Health Care Blog https://ift.tt/xU2ADRZ

Ami Parekh, Included Health

Ami Parekh is the to Chief Health Officer of Included Health. It provides navigation services & expert medical opinions (the original Grand Rounds) and virtual care (the old Doctors on Demand) and it then bought a smaller company called Included Health. Ami explains why navigation exists (clue: health plans have been terrible at it) and how it works, and what money it saves on trend (about 2%). They’re also reaching out asking about people’s “Healthy days” and are tracking that metric, and giving people more healthy days–Matthew Holt

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WEBINAR: The How-To of Healthcare Analytics: Implementation to Activation

SPONSORED POST

30% of the world’s data volume is being generated by the healthcare industry. We have more information available to us than any other industry but have yet to realize the potential of this information to create predictive, personalized care. To help us navigate the data complexities currently holding us back, Reuters Events has united informatics experts, from NYC Health + Hospitals, Sutter Health, & UnityPoint Health.

Register here for the March 28 (THAT’s THIS COMING FRIDAY!) 11am ET webinar: ‘The How-To of Healthcare Analytics: Implementation to Activation’.

from The Health Care Blog https://ift.tt/l81v7dz

Gen Z’s Mid-Life Crisis

By KIM BELLARD

These are not happy times in America.

Now, I’m not thinking about the increasing cultural wars, the endless political bickering, the troubles in the Med-East or Ukraine, the looming threat of climate crisis, or the omnipresent campaigning for the November 2024 elections, although all those play a part. I’m talking about quantifiable data, from the latest World Happiness Report. It found that America has slipped out of the top 20 countries for the first time, falling to 23^rd – behind countries like Slovenia and the U.A.E. and barely ahead of Mexico or Uruguay.

Even worse, the fall in U.S. scores is primarily due to those under 30. They ranked 62^nd, versus Americans over 60, who ranked 10^th. A decade ago those were reversed. Americans aged 30-44 were ranked 42nd for their age group globally, while Americans between the ages 45-59 ranked 17^th.

It’s not solely a U.S. phenomenon. Overall, young people are now the least happy, and the report comments: “This is a big change from 2006-10, when the young were happier than those in the midlife groups, and about as happy as those aged 60 and over. For the young, the happiness drop was about three-quarters of a point, and greater for females than males.”

“I have never seen such an extreme change,” John Helliwell, an economist and a co-author of the report, told The New York Times, referring to the drop in happiness among younger people. “This has all happened in the last 10 years, and it’s mainly in the English-language countries. There isn’t this drop in the world as a whole.”

Jan-Emmanuel De Neve, director of the University of Oxford’s Wellbeing Research Center and an editor of the report, said in an interview with The Washington Post that the findings are concerning “because youth well-being and mental health is highly predictive of a whole host of subjective and objective indicators of quality of life as people age and go through the course of life.”

As a result, he emphasized: “in North America, and the U.S. in particular, youth now start lower than the adults in terms of well-being. And that’s very disconcerting, because essentially it means that they’re at the level of their midlife crisis today and obviously begs the question of what’s next for them?”

Gen Z is having a mid-life crisis.

The researchers speculate that social media, political polarization, and economic inequality between generations contribute to the low scores for younger Americans. Jon Clifton, CEO of Gallup, believes: “Young people have more social interactions, but feel more lonely,” and that they aren’t as connected to their job, churches, or other institutions.

“One factor, which we’re all thinking about, is social media,” Dr. Robert Waldinger, the director of the Harvard Study of Adult Development, said in a NYT interview,. “Because there’s been some research that shows that depending on how we use social media, it lowers well-being, it increases rates of depression and anxiety, particularly among young girls and women, teenage girls.”

Others note the impact of the pandemic. Professor De Neve said: “general negative trend for youth well-being in the United States [was] exacerbated during covid, and youth in the U.S. have not recovered from the drop.” Similarly, Lorenzo Norris, an associate professor of psychiatry at George Washington University, who was not part of the World Happiness study, told NYT:

The literature is clear in practice — the effect that this had on socialization, pro-social behavior, if you will, and the ability for people to feel connected and have a community. Many of the things that would have normally taken place for people, particularly high school young adults, did not take place. And that is still occurring.

“It’s a very complex time for youth, with lots of pressures and a lot of demands for their attention,” Professor De Neve diplomatically observed.  It was not true in all countries that younger people were the unhappiest, and Professor De Neve suggests: “I think we can try and dig into why the U.S. is coming down in terms of wellbeing and mental health, but we should also try and learn from what, say, Lithuania is doing well.”

Did you ever expect Lithuania might be a role model for our young people?

Professor Helliwell told CNN that young people are reflecting what is going on around them: “Almost whatever institution you’re in, people in North America seem to be fighting over rights, responsibilities and who should be doing what to improve things and who is to blame for things not going well in the past.”

Amidst all the gloomy findings, the report did say: “The COVID crisis led to a worldwide increase in the proportion of people who have helped others in need. This increase in benevolence has been large for all generations, but especially so for those born since 1980, who are even more likely than earlier generations to help others in need.” They may be less happy, but Gen Z and millennials aren’t less charitable.

So there’s that.

Honestly, if young people aren’t depressed, they’re not paying attention. Social media is dominating their lives, whether Instagram is making them feel depressed or TikTok is driving them to harmful mental health content. They can see the impacts of climate change but not any sign that their elders plan to do anything about it. Their jobs are neither satisfying nor economically viable enough to allow them to build wealth, especially when suffering from crushing student loans. They don’t expect Social Security to help with their retirement, whenever that may be and whatever that might look like. They have no reason to think that the largely geriatric politicians understand them or their needs.

And when it comes to health care, they can see the attacks on women’s health, the inadequate support for mental health, and the gap in technology versus in the rest of their lives.

They have every reason not to be happy. 

The thing about mid-life crises is that they’re supposed to happen, you know, mid-life. Youth is supposed to be a time of optimism and exploration, of wanting to change the world. If current youth is already unhappy, we can’t assume they will grow happier, like those of us over 60 seem to have. This is the America we’re bequeathing them; the question is, are we OK with that?

Maybe a trip to Lithuania isn’t a bad idea after all.

Kim is a former emarketing exec at a major Blues plan, editor of the late & lamented Tincture.io, and now regular THCB contributor

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Disability Activist: Take Great Care When Seeing Bias Toward Disabled Citizens

By RANDY SOUDERS

During the years I served as Chairman of the Board for Jean Kennedy Smith’s Arts and Disability program, Very Special Arts (VSA at the Kennedy Center), I had there opportunity to meet a wide range of remarkable and courageous disabled Americans. Among the lasting friendships is a painter and visual artist, Randy Souders, who was rendered quadriplegic at the age of 17 in a 1972 accident. His concerns of late have been heightened by Trump and MAGA Republicans. I share his communication with his permission here in the hope that tech designers and others will be alert to the fact that great care is required at this point, lest history repeat. — Mike Magee MD

When I was injured at the age of 17 the world was still quite closed for people like me. That was a year before passage of HR 504 of the Rehabilitation Act of 1973. As I recall that law was the first to mandate access to public places that received federal funds. A year later Jean Kennedy Smith founded VSA (Very Special Arts) which has provided important arts opportunities to literally millions of people with disabilities around the globe. It was a very different world back then and artistic achievement was an important way people such as myself could prove their worth to a society that still saw little evidence of it.

It’s unbelievable to think there are serious threats to roll back many of those hard won gains in the name of deregulation and profitability. Disability is costly and people with disabilities are still woefully underemployed. So when a billionaire presidential candidate repeatedly mocks people with disabilities, how long till the “useless/ unworthy” excuses rise again? The old term describing a person with a disability as an “invalid” has another meaning. The adjective use is defined as “Not valid; not true, correct, acceptable or appropriate.”

Few today are aware that the first victims of the Holocaust were the mentally, physically and neurologically disabled people. They were systematically murdered by several Nazi programs specifically targeting them. The Nazi regime was aided in their crimes by perverted “medical doctors and other experts” who were often seen wearing white lab coats in order to visually reinforce their propaganda.

Branded as “useless eaters” and existing as “lives not worthy of life,” people with disabilities were declared an unbearable burden both to German society and the state. As Holocaust historians have documented, “From 1939 to 1941 the Nazis carried out a campaign of euthanasia known as the T4 program (an abbreviation of Tiergartenstrasse 4 which itself was a shortened version of Zentral Dienststelle-T4: Central Office T4) the address from which the program was coordinated.”

These most vulnerable of humans were reportedly the first victims of mass extermination by poison gas and cheaper CO2 from automobile exhaust fumes. But first “a panel of medical experts were required to give their approval for the euthanasia/ ‘mercy-killing’ of each person.”

In the end an estimated quarter million people with disabilities were killed in gas chambers disguised as shower rooms. This model for killing disabled people was later applied to the industrialized murder within Nazi concentration and death camps such as Auschwitz-Birkenau.”

Much has been written on this topic but few seem to know the chronology and diabolical history of how these “beneficial cleansings” of undesirables often start. The Nazi’s enlisted medical doctors to provide them with a veneer of moral justification for their atrocities.

Throughout history, authoritarian political despots have also worked diligently to silence dissent and co-opt religion in order to assist in their mutual quests for total control and dominance of others.

And theocrats are convinced their particular splinter of a schism is the ultimate authority on earth as well as the entire universe. Stoning, beheadings and the hanging of transgressors and non-believers are arbitrarily justified by interpretations of their particular holy book.

There is much to fear when politicians exploit the religious beliefs of medical professionals in order to pass laws denying the rights of others to control their own bodies. This blatant pandering for votes by promising to deliver on religious wedge issues creates a positive feedback loop resulting in politicians being deified by their religious influencers. This is aided by a campaign of rationalization absolving them of their obvious failings. Such a campaign of apologetics by religious leaders is active and widespread in America as I type.

Examples include “God doesn’t call the qualified…He qualifies the called” (Exodus Chapter 4) and “God calls imperfect men to do His perfect will.” Is there even a red line where such “imperfect men” becomes an existential threat? Apparently not. I’m sure most citizens of the Third Reich didn’t think so until everything imploded.

The current Republican candidate for President is on the record as being a believer in the “racehorse theory” – the idea that selective breeding can improve a country’s performance, which American eugenicists and German Nazis used in the last century to buttress their goals of racial purity. On September 18, 2020 he told a mostly white crowd of supporters in Bemidji, Minn. “You have good genes. A lot of it is about the genes, isn’t it? Don’t you believe? The racehorse theory. You think we’re so different? You have good genes in Minnesota.”

This is one of many such statements he has made regarding genetics that has resulted in his personal superiority and that of his family. The New York Times reports “Mr. Trump was talking publicly about his belief that genetics determined a person’s success in life as early as 1988, when he told Oprah Winfrey that a person had ‘to have the right genes’ in order to achieve great fortune.”

These statements combined with those “about undocumented immigrants poisoning the blood” of America should equate to a 100 alarm fire.

Randy Souders is a Professional Artist, an Arts & Disability Advocate and has been Quadriplegic since 1972

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Microplastics, Major Problem

By KIM BELLARD

It’s been almost four years since I first wrote about microplastics; long story short, they’re everywhere. In the ground, in the oceans (even at the very bottom), in the atmosphere. More to the point, they’re in the air you breathe and in the food you eat. They’re in you, and no one thinks that is a good thing. But we’re only starting to understand the harm they cause.

The Washington Post recently reported:

Scientists have found microplastics — or their tinier cousins, nanoplastics — embedded in the human placenta, in blood, in the heart and in the liver and bowels. In one recent study, microplastics were found in every single one of 62 placentas studied; in another, they were found in every artery studied.

One 2019 study estimated “annual microplastics consumption ranges from 39,000 to 52,000 particles depending on age and sex. These estimates increase to 74,000 and 121,000 when inhalation is considered.” A more recent study estimated that a single liter of bottled water may include 370,000 nanoplastic particles. “It’s sobering at the very least, if not very concerning,” Pankaj Pasricha, MD, MBBS, chair of the department of medicine at the Mayo Clinic, who was not involved with the new research, told Health. 

But we still don’t have a good sense of exactly what harm they cause. “I hate to say it, but we’re still at the beginning,” Phoebe Stapleton,a professor of pharmacology and toxicology at Rutgers University, told WaPo.

A new study sheds some light – and it is not good. It found that people with microplastics in their heart were at higher risk of heart attack, stroke, and death. The researchers looked at the carotid plaque from patients who were having it removed and found 60% of them had microplastics and/or nanoplastics. They followed patients for three years to determine the impacts on patients’ health and found higher morbidity/mortality.

“We are reasonably sure that the problem comes from a frailty of the plaque itself,” says Giuseppe Paolisso, a professor of internal medicine and geriatrics at the University of Campania Luigi Vanvitelli in Naples, Italy, and one of the study’s authors. “We suppose due to the fact that the plaques with microplastics and nanoplastics have a higher degree of inflammation, this kind of plaque can be broken more easily; and once they are broken, they can go into the blood streams.”

“This is pivotal,” Philip Landrigan, an epidemiologist and professor of biology at Boston College, who was not involved in the study, wrote in an accompanying opinion piece. “For so long, people have been saying these things are in our bodies, but we don’t know what they do.” He went on to add: “If they can get into the heart, why not into the brain, the nervous system? What about the impacts on dementia or other chronic neurological diseases?”

Scary stuff.

If that isn’t scary enough, an article last year in PNAS found: “Indeed, it turns out that a host of potentially infectious disease agents can live on microplastics, including parasites, bacteria, fungi, and viruses.” Even worse: “Beyond their potential for direct delivery of infectious agents, there’s also growing evidence that microplastics can alter the conditions for disease transmission. That could mean exacerbating existing threats by fostering resistant pathogens and modifying immune responses to leave hosts more susceptible.”

However much you’re worrying about microplastics, it’s not enough.

Marine ecologist Randi Rotjan of Boston University is blunt: “Cleaning up microplastics is not a viable solution. They are ubiquitous in our environment. And macroplastics are going to break down to microplastics for millennia. What we can do is try to understand the risk” Francesco Prattichizzo, one of the researchers in the new study, agrees, warning: “Plastic production is steadily increasing and is projected to continue increasing, so we must know how [and] if any of these molecules affect our health.” 

That’s easier said than done. As WaPo notes:

Part of the problem is that there is no one type of microplastic. The tiny plastic particles that slough off things like water bottles and takeout containers can be made of polyethylene, or polypropylene, or the mouth-twisting polyethylene terephthalate. They might take the form of tiny spheres, fragments or fibers.

Sherri Mason,director of sustainability at Penn State Behrend in Erie, Pa. told WaPo that, when it comes to assigning cause and effect: “Cigarettes are definitely easier than microplastics.” In the good news/bad news category, she added: “Probably over the next decade we’ll get a lot of good data. But we’ll never have all of the answers.”

Unfortunately, the amount of microplastics just keeps growing. Professor Stapleton told WaPo: “It’s almost like a generational accumulation. Forty years ago we didn’t have as much plastic in the environment as we do now. What will that look like 20 years from now?”

We can’t even imagine.

“The first step is to recognize that the low cost and convenience of plastics are deceptive and that, in fact, they mask great harms,” Professor Landrigan pointed out. Similarly, Lukas Kenner, a professor of pathology at the Medical University of Vienna, suggested to WaPo: “I’m a doctor, and we have our principle: ‘Don’t harm anybody. If you just spill plastics everywhere, and you have no idea what you’re doing, you’re going exactly against this principle.”

Microplastics are similar to cigarettes in that the health risks of the latter were pointed out years before any action was taken, and even then many people still smoke. It’s even more similar to climate change, in that we’ve had plenty of warning, and the impacts are starting to be clear, but the dangers accumulate over such a long period of time that no one feels compelled to act.

It’s also like climate change in that the fossil fuel companies bear a significant amount of the blame. Dr. Londrigan charges: “They realize that their market for burning fossil fuels is going down, yet they’re sitting on vast stocks of oil and gas and they’ve got to do something with it. So they’re transitioning it to plastic.” 

Perhaps biology will save us, with bacteria eating the microplastics. Or maybe it be robotics,  with nanobots doing the work. But we’ve been talking about engineering our way out of climate change for thirty plus years, and yet here we are, in climate crisis. I’m not holding my breath (although I’d ingest fewer microplastics that way) about fixing microplastics anytime soon.

We’ve all got a long list of things to worry about, but if microplastics isn’t already on yours, you should add it.

Kim is a former emarketing exec at a major Blues plan, editor of the late & lamented Tincture.io, and now regular THCB contributor

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The Latest AI Craze: Ambient Scribing

By MATTHEW HOLT

Okay, I can’t do it any longer. As much as I tried to resist, it is time to write about ambient scribing. But I’m going to do it in a slightly odd way

If you have met me, you know that I have a strange English-American accent, and I speak in a garbled manner. Yet I’m using the inbuilt voice recognition that Google supplies to write this story now.

Side note: I dictated this whole thing on my phone while watching my kids water polo game, which has a fair amount of background noise. And I think you’ll be modestly amused about how terrible the original transcript was. But then I put that entire mess of a text  into ChatGPT and told it to fix the mistakes. it did an incredible job and the output required surprisingly little editing.

Now, it’s not perfect, but it’s a lot better than it used to be, and that is due to a couple of things. One is the vast improvement in acoustic recording, and the second is the combination of Natural Language Processing and artificial intelligence.

Which brings us to ambient listening now. It’s very common in all the applications we use in business, like Zoom and others like transcript creation from videos on Youtube. Of course, we have had something similar in the medical business for many years, particularly in terms of radiology and voice recognition. It has only been in the last few years that transcribing the toughest job of all–the clinical encounter–has gotten easier.

The problem is that doctors and other professionals are forced to write up the notes and history of all that has happened with their patients. The introduction of electronic medical records made this a major pain point. Doctors used to take notes mostly in shorthand, leaving the abstraction of these notes for coding and billing purposes to be done by some poor sap in the basement of the hospital.

Alternatively in the past, doctors used to dictate and then send tapes or voice files off to parts unknown, but then would have to get those notes back and put them into the record. Since the 2010s, when most American health care moved towards using  electronic records, most clinicians have had to type their notes. And this was a big problem for many of them. It has led to a lot of grumpy doctors not only typing in the exam room and ignoring their patients, but also having to type up their notes later in the day. And of course, that’s a major contributor to burnout.

To some extent, the issue of having to type has been mitigated by medical scribes–actual human beings wandering around behind doctors pushing a laptop on wheels and typing up everything that was said by doctors and their patients. And there have been other experiments. Augmedix started off using Google Glass, allowing scribes in remote locations like Bangladesh to listen and type directly into the EMR.

But the real breakthrough has been in the last few years. Companies like Suki, Abridge, and the late Robin started to promise doctors that they could capture the ambient conversation and turn it into proper SOAP notes. The biggest splash was made by the biggest dictation company, Nuance, which in the middle of this transformation got bought by one of the tech titans, Microsoft. Six years ago, they had a demonstration at HIMSS showing that ambient scribing technology was viable. I attended it, and I’m pretty sure that it was faked. Five years ago, I also used Abridge’s tool to try to capture a conversation I had with my doctor — at that time, they were offering a consumer-facing tool – and it was pretty dreadful.

Fast forward to today, and there are a bunch of companies with what seem to be really very good products.

Nuance’s DAX is in relatively wide use. Abridge has refocused itself on clinicians and has excellent reviews, (you can see my interview and demo with CEO Shiv Rao here) and Nabla has just published a really compelling review from its first big rollout with Kaiser Permanente, Northern California in the NEJM no less. (FD I am an advisor to Nabla although not involved in its KP work). And others like DeepScribe, Ambience, Augmedix and even newcomers Innovaccer and Sudoh.ai seem to be good options.

If you take a look at the results of the NEJM published study that was done in Northern California using Nabla’s tool, you’ll see that clinicians have adopted that very quickly, with high marks for both its accuracy, and the ability to deliver a SOAP note and patient summary very quickly. And it has returned a lot of time to the clinician’s day.

The big gorilla on the EMR side, Epic, has integrated to some extent with Nuance and Abridge, but many of the other companies are both working to integrate with Epic and are inside other EMR competitors – for instance Nextgen is private-labeling Nabla. At the moment, for basically everyone integration really just means getting the note summary into the notes section of the EMR.

But there is definitely more to come. For many years, NLP companies like Apixio, Talix, Health Equity and more (all seemingly bought by Edifecs) have been working on EMR notes to aid coders in billing, and it’s an easy leap to assume that will happen more and more with ambient scribing. And of course, the same thing is going to be true for clinical decision support and pretty soon integration with orders and workflow. In other words, when a doctor says to a patient, “We are going to start you on this new drug,” not only will it appear in the SOAP note, but the prescription or the lab order will just be magically done.

But is it reasonable to suppose that we are just paving the cowpath here? Ambient scribing is just making the physician office visit data more accessible. It’s not making it go away, which is what we should be trying to do. But I can’t blame the ambient scribing companies for that. And as I have (at length!) pointed out, we are still stuck in a fee-for-transaction system in which the health services operators in this country make money by doing stuff, writing it up, and charging for it. That is not going away anytime soon.

But given that’s where we are, I think we can still see how the ambient scribing battle will play out. 

Nuance’s DAX has the advantage of a huge client base, but frankly, Nuance has not been an innovative company. One former employee told me that they have never invented anything. And indeed, the DAX system was massively enhanced by the tech Nuance acquired when purchasing a company called Saykara in 2021, some years after that unconvincing demo back at HIMSS 2018.

So innovation matters, but the other issue is the cost of ambient scribing, which in some cases is nearing the cost of a real scribe. Nuance’s DAX, Suki, and even new entries like Sunoh seem to be around the $400 to $600 a month per physician level. Sunoh is offered by eClinicalworks and has some co-ownership with that EMR vendor. What’s amazing is that at the price quoted at HIMSS of $1.25 per encounter the ambient scribing tool would cost a busy family practice doc seeing 25 patients a day as much as the EMR subscription, around $600 a month.

Abridge has been quoted at roughly $250 a month, and Nabla seems to be considerably less expensive, around $120. But realistically, the whole market will have to compress to about that level because the switching costs are going to be very trivial. Right now, with most of them requiring a paste and copy into the EMR, it’s almost zero.

Which then leads to some more technical issues. How good will these systems become? (Noting that they are already very good, according to reviews on the Elion site). And what will happen to the way they store data. Most of them are currently moving the data back to their cloud for processing. But this may not be acceptable for health systems that like to keep data within their firewalls. For what it’s worth, Nabla, being from the EU and very conscious of GDPR, has been pushing the fact that its process stays on the physician’s local machine – although I’m not sure how much difference that makes in the market.

The other technical issue is the reliance on the large LLMs like OpenAI, Google, etc., compared to companies that are using their own LLM. Again, this may just remain a technical issue that no one cares much about. On the other hand, accuracy and lack of anonymization will continue to be a big issue if more generic LLMs are used. Now the fascination with the initial ChatGPT type LLM is wearing off, there’s going to be a lot more concern about how AI is using health care as a whole–particularly its tendency to “hallucinate” or get stuff wrong. That will obviously impact ambient scribing, even if mistakes may not be as serious as perhaps patient diagnosis or treatment suggestions.

So it’s too early to know exactly how this plays out, but it’s not much too early. In some ways, it’s very refreshing to see the speed at which this new technology is being adopted. As it is, the number of American doctors using ambient scribing is probably below 10%. But it’s highly likely that number goes up to 70%+ in very short order.

The problem that it is fixing for doctors is one that has been around for thousands of years and also one that has been particularly acute for the last twenty years or so. It’s almost like we’re in a period where the doctor suffering with having to  type up their notes in Epic–written up so eloquently by Bob Wachter in his book, “The Digital Doctor,”– is going to be a historical artifact that lasted for fifteen years or so. Maybe it’s going to be talked about nostalgically, like those of us who reminisce about having to get online with dial-up modems.

I’m pretty sure that the winners will be apparent in a couple of years, and that somebody, possibly Microsoft, or possibly the investors in big rounds at 2021 style valuations for Abridge or Ambience, may be regretting what happened in a couple of years. Alternatively, one of them may be a monopoly winner that soon starts printing money.

I suspect, though, that ambient scribing will essentially become a close-to-free product for all different types of business and that clinical care will not be much of an exception. That suggests that a company like Anthropic or OpenAI with close connections to the tech titans, Amazon and Microsoft, will end up becoming more of a feature for the tech giants. My guess is that they will be delivering that product for free probably also into much of clinical care, including ambient scribing. Of course, Epic may decide that it wants to do the same thing, which may leave its partners including Microsoft in the lurch.

It’s reasonable to expect that all aspects of life, including education, general business, consumer activity, and more, will find note-taking, summaries, and decision support a natural part of the next round of computing. For instance, anyone who has had a conversation with their contractor when renovating a house would probably love to have the notes, to-dos and agreements automatically recorded. It’ll be a whole new way of “keeping people honest”. Same thing for health care, I suspect.

But to be fair, we are not there yet. My dictation tool took this whole thing while watching a water polo game on Sunday. And I think you’ll be modestly amused about how terrible the original transcript was. But then I put that entire mess of a text  into ChatGPT and told it to fix the mistakes. it did an incredible job and the output required surprisingly little editing.

AI is getting very smart at working on incomplete information, and health care (as well as clinicians and patients) will benefit.

Matthew Holt is the publisher of The Health Care Blog and one upon a time ran the Health 2.0 Conference

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What could we do if GLP-1 weight loss drugs were free? Would our obesity epidemic be solved for good?

By CECI CONNOLY and SAMI INKINEN

Unless you have been living under a rock, you likely have heard the names Ozempic, Wegovy or Mounjaro. Or perhaps been humming the jingle. Rarely has a class of drugs (in this case, GLP-1s) achieved such widespread attention in popular culture and the media, which has people clamoring for them in every doctor’s office in the nation.

And for good reason. What we know is that the efficacy and safety profile of these medications is substantially better than any weight loss drug in the past, while our obesity epidemic has only ballooned. As organizations committed to sound science and holistic patient care, we are encouraged by the benefits of these new therapies for diabetes. The clinical evidence shows that GLP-1s are highly effective for controlling blood glucose levels among patients living with Type 2 diabetes and certain co-morbidities. GLP-1s may even improve heart health for high-risk patients.

To date, the biggest worry with these weight loss therapeutics has been the hefty price tag, ranging from $800 to $1700 per person, per month. Conservatively, these weekly injections could cost the nation more than $100 billion dollars annually. Already, state Medicaid budgets are sagging under the financial burden. In North Carolina, for example, officials dropped coverage of GLP-1s for obesity, noting that two drugs alone would cost about $1 billion over 6 years, and that’s with a nice discount.

As troubling as the cost is, what we don’t know is what should really worry us. Amidst the excitement over patients rapidly shedding up to 15% of their body mass, fundamental questions remain about who should be taking GLP-1s, at what dosages and what the long-term health and economic consequences will be for patients and society. Ultimately, the price paid to people’s long-term health may be more concerning than the price paid out-of-pocket.

With the recent release of the SELECT trial data highlighting limitations of existing published studies of GLP-1s, it is now even clearer that the public isn’t getting the full picture.

Calls for widespread adoption are clearly premature. The stories touting GLP-1s clinical weight loss benefits often leave out that the studies are limited and based on a homogenous population, likely to further exacerbate existing inequities. For example, only 27.7% of the patients in the SELECT trial were women, compared with other trials in which they represented 74.1%. This smaller patient population rightfully leads to questions about the effectiveness in women and others not included in the trial. By only seeing part of the puzzle, we’re left to worry about the missing pieces such as what the GLP-1 cardiovascular benefit for people who are obese but without a prior heart condition could be.

Even more troubling are the unknown long-term effects. In people with diabetes, studies have found an increased risk of pancreatitis for some patients. For individuals taking GLP-1s for weight loss, usually at much higher dosages than for treating diabetes, we simply don’t know what the long-term implications, both positive and negative, will be because few longitudinal studies exist. Too many patients are prescribed GLP-1s for a lifetime without thought as to what comes next.

Pharmaceutical manufacturers will argue that anyone concerned about their weight would benefit from GLP-1s. However, based on the published evidence on weight re-gain, GLP-1s likely require a lifetime commitment to maintain weight loss and associated benefits. Many patients must contend with well-documented side effects such as nausea, diarrhea or the significant loss of lean body mass (ie. muscle) and bone density. Again, those are lifetime side effects. and some patients simply tire of giving themselves a weekly injection.

In a July 2023 study of real-world claims data from 16 million commercially insured members, Prime Therapeutics and MagellanRx researchers found that almost 70% of patients stopped GLP-1 treatment less than one year after starting. When you combine that data with the findings from a recent Journal of the American Medical Association study (in which patients regained two-thirds of the lost weight after switching to a placebo) you have the makings of a dangerous rollercoaster ride. We must consider whether the rider is prepared for the physical and mental implications of a weight-loss rollercoaster. The short-term benefit isn’t worth the long-term costs.

What we do know is that GLP-1s work best in combination with lifestyle modification and that clinicians need flexibility to determine the right combination for each individual. We can scale evidence-based nutrition treatments with proper support to deliver long-lasting results. Health plans, clinical teams, patients and – more broadly – society must deploy a full range of comprehensive population health tools to get the nation back to a healthy weight.

With so many unknowns about GLP-1s, a cautious approach is needed with continued focus on the evidence-based strategies that tackle root causes of obesity, including nutrition and socioeconomic factors. The work of population health is not as sexy as the slender models posting videos on Tik Tok, but it is the proven approach for many struggling with weight issues.

Clinicians and policy makers must resist the seeming quick fix of GLP-1s. Greater attention and resources must be devoted to treating the whole person and patiently evaluating the right and wrong candidates for GLP-1s.

A healthy lifestyle is likely the only sustainable, affordable and safe way to address our obesity epidemic and to deliver long-lasting results. By focusing on the drivers of obesity, we’re focusing on what we do know rather than being surprised by the unknowns.

Even if GLP-1s were free, they are not the magic pill to solve our obesity epidemic.

Ceci Connolly is the president and chief executive officer of the Alliance of Community Health Plans. Sami Inkinen is co-founder & CEO of Virta Health, a telemedicine and behavior treatment company focused on solving our T2 diabetes and obesity epidemic.

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Wait Till Health Care Tries Dynamic Pricing

By KIM BELLARD

Nice try, Wendy’s. During an earnings call last month, President and CEO Kirk Tanner outlined the company’s plan to try a new form of pricing: “Beginning as early as 2025, we will begin testing more enhanced features like dynamic pricing and day-part offerings along with AI-enabled menu changes and suggestive selling.” 

None of the analysts on the call questioned the statement, but the backlash from the public was immediate — and quite negative. As Reuters described it: “the burger chain was scorched on social media sites.”

Less than two weeks later Wendy’s backtracked – err, “clarified” – the statement. “This was misconstrued in some media reports as an intent to raise prices when demand is highest at our restaurants,” a company blog post explained. “We have no plans to do that and would not raise prices when our customers are visiting us most.”

The company was even firmer in an email to CNN: “Wendy’s will not implement surge pricing, which is the practice of raising prices when demand is highest. This was not a change in plans. It was never our plan to raise prices when customers are visiting us the most.”

OK, then. Apology accepted.

At this point it is worth explaining a distinction between dynamic pricing and the more familiar surge pricing. As Omar H. Fares writes in The Conversation: “Although surge pricing and dynamic pricing are often used interchangeably, they have slightly different definitions. Dynamic pricing refers to any pricing model that allows prices to fluctuate, while surge pricing refers to prices that are adjusted upward.”

Uber and other ride sharing services are well known for their surge pricing, whereas airlines’ pricing is more dynamic, figuring out prices by seat by when purchased by who is purchasing, among other factors.

Wendy’s wouldn’t be the first company to use dynamic pricing and it won’t be the last. Drew Patterson, co-founder of restaurant dynamic pricing provider Juicer, told The Wall Street Journal that dozens of restaurant brands used his company’s software. The company’s website doesn’t publicize those brands, of course. Still, he emphasized: “You need to make it clear that prices go up and they go down.” 

Dave & Busters is public about its pricing strategy. “We’re going to have a dynamic pricing model, so we have the right price at the right time to match the peak demand,” Dave & Buster’s CEO Chris Morris said during an investor presentation last year.  On the other hand, Dine Brands (Applebee’s/IHOP) Chief Executive John Peyton said. “We don’t think it’s an appropriate tool to use for our guests at this time.”

The potential revenue benefits are obvious, but there are risks, as Wendy’s quickly found out. Mr. Fares says: “One of the biggest risks associated with dynamic pricing is the potential negative impact on customer perception and trust. If customers feel that prices are unfair or unpredictable, they may lose trust in the brand.”

What Wendy’s tried to announce is not ground-breaking. Catherine Rampell pointed this out in a Washington Post op-ed:

In other words, things will be cheaper when demand is low to draw in more customers when there’s otherwise idle capacity. Lots of restaurants do this, including other burger chains. It’s usually called “happy hour.” Or the “early-bird special.” Non-restaurants do it, too. Think the weekday matinee deals at your local movie theater or cheaper airfares on low-traffic travel days.

Indeed, The Wall Street Journal reported: “An estimated 61% of adults support variable pricing where a restaurant lowers or raises prices based on business, with younger consumers more in favor of the approach than older ones, according to an online survey of 1,000 people by the National Restaurant Association trade group.” 

I wonder what the support would have been if the question had been about healthcare instead of restaurants. 

Like it or not, some form of dynamic pricing will come to healthcare. Want a private room instead of semi-private? Surge pricing. Willing to see a nurse practitioner instead of a physician? Dynamic pricing. Want to buy prescription drugs in the U.S. instead of in Europe? Surge pricing. Want a doctor’s appointment Monday morning instead of Tuesday? Surge pricing. Need an ER visit Saturday night instead of Sunday afternoon? Surge pricing.

Some of these healthcare has been doing for years. Others, and even more insidious ones, are coming.

We have to know that the private equity firms that have invested in healthcare have to be interested. Yashaswini Singh and Christopher Whaley wrote in The Hill: “Over the last decade, private equity firms have spent nearly $1 trillion on close to 8,000 health care deals, snapping up practices that provide care from cradle to grave: fertility clinics, neonatal care, primary care, cardiology, hospices, and everything in between.”

They go on to warn: “Although research remains mixed on how it affects quality of care, there is clear evidence that private equity ownership increases prices. These firms aim to secure high returns on their investments — upwards of 20 percent in just three to five years — which can conflict with the goal of delivering affordable, accessible, high-value health care.”

Dynamic pricing has to look good to these firms. Surge pricing would look even better.              

But one doesn’t have to be owned by private equity to be rapacious in healthcare. Everyone is looking for margins, everyone is looking to maximize revenue, and consumers – A.K.A. patients – grumble about prices but pay them anyway, especially if their health insurance company is paying most of the cost. In today’s healthcare world, if you are a CEO or CFO and you’re not considering dynamic pricing, it’s close to malfeasance.

To me, the scariest part of Wendy’s plan wasn’t the dynamic pricing but the “AI-enabled menu changes and suggestive selling.” Upcoding has been a problem in healthcare for as long as there has been coding, but when we get an AI-enabled menu of treatment options and suggested selling (aka treatments), well, we haven’t seen anything yet.

Maximize away.  

Look, I’m not going to Wendy’s even if they pay me, but I take my wife out on Valentine’s Day even though I know the restaurant has surged the hell out of its prices. Some things you pay for, and, when it comes to healthcare pricing, every day is Valentine’s Day.

I’m resigned to the fact that dynamic pricing has a toehold in healthcare already, but I’m holding out hope that we can use AI to help us make those recommendations and set those prices to deliver the most effective, efficient care, not just to maximize profits.

Wait Till Health Care Tries Dynamic Pricing

Nice try, Wendy’s. During an earnings call last month, President and CEO Kirk Tanner outlined the company’s plan to try a new form of pricing: “Beginning as early as 2025, we will begin testing more enhanced features like dynamic pricing and day-part offerings along with AI-enabled menu changes and suggestive selling.” 

None of the analysts on the call questioned the statement, but the backlash from the public was immediate — and quite negative. As Reuters described it: “the burger chain was scorched on social media sites.”

Less than two weeks later Wendy’s backtracked – err, “clarified” – the statement. “This was misconstrued in some media reports as an intent to raise prices when demand is highest at our restaurants,” a company blog post explained. “We have no plans to do that and would not raise prices when our customers are visiting us most.”

The company was even firmer in an email to CNN: “Wendy’s will not implement surge pricing, which is the practice of raising prices when demand is highest. This was not a change in plans. It was never our plan to raise prices when customers are visiting us the most.”

OK, then. Apology accepted.

At this point it is worth explaining a distinction between dynamic pricing and the more familiar surge pricing. As Omar H. Fares writes in The Conversation: “Although surge pricing and dynamic pricing are often used interchangeably, they have slightly different definitions. Dynamic pricing refers to any pricing model that allows prices to fluctuate, while surge pricing refers to prices that are adjusted upward.”

Uber and other ride sharing services are well known for their surge pricing, whereas airlines’ pricing is more dynamic, figuring out prices by seat by when purchased by who is purchasing, among other factors.

Wendy’s wouldn’t be the first company to use dynamic pricing and it won’t be the last. Drew Patterson, co-founder of restaurant dynamic pricing provider Juicer, told The Wall Street Journal that dozens of restaurant brands used his company’s software. The company’s website doesn’t publicize those brands, of course. Still, he emphasized: “You need to make it clear that prices go up and they go down.” 

Dave & Busters is public about its pricing strategy. “We’re going to have a dynamic pricing model, so we have the right price at the right time to match the peak demand,” Dave & Buster’s CEO Chris Morris said during an investor presentation last year.  On the other hand, Dine Brands (Applebee’s/IHOP) Chief Executive John Peyton said. “We don’t think it’s an appropriate tool to use for our guests at this time.”

The potential revenue benefits are obvious, but there are risks, as Wendy’s quickly found out. Mr. Fares says: “One of the biggest risks associated with dynamic pricing is the potential negative impact on customer perception and trust. If customers feel that prices are unfair or unpredictable, they may lose trust in the brand.”

What Wendy’s tried to announce is not ground-breaking. Catherine Rampell pointed this out in a Washington Post op-ed:

In other words, things will be cheaper when demand is low to draw in more customers when there’s otherwise idle capacity. Lots of restaurants do this, including other burger chains. It’s usually called “happy hour.” Or the “early-bird special.” Non-restaurants do it, too. Think the weekday matinee deals at your local movie theater or cheaper airfares on low-traffic travel days.

Indeed, The Wall Street Journal reported: “An estimated 61% of adults support variable pricing where a restaurant lowers or raises prices based on business, with younger consumers more in favor of the approach than older ones, according to an online survey of 1,000 people by the National Restaurant Association trade group.” 

I wonder what the support would have been if the question had been about healthcare instead of restaurants. 

Like it or not, some form of dynamic pricing will come to healthcare. Want a private room instead of semi-private? Surge pricing. Willing to see a nurse practitioner instead of a physician? Dynamic pricing. Want to buy prescription drugs in the U.S. instead of in Europe? Surge pricing. Want a doctor’s appointment Monday morning instead of Tuesday? Surge pricing. Need an ER visit Saturday night instead of Sunday afternoon? Surge pricing.

Some of these healthcare has been doing for years. Others, and even more insidious ones, are coming.

We have to know that the private equity firms that have invested in healthcare have to be interested. Yashaswini Singh and Christopher Whaley wrote in The Hill: “Over the last decade, private equity firms have spent nearly $1 trillion on close to 8,000 health care deals, snapping up practices that provide care from cradle to grave: fertility clinics, neonatal care, primary care, cardiology, hospices, and everything in between.”

They go on to warn: “Although research remains mixed on how it affects quality of care, there is clear evidence that private equity ownership increases prices. These firms aim to secure high returns on their investments — upwards of 20 percent in just three to five years — which can conflict with the goal of delivering affordable, accessible, high-value health care.”

Dynamic pricing has to look good to these firms. Surge pricing would look even better.              

But one doesn’t have to be owned by private equity to be rapacious in healthcare. Everyone is looking for margins, everyone is looking to maximize revenue, and consumers – A.K.A. patients – grumble about prices but pay them anyway, especially if their health insurance company is paying most of the cost. In today’s healthcare world, if you are a CEO or CFO and you’re not considering dynamic pricing, it’s close to malfeasance.

To me, the scariest part of Wendy’s plan wasn’t the dynamic pricing but the “AI-enabled menu changes and suggestive selling.” Upcoding has been a problem in healthcare for as long as there has been coding, but when we get an AI-enabled menu of treatment options and suggested selling (aka treatments), well, we haven’t seen anything yet.

Maximize away.  

Look, I’m not going to Wendy’s even if they pay me, but I take my wife out on Valentine’s Day even though I know the restaurant has surged the hell out of its prices. Some things you pay for, and, when it comes to healthcare pricing, every day is Valentine’s Day.

I’m resigned to the fact that dynamic pricing has a toehold in healthcare already, but I’m holding out hope that we can use AI to help us make those recommendations and set those prices to deliver the most effective, efficient care, not just to maximize profits.

Kim is a former emarketing exec at a major Blues plan, editor of the late & lamented Tincture.io, and now regular THCB contributor

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Roy Schoenberg, CEO, AmWell

AmWell is a now veteran telehealth platform. It used its IPO money to re-architect its entire platform and add companies like Conversa AI chat service and mental health service Silvercloud, as well as integrating deeply with EMRs & more. That change hit its earnings….so can they recover? Roy Schoenberg, CEO, tells you why this is good for AmWell and what happens next.–-Matthew Holt

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