Researchers have developed a functional precision medicine approach that targets cancer by combining genetic testing with a new way to test individual drugs on tumor samples. The results of the clinical study were published today in Nature Medicine.
This combined approach, developed by Florida International University cancer researcher Diana Azzam, was used successfully for the first time to guide treatment of relapsed pediatric cancer patients in collaboration with First Ascent Biomedical and Dr. Maggie Fader at the Helen & Jacob Shaham Cancer & Blood Disorders Institute at Nicklaus Children’s Hospital in Miami.
It resulted in 83% of the children showing improvement, including Logan Jenner, 8, whose relapsed leukemia was successfully treated through Azzam’s new guided approach.
“The results are exciting because cancer that comes back is much harder to treat. Seeing improvement in 83 percent of patients is incredibly promising,” said Azzam, the assistant professor of environmental health sciences at the FIU Robert Stempel College of Public Health and Social Work and Society for Functional Precision Medicine board member who led the study. “This could be the way we turn cancer into a manageable disease.”
Approximately 2 million people are diagnosed with cancer in the United States each year, according to the National Cancer Institute. Nearly 30 percent (more than 600,000) are expected to die.
Breakthrough approach
The approach Azzam is pioneering has a few advantages over existing precision medicine processes, including faster results and more treatment options for doctors.
Azzam’s approach involves taking a sample of blood or tumor and enriching and processing the cancer cells in the lab in a way that closely resembles how they would normally grow in the body. Then the cancer is exposed to more than 120 FDA-approved drugs, including both cancer and non-cancer drugs. These drugs also may be tested in various combinations recommended by the clinical team. The best cancer destroyers emerge. The entire process takes about a week.
“The Azzam lab approach gets rid of the guesswork and delivers a list of the most effective drugs that the oncologist can work with,” said Stempel College Dean Tomás R. Guilarte, who is also one of the authors of the Nature Medicine article. “It’s accelerating our understanding of which cancer treatments work best for patients and their specific needs.”
Logan’s story
At the age of 3, Logan Jenner was diagnosed with acute myeloid leukemia. He received chemotherapy and bone marrow transplant. The cancer came back 14 months later.
Fader, Logan’s oncologist and co-investigator on the study, enrolled him in the clinical trial.
“What’s unique is that it’s easy and fast to get results about what would be the most optimal regimen, so we can act quickly,” said Fader who is employed by KIDZ Medical Services and cares for patients at Nicklaus Children’s Hospital. “That’s important because we’re talking about a child with cancer getting worse day by day.”
Azzam’s test results revealed which combination of drugs might work well for Logan. Equally valuable, the results indicated that Idarubicin, known to cause cardiac toxicity at very high doses, could be withheld without impacting the efficacy of the treatment. Thirty-three days after starting treatment guided by Azzam’s results, Logan reached remission -; compared to the 150 days the previous time. Two years later, Logan remains cancer-free.
The trial returned recommendations for the 19 patients that participated. Six received treatment guided by Azzam’s results and five, including Logan, showed improved survival outcomes over the course of the study.
What’s next
This study is particularly relevant because the majority of the participants were members of ethnic minority populations, who can have different responses to FDA-approved drugs. Azzam also spearheads a National Institute on Minority Health and Health Disparities-funded research project as part of FIU’s Research Center in Minority Institutions to reduce health disparities in childhood cancer patients.
Larger personalized cancer treatment clinical trials for children and adults are ongoing.
With a $2 million appropriation from the State of Florida, Azzam’s lab is set to become the first federally certified large-scale lab dedicated to functional cancer drug testing in Florida.
De La Rocha., A. et al. (2024). Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers. Nature Medicine. doi.org/10.1038/s41591-024-02848-4.
Human papillomavirus (HPV) is the second most common cancer-causing virus, accounting for 690,000 cervical and other cancers each year worldwide. While the immune system usually clears HPV infections, those that persist can lead to cancer, and a new finding suggests that certain women may have a genetic susceptibility for persistent or frequent HPV infections. These genetic variants, identified in a study led by University of Maryland School of Medicine researchers, could raise a woman’s risk of getting cervical cancer from a high-risk HPV infection.
Findings were recently published in The European Journal of Human Genetics.
The research team conducted a genome-wide association study of high-risk HPV infections in a cohort of over 10,000 women, whose data were collected as part of the African Collaborative Center for Microbiome and Genomics Research (ACCME) cohort study. A total of 903 of the participants had high-risk HPV infections when the study began, with 224 participants having HPV infections that resolved, and 679 having persistent HPV infections. More than 9,800 HPV-negative women from the ACCME study served as controls.
We found certain genetic variants were associated with having high-risk HPV infections, while other variants and human leukocyte antigen (HLA) genes were associated with persistent infections, which increase the risk of developing cervical cancer. This is a critical finding that suggests genetic underpinnings for cervical cancer risk. It is the first sufficiently powered genome-wide association study of cervical high-risk HPV infections. Our polygenic risk score models should be evaluated in other populations.”
Sally N. Adebamowo, MBBS, MSc, ScD, Study Leader, Associate Professor of Epidemiology & Public Health at UMSOM
Specifically, she and her colleagues found that the top variant associated with prevalent high-risk HPV infection was rs116471799, on the fourth chromosome near the LDB2 gene, which encodes for proteins. They found persistent HPV was associated with variants clustered around the TPTE2, a protein encoding gene associated with gallbladder cancer. The genes SMAD2 and CDH12 were also associated with persistent high risk HPV infections, and significant polygenic risk scores. Together the findings enabled the research team to develop polygenic risk scores to determine the likelihood that a certain genetic profile would increase the risk of having prevalent or persistent HPV infections.
“Our findings can be used for risk stratification of persistent high-risk HPV infections for precision or personalized cervical cancer prevention. We hope to conduct long-term studies on the integration of PRS and genomic risk factors into the continuum of cervical cancer prevention,” said study corresponding author Clement A. Adebamowo, BM, ChB, ScD, Professor of Epidemiology & Public Health at UMSOM.
A recent report from the American Cancer Society found that cervical cancer among women ages 30 to 44 rose almost 2 percent a year from 2012 to 2019. This is after a big decline in cervical cancer rates over the past half-century due to early detection from Pap smears and HPV screening tests. In addition, rates of cervical cancer, have steadily declined among younger women who were among the first to benefit from HPV vaccines, which were approved for use in 2006.
In the U.S., more than half of women diagnosed with cervical cancer have never been screened or were not screened in the last five years, according to the Centers for Disease Control and Prevention. In Nigeria, only a small percentage of women have access to the HPV vaccine, so those included in the study were largely unvaccinated.
“The results provide insight into the role of antigen processing and presentation, and HLA-DRB1 alleles in immune surveillance and persistence of high-risk HPV infections,” said Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM, and Vice President for Medical Affairs, University of Maryland, Baltimore. “Confirmatory studies are crucial to validate these important findings in other populations, with the goal of reducing the burden of high-risk HPV related diseases on global health.”
Study co-authors included those from: the National Human Genome Research Institute in Bethesda, MD; Asokoro District Hospital in Abuja, Nigeria; Federal Medical Center in Keffi, Nigeria; Wuse General Hospital in Abuja, Nigeria; University College Hospital, University of Ibadan, Ibadan, Nigeria; Institute of Human Virology Nigeria, Abuja, Nigeria; Garki Hospital Abuja, Abuja, Nigeria; University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria; National Hospital Abuja, Abuja, Nigeria; Kubwa General Hospital, Abuja, Nigeria.
This work was supported by the African Collaborative Center for Microbiome and Genomics Research Grant (NIH/NHGRI 1U54HG006947), UM-Capacity Development for Research in AIDS Associated Malignancy Grant (NIH/NCI 1D43CA153792-01), and Polygenic Risk Score (PRS) Methods and Analysis for Populations of Diverse Ancestry – Study Sites (NIH/NHGRI 1U01HG011717).
Adebamowo, S. N., et al. (2024). Genome, HLA and polygenic risk score analyses for prevalent and persistent cervical human papillomavirus (HPV) infections. European Journal of Human Genetics. doi.org/10.1038/s41431-023-01521-7.
A single low dose injection of esketamine given immediately after childbirth reduces major depressive episodes in individuals with depressive symptoms during pregnancy (prenatal depression), finds a clinical trial published by The BMJ today.
The results suggest that low dose esketamine should be considered in new mothers with prenatal depressive symptoms.
Depression is common during pregnancy and shortly after giving birth and can have several adverse effects on new mothers and their infants.
Esketamine is made from a drug called ketamine. It’s used as an anesthetic and to treat depression, yet the effect for mothers with perinatal depression is unclear.
To examine this further, researchers based in China and the USA wanted to find out if a single low dose injection of esketamine given just after childbirth might reduce subsequent depression in mothers with pre-existing prenatal depression.
Their findings are based on 361 mothers (average age 32 years) enrolled from five Chinese hospitals from June 2020 to August 2022 with no medical history of depression and no diagnosis of depression in pregnancy, but who had scores on a scale consistent with mild prenatal depression and were preparing for childbirth.
None of the participants had severe pregnancy complications, or any condition that meant they couldn’t be given esketamine.
Information on factors including age, weight (BMI), education level, family income and existing health conditions was recorded at the start of the trial and participants were randomly assigned to either esketamine or placebo intravenously infused over 40 minutes after childbirth.
Participants were interviewed 18 to 30 hours after giving birth and again at 7 and 42 days.
Major depressive episode was diagnosed with the Mini-International Neuropsychiatric Interview at 42 days. Depression was also assessed using the Edinburgh depression score at 7 and 42 days, and the Hamilton Depression Rating Scale score at 42 days. No participant took antidepressants or received psychotherapy during the follow-up period.
At 42 days after giving birth, 12 of 180 (6.7%) of mothers given esketamine experienced a major depressive episode compared with 46 of 181 (25.4%) of those given placebo (a relative risk reduction of about three-quarters).
As expected, mothers given esketamine had lower Edinburgh depression scores at 7 and 42 days, and a lower Hamilton depression score at 42 days.
Based on these figures, the researchers estimate that, for every five mothers given esketamine, one major depressive episode would be prevented.
More neuropsychiatric adverse events such as dizziness and diplopia (double vision) occurred with esketamine (45% v 22%). However, symptoms lasted less than a day and none needed drug treatment.
The researchers acknowledge that excluding mothers with pre-pregnancy mood disorders may have affected the validity of their results, and the short follow-up period may have led to under-reporting of neuropsychiatric symptoms and other adverse events.
What’s more, most participants had only mild prenatal depressive symptoms, so it’s unclear whether esketamine is equally effective in those with more severe depressive symptoms.
Nevertheless, they conclude that for mothers with prenatal depressive symptoms, a single low dose of esketamine given shortly after childbirth decreases major depressive episodes at 42 days postpartum by about three quarters.
These results are generally consistent with previous work investigating the effects of low dose ketamine or esketamine on postpartum depression, mainly in mothers after cesarean delivery, and, importantly, the researchers say their trial “extends existing understanding by targeting women with pre-existing prenatal depression, who were therefore at high risk of postnatal depression.”
As such, they conclude that low dose esketamine should be considered in mothers with symptoms of prenatal depression.
Source:
Journal reference:
Wang, S., et al. (2024). Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ. doi.org/10.1136/bmj-2023-078218.
You have your mother’s eyes and your father’s smile, but genetics is much more than just what’s on the surface. In a study that spans more than a decade, researchers at Baylor College of Medicine have looked at generations of families in a specific population to reveal the role newly inherited DNA variants play on recessive disease traits, and in the process, they have created a population specific database revealing unique DNA information unseen in larger cohorts.
The findings, now published in Genetics in Medicine OPEN, revealed a correlation between occurrences of complex genetic disorders in those families with increased levels of consanguinity when compared to unaffected populations. Consanguinity is when both parents contribute similar genetic markers to an offspring, such as by sharing a common ancestor, and the genetic information from both the genome inherited from the father and that from the mother are identical.
“We observed that the areas on the chromosome known as ROH, regions of homozygosity, were longer in those individuals in which there was a higher degree of parental consanguinity when compared to those with less,” said Dr. Zeynep Coban-Akdemir, postdoctoral associate in molecular and human genetics at Baylor and currently assistant professor at UTHealth School of Public Health as well as co-lead author on the study. “We can see what is happening when consanguinity is at play and also when new genetic variations are introduced into the family unit of the clan or tribe representing more distant ancestors.”
Dr. Xiaofei Song, a former Baylor graduate student now working as an assistant professor at Moffitt Cancer Center, said, “We further applied a statistical method to systematically assess the impact of these genetic variations on disease. Our results indicate that the newly introduced genetic variations can better explain the clinical features observed in our patients.” Song also is co-lead author on the study.
“The published study contributes to the field of both rare disease and population genomics. From a trainee perspective, the article provides a valuable resource for comprehending fundamental concepts of human genetics and applying diverse computational methods to elucidate these concepts,” said Ph.D candidate Tugce Bozkurt-Yozgatli, with the Acibadem University in Istanbul, Turkey.
Coban-Akdemir, who worked in the Lupski Lab at Baylor where the research was conducted, says this is an important part of the findings because it reveals how genes act within different populations and clans to contribute to different recessive genetic disorders.
The population studied was a cohort of individuals originating from Turkey that is known to have different variations in genetic markers when compared to other populations from greater Europe. Researchers created and analyzed a database of variants derived from exome sequencing, a genomics assay providing a glimpse into genetic variation genomewide, of 773 unrelated volunteers who were affected with various suspected rare Mendelian disease traits, which are diseases caused by a mutation in a single gene and clearly passed down from one generation to the next in accordance with Gregor Mendel expectations. They were compared to another database created by the same researchers of 643 unaffected relatives.
Roughly half of the genetic variants in this Turkish group are not present in greater European control populations that are found in shared databases commonly used by genetic researchers.
“This group of Turkish individuals and families gives us insight into genetics that the average population doesn’t provide. What we found in this Turkish population is very unique. Not only is this group underrepresented in larger databases, but it shows us that they have an enriched genetic variation that is only seen within this population when compared to European populations,” Coban-Akdemir said.
Dr. Davut Pehlivan, assistant professor of pediatrics – neurology at Baylor, said on a single individual there are around 40 million Watson-Crick base pair variations within our DNA.
“The Human Genome Project opened the doors for researchers to investigate entire genomic DNA complement using next-generation sequencing technology. However, more struggles appeared with these advancements. For example, it is hard to pinpoint which variant is causing disease among 40 million variations of our DNA. Studying healthy populations helps us to eliminate many of these common variations from consideration. Thus, we studied both patients and their healthy relatives in the Turkish population.” Pehlivan said. “There are a lot of changes in the genome, and we don’t fully understand the meaning of all of those details, but the data from this population study will help all investigators around the world who are trying to interpret the results of other variants in the human genome DNA.”
Pehlivan described gathering the information and families wanting to participate in genomics research beginning in 2010, traveling long distances to rural areas where the patients were mostly located, a human interest story itself, to make sure the database and clinical information would show an accurate representation for these families.
“We discovered more than 200 genes that contributed to the existing body of disease gene associations. This will help us get closer to understanding, in this population and in others, what is causing these diseases and the human biological perturbation underlying a broad scope of diseases. Our studies will open new avenues of research in human biology and genome biology and eventually help to potentially bring nucleic acid treatments, something used to develop the COVID vaccine, to the patients and families” Pehlivan said.
This team of researchers is not just helping the population that they studied, but their findings also can be applied to many populations. We all are very different individuals on this planet, yet our genes act very similarly, and we all share a common humanity. So, understanding how genetic disorders work helps us to support affected families across the globe.”
Dr. James R. Lupski, the Cullen Foundation Endowed Chair in Genetics and Genomics at Baylor
In the past, Coban-Akdemir and Dr. Claudia M.B Carvalho, previously with Baylor and currently in her own laboratory at the Pacific Northwest Research Institute (PNRI) in Seattle who also contributed to this study, have worked on studying variants of genes to identify causes of diseases through production of truncated or altered proteins that take on a new or different function. Their work also focused on databases of populations with and without genetic disease. Their current work reflects the importance of diversity and inclusion as work continues to reveal causes of genetic diseases.
This work was supported in part by the U.S. National Human Genome Research Institute /National Heart Lung and Blood Institute grant number UM1HG006542 to the Baylor Hopkins Center for Mendelian Genomics (BHCMG), the U.S. National Human Genome Research Institute U01HG011758 to the Baylor College of Medicine for the Genomics Research to Elucidate the Genetics of Rare Disease consortium (BCM-GREGoR), the National Institute of Neurological Disorders and Stroke Q22 (NINDS) R35NS105078, and the National Human Genome Research Institute U54-HG003273. J.E.P. was supported by NHGRI K08 HG008986.
Coban-Akdemir, Z., et al. (2024). The impact of the Turkish (TK) population variome on the genomic architecture of rare disease traits. Genetics in Medicine Open. doi.org/10.1016/j.gimo.2024.101830.
As part of a comprehensive effort to improve cancer screenings among diverse communities, Penn Medicine’s Abramson Cancer Center (ACC) Community Outreach and Engagement team developed a culturally sensitive educational video to address prostate cancer screening disparities. In findings shared today at the American Association for Cancer Research (AACR) Annual Meeting 2024 (Abstract LB371), the team showed that the video increased knowledge about prostate cancer and screening, and reduced uncertainty about obtaining prostate cancer screening in a diverse group of more than 600 men over age 40 who viewed the video during 14 different community health events in the Philadelphia region. Based on post-video surveys, 93 percent of men said they intended to undergo a prostate-specific antigen (PSA) screening blood test for prostate cancer, which the research team offered at the same time as part of the community events.
We know that cancer screenings save lives, and part of our work is to dispel the myths and misconceptions around screening to help ensure that individuals from all backgrounds understand their screening options. The idea of a physical prostate exam is off-putting to many men, so we want them to know that a simple, non-invasive blood test to check PSA levels is also an option to screen for prostate cancer.”
Carmen Guerra, MD, senior author, professor and vice chair of Diversity and Inclusion in the division of Internal Medicine in the Perelman School of Medicine at the University of Pennsylvania and associate director of Diversity and Outreach at the ACC
Prostate cancer disproportionately affects Black men, who are more likely to be diagnosed with and to die from the disease, and less likely to undergo prostate cancer screening, compared to white men. Even so, research has shown that even when presented with the same educational material, Black men are less likely to receive prostate cancer screening than white man. Myths, medical mistrust, and financial barriers may all contribute to this disparity, so the research team designed the brief educational video to specifically address the Black community in Philadelphia.
The video was shared at health events hosted by trusted local organizations, including community, faith-based, and occupational groups; men could also receive a free PSA blood test to screen for prostate cancer during the events. The video featured a conversation between a urologist and a local pastor, who is a Black prostate cancer survivor. It covered prostate cancer facts, provided information about screening options, and addressed common myths and misconceptions about how symptoms, age, and family history factor into the disease and screening for it.
“By helping more men, especially those in at-risk populations, understand the benefits of prostate cancer screening, we hope to find cancer earlier, when it can be more easily treated,” said lead author Mallorie C. Jones, MA, a project manager in Internal Medicine and member of the ACC Community Outreach and Engagement team. “The overwhelming positive survey feedback to the video tells us that we’re on the right track to developing a useful resource that resonates with audience it’s meant to reach.”
The team will continue to evaluate the video during community outreach events in the greater Philadelphia area in 2024, with plans to fine-tune the content based on participant feedback, including evaluating ways to make the information more accessible and relevant to Spanish-speakers. They hope to make the final video available to share with other organizations as an educational resource.
The video development was supported by a grant from Flyers Charities, which also supports free community prostate cancer screenings as part of the Flyers Against Prostate Cancer initiative.
Genetic studies of diseases map segments of the genome driving disease. But to understand how those changes contribute to disease progression, it is important to understand how they may alter gene regulation of disease genes in cell populations assumed to be driving disease. “Enhancer-gene maps” link genomic regulatory regions to genes and are essential for understanding disease. But constructing them poses challenges due to limitations in current experimental methods, that make it difficult to apply the technique to rare cell populations and genes that only regulate specific cell types.
Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, have developed a statistical method called SCENT (single-cell enhancer target gene mapping). This method uses multimodal single-cell data to establish links between regulatory elements and genes, allowing them to pinpoint probable causal gene loci for both common and rare diseases. These insights might assist the development of treatments for various conditions.
The research team applied SCENT to nine multimodal single-cell datasets representing various human tissues, including immune, neuronal, and pituitary cells, aiming to understand the intricacies of DNA regulation in each specific cell type. With these data, they developed 23 distinct gene-enhancer maps, to investigate genetic variants and expression patterns associated with 1,143 diseases and traits. Notably, they discovered that, for immune diseases, crucial insights emerged not only from immune cells but also from cells within the affected tissues themselves.
For most autoimmune diseases, people assume that we need a general map of immune cells. But we find that the enhancer-gene maps of immune cells are different in affected disease tissues. We demonstrate how such a map can be used to interpret genetic data from rheumatoid arthritis and other autoimmune diseases.”
Soumya Raychaudhuri, MD, PhD, of the Brigham’s Division of Rheumatology, Immunology and Inflammation
Covering the American health care system means we tell some scary stories. This episode of “An Arm and a Leg” sounds like a real horror movie.
It uses one of Hollywood’s favorite tropes: machines taking over. And the machines belong to the private health insurance company UnitedHealth Group.
Host Dan Weissmann talks to Stat News reporter Bob Herman about his investigation into Medicare Advantage plans that use an algorithm to make decisions about patient care. The algorithm is owned by a subsidiary of UnitedHealth Group.
Herman tells Weissmann that some of UnitedHealth’s own employees say the algorithm creates a “moral crisis” in which care is unfairly denied.
Scary stuff! Such reporting even has caught the eye of powerful people in government, putting Medicare Advantage plans under scrutiny.
Previously, Dan was a staff reporter for Marketplace and Chicago’s WBEZ. His work also appears on All Things Considered, Marketplace, the BBC, 99 Percent Invisible, and Reveal, from the Center for Investigative Reporting.
Note: “An Arm and a Leg” uses speech-recognition software to generate transcripts, which may contain errors. Please use the transcript as a tool but check the corresponding audio before quoting the podcast.
Dan: Hey there–
So this is kind of a horror story. But it’s not quite the kind of story it might sound like at first.
Because at first, it might sound like a horror story about machines taking over, making all the decisions– and making terrible, horrifying choices. Very age-of-Artificial Intelligence.
But this is really a story about decisions made by people. For money.
It’s also kind of a twofer sequel– like those movies that pit two characters from earlier stories against each other. Like Godzilla vs King Kong, or Alien vs Predator.
Although in this case, I’ve gotta admit, the two monsters are not necessarily fighting each other.
Let’s get reacquainted with them.
On one side, coming back from our very last episode, we’ve got Medicare Advantage: This is the version of Medicare that’s run by private insurance companies.
It’s got a bright and appealing side, compared to the traditional Medicare program run by the federal government, because: It can cost a lot less, month to month — saving people money on premiums. And it often comes with extra benefits, like dental coverage, which traditional Medicare doesn’t offer. [I know.]
But Medicare Advantage can have a dark side, which is basically: Well, you end up dealing with private insurance companies for the rest of your life. You need something — a test, a procedure, whatever — they might decide not to cover it.
Which can be scary.
Our other returning monster — am I really calling them a monster? — well, last time we talked about them, in 2023, we had an expert calling them a behemoth. That’s United HealthGroup. You might remember, they’re not only one of the biggest insurance companies
— and maybe not-coincidentally the very biggest provider of Medicare Advantage plans —
they’ve also got a whole other business– under the umbrella name Optum. And Optum has spent the last bunch of years buying up a gazillion other health care companies of every kind.
That includes medical practices — they employ more doctors than anyone else, by a huge margin. It includes surgery centers, and home-health companies, and every kind of middleman company you can imagine that works behind the scenes — and have their hands in a huge percentage of doctor bills and pharmacy visits.
A few years ago, United bought a company called NaviHealth, which provides services to insurance companies that run Medicare Advantage plans.
NaviHealth’s job is to decide how long someone needs to stay in a nursing home, like if you’re discharged from a hospital after surgery, but you’re not ready to go home yet.
And the horror story– the stories, as dug up by reporters — starts after United bought NaviHealth.
And according to their reports, it involves people getting kicked out of those nursing homes who aren’t ready to go home.
People getting sent home who can’t walk up the stairs in their house. Who can’t walk at all. Who are on feeding tubes. People who NaviHealth’s own employees are saying, “Wait. This person isn’t ready to go home.”
But their new bosses have told them: You’re not really making these decisions anymore.
This is where machines do enter the picture.
NaviHealth’s distinctive offering has always been its proprietary algorithm– an algorithm that makes predictions about how long any given patient might need to stay.
Before United bought the company, that algorithm was used as a guide, a first-guess. Humans weighed in with their own judgment about what patients needed.
After United bought the company, people inside have told reporters, that changed: The new owners basically told their employees, If the algorithm says someone can go home after x days, that’s when we’re cutting them off.
Like pretty much any horror movie, this story’s got people running around trying to tell everyone: HEY, WATCH OUT! THERE’S SOMETHING BIG AND DANGEROUS HAPPENING HERE.
And in this case, they’ve actually gotten the attention of some people who might have the power to do something about it. Now, what those people will do? We don’t know yet.
And, by the way: Yes, I said at the end of our last episode that we’d be talking about Medicaid this time around. That’s coming! But for now, strap in for this one.
This is An Arm and a Leg, a show about why health care costs so freaking much, and what we can maybe do about it. I’m Dan Weissmann. I’m a reporter, and I like a challenge. So our job on this show is to take one of the most enraging, terrifying, depressing parts of American life, and bring you something entertaining, empowering, and useful.
So. I said that, like every horror movie, this one has people who are seeing what’s going on and are trying to warn everybody?
Like those movies, we’re gonna follow one of those people, watch them discover the problem, see how deep it goes, and start ringing alarm bells. Let’s meet our guy.
Bob Herman: My name is Bob Herman. I’m a reporter at STAT News
Dan: Stat is an amazing medical news publication. Bob covers the business of medicine there. Bob started working on this story in November 2022, after talking to a source who runs nursing homes. Bob’s source was complaining about Medicare Advantage.
Bob Herman: There were a lot of payment denials. They just weren’t able to get paid. And just offhandedly, the source mentioned like, um, you know, and they’re attributing everything to this algorithm. This algorithm said, You know, only 17 days for our patients and then time’s up and I went running to Casey Ross
Dan: Casey is a reporter at Stat who focuses on tech and AI in healthcare. Bob said, hey, what do you think of this? Wanna team up?
Bob Herman: And he was hooked.
Dan: They started talking to people who worked at nursing homes, talking to experts, and talking to families. And it was clear: They were onto something.
Bob Herman: It took so many families by surprise to be like, what do you mean we’re going home? The, you know, my husband, my wife, my grandma, my grandpa, they can’t go to the bathroom on their own. Like, what do you? It was just, it was so confusing to people. It seemed like such a, a cold calculation,
Dan: One person they ended up talking with was Gloria Bent. Her husband Gary was sent to a nursing home for rehab after brain surgery for cancer. He was weak. He couldn’t walk. And he had something called “left neglect”: His brain didn’t register that there was a left side of his body. Here’s Gloria testifying before a Senate committee about how — when Gary arrived at the nursing home — the first thing he got was a discharge date. That is…
Gloria Bent: Before the staff of the facility could even evaluate my husband or develop a plan of care, I was contacted by someone who identified themselves as my Navi Health Care Coordinator
Dan: Gloria says when she told the nursing home staff she’d heard from NaviHealth, they groaned. And told her what to expect.
Gloria Bent: I was told that I had just entered a battlefield, that I could expect a series of notices of denial of Medicare payment accompanied by a discharge date that would be two days after I got that notice.
Dan: Yeah, they said she’d get two days notice. Gloria says the nursing home staff told her she’d have 24 hours to appeal each of those, but even if she won, the denials would keep coming. In fact, they said,
Gloria Bent: If we won a couple of appeals, then we could expect that the frequency with which these denials were going to come would increase.
Dan: All of which happened. NaviHealth started issuing denials July 15, 2022, after Gary had been at the home for a month.
Gloria appealed. She told senators what the doctor who evaluated the appeal found: Gary couldn’t walk. He couldn’t even move — like from bed to a chair — without help from two people.. That reviewer took Gloria’s side.
Her husband’s next denial came a week after the first. Gloria won that appeal too. She says the reviewer noted that Gary needed maximum assistance with activities of daily living.
The third denial came four days later, and this time Gloria lost.
Gary came home in an ambulance: As Gloria testified, he couldn’t get into or out of a car without assistance from someone with special training.
And when he got into the ambulance, he had a fever. The next morning, he wound up in another ambulance — headed to a hospital with meningitis. He lost a lot of the functioning he’d picked up at the nursing home.
He died at home a few months later. When Gloria testified in the Senate, all of it was still fresh. She told them that as awful as Gary’s illness and decline had been, the fights with insurance were an added trauma.
Gloria Bent: This should not be happening to families and patients. It’s cruel. Our family continues to struggle with the question that I hear you asking today. Why are people who are looking at patients only on paper or through the lens of an algorithm
making decisions that deny the services judged necessary by health care providers who know their patients.
Dan: Bob Herman calls Gloria’s story heartbreaking, like so many others he’s seen.
And his attention goes to one part of Gloria’s story beyond denial-by-algorithm.
Because: It’s not just one denial. It’s that series of denials. You can appeal, but as Gloria testified, the denials speed up. And you have to win every single time. The company only has to win once.
I mean, unless you’re ready to get a lawyer and take your chances in court– which, in addition to being a major undertaking, also means racking up nursing home bills and legal bills you may never get reimbursed for, while the court process plays out.
Bob Herman: This appeal system is designed in such a way that people will give up. If you have a job, you know, even if you don’t, and you’re, and you’re also trying to take care of a family member, um, it’s a rigorous monotonous process that will chew people up and spit them out and then the people are inevitably going to give up. And I think in some ways insurers know that.
Dan: Going out on a limb to say: I think so too. So Bob and Casey’s first story on NaviHealth came out in March of 2023. They were the characters in the movie who go, “HEY, I THINK THERE’S SOMETHING REALLY BAD HAPPENING HERE.”
And people started paying attention. Like the U.S. Senate. which held that hearing where Gloria Bent told her story.
And like the federal agency that runs Medicare — the Centers for Medicare and Medicaid Services, CMS.
CMS finalized a rule that told insurers: You can’t deny care to people just from using an algorithm.
And something else happened too: Bob and Casey started suddenly getting a lot MORE information.
Bob Herman: We received so many responses from people and it just opened the floodgates for former employees, just patients and family members, just everyone across the board.
Dan: And not just former employees. Current employees. And what they learned was: There was absolutely a strategy at work in how this algorithm was being used. It was strategy some people on the inside didn’t feel good about.
And this strategy got developed after United HealthGroup — and its subsidiary, Optum– bought NaviHealth in 2020. And here’s what NaviHealth employees started telling Casey and Bob about that strategy.
Bob Herman: For some of us, it’s creating this moral crisis. Like we know that we are having to listen to an algorithm to essentially kick someone out of a nursing home, even though we know that they can barely walk 20 feet.
Dan: What Bob and Casey learned from insiders– and how it connects to United’s role as a health care behemoth– that’s next.
This episode of An Arm and a Leg is produced in partnership with KFF Health News. That’s a nonprofit newsroom covering healthcare in America. Their reporters do amazing work, and I’m honored to work with them. We’ll have a little more about KFF Health News at the end of this episode.
So, NaviHealth — the company with the algorithm — got started in 2015.. And the idea behind it was to use data to get people home faster from nursing homes if they didn’t actually need to be there.
Because there was a lot of evidence that some people were being kept longer than they needed.
Bob Herman: There is some validity to the idea that there’s, there’s wasteful care in Medicare, like, you know, there’s been cases in the past proving that people stay in a nursing home for way longer than is necessary. And obviously there’s financial incentives for nursing homes to keep people as long as possible.
Dan: Traditional Medicare does have limits on nursing home care — but if you need “post-acute care” — help getting back on your feet after leaving a hospital traditional Medicare pays in full for 20 days– pretty much no questions asked. One of the selling points of Medicare Advantage — like selling points to policy nerds and politicians — was that it could cut waste, by asking those kinds of questions. NaviHealth and its algorithm were designed to help Medicare Advantage plans ask those questions in a smart way.
Bob Herman: There were… a lot of believers within NaviHealth that were like, okay, I think we’re doing the right thing. We’re trying to make sure people get home sooner because who doesn’t want to be at home.
Dan: And as those employees told Bob and Casey: Before United and Optum came in, the algorithm had been there as a guide — a kind of first guess — but not the final word.
NaviHealth has staff people who interact directly with patients. And back in the day, the pre-United day, Bob and Casey learned that those staff could make their own judgments.
Which made sense, because the algorithm doesn’t know everything about any individual case. It’s just making predictions based on the data it has.
Bob Herman: And there was just, just this noticeable change after United and OptiMentor that it felt more rigid. There’s no more variation.
Dan: If the algorithm says you go, you are pretty much going.
Bob Herman: United has said, no, that’s not the case, but obviously these documents and other communications that we’ve gotten kind of say otherwise.
Dan: Because these employees weren’t just talking. They were sharing. Internal memos. Emails. Training materials. All making clear: The company wanted people shipped out on the algorithm’s timetable.
Bob Herman: Documents came in showing that like this was a pretty explicit strategy. You know, UnitedHealth was telling its employees. Listen, we have this algorithm. We think it’s really good. So when it tells you how many, how many days someone should be in a nursing home, stick to it.
Dan: Stick to it or maybe be fired. Bob and Casey got documents — employee performance goals– saying: How close you stick to the algorithm’s recommendations? That’s part of how we’re evaluating your job performance.
Bob Herman: It’s okay. Algorithm said 17 days, you better not really go outside of that because your job is on the line.
Dan: Here’s how closely people were expected to stick to it. In 2022, employee performance goals shared with STAT showed that workers were expected to keep actual time in nursing homes to within three percent of what the algorithm said it should be. Across the board.
So, say you had 10 patients, and the algorithm said they each should get 10 days. That’s 100 days. Your job was to make sure that the total actual days for those patients didn’t go past 103 days.
Then, in 2023, the expectations got more stringent: Stay within one percent of the algorithm’s predictions. 10 patients, the algorithm says 100 days total? Don’t let it get past a hundred and one.
Bob Herman: Like that is, almost nothing. Like what, what, your hands are tied. If you’re that employee, what are you going to do? Are you going to get fired? Are you going to do what you’re told?
Dan: And one person who ended up talking, to did get fired.
Bob Herman: Correct. Yes. Uh, Amber Lynch did get fired And what she said was what we had also heard just more broadly was it, it created this internal conflict, like, Oh my God, what I’m doing doesn’t feel right.
Dan: Amber Lynch was a case manager. She told Bob and Casey about onepatient who couldn’t climb the stairs in his home after knee surgery. But the algorithm said he was ready. Amber’s supervisor said, “Have you asked the nursing home staff if they’ve tried to teach him butt bumping?” Amber grit her teeth and made the suggestion to the rehab director.
Amber Lynch: And she looked at me like I had two heads. She’s like, he is 78 years old. He’s not going to do that. He’s not safe to climb the stairs yet. He’s not doing it. We’re not going to have it butt bump the stairs.
Dan: Amber told Bob and Casey that when she got fired, it was partly for failing to hit the one percent target and partly for being late with paperwork– which she told Bob and Casey she fell behind because her caseload was so heavy.
She wasn’t the only one with that complaint.
Bob and Casey’s story shows another NaviHealth case manager– not named in the story because they’re still on the job — in their home office, struggling to keep up.
That week, they were supposed to work with 27 patients and their families. Gather documents, hold meetings. Another week, shortly before, they’d had 40 patients.
“Do you think I was able to process everything correctly and call everyone correctly the way I was supposed to?” the case manager asked. “No. It’s impossible. No one can be that fast and that effective and capture all of the information that’s needed.”
Bob and Casey watched this case manager fill out a digital form, feeding the algorithm the information it asked for on a man in his 80s with heart failure, kidney disease, diabetes and trouble swallowing, who was recovering from a broken shoulder.
A few minutes later, the computer spat out a number: 17 days.
The case manager didn’t have a lot of time or leeway to argue, but they were skeptical that the algorithm could get that number exactly right based on only the data it had.
And what data is the algorithm working with? What’s it comparing the data on any given patient TO? Bob Herman says that’s a big question.
Bob Herman: It’s something that for sure, like Casey and I, it’s been bothering us. Like, what, how is this whole system? Like, what is it based on? And we were never really given straight answers on that. NaviHealth and Optum and United have said it’s based on millions of patient records over time. The sources of that, it’s, it’s a little unclear, where all that’s coming from.
Dan: Bob and Casey talked with an expert named Ziad Obermeyer, a professor at the University of California Berkeley School of Public Health, who is not anti-algorithm. He actually builds algorithmic tools for decision making in public health.
AND he’s done research showing that some widely-used algorithms just scale up and automate things like racial bias.
He told Bob and Casey: Using an algorithm based on how long other, earlier patients have stayed in a nursing home — that’s not a great idea.
Because people get forced out of nursing homes, in his words, “because they can’t pay or because their insurance sucks.” He said, “So the algorightm is basically learning all the inequalities of our current system.”
And leaving aside that kind of bias, it seems unlikely to Bob that any algorithm could predict exactly what every single patient will need every single time.
No matter how much data it’s got, it’s predicting from averages.
Bob Herman: It reminds me of, like, a basketball game where let’s say someone averages 27 points per game. They don’t have 27 points every single, the game they go out there. It just varies from time to time.
Dan: But the NaviHealth algorithm doesn’t have to be right every time for United to make money using it.
Using it to make decisions can allow United to boost profits coming and going.
Bob Herman: United health and the other insurance companies that use Navi health. Are using this technology to more or less kick people out of nursing homes before they’re ready. And that is the claims denial side where it’s like, okay, let’s save as much money as we can instead of having to pay it to a nursing home.
Dan: And that’s just one side of it. The insurance side. Claims denial. But United isn’t just in the insurance business.
United’s Optum side is in every other part of health care.
Including — in the years since United took over NaviHealth — home health services. The kind of services you’re likely to need when you leave a nursing home.
In 2022, Optum bought one top home health company in what one trade publication called a “monster, jaw-dropping mega-deal” — more than 5 billion dollars. In 2023, Optum made a deal to buy a second mega-provider.
Bob and Casey’s story says NaviHealth’s shortening nursing home stays is integral to United’s strategy for these acquisitions. It does seem to open up new opportunities.
Bob Herman: You’re out of the nursing home because our algorithm said so. Now we’re going to send you to a home health agency or we’re going to send some home health aides into your home. And by the way, we own them.
Dan: Oh, right, because: If you’re in a Medicare Advantage plan, your insurer can tell you which providers are covered.
Bob Herman: So the real question becomes, how much is United potentially paying itself?
Dan: That is: How much might United end up taking money out of one pocket — the health insurance side — and paying itself into another pocket, Optum’s home-health services?
We don’t know the answer to how much United is paying itself in this way, or hoping to. And United has said its insurance arm doesn’t favor its in-house businesses.
But it seems like a reasonable question to ask. Actually, it’s a question the feds seem to be asking.
Optum hasn’t wrapped up its purchase of that second home-health company yet, and in February 2024, the Wall Street Journal and other outlets reported that the U.S. Department of Justice had opened an anti-trust investigation.
And you don’t have to be in a Medicare Advantage plan run by United to get kicked out of a nursing home on an algorithm’s say-so.
Bob Herman says NaviHealth sells its algorithm-driven services to other big insurance companies
He says, put together, the companies that use NaviHealth cover as many as 15 million people — about half of everybody in Medicare Advantage.
Bob Herman: Odds are, if you’re in a Medicare Advantage plan, there’s a, there’s a really good shot that your coverage policies, if you get really sick and need nursing home care, for example, or any kind of post acute care, an algorithm could be at play at some point.
Dan: This is the dark side of Medicare Advantage.
Bob Herman: Everyone loves their Medicare Advantage plan when they first sign up, right? Because it’s offering all these bells and whistles. It’s, here’s a gym membership. It’s got dental and vision, which regular Medicare doesn’t have. And it’s also just, it’s, it’s cheaper. Like, if it’s just from a financial point of view, if, if you’re a low income senior, How do you turn it down? There’s, there’s so many plans that offer like free, there’s no monthly premiums in addition to all the bells and whistles. But Nobody understands the trade offs , When you’re signing up for Medicare and Medicare Advantage, you’re on the healthier side of, of being a senior, right?
Dan: And none of us can count on staying healthy forever. When you sign up for Medicare you’re signing up your future self — whether that’s ten or twenty or more years out. That future you, might really need good medical care.
And at that point, as we explained in our last episode, if Medicare Advantage isn’t working for you, you may not be able to get out of it.
Bob Herman: You could potentially not fully get the care that you need. We shouldn’t assume that, that this couldn’t happen to us because it can.
Dan: So, yeah. Kind of a horror story. But: Unlike some horror movies, when Bob and Casey started publishing their stories, they started getting people’s attention.
We mentioned the new rules from the feds and the senate hearings after Bob and Casey’s first story in March 2023
Later in the year, when Bob and Casey published their story with documents and stories from inside NaviHealth, a class-action lawsuit got filed.
Since then, CMS has said it will step up audits under its new rules.
Bob Herman: There was a memo that CMS sent out to Medicare advantage plans that said, Hey, listen, we’re telling you again, do not deny care solely on any AI or algorithms. Like just don’t do it.
Dan: And in February 2024, the Senate held another hearing.
Here’s Senator Elizabeth Warren at that hearing, saying these CMS rules aren’t enough. We need stronger guardrails.
Elizabeth Warren: Until CMS can verify that AI algorithms reliably adhere to Medicare coverage standards by law, then my view on this is CMS should prohibit insurance companies from using them in their MA plans for coverage decisions. They’ve got to prove they work before they put them in place.
Dan: So people — people with at least some power– are paying some attention.
Bob Herman: I don’t think this is necessarily going to escape. Political scrutiny for a while.
Dan: So, basically, the story isn’t over.
This isn’t one of those horror movies where the monster’s been safely defeated at the end, and everybody just starts cleaning up the mess. And it’s not one where the monster is just on the loose, unleashing the apocalypse.
Because it’s not a movie. There’s no ending. There’s just all of us trying to figure out what’s going on, and what we can maybe do about it.
One last thing: I got a lot of emails after our last episode, where we laid out a lot of information about Medicare Advantage and traditional Medicare. Most of it was along the lines of, Thank you! That was really helpful! Which made me feel really good.
And we got a couple notes about things we could have done better. Especially this: We said Traditional Medicare leaves you on the hook for 20 percent of everything, without an out of pocket limit.
Which is true — but only for Medicare Part B: Doctor visits, outpatient surgeries and tests. Which can add up, for sure.
Medicare Part A — if you’re actually hospitalized — covers most services at 100 percent, after you meet the deductible. In 2024 that’s one thousand, six hundred thirty-two dollars.
Thanks to Clarke Lancina for pointing that out.
There have been a bunch of other, amazing notes in my inbox recently, and I want to say: Please keep them coming.
If you go to arm and a leg show dot com, slash, contact, whatever you type there goes straight to my inbox. You can attach stuff too: documents… voice memos.
Please let me hear from you. That’s arm and a leg show dot com, slash contact.
I’ll catch you in a few weeks.
Till then, take care of yourself.
This episode of an arm and a leg was produced by me, Dan Weissmann, with help from Emily Pisacreta, and edited by Ellen Weiss.
Adam Raymonda is our audio wizard. Our music is by Dave Weiner and blue dot sessions. Extra music in this episode from Epidemic Sound.
Gabrielle Healy is our managing editor for audience. She edits the first aid kit newsletter.
Bea Bosco is our consulting director of operations. Sarah Ballama is our operations manager.
And Arm and a Leg is produced in partnership with KFF Health News. That’s a national newsroom producing in depth journalism about healthcare in America and a core program at KFF, an independent source of health policy research, polling and journalism.
Zach Dyer is senior audio producer at KFF Health News. He’s editorial liaison to this show.
And thanks to the Institute for Nonprofit News for serving as our fiscal sponsor, allowing us to accept tax exempt donations. You can learn more about INN at INN. org.
Finally, thanks to everybody who supports this show financially– you can join in any time at arm and a leg show dot com, slash, support — and thanks for listening.
“An Arm and a Leg” is a co-production of KFF Health News and Public Road Productions.
To keep in touch with “An Arm and a Leg,” subscribe to the newsletter. You can also follow the show on Facebook and the social platform X. And if you’ve got stories to tell about the health care system, the producers would love to hear from you.
To hear all KFF Health News podcasts, click here.
And subscribe to “An Arm and a Leg” on Spotify, Apple Podcasts, Pocket Casts, or wherever you listen to podcasts.
A new article in JBMR Plus, published by Oxford University Press, indicates that patient survival rates after hip or other bone fractures can be very poor. While patients and their families may dismiss a fracture as a minor injury, survival rates can be lower than those for many types of cancer.
Scientists have gathered a body of evidence about mortality outcomes in patients over 50, but survival rates following bone fractures are not often included in the statistics available to patients or caregivers. The aim of this current real-world population-based study of close to 100,000 subjects was to show the post-fracture prognosis in people over 65 years by examining the overall survival by gender, age groups, and types of fractures, using the database of the Ontario, Canada public healthcare system.
In the entire fracture cohort over 65, less than a third of men and half of women survived five years after a hip fracture, with overall survival rates being marginally better following vertebral fracture. The oldest patients, those over 85, had the worst prognosis. Female patients tended to have better post-fracture survival than men, but had a significantly higher risk for getting a fracture in the first place. The paper emphasizes that the greatest reduction in survival in both genders occurred within the initial month after a fracture, indicating a high relative impact of short-term factors. This suggests the most critical period for doctors to intervene to improve patient prognoses is immediately after a fracture.
The paper notes that the five-year survival rates after a diagnosis of different types of cancer relevant to older adults are as follows: 64% in patients 60 to 79 years with any type of cancer, 43% in those over 80 with any type of cancer, 94% in men of any age with prostate cancer, and 89% in women (any age) with breast cancer. Therefore, survival outcomes for fractures in older adults are comparable to or worse than those seen for patients afflicted by some common types of cancer.
This large study of Canadians over 65 strongly demonstrates that survival most dramatically declined within one month after most types of fracture, with a five-year survival being similar to or worse than some common cancers. These observations highlight the urgency to change our attitude towards these patients and offer them secondary prevention interventions before hospital discharge, as recommended by the American Society for Bone and Mineral Research.”
Vincent, G., et al. (2024). Post-fracture survival in a population-based study of adults aged ≥ 66 years: a call to action at hospital discharge. JBMR Plus. doi.org/10.1093/jbmrpl/ziae002.
No therapies currently exist that can halt the progression of chronic kidney disease in children or restore the ability of kidney cells to filter blood. Recently, researchers at the GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology in The Saban Research Institute of Children’s Hospital Los Angeles found new clues to understanding how chronic kidney disease progresses. By mapping the underlying genetic drivers of a type of chronic kidney disease called primary membranous nephropathy, they seek disease markers that could point the way to developing new treatments for children. In a paper published in the journal JCI Insight, the research team found that an unexpected mechanism was responsible for the loss of the kidney cells’ ability to filter toxins from blood.
We have a good idea of what happens in the process of various types of chronic kidney failure, but we still don’t know precisely why and where it happens. Our goal was to scrutinize the molecular processes of any underlying mechanisms that could cause kidney podocytes to fail and lose their blood filtering capacity. Membranous nephropathy, which affects adults, can serve as a disease model for other chronic kidney disease processes that affect children and adults alike. The glomerulus-on-a-chip platform that we developed at the GOFARR lab allowed us to agnostically query different pathways involved in disease progression and measure their impact.”
Stefano Da Sacco, PhD, Investigator, Urology Research at CHLA and study senior author
A different culprit entirely
In membranous nephropathy, infection-fighting autoantibodies destroy the kidney’s glomerular structures that contain the specialized podocytes that maintain the kidney’s filtration barrier. The researchers modeled membranous nephropathy caused by anti-phospholipase A2 receptor (PLA2R) antibodies. PLA2R is a target antigen recognized by the body’s immune system in about 70% of adults with membranous nephropathy. (Another antigen, SEMA3B, is prevalent in the rare pediatric cases that make up between 1% to 3% of total membranous nephropathy patients.) As the anti-phospholipase A2 receptor autoantibodies bind to the target PLA2R antigen-;which resides on the surface of kidney podocytes-;they trigger a cascade of events that leads to podocyte injury, destroying the kidney glomerular cells’ capacity to filter toxins from blood.
Previously, researchers believed that the membrane-attack-complex (MAC) was the sole driver of podocyte injury, and that inhibiting it was key to halting disease progression. The GOFARR research team discovered instead that signaling in the C3a/C3aR pathway plays a critical role in the progression of membranous nephropathy. The team tested this insight both in vitro and using the glomerulus-on-a chip-tissue model, showing that administering a C3aR antagonist could preserve the podocyte’s ability to filter blood. When Dr. Da Sacco’s team specifically blocked signaling in the C3aR gene pathway by silencing the C3aR gene in podocytes, they observed that the system retained filtration capabilities. But when the researchers prevented MAC formation, podocyte function kept deteriorating.
“By probing what is actually happening at the molecular level, we found that an entirely different pathway than we initially thought was the main driver for primary membranous neuropathy,” says Dr. Da Sacco, Assistant Professor of Research Urology at the Keck School of Medicine of USC. “We had previous knowledge that this pathway could cause damage to podocytes, but no confirmation that it was important in membranous nephropathy. We were a bit surprised and greatly encouraged. Finding what causes podocytes to fail is a step toward preventing-;and eventually reversing-;kidney deterioration. Our patients need better treatment options.”
This work was supported by grants from NIH/NIDDK (RO1, R01DK123234) and by the GOFARR Foundation from the Schenkman Family.
Zhang, Q., et al. (2024). C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy. JCI Insight. doi.org/10.1172/jci.insight.172976.
Weiping Jia et al., at Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital, China, conducted a study to explore the relationship between the complexity of glucose time series, as derived from continuous glucose monitoring (CGM), and the deterioration of glucose regulation. The study introduces the use of refined composite multi-scale entropy (RCMSE) analysis to calculate the complexity of glucose time series index (CGI) and demonstrates that a decrease in this complexity is associated with a decline in glucose homeostasis, ranging from normal glucose tolerance (NGT) to impaired glucose regulation (IGR) and type 2 diabetes (T2D).
Key findings from the study include: (1) The complexity of glucose time series progressively decreases across the glycemic continuum, with the most significant decrease observed in individuals with T2D compared to those with NGT and IGR; (2) The CGI was found to be significantly associated with various parameters related to insulin sensitivity and secretion, indicating a close relationship between glucose dynamics and insulin function. (3) The disposition index (DI), which reflects β-cell function after adjusting for insulin sensitivity, was identified as the only independent factor correlated with CGI, suggesting that it may serve as a novel marker for evaluating glucose homeostasis.
The study’s methodology involved a post-hoc analysis of a multi-center CGM study conducted in China from 2007 to 2009, including 756 subjects with complete CGM data. The participants were not on any hypoglycemic treatment before or during the study period. The research was approved by the ethics committees of each participating hospital, and all subjects provided informed consent.
The study’s results have implications for the clinical practice of diabetes management, as the complexity of glucose time series, calculated using RCMSE analysis, could potentially serve as a new marker for glucose metabolism status. This could aid in the early detection and management of diabetes, as well as provide insights into the characteristics of blood glucose in individuals with IGR.
Overall, the research contributes to the understanding of glucose dynamics and insulin function in the context of diabetes and its progression, offering potential avenues for future investigation and clinical application.
Source:
Journal reference:
Li, C., et al. (2022). Decreasing complexity of glucose time series derived from continuous glucose monitoring is correlated with deteriorating glucose regulation. Frontiers of Medicine. doi.org/10.1007/s11684-022-0955-9.
