Novel immunotherapy agent safe, shows promise against high-risk prostate cancers

 A new drug, a monoclonal antibody known as enoblituzumab, is safe in men with aggressive prostate cancer and may induce clinical activity against cancer throughout the body, according to a phase 2 study led by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. If confirmed in additional studies, enoblituzumab could become the first promising antibody-based immunotherapy agent against prostate cancer.

In a clinical trial, 32 men with high-risk or very high-risk prostate cancers who were scheduled for prostate cancer surgery were treated with six weekly infusions of enoblituzumab prior to surgery, and were followed for an average of 30 months thereafter. Twenty-one patients, or 66%, had an undetectable prostate-specific antigen (PSA) level 12 months following surgery, suggesting that there was no sign of residual disease. Additionally, the drug was well-tolerated overall; no patients had any surgical delays or medical complications during or after the operation.

A description of the work was published April 3 in the journal Nature Medicine.

If enoblituzumab continues to perform well in further larger randomized studies, it could represent a new pathway for immunotherapy against multiple cancers, and the first one that may have a role for prostate cancer, says lead study author and cancer immunology researcher Eugene Shenderov, M.D., Ph.D., assistant professor of oncology at the Johns Hopkins University School of Medicine. Other existing antibody-based immunotherapy drugs have targeted immune checkpoints, natural on/off switches mediating immune responses, such as CTLA-4, PD-1 and LAG-3. Cancer cells hijack these checkpoints, turning off the immune response to cancer. "Drugs that block these checkpoints have had success in other types of cancers, including lung cancer and melanoma, but not in prostate cancer," says Shenderov.

Enoblituzumab works by binding to a protein called B7-H3 that is overexpressed on prostate cancer cells and believed to impede the immune system's ability to attack cancer cells. The new therapy could pack a one-two punch against cancer, Shenderov says, by blocking B7-H3's inhibition of the immune system's recognition and elimination of cancer cells, and also triggering a process called antibody-dependent cellular cytoxicity (ADCC), which leads to tumor cell destruction by activating additional immune cells such as macrophages and natural killer cells.

"Enoblituzumab appears safe and seems to activate the immune system in a way that involves both T-cells and myeloid cells," Shenderov says. "What this means is if these results can be replicated in a larger, randomized study, it opens the possibility that combining this therapy with local, curative-intent therapies like surgical prostate removal or radiation therapy, would allow this drug to potentially kill micrometastatic disease hiding elsewhere in the body, and therefore prevent a significant number of men from experiencing recurring disease. That could be a paradigm shift in prostate cancer."

The median age of study participants was 64 (age range 48-74). About half (47%) had a PSA greater than 10 ng/mL at diagnosis, which is abnormally high, and 50% had Gleason grade group 5 at biopsy, meaning they had highly aggressive disease. Patients were enrolled from February 2017 through June 2019. Enoblituzumab was confirmed to penetrate into prostate tumors and to bind to B7-H3 in the vast majority of participants, according to prostate samples studied after surgery.

Side effects of enoblituzumab were generally mild and included fatigue, neurological symptoms such as headache or dizziness, and flu-like or cold symptoms. One patient developed inflammation of the heart (myocarditis), which fully resolved with steroid treatment, and is a known side effect of other immune checkpoint drugs.

Beyond safety and anti-tumor activity based on PSA dropping to undetectable levels, investigators also looked for changes in the tumor microenvironment before and after enoblituzumab treatment. They found increased markers of cytotoxicity after treatment, consistent with the concept that the immune system was activated against tumor cells. The tumors showed increased infiltration with granulocytes, leukocytes and effector T-cells, and there was roughly a doubling of the density of cytotoxic T cells after treatment.

"The findings are exciting but exploratory, and need to be confirmed in larger study cohorts," cautions senior study author Emmanuel S. Antonarakis, M.D., the Clark Endowed Professor of Medicine and director of GU Oncology for the University of Minnesota Masonic Cancer Center. Antonarakis was the senior investigator of the study while he was at the Johns Hopkins Kimmel Cancer Center.

"However, these results in high-risk prostate cancer patients, and the broader need for immunotherapeutic strategies with efficacy in prostate cancers, provide justification to further develop multipronged approaches that include targeting B7-H3 to optimize antitumor activity in prostate cancers and other solid malignancies," he says.

Investigators are now planning a larger, randomized trial of enoblituzumab in newly diagnosed prostate cancer patients to assess clinical activity of the drug compared to current standards of care.

Coauthors of the current study were Angelo M. De Marzo, Tamara L. Lotan, Hao Wang, Sin Chan, Su Jin Lim, Hogkai Ji, Mohamad El Allaf, Carolyn Chapman, Samuel R. Denmeade, Kenneth J. Pienta, Christian P. Pavlovich, and Drew M. Pardoll of Johns Hopkins. Other study authors contributing to the paper were from MacroGenics Inc. of Rockville, Maryland (the maker of enoblituzumab); NanoString Technologies Inc. of Seattle; Adaptive Biotechnologies of Seattle; CDI Labs of Baltimore; the Northwestern University Feinberg School of Medicine in Chicago; and Charles G. Drake formerly at Johns Hopkins, who currently leads Immuno-Oncology at Janssen Research and Development.

The work was supported by the National Institutes of Health (Cancer Center Support Grant P30 CA006973), an NCI SPORE in Prostate Cancer (P50CA58236), a Prostate Cancer Foundation Young Investigator Award, the Department of Defense (grants W81XWH-16-PCRP-CCRSA and W81XWH-18-2-0015), and the Bloomberg~Kimmel Institute for Cancer Immunotherapy and by Macrogenics Inc, of Rockville, Maryland.

E. Shenderov is a paid consultant to GT Biopharma, Guidepoint Global, FirstThought, GLG, and receives institutional research funding from MacroGenics Inc., manufacturer of enoblituzumab. These relationships are managed by The Johns Hopkins University in accordance with its conflict of interest policies. E. Antonarakis has served as a paid consultant for Janssen, Astellas, Sanofi, Bayer, Bristol Myers Squibb, Amgen, Constellation, Blue Earth, Exact Sciences, Invitae, Curium, Pfizer, Merck, AstraZeneca, Clovis and Eli Lilly; and has received research support from MacroGenics, Janssen, Johnson & Johnson, Sanofi, Bristol Myers Squibb, Pfizer, AstraZeneca, Novartis, Curium, Constellation, Celgene, Merck, Bayer, Clovis and Orion. These relationships are managed by the University of Minnesota (Antonarakis' current institution) in accordance with their conflict of interest policies.

Journal Reference:

1. Eugene Shenderov, Angelo M. De Marzo, Tamara L. Lotan, Hao Wang, Sin Chan, Su Jin Lim, Hongkai Ji, Mohamad E. Allaf, Carolyn Chapman, Paul A. Moore, Francine Chen, Kristina Sorg, Andrew M. White, Sarah E. Church, Briana Hudson, Paul A. Fields, Shaohui Hu, Samuel R. Denmeade, Kenneth J. Pienta, Christian P. Pavlovich, Ashley E. Ross, Charles G. Drake, Drew M. Pardoll, Emmanuel S. Antonarakis. Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial. Nature Medicine, 2023; DOI: 10.1038/s41591-023-02284-w

https://www.sciencedaily.com/releases/2023/04/230410123651.htm

Biden trans-sports rule reverses the intent of the law it ‘enforces’

 Decades from now, when scholars are debating how the executive branch jumped the rails of any legislative accountability or rational rules, the new Biden administration Title IX edict should be the prime exhibit.

It is a sweeping expansion of regulatory power, not in the service of the original goal of the underlying statute, but in opposition to it.

This is brazen even for the Biden administration of the student-loan-forgiveness program and the rent moratorium. 

The new draft rule forbids blanket bans on transgender athletes competing in sports against athletes of their adopted gender, but allows, in theory, more narrowly tailored prohibitions.

This is being portrayed as a moderate, compromise approach to the issue. It is nothing of the sort.

The more fundamental issue, though, is that it lacks any foundation in the law. 

Congress passed Title IX ensuring equal access “on the basis of sex,” and President Richard Nixon signed it into law in 1972.

The idea that Nixon and leaders in Congress — the likes of Tip O’Neill and Hale Boggs, Mike Mansfield and Robert Byrd — considered sex the same as gender identity is too ridiculous for words.

No one began seriously conflating the two until recently.

“The Department expects that sex-related criteria that limit participation of some transgender students may be permitted, in some cases,” the DOE fact sheet says.

AP/Jacquelyn Martin

If justice demands that Title IX encompass gender identity, then the solution is very simple — Congress should amend the statute.

Why bother with such Schoolhouse Rock notions, though, when Title IX can be rendered infinitely malleable?

First, the Biden administration last year redefined the law, without any warrant, so that “sex” includes “stereotypes, sex characteristics, pregnancy or related conditions, sexual orientation, and gender identity.”

And now there’s going to be an entire new regulatory regime devoted to ensuring the participation of trans athletes in sports meets the Biden administration’s standards. 

Congress passes a law protecting and encouraging women’s sports, and lo and behold, 50 years later the law is being used to ensure as many males as possible are competing against females. 

Here the road to hell isn’t even paved with good intentions, but bad-faith interpretations of the law imposed by people who know they can’t win democratic assent for their cultural agenda. 

The order tilts all one way. As a Department of Education fact sheet says, “the Department expects that sex-related criteria that limit participation of some transgender students may be permitted, in some cases.”

That makes it sound like such limits will be the exception rather than the rule — and for good reason. 

University of Pennsylvania athlete Lia Thomas received backlash as a transgender athlete after dominating in women’s swimming competition.

AP/John Bazemore

Congress passed Title IX ensuring equal access “on the basis of sex,” and President Richard Nixon signed it into law in 1972.

AP/John Hann

School districts and colleges are going to have to undertake what The New York Times calls “a multipronged assessment of whether or not to restrict transgender athletes from playing on their preferred team.”

They will have to evaluate criteria by sport, by level of competition and by grade and figure out whether a prohibition is “substantially related to the achievement of an important educational objective,” whatever that means.

A school’s rule will not pass muster, according to the department, if it “chooses not to minimize the harm” to transgender athletes. 

Given where the Biden administration is coming from on this issue, and the complexity involved, schools are going to default toward allowing male athletes to compete against women. 

When the final rule is issued, it will surely become even more proscriptive and the eventual enforcement regime will tighten up even further. Litigation by left-wing advocacy groups will add another layer of de facto enforcement.

The most physical sports — think football or wrestling — will likely remain separated by sex, but everything else will likely fall afoul of the new rule, or at the very least exist under a pall of potential regulatory and legal headaches. 

The draft rule is an affront to Congress, an affront to federalism (it clearly targets the roughly 20 states that have bans on males competing against females) and an affront to girls and women who simply want to compete against one another when they play sports.

The executive branch is now more beholden to woke imperatives than to the US constitutional system.

https://nypost.com/2023/04/10/biden-trans-sports-rule-reverses-the-intent-of-the-law-it-enforces/

Novel insights on brain development sequence through adolescence

 Brain development does not occur uniformly across the brain, but follows a newly identified developmental sequence, according to a new Penn Medicine study. Brain regions that support cognitive, social, and emotional functions appear to remain malleable—or capable of changing, adapting, and remodeling—longer than other brain regions, rendering youth sensitive to socioeconomic environments through adolescence. The findings were published recently in Nature Neuroscience.

Using magnetic resonance imaging (MRI), researchers charted how developmental processes unfold across the human brain from the ages of 8 to 23 years old. The findings indicate a new approach to understanding the order in which individual brain regions show reductions in plasticity during development.

Brain plasticity refers to the capacity for neural circuits—connections and pathways in the brain for thought, emotion, and movement—to change or reorganize in response to internal biological signals or the external environment. While it is generally understood that children have higher brain plasticity than adults, this study provides new insights into where and when reductions in plasticity occur in the brain throughout childhood and adolescence.

The findings reveal that reductions in brain plasticity occur earliest in "sensory-motor" regions, such as visual and auditory regions, and occur later in "associative" regions, such as those involved in higher-order thinking (problem solving and social learning). As a result, brain regions that support executive, social, and emotional functions appear to be particularly malleable and responsive to the environment during early adolescence, as plasticity occurs later in development.

"Studying brain development in the living human brain is challenging. A lot of neuroscientists' understanding about brain plasticity during development actually comes from studies conducted with rodents. But rodent brains do not have many of what we refer to as the association regions of the human brain, so we know less about how these important areas develop," said corresponding author Theodore D. Satterthwaite, MD, the McLure Associate Professor of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania, and director of the Penn Lifespan Informatics and Neuroimaging Center (PennLINC).

To address this challenge, the researchers focused on comparing insights from previous rodent studies to youth MRI imaging insights. Prior research examining how neural circuits behave when they are plastic uncovered that brain plasticity is linked to a unique pattern of "intrinsic" brain activity.

Intrinsic activity is the neural activity occurring in a part of the brain when it is at rest, or not being engaged by external stimuli or a mental task. When a brain region is less developed and more plastic, there tends to be more intrinsic activity within the region, and that activity also tends to be more synchronized. This is because more neurons in the region are active, and they tend to be active at the same time. As a result, measurements of brain activity waves show an increase in amplitude (or height).

"Imagine that individual neurons within a region of the brain are like instruments in an orchestra. As more instruments begin to play together in synchrony, the sound level of the orchestra increases, and the amplitude of the sound wave gets higher," said first author Valerie Sydnor, a Neuroscience Ph.D. student.

"Just like decibel meters can measure the amplitude of a sound wave, the amplitude of intrinsic brain activity can be measured with functional MRI while kids are simply resting in the scanner. This allowed our team to study a functional marker of brain plasticity safely and non-invasively in youth."

Analyzing MRI scans from more than 1,000 individuals, the authors found that the functional marker of brain plasticity declined in earlier childhood in sensory-motor regions but did not decline until mid-adolescence in associative regions.

"These slow-developing associative regions are also those that are vital for children's cognitive attainment, social interactions, and emotional well-being," Satterthwaite added. "We are really starting to understand the uniqueness of human's prolonged developmental program."

"If a brain region remains malleable for longer, it may also remain sensitive to environmental influences for a longer window of development," Sydnor said. "This study found evidence for just that."

The authors studied relationships between youths' socioeconomic environments and the same functional marker of plasticity. They found that the effects of the environment on the brain were not uniform across regions nor static across development. Rather, the effects of the environment on the brain changed as the identified developmental sequence progressed.

Critically, youths' socioeconomic environments generally had a larger impact on brain development in the late-maturing associative brain regions, and the impact was found to be largest in adolescence.

"This work lays the foundation for understanding how the environment shapes neurodevelopmental trajectories even through the teenage years," said Bart Larsen, Ph.D., a PennLINC postdoctoral researcher and co-author.

Sydnor elaborated, "The hope is that studying developmental plasticity will help us to understand when environmental enrichment programs will have a beneficial impact on each child's neurodevelopmental trajectory. Our findings support that programs designed to alleviate disparities in youths' socioeconomic environments remain important for brain development throughout the adolescent period."

More information: Valerie J. Sydnor et al, Intrinsic activity development unfolds along a sensorimotor–association cortical axis in youth, Nature Neuroscience (2023). DOI: 10.1038/s41593-023-01282-y

https://medicalxpress.com/news/2023-04-reveals-insights-brain-sequence-adolescence.html

Gut microbiota, Alzheimer's and the central nervous system

 University of Nevada, Las Vegas, researchers have identified a correlation between Alzheimer's disease and specific gut microbiota populations. In a paper published in Scientific Reports titled "Genetic correlations between Alzheimer's disease and gut microbiome genera," the researchers explain how they narrowed the search down to a half dozen disease-correlated microbes, with one related to the most significant risk.

The study authors point to a growing body of research suggesting that disruptions in regular ratios and lower diversity of gut microbiota are associated with neurodegenerative diseases via neuroinflammatory processes across the microbiota-gut-brain axis. Previous studies have also indicated that Alzheimer's patients have just such reduced microbiome diversity.

Researchers used polygenic risk scores, a risk assessment based on known genetic correlations to disease, of 119 microbiome species for each individual from a discovery sample of 1,278 cases with 1,293 controls. They found that 20 out of the 119 genera were significantly associated with Alzheimer's disease diagnosis.

Among the 20 significant species, six were identified as likely risk species and the other 14 potentially protective species for Alzheimer's diagnosis.

Risk genera included Alistipes and Bacteroides from the Bacteroidetes phylum, Lachnospira and Veillonella from the Firmicutes phylum, and Collinsella from the Actinobacteria and Sutterella from the Pseudomonadota phyla. The most significant risk-associated species was Bacteroides.

For protective species, 11 out of 14 were from the Firmicutes phylum, two were from Actinobacteria, and one was from Bacteroidetes (Prevotella 9). The most significant protective genus was Intestinibacter.

These findings alone would make for an interesting paper, but the researchers seemed more interested in doing good science, so they challenged their results with a follow-up analysis.

A second database was used from GenADA, a multi-site Canadian collaboration study of Alzheimer's patients. The same techniques were used to find correlations between the microbiota in 799 cases with 778 controls. The data from this replication study differed from the first in some areas, but where the two experiments overlapped in four significant correlations pointed to the most likely culprit.

APOE4

Apolipoprotein E (APOE) is the central nervous system's major cholesterol and lipid carrier protein. Of the three major human versions of the protein, APOE2, APOE3, and APOE4, the genetic expression of APOE4 is one of the most significant risk factors linked to the development of late-onset Alzheimer's disease.

When the researchers looked deeper into the overlapping microbial associations with Alzheimer's, they found that these patients had something else interesting in common. Polygenic risk scores of the four microbiota species had significant associations with a specific version of the APOE genotype rs429358-C.

Collinsella from the phylum Actinobacteria was identified as a risk factor for Alzheimer's in both the discovery and replication samples and had the most significant associations with the APOE genotype at rs429358-C.

The paper points out that previous studies have found that Collinsella correlates with higher serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol in healthy adults, which the researchers speculate may be connected to interactions between Collinsella and APOE.

The researchers conclude that future research is needed to explore the relationship between Collinsella, lipid metabolism, and inflammatory signals to elucidate how their interaction influences Alzheimer's and other diseases.

More information: Davis Cammann et al, Genetic correlations between Alzheimer's disease and gut microbiome genera, Scientific Reports (2023). DOI: 10.1038/s41598-023-31730-5

https://medicalxpress.com/news/2023-04-gut-microbiota-alzheimer-central-nervous.html

Mild COVID during pregnancy does not slow brain development in babies: study

 Columbia researchers have found that babies born to moms who had mild or asymptomatic COVID during pregnancy are normal, based on results from a comprehensive assessment of brain development.

The findings expand on a smaller study that used maternal reports to assess the development of babies born in New York City during the first wave of the pandemic. That study found no differences in brain development between babies who were exposed to COVID in utero and those who were not exposed.

For the new study, the researchers developed a method of observing infants remotely, adapting a developmental assessment tool that is typically administered in person to make the study COVID-safe (babies were assessed between March 2021 and June 2022). The researchers studied 407 infants between 5 and 11 months of age from three geographic areas: New York City, Salt Lake City, Utah, and Birmingham, Alabama. Overall, nearly a third of the infants were born to mothers who had COVID during pregnancy.

Before the evaluation, each of the participating families received the same set of baby toys and food items so that the researchers could observe and compare the babies' fine and gross motor skills in a standardized fashion. The researchers also assessed cognitive and language skills. They did not know which babies had been exposed to COVID in utero.

"The idea for our novel method to assess development remotely came from Columbia clinicians who quickly began performing telehealth visits at the start of the pandemic in an effort to continue to deliver high-quality care in safe ways," says study leader Dani Dumitriu, MD, Ph.D., assistant professor of pediatrics and psychiatry at Columbia University Vagelos College of Physicians and Surgeons.

"But over time, we also realized that evaluating the babies remotely would allow us to observe how the babies were developing in their home environment, which may actually offer a better idea of how the infants are developing than when we see them in the research lab, where they may be scared or anxious."

The researchers found that babies whose mothers had mild or asymptomatic COVID-19 at any point during pregnancy were developing similarly to those whose mothers had never had COVID.

"The current study, which used a more rigorous method to evaluate babies born during the pandemic, provides further reassuring evidence that having a mild or asymptomatic case of COVID during pregnancy does not affect brain development in infants," Dumitriu says. "Additional studies are needed to tell us about the impact of more severe COVID on a developing infant's brain."

The paper is published in the journal JAMA Network Open.

More information: Morgan R. Firestein et al, Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy, JAMA Network Open (2023). DOI: 10.1001/jamanetworkopen.2023.7396

https://medicalxpress.com/news/2023-04-mild-covid-pregnancy-brain-babies.html

Collapsed Complexity Predicts Heart Attacks And Market Reversals

 By Dhaval Joshi of BCA Research

Executive Summary

• The world we inhabit, physiologic systems, and even the healthy functioning of markets are all founded on complexity.

• The complexity arises from the number of crucial interacting drivers that are driving the system.

• When this complexity collapses, it is warning that some of the crucial drivers are not working sympathetically.

• Therefore, the collapsed complexity of a heartbeat is a warning of cardiac risk.

• In the financial markets, the collapsed complexity of price action is an excellent predictor of market turning-points – rebounds after depression, and reversals after euphoria.

• Right now, some rebound candidates are USD/CZK, TSN and CVS.

• And some reversal candidates are Gold and GE.

The world we inhabit, physiologic systems, and even the healthy functioning of markets are all founded on complexity. So, when this complexity collapses, it is a warning of impending tail-events, heart attacks, and reversals in the markets. But what is complexity, and how do we know when it has collapsed?

Measuring Complexity, And Its Collapse

Intuitively, the complexity of any structure can be measured by the length of its shortest description. This intuition was codified as long ago as the 14th century in the principle of Occam’s Razor, which states that the simplest explanation is the shortest one. Hence, if the shortest description is long, it indicates complexity. But if it is short, it indicates a lack of complexity. Consider the following three patterns of daily returns:

-4, 1, -2, 0, 5, 4, 1, 5, -2, -3, 1, 4, -1, 1, 5, 1

1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, -1

1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1

The first pattern we cannot describe in any shorter way than writing out the string in full. The shortest description is long,  signifying complexity.

The second pattern we can describe as ‘14 1s, then 3, then -1.’ A much shorter description, signifying low complexity.

The third pattern we can describe as just ‘16 1s’. The shortest possible description, signifying no complexity.

Can we go one step further and formalize this complexity more precisely? The answer is yes. The so-called ‘fractal  structure’ or ‘fractal dimension’ of a structure or pattern is the mathematical measure of its complexity, with 1 indicating no complexity and a number higher than 1 indicating increasing complexity (Box 1).

The first pattern has a fractal dimension of 1.34, confirming its complexity. The second pattern has a fractal dimension of 1.04, confirming its low complexity. And the third pattern has the lowest possible fractal dimension of 1, confirming it has no complexity.

What do these dimensions 1.34, 1.04, and 1 represent? The answer is they measure how much extra information you see by looking at the whole pattern through a magnifying glass. In the first pattern, zooming in on the differing daily returns  provides 1.34 times more information. Thereby, it exhibits some complexity. By contrast, in the third pattern, zooming in on the 16 consecutive ‘1s’ provides no extra information. It exhibits no complexity (A fractal dimension is a scaling rule comparing how a pattern's detail changes with the scale at which it is considered. This is what we mean by complexity).

Collapsed Complexity Predicts Heart Attacks

If all this sounds like abstract mathematics, think again. It is a matter of life or death. A collapsed complexity of your heartbeat is a warning sign of an impending heart attack. Medical researchers point out “the output of healthy physiologic systems reveals complexity, as measured by a high fractal dimension. This complexity appears to degrade with ageing and disease. Further, this collapse in complexity may be quantified, with applications for diagnosis and prognosis.”

What is the source of this complexity? The answer is that it arises from the number of distinguishable interacting drivers that are driving a system. A healthy heartbeat exhibits high complexity – a high fractal dimension – because the heartbeat is the output of many interacting parts of the heart working sympathetically. The result is complexity (Figure 1).

Unfortunately, when this complexity collapses, it is warning that some of the crucial drivers are not working sympathetically, and therefore presages cardiac risk (Figure 2).

For subjects at high risk of sudden death, fractal organization breaks down. Application of fractal analysis may provide new approaches to assessing cardiac risk and forecasting sudden cardiac death, as well as to monitoring the ageing process.

So, the best piece of advice you get from me may not be investment advice. It may be medical advice. Get a fractal analysis of your heartbeat.

Collapsed Complexity Predicts Market Reversals

Just as the output of healthy physiologic systems reveals complexity, so does the output of healthy financial markets. And just as physiologic complexity arises from the sympathetic output of interacting parts, so does financial market complexity. But what are the interacting parts in the financial markets?

The interacting parts in the financial market are the different investment time-horizons.

A healthy market exhibits high complexity – a high fractal dimension – because the price action is the output of more than one investment time-horizon working sympathetically. This creates the price action’s complexity. Hence, when complexity and the fractal dimension collapse, it is a red flag that the time-horizons are no longer working sympathetically, and therefore presages a potential price rebound or reversal.

Essentially, a fractal dimension of a price action quantifies the relative contribution of the longer-term investor versus the shorter-term investor in driving that price action. For example, the 130-day fractal dimension compares the contribution of the 130-day investment horizon relative to the 1-day investment horizon in driving the 130-day price action. The lower the fractal dimension and complexity, the lower the contribution from the longer-term investor.

It follows that when the fractal dimension has collapsed to its lower bound, the longer-term investor is no longer driving the price action. It has become a pure short-term momentum market, characterised by a complete loss of complexity.

So just as fractal organization breaks down for the heart ahead of a sudden cardiac event, fractal organization also breaks down for investments ahead of a sudden reversal.

This is because if the short-term momentum is upwards and a shorter-term investor wishes to get off the trend, there are no more shorter-term investors left to sell to. The buyer must be a longer-term investor, who will buy only at a value-based lower price, catalyzing a price reversal.

Of course, there is the alternative possibility that the longer-term investor joins the mania (or depression), continuing the momentum market. But this is both theoretically and empirically a lower likelihood outcome.

Therefore, the collapsed complexity of price action is an excellent predictor of market turning-points – rebounds after depression, and reversals after euphoria.

Using this approach, recent successes include pinpointing the sharp rebounds in USD/HUF (Chart 1) and USD/SGD (Chart 2). And pinpointing the sharp reversal in Rio Tinto after the ‘China reopening’ induced euphoria (Chart 3). In fact, the approach has generated a 77 percent success rate over the past six months and a 68 percent success rate over the past year.

A full and evolving list of current investments exhibiting collapsed complexity – and therefore vulnerable to reversal or rebound – is available on our website: BCA Research - Counterpoint.

Right now, some rebound candidates are USD/CZK, TSN and CVS (Charts 4-6).

And some reversal candidates are Gold and GE (Charts 7-8).

Out of these, our chosen structured trade is to go long USD/CZK, setting a profit-target and symmetrical stop-loss of 5 percent.

But I will finish by repeating the much more important message. Get a fractal analysis of your heartbeat. It might save your life.

https://www.zerohedge.com/markets/collapsed-complexity-predicts-heart-attacks-and-market-reversals