Further evidence supports controversial claim that SARS-CoV-2 genes can integrate with human DNA

After being challenged, research team provides more data to back its controversial hypothesis but the relevance to human health is unclear

Science‘s COVID-19 reporting is supported by the Heising-Simons Foundation.

A team of prominent scientists has doubled down on its controversial hypothesis that genetic bits of the pandemic coronavirus can integrate into our chromosomes and stick around long after the infection is over. If they are right—skeptics have argued that their results are likely lab artifacts—the insertions could explain the rare finding that people can recover from COVID-19 but then test positive for SARS-CoV-2 again months later.

Stem cell biologist Rudolf Jaenisch and gene regulation specialist Richard Young of the Massachusetts Institute of Technology, who led the work, triggered a Twitter storm in December 2020, when their team first presented the idea in a preprint on bioRxiv. The researchers emphasized that viral integration did not mean people who recovered from COVID-19 remain infectious. But critics charged them with stoking unfounded fears that COVID-19 vaccines based on messenger RNA (mRNA) might somehow alter human DNA. (Janesich and Young stress that their results, both original and new, in no way imply that those vaccines integrate their sequences into our DNA.)

Researchers also presented a brace of scientific criticisms, some of which the team addresses in a paper released online today by the Proceedings of the National Academy of Sciences (PNAS). “We now have unambiguous evidence that coronavirus sequences can integrate into the genome,” Jaenisch says.

SARS-CoV-2, the virus that causes COVID-19, has genes composed of RNA, and Jaenisch, Young, and co-authors contend that on rare occasions an enzyme in human cells may copy the viral sequences into DNA and slip them into our chromosomes. The enzyme, reverse transcriptase, is encoded by LINE-1 elements, sequences that litter 17% of the human genome and represent artifacts of ancient infections by retroviruses. In their original preprint, the researchers presented test tube evidence that when human cells spiked with extra LINE-1 elements were infected with the coronavirus, DNA versions of SARS-CoV-2’s sequences nestled into the cells’ chromosomes.

Many researchers who specialize in LINE-1 elements and other “retrotransposons” thought the data were too thin to support the claim. “If I would have had this data, I would have not submitted to any publication at that point,” says Cornell University’s Cedric Feschotte, who studies endogenous retrovirus chunks in the human genome. He and others also said they expected higher quality work coming from scientists of the caliber of Jaenisch and Young. In two subsequent studies, both posted on bioRxiv, critics presented evidence that the supposed chimeras of human and viral DNA traces are routinely created by the very technique the group used to scan for them in chromosomes. As one report concluded, the human-virus sequences “are more likely to be a methodological product, [sic] than the result of genuine reverse transcription, integration and expression.”

In their new paper, Jaenisch, Young, and colleagues acknowledge that the technique they used accidentally creates human-viral chimeras. “I think it’s a valid point,” Jaenisch says. He adds that when they first submitted the paper to a journal, they knew it needed stronger data, which they hoped to add during the review process. But the journal, like many, requires authors to immediately post all COVID-19 results to a preprint server. “I probably should have said screw you, I won’t put it on bioRxiv. It was a misjudgment,” Jaenisch says.

In the new PNAS paper, the team provides evidence that artifacts alone can’t explain the detected levels of virus-human chimeric DNA. The scientists also show that portions of LINE-1 elements flank the integrated viral genetic sequence, further supporting their hypothesis. And they have collaborated with one of the original skeptics, Stephen Hughes of the National Cancer Institute, who suggested an experiment to clarify whether the integration was real or noise, based on the orientation of the integrated viral sequences relative to the human ones. The results support the original hypothesis, says Hughes, a co-author of the new paper. “That analysis has turned out to be important,” he says.

“The integration data in cell culture is much more convincing than what was presented in the preprint, but it’s still not totally clean,” says Feschotte, who now calls Jaenisch’s and Young’s hypothesis “plausible.” (SARS-CoV-2, he notes, can also persist in a person for months without integrating its genes.)

The real question is whether the cell culture data have any relevance to human health or diagnostics. “In the absence of evidence of integration in patients, the most I can take away from these data is that it is possible to detect SARS-CoV-2 RNA retroposition events in infected cell lines where L1 is overexpressed,” Feschotte says. “The clinical or biological significance of these observations, if any, is a matter of pure speculation at this point.”

Jaenisch’s and Young’s team do report hints of SARS-CoV-2 integration in tissue from living and autopsied COVID-19 patients. Specifically, the researchers found high levels of a type of RNA that is only produced by integrated viral DNA as the cell reads its sequence to make proteins. But, Young acknowledges, “We do not have direct evidence for that yet.”

Harmit Malik, a specialist in ancient viruses in the human genome at the Fred Hutchinson Cancer Research Center, says it’s a “legitimate question” to ask why people who should have cleared the virus sometimes have positive polymerase chain Reaction tests for its sequences. But he also remains unconvinced that the explanation is integrated virus. “Under normal circumstances, there is so little reverse transcription machinery available” in human cells, Malik says.

The controversy has grown decidedly more civil since December. Both Young and Jaenisch say they received more intense criticism for their preprint than any studies in their careers, in part because some researchers worried it played into the hands of vaccine skeptics spreading false claims about the newly authorized mRNA vaccines. “If there ever was a preprint that should be deleted, it is this one! It was irresponsible to even put it up as a preprint, considering the complete lack of relevant evidence. This is now being used by some to spread doubts about the new vaccines,” Marie-Louise Hammarskjöld, a microbiologist at the University of Virginia, posted in a comment on bioRxiv at the time.

And what of the original journal submission? “They rejected it,” Jaenisch says. source

A terrarium is a self-sustaining miniature ecosystem, capturing a slice of nature within glass. With the right conditions, terrariums can last for years, creating a thriving environment for plants to grow with minimal maintenance. But just how long can a terrarium live? Some have been known to survive for decades, even over a century, without intervention. The longest-living terrarium on record has been growing strong for more than 60 years, proving that with the right balance of water, light, and airflow, a terrarium can thrive indefinitely.

In 1960, David Latimer planted a tiny garden inside of a large glass bottle and sealed it shut. He opened the bottle 12 years later in 1972 to add some water and then sealed it for good. The self contained ecosystem has flourished for nearly 60 years.
For those who are wondering how this is even possible: the garden is a perfectly balanced and self-sufficient ecosystem. The bacteria in the compost eats the dead plants and breaks down the oxygen that is released by the plants, turning it into carbon dioxide, which is needed for photosynthesis. The bottle is essentially a microcosm of earth.

the plant used in this long experiement is tradescantia

The World’s Oldest Terrarium

The longest-living closed terrarium was planted by David Latimer in 1960. He sealed the glass container in 1972, and since then, it has remained almost completely untouched. Despite being watered only twice in over 50 years, the terrarium has continued to thrive. The plants inside recycle nutrients through a self-sustaining water and air cycle, proving how resilient a closed ecosystem can be.

The Glass Container and Initial Setup

Latimer used a 10-gallon glass carboy, a large, globular glass jug originally intended for storing liquids. On Easter Sunday in 1960, he carefully placed composted soil at the base of the carboy, along with a small amount of water. To plant the cuttings inside, he used a piece of wire to lower them through the narrow opening. The jar was sealed with a greased cork stopper, ensuring an airtight environment. Twelve years later, in 1972, Latimer decided to open the bottle just once to add a bit more water. Since then, the terrarium has remained sealed, functioning entirely as a self-sustaining ecosystem without any outside interference.

The Self-Sustaining Ecosystem

Inside the carboy, the spiderwort plant (Tradescantia) has thrived by cycling water, nutrients, and air. The plant’s leaves release moisture through transpiration, which condenses on the inside walls of the glass and falls back into the soil creating a miniature water cycle. The fallen leaves decompose naturally, providing essential nutrients for continued growth.

Despite being completely sealed, the ecosystem continues to regulate itself. During the day, the spiderwort undergoes photosynthesis, producing oxygen, while at night, it consumes oxygen and releases carbon dioxide. The balance of gases, along with decomposing organic matter, has allowed the terrarium to sustain itself for over 60 years.

David Latimer’s Perspective

Latimer originally created the terrarium as an experiment, inspired by the bottle garden craze of the 1960s. He never expected it to last for decades but was fascinated by its self-sustaining nature. The terrarium has been kept in the same spot in his home, about six feet from a window, where it receives only indirect sunlight. Occasionally, he rotates the bottle to ensure even light exposure, but otherwise, it requires no care. Over the years, the terrarium has drawn interest from scientists and gardening enthusiasts alike. It has been cited as an example of how plants could sustain themselves in closed environments, similar to the concept of self-sustaining life support systems in space exploration.

Latimer’s Own Reflections and Statements

David Latimer has shared his personal impressions of the terrarium in various interviews, especially after the story caught public attention around 2013. For many years, the bottle garden quietly sat in his home (in the hallway under the stairs) without fanfare. Latimer eventually sent a photograph of the flourishing sealed garden to the BBC Radio program “Gardener’s Question Time” in the early 2010s, asking the panel of experts if his bottle garden was of any scientific or horticultural interest. This sparked media interest in his experiment – soon reporters and scientists were inquiring about the 50-year-old terrarium. The story was covered in major outlets like The Daily Mail and The Times, and Latimer, then about 80 years old, gave interviews describing the history of his unique houseplant.

It’s true that Latimer created a self-sustaining ecosystem inside a sealed bottle in 1960 that survived for more than half a century.

In speaking about his sealed terrarium, Latimer has emphasized how effortless its care really is. He has called it “the definition of low-maintenance,” noting that he’s “never pruned it” and essentially does nothing beyond occasional turning of the bottle. The plant seems to have self-regulated its growth once it filled the space, so there’s little for a gardener to do. In fact, Latimer humbly admitted that the bottled garden is “incredibly dull and doesn’t really do anything” on a day-to-day basis there are no dramatic changes to observe in a given week or month. However, he remains deeply proud and fascinated by its long-term survival. Latimer has expressed excitement to see “just how long it will last,” keeping the experiment going for as long as possible.

Now in his old age, he has even joked about the terrarium outliving him. He hopes to pass on this living bottle garden to his children in the future – and if his family isn’t interested in keeping it, Latimer has said he would like to donate the terrarium to the Royal Horticultural Society so that it can continue to be cared for and studied by others. Through his interviews and statements, David Latimer comes across as a pleasantly surprised caretaker: he started the project out of simple curiosity, and decades later he is as amazed as anyone that his sealed bottle terrarium is still green and thriving. It stands as a testament to nature’s resilience and the elegance of closed ecosystems, all born from one man’s idle experiment back in 1960.

Latimer, a retired electrical engineer from Surrey, England, created his bottle garden in 1960.

“At the time the chemical industry had changed to transporting things in plastic bottles so there were a lot of glass ones on the market,” Latimer told the Daily Mail in 2013. “Bottle gardens were a bit of a craze and I wanted to see what happened if you bunged the thing up.”

The concept was simple: He planted a spiderwort plant (tradescantia) inside a 10-gallon glass carboy and sealed it off from the outside world with a cork. He watered the plant once in 1972, and since then, the ecosystem has been entirely self-sustaining, requiring no further intervention.

The garden’s longevity testified to the principles of a closed ecological system. Inside the sealed bottle, the spiderwort plant undergoes photosynthesis — the process by which plants convert light energy into chemical energy to produce food and release oxygen — which sustains its own growth and the survival of microorganisms within the ecosystem. The water cycle is also self-contained, with moisture released by the plant condensing and returning to the soil. This self-sustaining cycle continued for more than 50 years.

“It’s 6ft from a window so gets a bit of sunlight. It grows towards the light so it gets turned round every so often so it grows evenly,” Latimer told the Daily Mail. “Otherwise, it’s the definition of low-maintenance. I’ve never pruned it, it just seems to have grown to the limits of the bottle.”

Latimer’s sealed bottle garden has sparked discussions about the potential applications of closed ecological systems in various fields, including space exploration and environmental conservation.

NASA’s research has shown that plants not only produce oxygen through photosynthesis but also help regulate carbon dioxide levels with their so-called air-scrubbing qualities, provide fresh food and even purify water, making long-duration space missions more sustainable and self-sufficient.

The Weather Channel’s story in 2016 was the last public update on the garden that Snopes could find; its status in 2024 was unclear. The Daily Mail reported that Latimer hoped to leave his bottle garden to his children, and if they didn’t want it he planned to donate it to the U.K.’s Royal Horticultural Society.

How Does a Terrarium Live for Decades?

The longevity of a terrarium depends on several key factors. When carefully designed, a terrarium can function like a miniature rainforest, where moisture, air, and nutrients continuously cycle through the system. Here’s how:

1. The Water Cycle A closed terrarium creates its own rain cycle. Water evaporates, condenses on the glass, and then drips back down to nourish the plants. This process prevents the need for frequent watering and ensures a steady supply of moisture.

2. Photosynthesis and Oxygen Exchange Plants in a sealed terrarium generate oxygen during the day through photosynthesis. At night, they release carbon dioxide. This natural cycle allows the terrarium to regulate itself without outside interference.

3. Decomposers Keep the Ecosystem Clean Fallen leaves and organic matter break down naturally, thanks to beneficial bacteria and microorganisms. These act as decomposers, recycling nutrients back into the soil, just as they would in a real forest.

4. Balanced Light and Temperature Terrariums need indirect light to keep the plants healthy without overheating the system. Excess heat or direct sunlight can cause condensation to build up too quickly, potentially leading to mould or plant stress.

Can Your Terrarium Live Forever?

In theory, a well-maintained terrarium could last indefinitely. If the balance of light, water, and nutrients remains stable, the ecosystem will continue cycling without the need for human intervention. However, external factors like overwatering, insufficient light, or an imbalance in plant life can shorten its lifespan.

To give your terrarium the best chance at longevity:

Choose hardy plants that thrive in humid environments, such as moss, ferns, and fittonia. Avoid overwatering – a single watering when setting up the terrarium is often enough for months or even years. Provide indirect light to encourage healthy photosynthesis. Monitor for mould and remove any decaying plant matter to maintain a healthy balance.

The longest-living terrariums prove that a well-balanced, closed ecosystem can last for decades with little to no care. Whether you’re starting your first terrarium or looking to improve your current one, focusing on the right conditions can help it thrive for years to come.

Thinking about making your own long-lasting terrarium? Explore our shop for DIY terrarium kits, beautiful glass containers, and everything you need to create a self-sustaining world of your own. source

The Sigma Male: Traits, Characteristics & FAQs

You have most likely heard the term “sigma male” before, and wondered what on Earth that even means, and what personality traits make him unique.

In this blog post we are going to break down what a sigma male is. We will talk about male archetypes, in particular the alpha male archetype vs the sigma male archetype, and discuss their differences.

We will also list some of the signs and characteristics of a sigma male.

And lastly, we will see whether you can see yourself as the lone wolf!

Definition: What is A Sigma Male?

The archetypal sigma male is a term used to describe a man who can rely upon himself, is successful, self-reliant and feels comfortable spending time alone.

Sigma males are seen as lone wolves – although not in the negative way a lot of us tend to think of “lone” people.

As we mentioned above, most of you will most likely put alpha males at the top of hierarchy.

And you most likely are correct.

However, that does not mean that a sigma male is beneath an alpha.

Actually, alpha and sigma males are pretty equal.

The major difference being that sigma males like to live their lives outside of the normal hierarchy structure.

They neither want to lead nor follow, but rather be on their own.

Even if a sigma male has all the abilities to lead, or to be the one in a social group of people that everyone admires, they prefer to be away from all of that.

A sigma male can walk alone, and be 100% comfortable doing his own thing, in his own way.

Another really interesting trait which is found amongst sigmas is that they never require validation by others.

This could be in the form of a new job title, or having a title within a community.

Many refer to sigmas as “lone wolves” or “lone wanderers”.

Just like the alpha, the sigma is seen in the eyes of others as someone with high status.

There are, however, a few noticeable and obvious differences between sigma and alpha males.

But there are also quite a few common traits which both sigmas and alphas share.

Let’s breakdown some of the common traits and differences between sigma males and alpha males.

Common Traits Between Sigmas & Alphas

Some common similarities between sigma and alpha males include:

• Self confidence is at a high level
• Seen as attractive by others
• Posses leadership qualities
• High level of intelligence

Sigma males could go down the path of becoming alpha males if they chose to. They definitely possess the qualities needed.

But for most, the life of a sigma is just too much of an attractive way of life to give up.

Sigma males do not want to be in the position of the alpha.

They don’t want to be at the top of some sort of social ladder, where many people look up to him.

https://youtu.be/p-B4SMTyptE

Main Differences Between Sigmas & Alphas

Below are a few ways in which sigma males are different to alpha males:

• Sigma has no reason to maintain any type of appearance
• More comfortable being alone for longer periods of time
• No need to rise to the top of any social ladder
• A lot more independent
• Great at listening to what others have to say
• Does not seek out a lot of friends. Sigmas carefully select a few friends
• Not invested in making and maintaining tribal connections
• Sigma thinks freely and independently

The differences are pretty obvious, but they are still interesting.

If you think you might be a sigma male, then keep on reading!

Is A Sigma Male Better Than An Alpha Male?

As you will see in the diagram below shortly, it’s hard to say whether a sigma male is better than an alpha male.

This is because whilst the alpha male sits at the top of the social sexual hierarchy, the sigma male stays completely out of the social hierarchy by choice.

 

Where On The Socio Sexual Hierarchy Does The Sigma Male Fit?

Whilst the sigma male is seen as a “lone wolf”, if you take a look at the graphic below, you’ll see that he is equal to the alpha male.

Just because you like to march to the beta of your drum, and prefer to stay away from big social groups and trying to be seen as the leader, does not mean you cannot be top dog.The graphic above really simply illustrates how an alpha and sigma are on the same level.If you aren’t sure whether you think you might be a sigma or alpha, then check out some of the common signs you might just be a sigma.

The Main Traits Of A Sigma Male

Below are a few signs of sigma men.

You might be able to use these signs and traits to determine if you are a sigma male or not.

Let’s get cracking!

#1: Does Not Conform

We start off with definitely one of the big traits of all sigma males.

They do not like to conform, and do things the way they feel they should.

You won’t see a sigma following a leader, or being happily told what to do on a daily basis.

On top of that, sigmas don’t follow the crowd.

They actually often tend to go the other way, and make this decision solely based on their honest thoughts.

No outside pressures will affect a sigma’s decision.

They stay true to their own, internal values and beliefs.

Bottom line is, a sigma won’t go down a path or follow something because their friends or family are expecting that of them.

#2: Self Sufficient

Being self sufficient is one of the strongest traits found in any sigma.

Sigmas enjoy wandering off by themselves, often travelling the world or just being alone in strange places for weeks at a time.

They have the ability to adapt and feel really comfortable in any of these situations or environments.

No one feeds them.

No one gives them money.

They are their own men.

They submit to no one, and go out and get something whenever needed.

They truly are “lone wolves”, and I mean that in a high regard!

#3: Treat People Equally

Sigma males tend to get along with people from all different social levels.

They are genuine when engaging with other people, no matter how high or low the people are on the social ladder.

Whereas an alpha male wants to exert a form of dominance or get something out of someone, sigmas are happy to just treat people all as equals.

#4: Adaptable

This one goes hand in hand with being self sufficient.

When a sigma finds himself in a new, strange situation, he can quickly adapt and make himself comfortable.

Regardless of the company he finds himself in, he can easily go with the flow and be part of the conversation or situation.

An alpha differs in this situation.

He isn’t as comfortable being placed into any social situation, especially if it involves people that he may see as a threat.

So if a sigma finds himself at a table filled with various personalities, he can easily navigate his way around that.

And an alpha? Not so much.

#5: Comfortable Being Alone

Whilst the term “lone wolf” is often used to describe sigma males, it is often misunderstood.

A sigma is only a “lone wolf” to the degree that he is 100% comfortable with his own company, no matter where he is.

I actually think this is a skill more men need to learn.

Being alone and being completely comfortable whilst being alone is an awesome skill that really allows you and your mind a little down time.

#6: Self Aware

As sigmas have made the decision not to join the roles expected of them within a normal hierarchy, they have become a lot more self aware, and know what they want out of life.

Sigmas know what they are good at, what they are not good at, and what they want to do in life.

If they ever go wrong, they have the quick ability to self-correct.

This is due to their high level of self awareness.

#7: Small, Close Social Circles

Sigma males choose to rather have a really close circle of friends who they can trust 100%, instead of hanging out with larger crowds.

Usually, their friends see life the same way they do.

This has nothing to do with being anti social, rather they just prefer to have a select few set of friends.

#8: Don’t Seek Attention

Attention is never required for a sigma male.

Sigmas prefer to blend in, and often step into the background where they can rather observe and listen to any given situation.

#9: Not Driven By Outside Validation

Sigmas don’t strive for validation or getting a pat on the back.

This may be at their workplace, or just in life in general.

They do not want to be in the limelight.

In fact, you could go as far as saying that sigma males want to be invisible.

They don’t do a job to be told how great or poorly they did.

They don’t travel to other places across the globe to be able to brag about it.

Sigmas live their lives, based on how they want to.

#10: Quiet

This is definitely a predictable trait of a sigma male, especially considering the above information.

As sigmas prefer to stand back and listen and observe, they tend to be a bit more held back when speaking.

This isn’t due to the fact that they are shy or unsocial.

It’s more to do with the fact that they prefer to think deeply before speaking.

#11: Self Priority

This might come across as selfish to a certain degree, but it actually isn’t.

A sigma male has his own personal goals and objectives, and will work hard to achieve these goals.

Whereas an alpha also does have goals and objectives, he would often prioritize highly valued people of their social circle over themselves.

A sigma just wants to be left alone, and work on his dreams and aspirations.

They don’t care how they are perceived by others.

They just want to achieve whatever it is he sets out to achieve.

#12: Don’t Get Jealous

I recently read an article about women dating sigma men, and the jealousy topic was brought up.

In general, sigma males are not the jealous type.

This is down to the fact that they have faith in their decision making, and they too enjoy spending time alone.

A sigma male will give his partner space, as he too enjoys this same space.

#13: Introvert

The sigma is more introverted than the alpha male.

Sigma guys prefer spending time alone rather than being in crowds all the time. Whilst they are comfortable being in social groups, they often choose to spend time alone.

Being alone gives sigma guys time to think more, and be more in tune with his thoughts and feelings.

#14: Good Listener

If you think about when you are in a group conversation with an alpha, he usually tends to try and always dominate the conversation.

A sigma, on the other hand, will usually rather listen and give a thoughtful response.

Some might see sigmas as being more of the “silent type”. However, they just seem to be better listeners, intently listening to someone, and giving you his full attention.

Why Do Girls Like Sigma Men?

Women in general are drawn to sigma men for a number of reasons.

As you will know by now after reading this article, a sigma man is a confident, comfortable and self sufficient man who needs no external validation whatsoever.

This also means that he is willing to walk away from situations which he doesn’t want or need.

This in itself is extremely attractive to women.

Females like a confident guy who is independent, and this shows both of those traits.

Sigmas also are not jealous, clingy or needy. These traits alone make them desirable.

On top of all of that, a sigma is somewhat mysterious. And women like this too!

Benefits Of Being Sigma Male

Walking your very own path, not following the crowds and being a bit of a “lone wolf” definitely has many benefits.

For me personally, there are two really big benefits that are clear.

#1: Freedom

Freedom is definitely the biggest benefit that comes from being a sigma.

When you don’t even care to pay attention to what other people think about you or the way you live your life, you definitely will feel a lot more freedom.

Both mentally, emotionally and probably physically too.

The sigma lives life on his own terms, and never bends to what others might have to say.

This is the ultimate freedom – going about life on your terms 100%.

Draw

#2: Efficient

As a sigma, you don’t live life based on what is expected of you.

You don’t keep up with the crowd. Nor do you follow the crowd in any way, shape or form.

And with this comes a high level of efficiency.

You get shit done.

And you get shit done quickly.

This is due to the fact that you are used to being your own captain, and trying to achieve anything you set your sights on.

Drawbacks Of Being A Sigma Male

Although there are a few benefits that come with being a sigma, there are also a few drawbacks.

You could probably imagine what some of these drawbacks might be, but for this article I want to focus on the main drawback of being a sigma male – you have no tribe, so it can get lonely.

Sigmas by definition do not need a tribe. They don’t have to be the leader of the pack. They are their own pack.

And this is great.

But it can also get lonely.

It’s kind of funny that the best thing about being a sigma and the worst thing is the same – you are a lone wolf.

But remember you can transition and create a tribe.

Just because you are a lone wolf today doesn’t mean it has to be like this for life.

Sometimes we need to live the sigma male lifestyle for a bit, though, in order to focus on what we want to achieve in life.

Can You Go From Alpha Male to Sigma Male?

I honestly do believe you can.

We are not ever supposed to constantly be the same man.

Time happens.

Things happen.

And people change.

I think I can speak from personal experience in saying that you can rather easily, without even knowing it, go from being more of an alpha male to a sigma male.

Up until a few years ago, I had many traits that would say I leant more towards being an alpha.

But I then started travelling and backpacking solo for about two years, and things started changing without me even noticing.

I started enjoying being alone more, I loved the peace and quiet, and my thoughts about my own life became more clear.

Ever since then, I have been on the path to becoming a sigma male.

And I love it! source

What Are “Sigma Males”

You’ve probably come across a strong and dominating alpha male at least once in your life. This character trait appears to be the focus of both men and women focus. Although men are taught to behave like alphas, some break the rules and still manage to be desirable. So, believe it or not, alpha guys aren’t always what they seem. The sigma male characteristics is a new kind that we will introduce to you.

Now let’s talk about Sigma Males

A sigma male is a guy who does not require external approval. He’s not boisterous, but rather calm and composed. A sigma man is an introverted but self-assured individual. Sigmas are out of the ordinary, and they don’t usually fit into groupings since they are unique.

Who is better, Alpha male or Sigma male?

Both alpha and sigma males have several features in common. They’re both self-assured in their life choices and strive for greatness. The biggest distinction is in their mentality. Sigmas like to be at the bottom of the hierarchy, whereas Alphas prefer to be at the pinnacle. Climbing the hierarchical pyramid is how the latter attain success. Sigmas, on the other hand, have no affiliation with any group. They are self-sufficient in every way. In many scenarios, Sigmas rule the game.

5 Major Traits of a Sigma Male

• Expectations are unimportant to them –

Alphas are the leaders, betas are the disciples, and sigmas, well, they just don’t fall into the category. For sigmas, authority is pointless, and all of society’s (including alphas’) rules and tendencies are irrelevant. You can’t teach them how to act or dress. They are free to do anything they choose.

• They are rebellious to the rules

Sigma males, like alphas, fight with power. Sigmas are generally self-employed and place a great value on tranquility and flexibility. They should operate alone since they are capable of managing their time and arranging themselves.

• They don’t look for approval

Extravagances aren’t necessary for Sigma males to feel fulfilled and accomplished. They realize that economic goods can’t replace self-worth; therefore they don’t strive to legitimize themselves with pricey items. So they operate whatever they want, dress whatever they want, and don’t follow the orders of the alphas.

• They are modest rulers

Sigma males are lone wolves who can transform into great leaders in the appropriate conditions. They are an inspiration to others because of their devotion and enthusiasm. High-ranking Sigmas are never arrogant or arrogant, which is why they are admired.

• They place a high value on their personal lives

Sigma males are particular about their habits, and nothing irritates them more than someone who is overbearing. They don’t live up to others’ expectations. Sigmas will only change if they genuinely want to.

Why Sigma Male is Trending?

“What the fuck is going on with men?” asked Twitter user @LilySimpson1312 on January 25th, 2021, alongside many photos of Sigma Males. In less than 24 hours, the tweet had received over 25,000 retweets, 11,000 quote-tweets, and 190,000 likes. Many of the comments to the tweet laughed about the over-classification of males in social contexts, indicating that it was many people’s first introduction to the notion of “Sigma Males.” source

The Sigma Male Explained: Understanding the Lone Wolf

What is a sigma male? (Sigma male definition)

A sigma male is a man within the socio sexual hierarchy who chooses to live his life outside of the normal social dominance hierarchy structures of society. Sigma males share many traits in common with the alpha archetype, though their tendency to walk outside of the lines of traditional social dominance hierarchies sets them apart and makes them different.

The archetypal sigma male is defined above all else by his tendency to forsake the traditional social dominance hierarchies of modern society.

These men walk a more solitary path. They’re sometimes called ‘lone wolves’ or ‘wanderers.’

The socio sexual hierarchy, originally attributed to Vox Day, is a system for describing how men and boys relate to one another and organize themselves into different archetypes.

These archetypes categorize men based on who they are, how they behave, what their inclinations are likely to be, and how they’re perceived by women in the sexual marketplace.

But today, we’re going to go beyond the sigma male meaning and answer the pressing question that likely landed you here:

Where Does the Sigma Male Fit on the Socio Sexual Hierarchy?

The exact role of the ‘Sigma Male’ archetype in modern socio sexual hierarchy is somewhat hotly debated. But for all intents and purposes, it describes a man who goes his own way—living as a lone wolf.

I’ve found that the term is often used in conjunction with MGTOW philosophy (men going their own way). Men who believe in the MGTOW movement tend to identify strongly with the sigma archetype.

They see the idea of walking away from social dominance hierarchies and becoming a lone wolf as synonymous with the MGTOW mandate of walking away from both women and a society which has been quote “destroyed by feminism” end quote (I didn’t say it—that’s just one perspective).

But despite the obvious ideological link between the sigma male archetype and MGTOW, that’s not the only filter through which to view the true identity of the sigma male.

To get a truly accurate view of exactly how a sigma fits into the modern socio sexual hierarchy, we need to pull the lens back and take a larger look at how the different male archetypes fit together.

What Motivates the Sigma Male?

If the alpha male is the king, and if he’s served by a court filled with beta males, then the sigma male is the traveling bard, storyteller, or wanderer who visits the king.

He may dine with the king. He may even hold the king’s favor. His exploits or successes, while not necessarily well known, may earn him respect and admiration.

He doesn’t take a wife. Instead, he sleeps with his pick of the most beautiful women from the king’s court and then leaves as quickly as he arrived to continue his journey.

For the sigma, the journey itself is the true goal. This is what he lives for.

Unlike the betas, he doesn’t lust for the king’s power or favor. In fact, he probably truly doesn’t care if the king likes or dislikes him—because those things are meaningless to him as a sigma.

He also frees himself from the trappings and challenges of trying to compete with the betas.

Why?

Because, once again, he just doesn’t care enough about the social dominance hierarchy to bother with trying to secure himself a place within it.

Sigma Male vs Alpha Male

Unlike the alpha king, the sigma has no reason to maintain a certain public appearance. He has no incentive to please the masses or to appease anyone else’s opinion.

Also unlike the alpha king, he has little interest in competing within the social dominance hierarchy to rise to the top of the social order.

The sigma male willingly forfeits the benefits of the alpha position.

He does this because he sees the benefits of the sigma archetype as superior when you filter them for costand value.

Unlike the alpha archetype, the sigma doesn’t have to play political games or run every thought process through a tribe mentality filter to produce the results he wants in life.

He’s as self-sufficient as men can get. Alphas are also self-sufficient—though part of their self-sufficiency comes from their investments into the social dominance hierarchies that they choose to be a part of.

Alpha males typically spend more resources building tribes and climbing through the hierarchies.

As a result, they reap the rewards of strong tribalconnections, tribal resources, and higher social status. 

The returns on these tribal investments are doubtlessly valuable. But the alpha also takes on a great deal of responsibility, stress, and effort in exchange for these benefits.

This is even documented among Chimpanzee tribes.

This talk may be about chimpanzees, but human alphas aren’t so different.

The sigma male shuns the social responsibilities of the alpha (at least in theory).

He sees the resource investments into the tribe as high-risk, low reward. The sigma also sees the delicate framework of the social dominance hierarchy as a fragile house of cards.

He chooses to walk away from it because he sees it as smarter and more self-sufficient than hedging his bets on what other unreliable humans may choose to do.

This is perhaps an oversimplification—but it serves to lay the groundwork for the basis of the sigma male archetype, and how it typically fits in with alpha and beta archetypes.

Personality Differences Between the Alpha and the Sigma

It doesn’t take a rocket scientist to see that sigma males and alpha males also tend to have very different temperamentsand personality types. 

And these personality types definitely play into which archetype a man will gravitate toward.

For example—I’m an alpha male. But I intentionally choose this path because several of my strongest personality traits give me huge strengths in the alpha archetype arena.

For example:

• I’m highly extroverted
• I have a natural talent for reading people
• People energize me
• I have strong natural leadership skills
• I have high emotional intelligence
• I’m highly empathetic

If I were to walk away from the dominance hierarchy and go my own way as a sigma male, I would fail to maximize the returns on my most significant personality strengths.

Plus, since people energize me, I would probably be exhausted by the solitary life of the wandering sigma.

Sure, these personality traits could all help me as a sigma male. But in the end, after taking my personal strengths into account, it’s a far more valuable use of my natural talents and abilities to pursue the path of the alpha.

As an alpha male who exists at the top of several dominance hierarchies in my life, I would be forfeiting my biggest personality-type advantages by choosing to walk the path of the sigma male.

It’s important to understand that the sigma mentality, much like the alpha mentality, is a mentality that fits certain types of men very well.

If a man embodies some or all of the natural sigma traits as his dominant personality traits, then he would stand to gain the most from choosing to live his life according to the sigma male archetype.

Which do Women Prefer?

This is one of the first questions I usually hear when I talk about alpha and sigma archetypes.

The truth is that both types of men can do extremely well with the ladies—albeit for different reasons.

Alpha Male Advantages With Women

Alpha males have high status and power. These are benefits that sigma males are automatically going to struggle with because both of these benefits are closely tied to existing at or near the top of the social dominance hierarchy.

It’s no secret that women love men with high status and power.

The reasons for this are fairly obvious. But I believe that David M. Buss described it best in the following quote from his book The Evolution of Desire: Strategies of Human Mating:

Evolution has favored women who prefer men who possess attributes that confer benefits and who dislike men who possess attributes that impose costs.

High status and power confer numerous benefits. And so, an alpha male who exists at the top of the social order is automatically at an advantage when it comes to attracting the attention of the highest value women in the tribe.

If you want to learn how to achieve this and more importantly, keep women interested in you long-term, check out my Dating & Masculinity Transformation System.

Sigma Male Advantages With Women

Sigmas bring a few of their own advantages to the table.

Foremost, sigmas are characterized by the mystery and fluidity of their solitary lives. But they’re also characterized by how they’re impossible to ‘tie down’into a normal relationship.

The unattainability of a prolonged and secure romantic relationship with a sigma male sets them apart from betas, and even from alphas to a certain extent.

And both of these attributes drive women crazy (in a good way).

In fact, Esther Perel describes the relationship between mystery and desire quite poetically in her book Mating In Captivity: Unlocking Erotic Intelligence. 

Love enjoys knowing everything about you; desire needs mystery. Love likes to shrink the distance that exists between me and you, while desire is energized by it. If intimacy grows through repetition and familiarity, eroticism is numbed by repetition. It thrives on the mysterious, the novel, and the unexpected.

When coaching men, I often talk about the importance of cultivating mystery when building connections and sexually escalating with women.

Some men really struggle with building mystery. It requires a certain level of quiet confidence that few men possess.

Alphas need to work a bit harder at this than sigma males do. Sigma males tend to cultivate it more naturally due to their off-the-beaten-path approach to life.

Another powerful advantage that sigma males have in the dating marketplace is that they don’t care about social hierarchy.

This gives them a ‘rebel’ type of vibe that many women find incredibly sexy.

One look at the character Han Solo, played by Harrison Ford in the Star Wars movies, will tell you exactly what I mean!

7 Traits of a Sigma Male

To fully understand the sigma male archetype, you need to closely examine the most predominant sigma male traits.

I feel like he does a pretty good job of describing some of the more predominant sigma traits.

With that being said, these 7 traits describe the most distinguishing personality features of men who fit into the sigma male archetype.

Let’s jump in and talk about them.

1. Non-Conformity

Above all else, the true sigma male is a nonconformist. He marches to the beat of his own drum.

If the crowds are following the path to the right, the sigma will tend to strike out on his own and go left. 

There are many reasons why this is the case. Firstly, it’s because Sigma males value different things than other men.

Almost every other archetype is going to place a priority on how a certain action or trend will affect their societal status.

But sigmas are an outlier on this front. They systematically rule out societal pressures and expectations as useless.

Their decisions are based purely on the intrinsic value of what they’re pursuing, rather than the extrinsic value placed upon something by society or the masses. 

2. Self-Sufficiency and Independence

The sigma male is perhaps the most self-sufficient of all the male archetypes.

It’s not uncommon for sigma males to wander or travel. They may not even own a house or an apartment. They may be just as comfortable with nothing but a backpack of essentials as they would be with a home of their own.

The reason for this is that sigmas are strong natural survivors.

Since sigmas are almost always ‘lone wolves,’ they quickly adapt to taking care of themselves.

They feed themselves. They earn their own money. They pay their own bills. They provide themselves with their own company, nurturing, companionship, and value in life.

If they want something, they go out and get it. If they need something, they find a way to acquire it on their own.

They call no other man ‘master,’ and they submit to no one.

3. They Don’t Need the Social Hierarchy to Thrive

To me, this is one of the most fascinating traits of the sigma.

Sigma males are definitely loners. But that doesn’t mean that they never spend time with other people.

They may work standard jobs. They may even spend time with friends, family, and/or dating partners.

All of these situations require a certain level of assimilation into their respective social dominance hierarchies—and the sigma male rises to the challenge in a truly effective fashion.

But make no mistake. He’s also capable of escaping reliance upon these hierarchies. 

In other words—he may go to work and do his work dutifully.

But he’s never dependent upon his boss, his co-workers, or the income to maintain his life or happiness.

If he grows tired of that specific workplace, walking away is easy for him.

Even if he’s well-liked and well-respected by the other members of those hierarchies, he naturally avoids entangling himself in such a way that walking away would be problematic for him.

This is the nature of the sigma male. He’s always ready, willing, and able to walk away and strike out on his own.

4. Adaptability

Sigma males are highly adaptable by nature.

In fact, sometimes their adaptability is so natural and convincing that they may give off the appearance of true assimilation into the hierarchy. 

For example—a sigma male who starts attending Catholic Church services may start to wear a crucifix, carry a rosary, and observe Catholic rites.

He may even attend events as regularly as any other member of the Church.

But don’t mistake this temporary social participation for permanent assimilation into the hierarchy.This is what makes the sigma different from the alpha.

The alpha male will be constantly aware of how his actions within the Church will affect his position at the top of the hierarchy, because his position within the hierarchy is valuable to him.

A sigma, on the other hand, rejects all notions of climbing the hierarchy. If he assimilates to any degree, it’s probably because he finds some measure of personal value in it—or because he wishes to share in the experience for his own enjoyment, fulfillment, or benefit.

You can also be sure that he’s fully capable of walking away from it without a second thought. And at some point, he probably will.

5. Self-Priority

The sigma male puts his own dreams and happiness over everyone and everything else.

This may sound similar to the ideology of the alpha—and to a point, it’s very similar. But there’s one profound difference.

Alpha males will alwaysprioritize highly valued members of their tribe over themselves.

For the alpha, tribal investments often take precedence over his own wants, needs, and desires. This is part of the sacrifice of being the alpha.

But sigma males reject the notion that tribal investments will lead to worthwhile benefits.

They’re also unconcerned with appearances, or how they’re perceived by others.

They don’t want anything to do with the tribe unless the tribe serves a rational, practical purpose for them in the short term.

You’re much more likely to find the sigma male alone in his apartment, working on his business or his goals.

He prioritizes these goals over everything else in life.

Even when he dates, he doesn’t date to take care of a woman or to enter into a ‘typical’ relationship.

He’s a free spirit. He dates for enjoyment, novelty, and new experiences—and because he’s a sexual being with sexual desires.

He’s perfectly willing to walk away from the relationship if it ever ceases to be worth the investment to him.

This is how the sigma male prioritizes himself at all times.

6. They Love to Be Alone Because Companionship Slows Them Down

Sigma males often see companionship as a hindrance to what they truly want in life.

Since they care very little about how others perceive them, human relationships are often tedious and meaningless to them.

For the sigma, it’s glaringly obvious that companionship also comes withbaggage.

It also tends to offer very little to no value to counterbalance this baggage.

Sure, sigmas may develop a few close, intimate friendships that truly enrich their lives. But aside from this, most humans aren’t going to be worth their time or effort.

Besides, traveling with companions is more expensive, requires more effort, and is less efficient.

Couple this with the fact that sigmasare naturally fast-moving when motivated, and you’ll quickly realize that most humans can’t keep up with them anyway.

I have one friend who is a sigma male. He’s very careful about how he spends his socialization time.

I message him about every two weeks to see if he wants to hang out. Last time I messaged him, this is how he responded:

“Hey Josh what’s up. Thank you for the invite, but I’m not ready to meet up just yet.”

He takes control of his social energy and uses it exactly as he wants to use it.

I respect it, and we have a very fruitful and rewarding friendship as a result.

Further Reading

Why Do I Want a Girlfriend So Bad? 11 Likely Reasons and What to Do Next

Come learn the natural masculine truth for why you want a girlfriend so bad and learn what to do with that desire to help you land the girl of your dreams.

7. They Don’t Need Attention and Strive to Be Invisible

This is perhaps the most often misunderstood sigma male trait.

Sigma males actually strive to be invisible. 

At work, they neither neednor desire recognition for their effort or performance.

They would much rather just be left alone to fulfill their duties in peace.

They don’t strive to be in the limelight. They don’t want people to look at them and think highly or poorly of them.

They don’t need their good deeds to be known or published. They don’t want a public image, and they don’t care if anyone recognizes them or not.

Why?

Because sigmas aren’t driven by outside validation or praise. 

They’re loners. The trappings of society and the praise of fellow humans hold little to no value for them.

They live the majority of their lives in their own mind. 

They don’t travel to other countries to brag about it to their friends. They’re just as likely to travel, return, and never mention it to anyone else. 

They don’t publish blog posts because they hope to become famous.

If they publish a blog post, it’s because they wanted to publish it for their own creative expression and enjoyment. 

Perhaps Most Importantly: Don’t Mistake the Sigma’s Rejection of Society as a Response to Being Hurt or Alienated

That is actually an omegatrait and isn’t to be confused with sigma behavior.

Sigmas don’t reject society because they were hurt and are now shunning themselves or feeling sorry for themselves.

Unlike omegas, sigmas have not given up on society out of frustration.

They reject society for one reason and one reason alone:

They never caredabout itin the first place.

Benefits of a Sigma Male Lifestyle

There are many benefits to walking the path of the sigma. Here are the 3 most compelling advantages of choosing to journey through life as a lone wolf.

Freedom

The main benefit of living the sigma male lifestyle is freedom. 

Releasing yourself from the burden of caring about what other people think of you gives you the inner power to live life unapologetically on your terms. 

This encapsulates many of the benefits of being a sigma—and is perhaps the number-one thing that true sigma men care about most.

Attraction

Women are drawn to the sigma male archetype for many reasons.

First off, sigma males are always willing to walk away.

This is a highly attractive trait to women because it shows that the man is confident and likes himself enough to be content with his own company.

This is a serious high-value marker and exists at the opposite end of the spectrum from unattractive traits like clinginess, neediness, and desperation.

Women are also intensely attracted to novelty and mystery—and the nomadic sigma male fits this stereotype perfectly.

In fact, in the first chapter of their highly acclaimed book Why Women Have Sex, Cindy M. Meston and David M. Buss say this:

Indeed, a certain amount of “mystery” can be sexually motivating for women, or for men for that matter. Not only can mystery stoke attraction; too much familiarity can squash it. As one woman said in her sexual memoir, “proximity can kill sex faster than fainting.”

Efficiency

As a sigma male, you’re not bound to the usual ‘trappings’ of society, expectations, or normal societal pressures.

Therefore, instead of wasting a bunch of time and money ‘keeping up with the Joneses,’ you can live life on your own terms, go where you want, move at your own pace, and spend your resources to further your ownpersonal goals and plans.

Sigma males aren’t dependent upon anyone else’s viewpoint or judgment. Therefore, the need to impress other people goes right out the window—allowing them to be 100% genuine and authentic.

Drawbacks of Being a Sigma Male

Unfortunately, as with every other archetype, sigma males do face some challenges.

They Don’t Have A Tribe

This is probably the number-one downside to being a sigma. And while it’s possible to mitigate this one with some forethought and planning, it’s stillimportant to note.

There are many benefits to being part of a tribe. Friendship, companionship, safety in numbers, having people to help you and take care of you when you’re sick, etc.

Walking away from the social dominance hierarchy certainly comes with some upsides. But the biggest downside is exactly the same as the biggest upside:

You’re alone. 

For this reason, some sigmas don’t see the lone wolf sigma male lifestyle as a lifelong pursuit.

These men pursue the ‘wanderer’s life’ as younger men, and then transition back into tribal living as they start to get older.

There are a lot of benefits to having a family, a community, a home base, and a support network. And while the dangers of being a lone-wolf are mostly minimized in our modern culture, they’re still present—and they’re still a factor.

Some Sigmas End Up Creating Their Own Dominance Hierarchies, And Become Their Own Version Of An ‘Alpha’

A perfect example of this is the man who works alone in his office or bedroom to build his business.

But once he has amassed his wealth, he may build a larger company and hire employees to help him.

He builds a team and a tribe—and in so doing, creates his own dominance hierarchy.

He’s still free to live the life he wishes—but he also inherits many of the benefits of being an alpha at the same time. source

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Sigma Male – Everything You Should Know About Him!

SUMMARY
A Sigma male is a confident and self-reliant man who likes to stay alone.

A sigma male aka the lone wolf is a confident, self-reliant, charming, mysterious, and introverted man. He’s not ready to commit to anyone and only has a few friends in his life.

He’s almost the same as an alpha male but he doesn’t have a pack following him. He loves risks and adventures and is a self-aware man. So, if you want to know more about him, keep reading!

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Sigma Male Traits

If you know a sigma male in your life, you probably feel that you hardly know him… after all, he’s so introverted and hardly expresses himself. So, to know him even better, know his personality traits and understand him here…

1. He doesn’t want to belong anywhere

The sigma male is an introvert and likes to spend time in solitude. He doesn’t want to be in any kind of group… neither as a follower nor as a leader.

Within a group, he must pay attention to everyone’s interests. Others will depend on him to perform according to their standards. He doesn’t fancy the endless responsibilities.

He’s comparable and sometimes even better than an alpha. So, he can easily be the leader and enjoy many benefits. But he prefers dancing to the beat of his own drum.

2. He never tries to prove himself to others

The sigma man knows about his capabilities. He’s extremely aware that he can beat any alpha male around him. He has enough faith in himself and hardly ever tries to convince others about that.

He doesn’t value others’ validation or appreciation to feel good about himself. Instead, he only proves his worth to himself. If he ever doubts his capabilities, he challenges himself in different ways.

3. He rebels against social norms

A sigma male is also known to be morally gray. Now, don’t assume that he’s a criminal, it’s rather a difference in opinions. He doesn’t follow the traditional norms which makes no sense. Instead, he violates them to test their truthfulness.

He never follows rules forcibly until they have legit reasons. He doesn’t want to be a good guy that plays by the rules. He’s pretty much an anti-hero.

4. Silence is valuable to him

Sigma men love silence as it helps them in multiple ways. Due to their introversion, they dislike speaking a lot. They also dislike any sort of superficial small talk. However, when they break the silence, it’s always something important.

In silence, they can also observe their surroundings better. This also turns them into good listeners. So, if you want to vent out to someone, these men know how to make others feel better.

So, your social media feed is buzzing with sigma male memes and rules? Wondering what it even means? Or, did someone say you’re a sigma male?

Whoa there… even if you want to know something else about sigma males, wait up. Well, whatever your question might be, this think-piece is a comprehensive guide for all of them.

Your curiosity about a sigma male will be quenched here, so you won’t return disappointed.

C’mon, let’s start exploring…

Table of contents  hide 

Sigma Male Infographic

What is a Sigma Male?

Sigma Male Traits

Strengths and Weaknesses of a Sigma Male

Pros and Cons of being a Sigma Male

Sigma Male vs Alpha Male

Sigma Male vs Beta Male

Sigma Male vs Delta Male

Sigma Male vs Gamma Male

Sigma Male vs Omega Male

Sigma Male Celebrities

Sigma Male Zodiac Signs

Sigma Male at Work

Sigma Male Careers

Sigma Male Relationship

Dating a Sigma Male

How to be a Sigma Male?

What to do if you’re a Sigma Male?

How to identify you’re a Sigma Male?

How to deal with a Sigma Male?

FAQs about Sigma Male

A word from ThePleasantPersonality

Sigma Male Infographic

What is a Sigma Male?

SUMMARY
A Sigma male is a confident and self-reliant man who likes to stay alone.

A sigma male aka the lone wolf is a confident, self-reliant, charming, mysterious, and introverted man. He’s not ready to commit to anyone and only has a few friends in his life.

He’s almost the same as an alpha male but he doesn’t have a pack following him. He loves risks and adventures and is a self-aware man. So, if you want to know more about him, keep reading!

Sigma Male Traits

If you know a sigma male in your life, you probably feel that you hardly know him… after all, he’s so introverted and hardly expresses himself. So, to know him even better, know his personality traits and understand him here…

1. He doesn’t want to belong anywhere

The sigma male is an introvert and likes to spend time in solitude. He doesn’t want to be in any kind of group… neither as a follower nor as a leader.

Within a group, he must pay attention to everyone’s interests. Others will depend on him to perform according to their standards. He doesn’t fancy the endless responsibilities.

He’s comparable and sometimes even better than an alpha. So, he can easily be the leader and enjoy many benefits. But he prefers dancing to the beat of his own drum.

2. He never tries to prove himself to others

The sigma man knows about his capabilities. He’s extremely aware that he can beat any alpha male around him. He has enough faith in himself and hardly ever tries to convince others about that.

He doesn’t value others’ validation or appreciation to feel good about himself. Instead, he only proves his worth to himself. If he ever doubts his capabilities, he challenges himself in different ways.

3. He rebels against social norms

A sigma male is also known to be morally gray. Now, don’t assume that he’s a criminal, it’s rather a difference in opinions. He doesn’t follow the traditional norms which makes no sense. Instead, he violates them to test their truthfulness.

He never follows rules forcibly until they have legit reasons. He doesn’t want to be a good guy that plays by the rules. He’s pretty much an anti-hero.

4. Silence is valuable to him

Sigma men love silence as it helps them in multiple ways. Due to their introversion, they dislike speaking a lot. They also dislike any sort of superficial small talk. However, when they break the silence, it’s always something important.

In silence, they can also observe their surroundings better. This also turns them into good listeners. So, if you want to vent out to someone, these men know how to make others feel better.

5. He gets women even without trying

Sigma males don’t talk a lot about themselves and seem mysterious to women. Since they go against the grain women can’t help but feel intrigued by them. They want to solve this masculine mystery and have them.

However, sigma men never chase or even try to grab women’sllar attention. Moreover, they don’t even want to commit too fast to anyone. This is partly because they treasure their freedom and just can’t tie themselves down. Partly, they don’t want to settle for shallow relationships.

6. Self-awareness and self-improvement are his forte

The sigma male isn’t delusional at all. He’s one of the best or even better than an alpha. But, he doesn’t assume that he’s invincible. Instead, he knows about his flaws and eagerly works on those. He always desires to become better than his present self.

If anyone constructively criticizes him, he doesn’t feel offended, unlike the alpha male. Instead, he’s glad to have genuine critics.

7. He tries to blend in as much as possible

A sigma man doesn’t want any attention at all. In social situations, he tries to merge with the crowd as much as possible. He doesn’t want anyone to notice him. He’s introverted and hates depthless conversations.

He usually avoids any sort of social setting. But whenever he attends them, he tries to blend in or take refuge in an inconspicuous corner. However, the lone wolf often gains unwanted attention due to his charismatic vibe.

8. He’s a trendsetter without following them

The sigma male is infamous for looking down on trends. Whether it’s the new trends on social media or the latest fashion, he can’t care any less.

So, fitted shirts are more popular nowadays? He’ll still wear his shirts as they are without any alteration. While everyone posts their achievements on social media, he won’t even be active online.

Since he’s so different and still mysterious and successful, he always sets new trends.

9. Hierarchy is not his thing

According to Vox Day’s socio-sexual hierarchy, the alpha males are the most powerful while beta, delta, gamma, and omega follow behind. A sigma male despises and rebels against this concept. He’s an avid believer in equality and judges nobody based on their social status.

He doesn’t cower in front of people with high status. But he’s always grateful and kind to the working class and service workers. To him, everyone is equally intelligent in different areas of their lives.

10. He won’t compromise without benefits

A sigma male is understanding and compassionate. If needed, he adjusts with others whenever needed instead of getting mad and delaying the process. However, he adjusts with others only when that’ll benefit him. He won’t ever help others if he’ll be on the losing side completely.

Just like an anti-hero, he won’t save the world just out of goodwill. He must see something equally beneficial in it to do it.

Wondering if he’s a flawless person or if he has any imperfections at all? Let’s know it here…

Strengths and Weaknesses of a Sigma Male

To sum it up, human beings aren’t ever flawless. So, even the wonderful sigma male isn’t all that wonderful all the time. His personality has some legit issues too. But first, let’s know some strengths here…

Strengths

1. He’s self-reliant

The sigma male doesn’t depend on others for anything. He dislikes group activity because it makes him dependent on others’ performance to reach his goals.

He doesn’t like following a leader as he can’t do things his way. So, he depends solely on himself to fulfill his desires. He also doesn’t need others to show him right and wrong. Even if things don’t follow the plan, he never approaches others.

2. He doesn’t let others control his life

The sigma man is the master of his own mind and he aims to keep it that way. He won’t commit to a lover or take on a big group’s responsibilities. He’s not tied down by things, so he can unfurl his wings and charge toward his goals without second thoughts.

He detaches himself from others which seems selfish. However, this only helps him in the long run to reach unimaginable heights of success.

3. He’s peace-loving

A sigma male loves peace and silence. So, he can’t afford to have any sort of drama in his life. For that, he tries to keep his circle as small as possible. He’s close to a handful of people only.

He understands that everyone is different and has unique perceptions. So, more people with varied views will definitely misunderstand each other and create drama.

To avoid unnecessary troubles, he gets close to as few people as possible.

4. He’s flexible

Alpha and beta males are pretty rigid. The alpha men never compromise and feel this sense of entitlement for being the best or the leader. They want to have everything their way.

On the other hand, beta men are just too lenient. Whenever there’s a clash of opinions, he always lets the other guy win. He never fights for himself and always gets the shorter side of the stick.

But sigma males know just what they need to do to work on a situation. They can be lenient and even fight for their demands and always maintain a balance.

5. He’s a friendly leader

Both sigma and alpha males are great leaders… but most people would like a sigma male leader more. The reason? Unlike alphas, he doesn’t expect others to follow his lead blindly.

He doesn’t abuse his power or treat others like puppets. He teaches others by practically setting examples. He doesn’t expect anyone to know everything and treats his team members kindly. Moreover, he doesn’t try to take others’ credit or hard work under his name.

After reading those, you might assume that a sigma male has no weakness. But let’s find the truth here…

Weaknesses

1. He’s a commitment-phobe

If you analyze the sigma male personality traits closely, you’ll notice that he’s emotionally unavailable. His guards are always up and he hardly lets others in his heart. He’s also not ready to settle down, commit to family or friends, or even trust others easily.

This leads to him being a commitment-phobe and having troubles in his relationships later on. Even if he falls in love, he might doubt his feelings. He’ll try to get away from others the moment he feels he’s slipping.

2. He’s socially awkward

A sigma male is an introvert and stays miles away from socializing. He doesn’t want any attention on himself at all. But at times, even they can’t ignore some situations and try to participate in small talk.

However, superficial conversation is just not his thing even if he tried. The lack of emotion in his replies and the straightforward dry conversation without flattery offend the other person. A sigma male faces many troubles due to poor social skills.

3. He might be alone forever

A sigma male can’t commit and is seldom ready to settle in romantic relationships. He’s picky and wants a serious connection when both he and his partner are ready for it. Moreover, he only has a handful of friends and doesn’t make new ones easily.

He’s bound to end up alone without a partner or a friend beside him in the later years. After all, it becomes harder to find a partner in the older years. On the other hand, his friends will become busy with their families. He’ll hardly have anyone around and might even suffer from it.

4. Luxury doesn’t motivate him

The spotlight, public appreciation, others’ validation, etc… doesn’t attract him. A sigma male has eccentric likes which others probably can’t offer or even think about.

It’s hard to motivate him with anything. In the workplace, his employers can’t make him work harder for their goals due to his lack of motivation. It can stunt his personal growth as nothing motivates him.

5. He can’t focus on one thing at once

Sigma males like adventures and one goal at once just don’t make it. So, they often try to have multiple goals in their lives. Even before one plan wraps up he fantasizes about other plans.

To add a hint of excitement and challenge, he’s ready to take up multiple goals. However, this might lead to major troubles if one or more plans don’t work out.

Pros and Cons of being a Sigma Male

Being a sigma male yourself brings you a lot of benefits. You’re one of the outstanding men around you and almost everyone wants to be like you. So, first, let’s know why they want to be like you

Pros

1. People never feel judged by you

When someone’s stuck in a negative situation, people always assume the worst about them. People of different races feel judged the most in these situations.

Others always have a negative notion about them based on race. They talk in absolutes like “I know all *** people are robbers” or “It was only a matter of time until these *** showed their true colors.”

However, you only ever judge after knowing the full truth. So, nobody feels unfairly treated around you.

2. You have high emotional intelligence

Your EQ is extremely high compared to alpha, beta, or other people. You can read the emotions of any room pretty fast.

This is also because you like silence and are a good listener. You know exactly what the other person wants to hear and can calm them with your sharp intuition.

People assume that you’re not good at emotional things and don’t even realize how wrong they are.

3. You’re self-motivated

Due to your sigma male personality traits, you’re blessed with extreme motivation. No amount of failure or blunder drags down your spirits. After every defeat, you only push through harder and stronger. When people criticize your plans and demotivate you, you don’t pay them any mind.

When it’s about your goals, you’re stubborn. This sets you apart from the rest and helps you thrive more than them in the long run.

4. You can deal with any storm

When situations worsen, people usually lose their minds and make more mistakes. However, you never let anything or anyone get the better of your emotions.

If someone tries to hurt you, you don’t react to them. You know that if you show your emotions, they’ll know your weaknesses. You keep a mask on, control your feelings and deal with tough situations.

You find ways to deal with situations by yourself. And once you’re prepared you deal with the troubles like the wolf you are.

5. You’re always ready to grab opportunities

Opportunities always appear in the form of crazy risks. So, most people are afraid of taking them. Even if they promise great growth, people are afraid of losing the existing peace and stability in their lives.

However, as a sigma male, you’re eager about the growth possibilities in your life. You don’t fear instability and charge right through which leads to your growth.

Despite many pros, there are also some cons to your personality. Most people don’t even know about it. So, learn the entire truth of your personality here…

Cons

1. Some treat you like a loner

You’re in love with solitude like if you had the option, you’d have married it. You feel energized when you’re alone.

However, others don’t get your feelings and assume that you’re pretending to be fine or trying to be optimistic. They pity you and force their company on you. But you only feel more uncomfortable with it.

You face such issues almost everywhere and you’re tired of explaining your likes to them.

2. People misunderstand your words

You’re a great person from the heart. You’re emotionally intelligent and intuitive, so figuring out others’ feelings is a piece of cake for you. When people want you to listen to them, you know exactly what to do.

However, when people make shallow conversations, you lose that touch. You can’t show fake emotions and flattery when you know the topic isn’t valuable to either of you. So, people often misunderstand you and get offended.

3. People don’t like your risk-taking nature

Sigma males love to take risks and live life on the edge. Without a little bit of challenge, they don’t feel that they are alive. They always seek a challenging job or take the harder path to enjoy the excitement.

Though it feels great for you, your choices make your loved one anxious. Though sigma males deny all responsibilities for freedom, someone depends on you. Their anxieties worsen your relationships.

4. Your romantic life is in a mess

You only settle for serious relationships and dislike modern-day casual dating and relationships. Usually, you don’t want to settle into romantic relationships, but once you do, you only have eyes for them.

However, your romantic partner can’t understand this because you don’t express yourself clearly. They doubt your feelings and test you out. Since you’re a considerate and dedicated partner, you can’t stand this and give them no second chance.

5. Your beloved solitude might become a curse later

Being an introvert, you love silence and solitude. This is the greatest gift anyone can ever give you. As a form of self-love, you avoid spending time with others, or else you feel drained. You don’t communicate much and try to keep your inner circle from growing.

You neither commit to lovers easily nor open yourself to prospective friends. Though your friends have time now, they eventually won’t.

You do almost the bare minimum like an alpha male. However, people often say you’re much like him. If you’re also curious about an alpha, let’s check here…

Sigma Male vs Alpha Male

Most say that sigma and alpha males have a lot in common. But they hardly notice the differences and you probably get offended when everyone assumes you’re just like an alpha. So, it’s time to compare yourself with alphas here…

1. Sigma males are flexible but alpha males are rigid

Sigma males are quite adaptable to any situation. If anything doesn’t work out, they know better than to put up fights. They don’t waste their time denying the truth. Instead, with a calm mind, they figure out ways to tackle their situation.

On the other hand, alpha males aren’t flexible at all. They want things to go their and only their way. They are rather stubborn and take too long to accept the truth.

2. Sigma males enjoy small circles unlike alphas

Sigma males are introverted and don’t like to socialize a lot. They also avoid drama and take responsibility for a lot of people. So, they feel more comfortable in a smaller circle. They let their guard down only around a few people and it takes a long time for them to bond.

On the flip side, alpha males are more into creating their own tribe. They expand their connections to grow their circle and dominate them.

3. Sigma males are listeners while alpha males are talkers

Sigma males like silence more than busy talkative moments. They can not only recharge better in silence, but they also focus on deeper aspects of life. So, they also become good listeners and can catch important facts way better than others.

But, alpha males aren’t into listening. They’d rather have others listen to them instead. They only want to boast about themselves, share their views, and have others focus on their words.

4. Sigma males stay low but alpha males attract attention

Sigma males want no attention in their life at all. Even if they make great achievements, they’ll never boast about it. Unlike others, they won’t even post it on social media.

They don’t want others’ validation and are content with just knowing these facts themselves. They even try to blend in any social situation as much as possible.

However, alpha males only want others to know about their power. They want to show others the difference between their positions.

5. They both get many suitors

Sigma males attract women due to their aloof nature. Women just can’t get enough of their mysterious aura. They chase them even though they’re not easy to get. They feel attracted to how down-to-earth they are even after being amazing in everything.

Women that seek a provider partner can’t resist alpha males. Since they take charge of everything and let others sit back, women feel protected around these men.source

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Sigma Male Traits

If you know a sigma male in your life, you probably feel that you hardly know him… after all, he’s so introverted and hardly expresses himself. So, to know him even better, know his personality traits and understand him here…

1. He doesn’t want to belong anywhere

The sigma male is an introvert and likes to spend time in solitude. He doesn’t want to be in any kind of group… neither as a follower nor as a leader.

Within a group, he must pay attention to everyone’s interests. Others will depend on him to perform according to their standards. He doesn’t fancy the endless responsibilities.

He’s comparable and sometimes even better than an alpha. So, he can easily be the leader and enjoy many benefits. But he prefers dancing to the beat of his own drum.

2. He never tries to prove himself to others

The sigma man knows about his capabilities. He’s extremely aware that he can beat any alpha male around him. He has enough faith in himself and hardly ever tries to convince others about that.

He doesn’t value others’ validation or appreciation to feel good about himself. Instead, he only proves his worth to himself. If he ever doubts his capabilities, he challenges himself in different ways.

3. He rebels against social norms

A sigma male is also known to be morally gray. Now, don’t assume that he’s a criminal, it’s rather a difference in opinions. He doesn’t follow the traditional norms which makes no sense. Instead, he violates them to test their truthfulness.

He never follows rules forcibly until they have legit reasons. He doesn’t want to be a good guy that plays by the rules. He’s pretty much an anti-hero.

4. Silence is valuable to him

Sigma men love silence as it helps them in multiple ways. Due to their introversion, they dislike speaking a lot. They also dislike any sort of superficial small talk. However, when they break the silence, it’s always something important.

In silence, they can also observe their surroundings better. This also turns them into good listeners. So, if you want to vent out to someone, these men know how to make others feel better.

5. He gets women even without trying

Sigma males don’t talk a lot about themselves and seem mysterious to women. Since they go against the grain women can’t help but feel intrigued by them. They want to solve this masculine mystery and have them.

However, sigma men never chase or even try to grab women’sllar attention. Moreover, they don’t even want to commit too fast to anyone. This is partly because they treasure their freedom and just can’t tie themselves down. Partly, they don’t want to settle for shallow relationships.

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Learn more about the Sigma Males …..

Alpha vs Sigma: The Dominant Sigma Male

What Sigma Men Hate! – The Ultimate Guide to Sigma Males

How To Become A High Value Man

Why is a sigma male so irresistible to women?

The Sigma Male Explained: Understanding the Lone Wolf

Sigma Males Destroy Controlling and Manipulative People

Why Are Sigma Males So Confident its Intimidating?

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Learn More About on Stoicism – The Stoic Man An Unstoppable Force to Reckon With…..

Want An Unconquerable Mind? Try Stoic Philosophy

What is Stoicism? A Definition & Stoic Exercises To Get You Started

9 Principles of Stoicism which will Improve your Life

A Complete Guide to Stoicism: How You Can Use this Ancient Philosophy to Live a Better Life

Stoicism, Virtue, and Mental Health

The Stoic Man – Indifference is a power – Stoicism 101

What is Stoicism and How Can it Turn your Life to Solid Gold?

Stoic Quotes on Control – The Absolute Man

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Other Men’s Health Topics Below

Good Habits That Will Help You Become Rich

How To Become A High Value Man

What every woman loves in a man?

 

Although this skin disease is prevalent, many people are still unaware of its impact. Unfortunately, there are many misconceptions about the disease; for example, that it is contagious.

What is Psoriasis?

Psoriasis isn’t just a skin disease; it is actually am autoimmune condition that has the potential to cause widespread systemic effects. These widespread systemic effects are most commonly described as effects on the skin, joints and heart. There are different forms of Psoriasis and some are more common than others.

Psoriasis is a chronic autoimmune disease that causes skin cells to multiply up to 10 times faster than normal. This makes the skin build up into bumpy red patches covered with white scales that can grow anywhere, but typically appear on the scalp, elbows, knees, and lower back. Psoriasis is not contagious nor is it caused or worsened by poor personal hygiene. Psoriasis may be inherited and can range from a very mild, hardly noticeable rash to a severe eruption that covers large areas of the body. Affiliated Dermatology’s Dr. Andrew Newman shares some facts about psoriasis:

“Although psoriasis is typically thought to be a condition that only affects the skin, it affects the ENTIRE body.  In fact, joint disease, heart disease, and depression are common features in psoriasis. It’s caused by many factors including genetic predisposition, certain medications, and some infections such as strep throat. People with psoriasis most often are regularly taken care of by a dermatologist.”

In some patients, psoriasis causes nail changes and joint pain (psoriatic arthritis). The first episode usually strikes between the ages of 15 and 35. This chronic condition will then cycle through flare-ups and remissions throughout the rest of the patient’s life.

What are the different forms of Psoriasis?

The most common form of the disease, plaque psoriasis, appears as raised, red patches covered with an accumulation of white dead skin cells. Other areas affected by the different types of psoriasis include the face, skin folds, hands, feet, genitals, and nails.

Most individuals will be afflicted with one form of Psoriasis at a time, there are known treatments for Psoriasis, but currently there is no known cure. Occasionally, when one form of Psoriasis clears up and symptoms reside, another form may appear due to exposure to a trigger. Triggers include but are not limited to; skin injury, stress, certain medications, infections, weather, diet and allergies.

1. Plaque Psoriasis – Plaque Psoriasis is the most common type of Psoriasis; it can also be called ‘Psoriasis Vulgaris’. This type of Psoriasis appears as red, inflamed patches of skin covered with a white or silvery buildup of dead skin cells (known as plaque). It can cause the skin to feel painful to the touch and itchy and typically effects the knees, elbows, scalp or lower back, however … it can occur anywhere on the body.

2. Inverse Psoriasis – Inverse psoriasis makes bright red, shiny lesions that appear in skin folds, such as the armpits, groin, and under the breasts.

Inverse Psoriasis appears as areas od shiny, red and inflamed skin. This type of Psoriasis is typically located in the folds of the body; under the arm pits or breasts, behind the knees, around the groin or even the skin folds that surround the genitals.

3. Guttate Psoriasis – Guttate psoriasis often starts in childhood or young adulthood, causes small, red spots, mainly on the torso and limbs. Triggers may be respiratory infections, strep throat, tonsillitis, stress, injury to the skin, and taking antimalarial and beta-blocker medications.

Guttate Psoriasis will more commonly present in childhood or amongst young adults. Symptoms appear as small pinkish-red spots or lesions, typically on the arms, legs and torso.

4. Erythrodermic Psoriasis – Erythrodermic psoriasis causes fiery redness of the skin and shedding of scales in sheets. It’s triggered by severe sunburn, infections, certain medications, and stopping some kinds of psoriasis treatment. It needs to be treated immediately because it can lead to severe illness.

This is one of the least common types of Psoriasis but it one of the most serious. More severe symptoms include severe burning, itching and peeling of the skin, changes in body temperature and a faster heart rate. If you believe you are suffering from this type of Psoriasis, see your doctor immediately, it can cause severe illness.

5. Pustular Psoriasis –  Pustular psoriasis causes red and scaly skin with tiny pustules on the palms of the hands and soles of the feet.  Pustular Psoriasis is another typically uncommon type of Psoriasis that mainly appears in older adults. Symptoms include pus-filled bumps, known as pustules, the surrounding skin can appear red and inflamed, oftentimes looking infectious (however, it is not). This type of Psoriasis can appear mainly on the hands and feet but can appear on other parts of the body as well. Symptoms of Pustular Psoriasis can include; nausea, fever, chills, muscle weakness, and rapid heart rate.

6. Psoriatic Arthritis – Psoriatic Arthritis is a variant of the condition where the individual has both arthritis (joint inflammation) and psoriasis. Typically, this condition appears years after the onset of Psoriasis symptoms. Symptoms can include; warm or discolored joints, swelling of the joints – fingers and toes, and stiff, painful joints that are worse after rest or in the mornings.

7. Nail Psoriasis – Nail Psoriasis is another variant of the condition and it more commonly affects those who are afflicted by Psoriatic Arthritis. Symptoms can include; painful, tender nails, color changes to the nails, a white chalk-like material under your nails, pitting of your nails, separation of the nail from the nail bed.

8. Scalp psoriasis can cause dandruff-like itching and flaking. Psoriasis happens when the immune system triggers too many skin cells to grow on various parts of the body. That can include your scalp. People with psoriasis may be more likely to get dandruff, but psoriasis is not dandruff.

Living with Psoriasis can affect your quality of life; however, certain treatments are available. You can work with your doctor to develop a plan of care and guide you in figuring out what your environmental triggers are or other lifestyle factors. Triggers and lifestyle factors could be the culprit behind flare-ups.

What causes Psoriasis?

Although psoriasis appears on the skin, it is an immune system disease that is not caused or worsened by poor personal hygiene. People with the disease have a genetic tendency to develop it. There are certain things that can trigger flare-ups including skin injury, stress, hormonal changes, infection, and medications. Most people with the disease experience cycles of clear skin and outbreaks. Dr. Dustin Mullens of Affiliated Dermatology spoke on how Psoriasis starts:

“The nervous system and stress affect a multitude of skin conditions in humans. There are many types of cells in the skin affected such as immune cells and endothelial cells, both can be regulated by neuropeptides and neurotransmitters, which are chemicals released by the skin’s nerve endings. Stress can result in the skin’s nerve endings releasing an increased level of these chemicals and when this occurs, it can lead to inflammation of the skin. This is why people often experience a flare-up of their inflammatory skin conditions such as psoriasis during times of stress.”Things that can trigger an outbreak of psoriasis include:

• Cuts, scrapes, or surgery
• Emotional stress
• Strep infections
• Medications, including
• Blood pressure medications (like beta-blockers)
• Hydroxychloroquine, antimalarial medication

Symptoms of Psoriasis

The truth is that there are many people with psoriasis who don’t even know they have it! Skin rashes are not uncommon so dermatologists need to rule out a list of other possible causes like an allergy to food/medication and viruses. Careful visual inspection is needed for diagnosing psoriasis, but sometimes there is a need for a skin biopsy.

Is infection a possibility? Infections are actually quite rare due to the fact that psoriasis itself is due to an overactive immune system. That being said, repeated scratching and excoriation can disrupt the skin barrier and facilitate bacterial invasion and is thus strongly discouraged. All patients with psoriasis should be seen at the very least annually by a dermatologist and when treatment and medications are ineffective at controlling disease severity and flares. Patients requiring systemic treatment should be seen every 3 months for check-ups while on these more sophisticated/complex medications.

How to Treat Psoriasis?

There’s currently no cure for this chronic autoimmune condition, but caring for psoriasis can slow down the growth of skin cells and relieve pain, itching, and discomfort. Treatment of psoriasis depends on a patient’s overall health, presence of joint pain, and severity of skin involvement. When asked about treatment for psoriasis, Dr. Newman shares,

“The type of treatment used depends on the total body surface area involved and severity, etc. In mild psoriasis, I think natural medicines work well. Some people find benefit from taking the natural anti-inflammatories quercetin and curcumin. Additionally, they may find that applying aloe vera gel to the skin does wonders. Lastly, sunlight also helps with mild psoriasis. That’s right, the UV rays of the sun decrease the skin inflammation in psoriasis! In fact, this explains why my colleagues and I see less psoriasis where we practice in the sun-rich Phoenix, Arizona, compared to areas like the midwest.”

In mild cases, topical corticosteroids and medications are prescribed. Psoriasis is not curable, but it is controllable. No single approach works for everyone. Therapy is individually tailored and based on your health, goals, and a careful assessment of potential risks and benefits of treatment. Treatments can be divided into four main types:

• Topical treatments
• Light therapy
• Systemic medications
• Biologics

Dr. Newman goes on to say, “For more serious psoriasis, it will be almost impossible to successfully manage the disease without sophisticated prescription medicines. Usually, this will entail potent topical corticosteroids and/or certain oral or injectable medicines that help regulate the body’s immune system (which has gone haywire in psoriasis). Importantly, if you have psoriasis (mild or severe), you should discuss the use of both natural and prescription medicines with your primary care doctor and your dermatologist.”

Find Relief for Psoriasis

The best treatment varies by individual, taking into consideration the type of psoriasis you have, where it is on your body and the possible side effects of medications. Another AffDerm dermatologist, Dr. Mitchell Manway, gave us some extra tips on what to do when you have psoriasis.

Moisturizers: which kind are the best? “In general, the thicker or greasier the moisturizer, the better. Creams and ointments that come in a tub or jar are more effective at restoring the skin barrier than lotions or products that come in pump-dispensers. Products containing petrolatum or ceramides can be particularly effective or preferred,” says Dr. Manway.

Scale softening products? What ingredients work best? Dr. Manway advises, “Products that contain lactic acid (Amlactin/Lac Hydrin), salicylic acid (Salex), or urea are more effective at removing scale and improving skin texture.”

Cold showers/cold packs or warm baths/heating pads? According to Dr. Manway, “Ice-packs and heat may be effective at treating symptoms of itch by distracting nerve receptors, but I would avoid exposure to showers or bathing as this may promote further water-loss and drying of the skin.”

Stress relief options like meditation, acupuncture, etc? “Studies directly involving acupuncture and treatment of psoriasis are still inconclusive, with some proposing benefit and others with no significant results. However, anything that can promote stress relief may be helpful at preventing and controlling flare-ups as stress can be a major contributor for worsening of the disease,” said Dr. Manway

Exercise? “Daily or weekly exercise can stimulate and regulate the immune system and decrease stress levels, and thus is an important part of disease management.”

Over-the-counter remedies like calamine lotion? “In my experience calamine lotion is not very effective at reducing itch or pain. Topical preparations that contain pramoxine (Sarna Sensitive) or menthol (Sarna) are preferred.  Surprisingly, brief periods of exposure to sunlight and UV rays can also benefit psoriasis, but limited exposure should be stressed due to the increased risk of skin cancer associated with chronic UVA and UVB damage,” said Dr. Manway.

Prescription medications? Dr. Manway agrees, “Rx medications are by far the most effective topical treatment approach available and help to decrease inflammation at the site of disease. Potent topical steroids such as clobetasol or betamethasone are the most common medications prescribed, but other mechanisms such as vitamin D analogues and calcineurin inhibitors can provide significant and adjunct benefits towards the reduction of psoriatic plaques with less risk of long-term local side-effects. When local disease can not be maintained on topical medications or development of psoriatic arthritis is present, systemic oral medications or biologic therapy/injections are necessary.”

When should you see your dermatologist for psoriasis? Look out for any suspicious changes such as lesions that show signs of persistent flaking, scaling, roughness, redness, scabbing, bleeding, or otherwise non-healing areas. These symptoms are uncomfortable and could be an indication of something more serious.

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Genetics of Generalized Pustular Psoriasis: Current Understanding and Implications for Future Therapeutics

1. Introduction

Psoriasis is a common chronic inflammatory skin disease with a variety of clinical manifestations [1]. Psoriasis may be classified into non-pustular and pustular forms. Pustular psoriasis may be further stratified into localized and generalized forms [2]. It is believed that both environmental and genetic factors participate in the immune mechanisms of psoriasis [3]. Current studies have demonstrated genetic susceptibility to psoriasis involving components of both innate and adaptive immune systems [1]. Prolonged inflammation results in dysregulated keratinocyte proliferation and differentiation, and the keratinocytes participate in both the initiation and maintenance phases of psoriasis [4].

Psoriasis vulgaris (PV) is known to be the most common subtype of psoriasis. Both immune and genetic studies have identified interleukin (IL)-23 and IL-17 as the main drivers of psoriasis vulgaris [5,6]. It is characterized by relatively stable and localized erythematous scaly plaques. On the other hand, pustular psoriasis (PP) is rarer but potentially life-threatening and is associated with innate immune system overactivation. It may present with erythematous, scaly skin, including pustules and systemic neutrophilia. Pustular psoriasis can present in various forms, including localized pustules, as in acrodermatitis continua of Hallopeau (ACH) or palmoplantar pustulosis (PPP), or diffuse, non-acral pustules with systemic inflammation, as in generalized pustular psoriasis (GPP) [2].

GPP is a severe type of psoriatic disease. It is characterized by the onset of widespread, macroscopically visible pustules on non-acral skin with or without systemic symptoms such as fever, neutrophilia, and elevated serum levels of C-reactive protein [7]. The extent of systemic symptoms varies among patients as well as between flares within the same patient.

Clarifying the immune mechanisms behind GPP helps to develop potential therapeutic targets for this disease. Meanwhile, we should also keep in mind that the age of onset and the frequency of genetic mutations vary significantly among different subtypes [8].

In 2017, Akiyama et al. first proposed the term “autoinflammatory keratinization diseases” (AiKDs) to describe the inflammatory keratinization of the skin due to genetic autoinflammatory pathomechanisms [9]. As the pathogenic mechanism of AiKD becomes elucidated, there will be more appropriate treatment methods and precision medicines available [10]. This novel concept also sheds light on the development of therapeutic agents for pustular psoriasis.

Recent studies of the molecular pathomechanisms of pustular psoriasis suggest that the inhibition of specific cytokines, including the IL-36 axis, is a potential therapeutic strategy to control the disease activity of pustular psoriasis [11].

Autoimmunity is characterized by the activation of the adaptive immune system, including T and B cells, while autoinflammatory responses are driven by endogenous danger signals as well as inflammatory mediators and cytokines. In complex inflammatory conditions such as psoriasis, these two processes frequently coexist and can influence and trigger each other. This review will discuss the mechanism of psoriasis based on the autoimmune and autoinflammatory processes that are activated. We also aim to provide an up-to-date elucidation of the genetic mutations associated with different subtypes of pustular psoriasis and, ultimately, focus on biological treatments available for GPP.

2. Genetics of Pustular Psoriasis

Although the first GPP case was reported a century ago, its etiology and detailed pathogenesis have only been discussed within the last ten years (Table 1). It was not until 2011 that IL36RN was initially discovered as a gene responsible for causing GPP [12,13]. Since then, a growing number of genetic mutations such as CARD14, AP1S3, MPO, and the SERPIN family have been identified as associated with GPP. However, not all GPP patients carry mutations of these genes, suggesting that there are still other genetic factors to be discovered. These disease-causing genes may participate in common or similar pathogenic molecular pathways [14].

Table 1. Genetic mutations associated with generalized pustular psoriasis and their proposed effects.

Ethnic differences in GPP should also take into consideration. For example, pathogenic mutations of AP1S3 have been reported in individuals of European origin but not in Malaysian populations [15,16], while MPO and SERPINA3 variants were identified in patients of European descent [17,18]. Associations with other ethnic groups remain to be elucidated.

The cases of pustular psoriasis are classified into GPP, PPP, and ACH according to the ERASPEN criteria [2]. Assan et al. suggested that PPP and ACH might be separate diseases while still maintaining some overlap [19]. Accordingly, there are prospective phenotype–genotype and multi-omics studies to better recognize the mechanisms of each subgroup. Another study conducted in Italy in a real-life setting revealed the concomitant rate of plaque psoriasis, which was the greatest in GPP and the least in ACH [20]. To distinguish GPP alone from those with PV is quite important since the selection of treatment is based on the disease mechanism and the clinical phenotype, which can include GPP alone, ACH alone, predominate ACH, ACH evolving into GPP, and ACH with GPP.

Adult-onset immunodeficiency syndrome (AOID) is known as an AIDS-like illness with abnormal interferon-γ (IFN-γ)/IL12 signaling. It is associated with high-titer neutralizing antibodies to IFN-γ, the controller of numerous pathogens [21]. The majority of cases exhibit skin-related symptoms, such as reactive skin conditions (82%) and infectious skin diseases (45%), with neutrophilic dermatoses being the most common among them [21,22]. A recent study conducted by Piranit et al. supports that both GPP and AOID involving pustular reactions are diseases caused by dysregulated proteolytic and apoptotic processes [23]. Clinically and genetically, GPP and AOID are likely to share some common pathogenetic mechanisms. To date, there have been no reports of AOID and GPP occurring in the same individuals or within the same families. However, genetic research has found heterozygous variants in the SERPINA3 and SERPINA1 genes in patients with AOID and GPP, respectively [24,25].

2.1. IL36RN

IL-36 cytokines are relatively novel and belong to the IL-1 family, which has members that are produced by many sources, such as epithelial cells, myeloid dendritic cells, and monocytes. IL36RN encodes for IL-36Ra, which inhibits the pro-inflammatory effects of IL-36 cytokines by binding their receptors, then preventing the release of mediators that stimulate the pustule formation seen in GPP [26].

Onoufriadis et al. reported that IL-36RN mutations can cause sporadic GPP, and according to their study, IL-36 mutations underline sporadic European GPP, as well as Tunisian autosomal recessive GPP [12]. Additionally, the first Asian case of GPP associated with IL36RN mutations was reported in 2012, therefore indicating that IL36RN mutations are common in some GPP cases worldwide [27]. The prevalence of IL36RN mutations among pustular psoriasis subtypes is different; patients with GPP have the highest prevalence of these mutations (23.7%). This is followed by ACH, which has the second-highest prevalence (17.4%), and lastly, PPP demonstrates the lowest prevalence of these mutations (5.1%) [8].

Hence, in order to ascertain if IL36RN alleles are the crucial determinants of pustular psoriasis across various disease subtypes, a regression analysis was carried out, incorporating clinical diagnosis as a covariate [28]. Individuals with homozygous mutations of IL36RN tend to experience more severe disease manifestations compared to those with heterozygous mutations, and these mutations are inherited through an autosomal recessive pattern [29]. Another study indicated that IL36RN mutations are almost not seen in individuals with both PPP and GPP [30]. Accordingly, this finding suggests that a large proportion of cases of GPP alone are caused by homozygous or compound heterozygous mutations of IL36RN.

On the other hand, the presence of IL36RN disease alleles demonstrated a dose-dependent influence on the age of onset across all types of pustular psoriasis [28]. According to genetic analyses, the frequency of IL36 mutations plays a role in differentiating pustular psoriasis subtypes [8]. Sophie et al. found that the percentage of individuals carrying IL36RN disease-associated alleles was higher in those with GPP and ACH. Individuals with GPP and ACH were more likely to have biallelic mutations compared to those affected by PPP.

2.2. CARD14

Caspase recruitment domain family member 14 (CARD14) is a gene located in the psoriasis susceptibility locus 2 (PSORS2). CARD is a protein-binding molecule that facilitates the formation of complexes containing CARD proteins, which are involved in apoptosis and NF-κB signaling pathways. Among them, CARD14 is found to be specifically expressed in diseases of the skin and is primarily localized in the basal and suprabasal epidermal layers [31]. Some CARD proteins are related to chronic inflammatory skin diseases, such as early-onset sarcoidosis or amyopathic dermatomyositis [32]. The role of CARD14 mutations as either causal factors or disease susceptibility factors for PV, GPP, or pityriasis rubra pilaris may depend on the specific mutation or variant position within the CARD14 gene. [28].

Differences in ethnical groups and geographic areas affect the outcome to some extent. A study revealed that the carrier rate of the CARD14 variant in Japanese individuals is higher than in Europeans. Therefore, we can consider CARD14 an important predisposing factor for GPP with PV in the Japanese population [33,34].

2.3. AP1S3

The AP1S3 gene, which encodes adaptor protein complex 1 (AP-1), plays a crucial role in stabilizing AP-1 heterotetramers that participate in vesicular trafficking between the trans-Golgi network and endosomes [35]. Cells with mutations in AP1S3 have decreased autophagosome formation in keratinocytes, leading to p62 build-up and resulting in enhanced NF-κB signaling [16]. Loss-of-function mutations of the AP1S3 gene were found relevant in GPP, which implies pustular psoriasis as an autoinflammatory manifestation resulting from impaired vesicular trafficking [15].

The pathogenic variants are distributed mainly in Europeans and rarely in East Asians and Africans. The variant frequency of AP1S3 in GPP patients of European ancestry is about 10.8% [15]. Suppressing AP1S3 expression in human keratinocytes and HEK293 cells eliminates endosomal activation by polyinosinic-polycytidylic acid, a TLR3 agonist involved in responding to viral infections. Researchers suggested that abnormalities in vesicular trafficking could be a significant pathological basis for the autoinflammatory process in pustular psoriasis [15].

Another study investigating genetic variations in patients with pustular psoriasis found that AP1S3 mutations were in fewer GPP cases than IL36RN, and patients with AP1S3 disease alleles were mainly female [8].

2.4. MPO

Deficiencies in MPO, a heme-containing peroxidase secreted by neutrophil granulocytes that catalyzes the formation of reactive oxygen species (ROS), have just been identified in association with GPP [14]. The association between MPO deficiency and pustular skin disease was first recognized by Vergnano et al. with phenome-wide association studies [36], and in vitro functional studies showed that mutations in the MPO gene lead to elevated neutrophil accumulation and activity, suggesting a role of MPO mutations in the pathogenesis of GPP [37].

The quantity of mutant MPO alleles was positively correlated with a younger age of onset, which is similar to the genotype-phenotype correlation of the IL36RN gene and further validates the genetic correlation of GPP [17]. The discovery that the MPO gene plays a pathogenic role in GPP provides perspectives on understanding GPP pathogenesis.

2.5. SERPINA1, SERPINA3

SERPINA1 and SERPINA3 are inhibitors of cathepsin G, the primary serine protease involved in cleaving and activating IL-36 precursors. The loss of function of these protease inhibitors may induce severe inflammatory effects [25]. Additionally, heterozygous loss-of-function mutations in both SERPINA1 and SERPINA3 were identified in individuals with GPP, and decreased protease inhibitor activity may result in enhanced IL-36 activation [18].

A study conducted by Piranit et al. reinforced the concept that the biological functions of SERPINB3 involve inhibiting cysteine proteases when mutated, and the subsequent overactivation of proteases leads to an intensified inflammatory reaction accompanied by heightened neutrophil recruitment [23]. Patients carrying SERPINB3 mutations exhibit aberrant SERPINB3 expression. The accumulation of misfolded SERPINB3 proteins causes the overactivation of cathepsin L, followed by the inactivation of SERPINA1, finally evolves into AOID with pustular reactions [38,39].

2.6. BTN3A3

BTN3A3 belongs to the human butyrophilin (BTN) 3 family, which has the ability to activate the NF-κB pathway, resulting in an excessive inflammatory response by suppressing the expression of IL-36Ra. To investigate the molecular pathogenesis of GPP, Q. Zhang et al. conducted a whole-exome sequencing study in the Chinese Han population [40]. However, the result found only two loci identified with exome-wide significance: the strongest one was in the IL36RN gene, and the other was located within the MHC region. A subsequent gene burden test demonstrated a correlation between BTN3A3 and GPP. Subtype analysis revealed that both IL36RN and BTN3A3 were markedly linked to GPP alone and GPP with PV. The BTN3A3 gene carried two LOF mutations with the most significant association. As a previously unreported determinant of GPP, BTN3A3 acted as a key regulator of cell proliferation, and its expression was associated with inflammatory imbalance.

2.7. TGFBR2

TGF-β signaling is recognized for its inhibitory effects on cell proliferation and immune system suppression [41]. Thus, the hyperproliferation of keratinocytes in the psoriatic epidermis is consistent with disrupted TGF-β signaling because of heterozygous loss-of-function TGFBR2 mutations. Concomitant with the overexpression of KRT17, there is an increase in keratinocyte proliferation and subsequent recruitment of neutrophils [42]. The overexpression of KRT17 is thus in line with a potential role for diminished TGFBR2 function in both GPP and AOID. Whole-exome sequencing (WES) was carried out on a total of 53 patients, comprising 32 individuals exhibiting pustular psoriasis phenotypes and 21 individuals with AOID presenting with pustular skin reactions [43]. The result showed that 4 Thai patients displaying similar pustular phenotypes, including two diagnosed with GPP and two with AOID, were found to carry the same rare TGFBR2 frameshift mutation. It is concluded that AOID might share pathogenic mechanisms with GPP.

Mechanistically, TGFBR1 and TGFBR2 are transmembrane serine/threonine kinases [44]. TGFBR2 expression is remarkably reduced or absent in psoriatic skin. As a result, it has been suggested that genetic variations in TGFBR2 could enhance susceptibility to GPP and AOID in some patients.

3. Current and Potential Therapeutic Agents Targeting Immune Mediators in Generalized Pustular Psoriasis

The phenotype and pathogenesis of different psoriasis subtypes are on a spectrum. On the one hand, plaque psoriasis is associated with the overactivation of the adaptive immune system, including T and B cells, and is thought to involve self-perpetuating inflammatory mechanisms through the IL-23/Th17 axis [45]. On the other end, pustular psoriasis has been associated with the stimulation of innate immune responses and the activation of IL-36 cytokine pathways [46]. Based on the pathomechanism, therapeutic agents for patients who have plaque psoriasis and GPP at the same time need to target not only the adaptive immune pathways but also the innate immune axis [47].

IL-36 cytokines are members of the IL-1 superfamily, and the IL-1/IL-36–chemokine–neutrophil axis plays a significant role in driving disease pathology in GPP. The first pathogenic variant found to be linked with GPP was a homozygous mutation of the IL36RN gene [48], and further studies have looked into the distribution over different populations [48,49].

Progress in understanding the relationship between autoinflammation and clinical phenotypes has contributed to the development of highly efficacious targeted treatments such as TNF-α, IL-17, IL-23, IL-1α/β, or IL-36 inhibitors or receptor blockers, as well as small molecule drugs such as PDE4 inhibitors, JAK inhibitors, and ROR-γt inhibitors.

Well-established treatment guidelines for GPP are currently lacking, and multiple biologic and non-biologic treatments exist. Considering the variety of comorbidities and severity associated with GPP, personalized treatments should be tailored. Figure 1 shows a graphical abstract of current and emerging biologic agents for GPP.

Figure 1. Graphical abstract of mechanisms of current and potential biologic agents for generalized pustular psoriasis.

3.1. IL-36 Pathway Inhibitors

Anti-IL-36 receptor antibodies can be employed to block the signaling pathway responsible for GPP flares and can be effective for patients with mutant IL36RN [48].

At present, only a single GPP-specific treatment, spesolimab, an interleukin-36 receptor antagonist, has received approval for use in the United States. With the experience of GPP complete remission after two doses of spesolimab [50], spesolimab was then approved by European Commission in adult GPP flares [51]. Spesolimab has been demonstrated to reduce the levels of relevant serum biomarkers and cellular populations in the skin lesions of patients with GPP, such as CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing cells.

In patients with GPP, spesolimab has been observed to induce rapid changes in commonly disrupted molecular pathways in both GPP and PPP, suggesting that it may have the potential to improve clinical outcomes [52]. The results of a randomized controlled trial indicated that a 900 mg intravenous infusion of spesolimab led to greater lesion resolution in a patient group experiencing active GPP flare-ups after one week [53]. The improvement of the condition was evaluated using the GPPGA, which is a standardized assessment of a subject’s skin status based on three factors: erythema, pustules, and scaling/crusting [54]. After one week, there were almost four times the number patients who received spesolimab and achieved a GPPGA total score of 0 or 1 compared to control patients. Furthermore, it was found that spesolimab may relate to a higher incidence of infection, though neither opportunistic nor severe [55]. Long-term management options also were assessed; patient-reported outcomes were improved, and markers of systemic inflammation were normalized [56]. Recent research also indicates that spesolimab is effective for patients with GPP without IL36RN mutations [57].

Additional potential therapies targeting the IL-36 pathway for GPP are currently under development. Imsidolimab, an IL-36 inhibitor, recently passed through a phase 3 clinical trial to evaluate its efficacy and safety [58]. Patients received 750 mg of IV imsidolimab on day 1 and added 100 mg of subcutaneous imsidolimab every 4 weeks until day 85. Imsidolimab exhibited a rapid and sustained alleviation of symptoms and pustular eruptions in patients with GPP.

There are currently efforts underway to develop small molecule inhibitors of IL-36γ, which could have the potential to treat GPP. A-552 was identified as a potent inhibitor of IL-36γ in humans [59]. Phenotypic analysis of individuals without the IL-36R-encoding gene disclosed that they do not exhibit severe immunodeficiency, further supporting that the IL-36 pathway is a promising therapeutic target with minimal side effects [60].

3.2. IL-1RAcP

Interleukin-1 receptor accessory protein (IL-1RAcP) antibodies represent another feasible treatment alternative for GPP patients. IL-1RAcP, a member of the immunoglobulin superfamily proteins, has a crucial function in the signaling of the IL-1 family cytokines, such as IL-1, IL-33, and IL-36. Blocking IL-1RAcP’s ability to form a dimer with IL-36R could prevent the overactivation of the IL-36 pathway and subsequent inflammation [61]. Zarezadeh et al. indicated IL-1RAcP as a potential therapeutic target for inflammatory and autoimmune diseases [62]. However, the long-term safety and effectiveness of IL-1RAcP antibodies need to be determined since IL-1RAcP is expressed in a wide range of cell types, and excessive suppression may result in multiple toxic effects [63].

3.3. TNF-α Inhibitors

TNF-α, produced by activated plasmacytoid dendritic cells (DCs) and damaged keratinocytes, can stimulate the IL-36 pathway. TNF-α inhibitors indirectly suppress the expression of IL-36γ, resulting in reduced activation of the pro-inflammatory IL-36 pathway [64]. Adalimumab, infliximab, and certolizumab pegol are TNF-α inhibitors that have been approved for GPP treatment in Japan [65]. Cases with rapid and sustained resolution of skin lesions after infliximab used were reported in Poland [66]. A retrospective study showed the treatment efficacy rate of pustule clearance, which was 100% in the adalimumab + acitretin group [67].

However, paradoxical GPP is a potential adverse effect of TNF-α inhibitors. A study conducted in Turkey involving 156 GPP patients revealed that TNF-α inhibitors were the only biologic that triggered paradoxical GPP [68]. It is estimated that 0.6%-5.3% of patients receiving TNF-α inhibitors developed paradoxical GPP, with infliximab being the most frequently associated biologic with this condition [69].

3.4. IL-17 Inhibitors

Secukinumab, ixekizumab, and brodalumab are biologics that have been proven to manage GPP patients in Japan [70,71,72]. A retrospective study in Germany compared the rate of excellent response to GPP patients, with 60.0% in the secukinumab group and 50.0% in the ixekizumab group [73]. A phase IV, multicenter, open-label randomized control trial in Japan demonstrated that skin lesions mostly resolved in GPP patients under ixekizumab treatment, and there were no side effects reported [74].

However, there was a case of a Japanese individual that developed increased serum levels of liver enzymes during treatment with brodalumab for generalized pustular psoriasis [75]. The relationship between brodalumab and autoimmune hepatitis (AIH)/primary biliary cholangitis (PBC) overlap syndrome should be noted.

These IL-17 inhibitors mentioned above have been shown to be effective in controlling flares in the acute phase or as maintenance therapy in adult patients with GPP.

3.5. IL-23 Inhibitors

IL-23 regulates the production of IL-17, which subsequently stimulates the synthesis of pro-inflammatory IL-36R agonists, leading to the overactivation of the IL-36 pathway. The IL-23 inhibitors risankizumab and guselkumab are indicated for the treatment of GPP in Japan [76,77]. Ustekinumab, as an IL-12/23 antagonist, has been introduced to GPP patients, who achieved complete remission after its dose was titrated [78]. Additionally, both newly diagnosed ACH cases and already known therapy-refractory ACH cases had satisfactory and sustained therapy responses to guselkumab and risankizumab [79].

This suggests that IL-23 inhibitors may control flares in the acute phase or as maintenance therapy in adult patients with GPP.

3.6. Additional Biological Therapy and Non-Biologic Options

While the TNF-α/IL-17/IL-23 axis is predominantly targeted in plaque psoriasis, the IL-1/IL-36–chemokine–neutrophil axis shows greater potential as a therapeutic target in GPP. Previous studies have explored the use of IL-1 targeting biologics, such as the IL-1α receptor antagonist anakinra, as well as the IL-1ββmonoclonal antibodies gevokizumab and canakinumab, in GPP patients [80]. Anakinra is a successful treatment in patients with GPP carrying mutant IL36RN genes, while gevokizumab and canakinumab are effective in blocking the pro-inflammatory cytokine IL-1β [81].

As for non-biologic immunomodulatory management, methotrexate, cyclosporine, apremilast, and retinoids have been used for the treatment of GPP, but the efficacy is only based on case reports and non-randomized studies. Japanese guidelines have suggested the use of topical treatments as maintenance therapy following flares or as a supplementary therapy to address psoriasis-like symptoms [65].

4. Conclusions

GPP is a severe inflammatory disease distinct from PV [82]. Recent genetic observations and investigations provided us with insight into the disease. We found specific genes that are associated with pustular skin disease, including IL36RN, CARD14, AP1S3, MPO, SERPINA1, SERPINA3, BTN3A3, and TGFBR2. The immunologic pathway implicates IL-36 as a central node cytokine. That is, GPP constitutes a large IL-36-dominated keratinocyte cytokine storm and epidermal neutrophil aggregation.

The advances in our comprehension of GPP and its treatment options have the potential to improve patient care. It is known that the IL-36 pathway is the main inflammatory pathway implicated in GPP, but it is neither necessary nor sufficient to cause the disease. Aside from genes that play a role in the regulation of IL-36 signaling, there are IL36RN-negative GPP cases that have been noted. Due to the rarity of GPP, it has been challenging to identify additional disease-causing genes in the past. However, by combining whole-exome sequence data from various centers and targeting cases that are more prone to be monogenic in origin, progress could be achieved.

Progressive biologic therapies that target different chemokine receptors show efficacy, but there are also safety considerations. As more relevant and efficacious treatment options become available, patient outcomes and quality of life will improve. We should also keep in mind that immediate treatment goals during GPP flares are to alleviate skin inflammation and minimize the impact of systemic symptoms to avoid complications such as cardiovascular aseptic shock, heart failure, acute respiratory distress syndrome, prerenal kidney failure, neutrophilic cholangitis, uveitis, and severe infections [80,83]. Prevention of flare-ups of GPP is another treatment goal, and further clinical studies are indicated to evaluate the efficacy of the prevention of GPP flares. Additionally, the prevalence of genetic mutations of GPP varies in different countries and ethnic groups. It is important to investigate if patients with different genetic mutations of GPP have different short-term and long-term treatment responses.

Author Contributions

Conceptualization, S.-F.Y., M.-H.L., P.-C.C., S.-K.H., S.-Y.S., H.-S.Y. and S.Y.; literature review, S.-F.Y., M.-H.L., P.-C.C., S.-K.H., S.-Y.S. and S.Y.; writing—original draft preparation, S.-F.Y.; writing—review and editing, S.-F.Y., M.-H.L., P.-C.C., S.-K.H., S.-Y.S., H.-S.Y. and S.Y.; supervision, H.-S.Y. and S.Y.; project administration, S.Y.; funding acquisition, S.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the Taiwan National Science and Technology Council (MOST-110-2628-B-037-007 and NSTC-111-2314-B-037-042) to S.Y. and grants from Kaohsiung Medical University Hospital (KMUH110-0R61 and KMUH111-1R59) to S.Y.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

This study is supported partially by Kaohsiung Medical University Research Center Grant (KMU-TC111B02).

Conflicts of Interest

S.Y. a guest editor of the Special Issue: Genetics of Complex Cutaneous Disorders, had no role in the peer review process or decision to publish this article.

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84. source

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Generalized Pustular Psoriasis: Divergence of Innate and Adaptive Immunity

Abstract

Generalized pustular psoriasis (GPP) is a severe, relapsing, immune-mediated disease characterized by the presence of multiple sterile pustules all over the body. The exact pathomechanisms behind GPP remain elusive, although increased interest in the genetic basis and immunological disturbances have provided some revealing insights into the underlying signaling pathways and their mutual interaction. The genetic background of GPP has been thoroughly investigated over the past few years. The conducted studies have identified genetic variants that predispose to pustular forms of psoriasis. The loss-of-function mutation of the interleukin 36 receptor antagonist gene, along with rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14), are examples of the uncovered abnormalities. Interleukin 36 (IL-36), along with neutrophils, is now considered a central cytokine in GPP pathogenesis, with IL-36 signaling providing a link between innate and adaptive immune responses. More recently, a new concept of inflammation, caused by a predominantly genetically determined abnormal activation of innate immune response and leading to inflammatory keratinization, has arisen. GPP is currently considered a representative of this novel group of skin conditions, called autoinflammatory keratinization diseases. As no therapeutic agents have been approved for GPP to date in the United States and Europe, the novel anti-IL-36R antibodies are particularly promising and may revolutionize management of the disease.

Keywords:

generalized pustular psoriasis; von Zumbusch; IL-36; autoinflammation; innate immunity; genetics

 

1. Introduction

Generalized pustular psoriasis (GPP) is a rare, chronic, highly inflammatory, and potentially life-threatening variant of psoriasis [1,2,3]. GPP is more prevalent in Asians than Caucasians (annual prevalence of 7.46 cases/million people in Japan in contrast to 1.76 cases/million in France) and accounts for about 1% of all psoriasis cases [4,5,6,7]. GPP is approximately twice as common in women than in men, as was reported in both European and Asian cohort studies [8,9]. The mean age of onset of GPP is 31 years, which is lower than that of palmoplantar pustulosis or acrodermatitis continua Hallopeau [8]. Epidemiological data on GPP are in contrast to those on plaque psoriasis, which is reported to be equally prevalent among men and women and to occur most frequently between the ages of 15–20 years, with a second smaller peak occurring at 55–60 years [10]. GPP is characterized by recurrent episodes of widespread neutrophilic aseptic pustular eruptions, with accompanying symptoms of systemic inflammation [11]. The acute onset of GPP is usually associated with one or several general symptoms, such as pyrexia, malaise, and fatigue, and extracutaneous manifestations including arthritis, uveitis, acute respiratory distress syndrome, cardiovascular shock, and neutrophilic cholangitis [3,12,13]. Typical laboratory abnormalities include elevated C-reactive protein, leukocytosis, neutrophilia, and elevated liver function tests [3,13,14]. Acute GPP flares are associated with significant morbidity and mortality, if inadequately treated [2,15]. GPP may either be associated with pre-existing plaque psoriasis or can develop independently [16]. In a minority of cases, typical plaque-type psoriasis lesions arise after GPP has appeared [1]. Due to its low prevalence, GPP is regarded as an orphan disease (ORPHA:247353) [3,4,5,15]. GPP has a relapsing–remitting course with a highly variable clinical phenotype and pattern of flares. In some patients, the skin is entirely cleared between episodic acute flares, whereas in others a more persistent course is characterized by sharply defined localized or widespread erythematous plaques, with or without pustules [17]. GPP flares are idiopathic in most cases, although elicitation by certain endogenous and exogenous trigger factors, including infection, pregnancy, withdrawal of corticosteroids, and certain medications (e.g., ustekinumab, infliximab) is not uncommon [3,15,18,19]. Histologically, GPP is characterized by spongiform pustules of Kogoj and Munro’s subcorneal microabscesses, with the presence of an excessive amount of infiltrating neutrophils [20]. The most important clinical and histopathological differential diagnosis of GPP is acute generalized exanthematous pustulosis (AGEP), a rare and severe pustular skin reaction. Clinically, AGEP has a more abrupt onset, shorter duration, usually does not recur, and the patients do not have a personal or family history of psoriasis [21]. Moreover, AGEP has been strongly linked to certain drugs, such as ampicillin/amoxicillin, fluoroquinolones, sulfonamides, terbinafine, and diltiazem [21]. Although the microscopic features of these two pustular eruptions can be very similar, in most cases it is possible to differentiate them based on clinicopathological features [20].

GPP is traditionally classified as a variant of psoriasis. However, the distinct clinical, histological, and genetic features of the former suggest that these two diseases have, at least partially, different pathogenic mechanisms. It has been thus suggested that GPP should be regarded as a separate entity and that it requires a different therapeutic approach [4,16,22,23,24]. To date, no standard treatment guidelines exist for GPP in the United States and Europe; however, both conventional and biological agents used for plaque psoriasis have been incorporated into the therapeutic regime. Non-biological systemic therapy in adult patients typically includes acitretin, cyclosporine A, and methotrexate [25,26]. Only in Japan, several biologics have been approved for the treatment of GPP in patients who had an inadequate response to conventional therapy, including monoclonal antibodies against interleukin (IL)-17 (secukinumab and ixekizumab) or its receptor (brodalumab) and against IL-23 (risankizumab and guselkumab) [27,28,29,30,31,32,33,34]. Since the adaptive immune system plays a critical role in the pathogenesis of plaque psoriasis, agents specifically targeting elements of adaptive immunity are highly efficacious for the treatment of chronic plaque psoriasis [35]. It is worth noting that these therapies are generally less effective in the management of GPP than plaque psoriasis. This again suggests a divergent underlying pathogenic mechanism in the pustular variants of psoriasis [36]. It also needs to be pointed out that a paradoxical induction of GPP has been reported with biological agents [18,19,37,38]. Case reports, case series, and small open-label clinical trials have been published on novel biologics that target the cytokines involved in GPP pathogenesis. Recent gene expression analyses have demonstrated that the transcriptome of GPP shares some common features with that of plaque psoriasis. However, it is dominated by innate immune system activation and autoinflammation, whereas adaptive immune responses predominate in plaque psoriasis [39,40].

This article aims to elucidate and discuss the intricate interaction between the innate and adaptive immune mechanisms in the autoinflammatory pathogenesis of GPP. It also summarizes the up-to-date knowledge on the genetic background of this disease, discussing the clinical significance of the uncovered mutations. Moreover, it provides an overview of the current options for targeted therapies for GPP, including data from the most recent clinical trials.

2. Gene Mutations in GPP

The first indication that genetic abnormalities may lead to pustular dermatitis was the identification of homozygous mutations in IL-1 receptor antagonist (IL-1Ra) gene (IL1RN) in six families with a deficiency of IL-1Ra (DIRA) [41]. The absence of IL-1Ra allows the unopposed action of pro-inflammatory cytokines IL-1α and IL-1β, which results in life-threatening systemic inflammation with skin and bone involvement. This was first described in nine children harboring mutations that lead to the synthesis of a truncated non-functional form of IL-1Ra. All but one of those patients suffered from pustular skin disease of varied severity, ranging from localized pustules to generalized severe pustulosis [41]. Similar cases involving acute pustular rash with severe systemic symptoms have been reported by several other groups [42,43,44,45].

Although the first patient with GPP was described in 1910, it was not until over 100 years later that the etiology and detailed pathogenesis were elucidated. The high severity of inflammation seen in GPP patients and the existence of numerous familial cases led to the hypothesis of a monogenic inheritance pattern. This hypothesis was proved by the identification of homozygous and composite heterozygous loss-of-function mutations of IL-36 receptor antagonist gene (IL36RN) in 2011. The acronym DITRA (deficiency of interleukin thirty-six-receptor antagonist) is often used for those cases of GPP in which IL36RN mutation is detected [46]. Pathogenic IL36RN mutations were originally identified in consanguineous GPP pedigrees of Tunisian origin and in five isolated cases from the UK [46,47]. The knockout of the IL-36 receptor (IL-36R) in a murine model of deficiency of IL-36R antagonist led to the dramatic resolution of skin inflammation, making the blockade of IL-36R signaling a novel and promising therapeutic approach for patients with pustular variants of psoriasis [48,49]. Other important mutations that underlie the enhanced inflammatory cascade and the recruitment of neutrophils and macrophages have also been described in different groups of GPP patients. These include mutations in the CARD14 gene that encodes caspase-activating recruitment domain member 14 and in the AP1S3 gene that encodes adaptor protein complex 1 subunit sigma 3 [24,47,50,51,52]. Additional disease-associated variants in CARD14 and/or AP1S3 were identified in 15% of IL36RN mutation carriers, indicating an oligogenic instead of monogenic inheritance pattern [53].

2.1. Mutations of IL-36 Receptor Antagonist

The IL-36 family is a relatively novel group of cytokines that belongs to the IL-1 superfamily and consists of three pro-inflammatory agonists, IL-36α, IL-36β, and IL-36γ, and two antagonists, IL-36 receptor antagonist (IL-36Ra) and IL-38. These IL-36 cytokines are expressed in epithelial and immune cells and function through a shared receptor (IL-36R) to modulate innate and adaptive immune responses [54]. IL-36 cytokines can induce the downstream pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways via an intracellular signaling cascade by binding to IL-36R. Subsequently, the release of inflammatory mediators and chemotaxis that promote activation of neutrophils, macrophages, dendritic cells, and T cells is induced, ultimately causing the amplification of inflammatory responses [55].

IL36RN encodes the IL-36Ra, which suppresses the pro-inflammatory effects of IL-36 cytokines (namely IL-36α, IL-36β, and IL-36γ) by binding their receptor, interleukin-1 receptor-like 2 (IL-1RL2), and preventing the release of chemokines that stimulate the activation of neutrophils, macrophages, dendritic cells, and T cells; inducing neutrophil chemokine expression, infiltration, and pustule formation in GPP [56,57]. In vitro and ex vivo observations revealed that GPP alleles abolish the antagonistic effect of IL-36Ra; thus, IL-36 stimulation of patients’ cells results in enhanced production of pro-inflammatory cytokines such as IL-1, IL-6, and IL-8 [46,47]. Mutations in IL36RN, which were first described in 2009 in two families with severe pustular psoriasis, lead to functional impairment of IL-36Ra and subsequent amplification of the downstream inflammatory responses [46,47]. Such mutations in IL36RN gene were initially identified in north-African families suffering from autosomal recessive GPP. They were homozygous missense mutations, with the substitution of proline for leucine at position 27 (p.Leu27Pro) [46]. In another pioneering study of five European cases of GPP, three individuals were found to have mutations in IL36RN, including a novel homozygous missense mutation (p.Ser113Leu) and one compound heterozygote carrier (p.Ser113Leu and p.Arg48Trp) [47]. IL36RN mutations do not contribute to the risk of plaque psoriasis. In fact, most IL36RN mutations are identified in patients with GPP that do not suffer from concurrent plaque psoriasis [58]. This observation was confirmed by Sugiura et al., who first screened for IL36RN gene within two subgroups of patients with GPP (GPP alone and GPP with concurrent psoriasis vulgaris). They showed that all GPP patients without psoriasis vulgaris carried homozygous or compound heterozygous mutations in the IL36RN gene, whereas only 2 out of 20 cases of GPP with psoriasis vulgaris harbored compound heterozygous mutations [24]. Based on these results, it was suggested that GPP alone may represent a distinct subtype of GPP that is etiologically distinguishable from GPP occurring with psoriasis vulgaris [24].

Several types of IL36RN mutations, including substitution, frameshift, and splicing defects, have been reported as the causative genetic background in numerous GPP cases, in various geographical regions [8,24,46,47,53,59,60,61,62,63]. In addition, Hussain et al. demonstrated that IL36RN mutation carriers exhibit a more severe clinical phenotype (e.g., earlier age of disease onset, increased risk of systemic manifestations) and the absence of co-existing plaque psoriasis, when compared to individuals without IL36RN mutation [64]. The most recent analysis, which included a cohort of 251 unrelated patients with GPP from multiple countries, also showed that IL36RN gene mutations were associated with an early age of onset, prevalence of psoriasis vulgaris, and high recurrence rate of GPP [8]. On the basis of the findings of their study, the authors recommended that patients who present with GPP before the age of 30 should be screened for IL36RN mutations [8]. Overall, the prevalence of IL36RN mutations in patients with GPP has ranged between 10% and 82%, and was significantly lower in cases with associated plaque psoriasis than in those linked to GPP alone [23,65,66]. Biallelic IL36RN mutations are known to be disease-causing or disease-contributing in 21–41% of patients with GPP [24,46,47,53,64].

2.2. CARD14 Mutations/Variants

Rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14) were found to be causative of familial psoriasis vulgaris and familial pityriasis rubra pilaris in 2012 [67]. CARD14, expressed and localized predominantly in keratinocytes, is a scaffold protein that mediates NF-κB signal transduction, thus contributing to inflammatory responses within the epidermis [52,67,68,69,70]. Interestingly, CARD14 expression is essentially confined to the basal layer of epidermis in unaffected skin. However, it is upregulated in the granular layers in the skin of patients with GPP [69]. In 2019, Shao et al. reported that neutrophils isolated from patients with GPP induced the upregulated expression of inflammatory genes, including IL-1b, IL-36G, IL-18, tumor necrosis factor alpha (TNF-α), and C-X-C motif chemokine ligands in keratinocytes, and more than normal neutrophils. Moreover, neutrophils from patients with GPP secreted more exosomes than the controls. These neutrophils were then rapidly internalized by keratinocytes, which increased the expression of these inflammatory molecules by activating the NF-κB and MAPK signaling pathways [71]. Two independent groups reported that variants of the CARD14 gene are associated with GPP and palmoplantar pustular psoriasis [52,72]. Moreover, the first autosomal dominant familial pedigree of GPP associated with CARD14 mutations was described in [73]. Mutations in CARD14 gene account for only a small proportion of cases of GPP; in most cases they are present in GPP patients with concomitant psoriasis vulgaris, but were only rarely identified in GPP alone [8]. No mutations of the CARD14 gene that are specific to patients suffering from psoriasis vulgaris and GPP have yet been found. Therefore, the correlation between CARD14 gene mutations and the onset of GPP remains to be further elucidated.

2.3. AP1S3 Mutations

Adaptor-related protein complex 1 (AP-1) is a highly-conserved heterotetramer that plays a pivotal role in vesicular trafficking between the trans-Golgi network and endosomes [36]. In 2014, mutations in AP1S3, the gene encoding AP-1 complex subunit sigma 3, were found in unrelated individuals with severe pustular psoriasis, including patients with GPP not harboring IL36RN and CARD14 mutations [50]. In addition, Mahil et al. reported that knockout of AP1S3, which is highly expressed in keratinocytes, disrupted keratinocyte autophagy in several cell lines. This alteration results in the abnormal accumulation of p62, an adaptor protein mediating NF-κB activation, and thereby upregulation of IL-1 signaling and overexpression of IL-36α among other cytokines [51]. To date, there are fewer mutational reports on AP1S3 than on IL36RN or CARD14, as they only account for approximately 11% of GPP cases in Europe and are rarely found in East Asians [32,50].

2.4. TNIP1 Mutations

Three cytokine signaling pathways important in GPP pathogenesis (including angiopoietin signaling, NF-κB signaling, and retinoic acid receptor activation) were significantly associated with the TNIP1 gene encoding TNF-alpha induced protein 3-interacting protein 1 (TNIP1). This led to the designation of TNIP1 as a potential candidate susceptibility gene for GPP [74,75]. In a study of 73 patients with GPP in a Han Chinese population, six polymorphisms were identified in TNIP1 gene locus; however, they were shown to be only weakly associated with GPP [76].

2.5. SERPINA3 Mutations

SERPINA3 (Serpin Family A Member 3) encodes serine protease inhibitor A3 (serpin A3, also known as α1-antichymotrypsin), which specifically inhibits several proteases [77]. More recently, a new candidate gene for GPP was proposed in a publication by Frey et al. They detected a novel, rare loss-of-function variant in SERPINA3 in 2 out of 25 independent patients via whole exome sequencing [78]. SERPINA3 strongly inhibits the neutrophil protease cathepsin G (CTSG), which has been shown to process full-length secreted IL-36 cytokines to their more active forms, thereby increasing their pro-inflammatory activity ~500-fold [23,79,80].

2.6. MPO Mutation

The MPO gene encodes myeloperoxidase (MPO), an essential component of neutrophil azurophil granules [81]. Although the relationship between MPO deficiency and pustular psoriasis was first described in 1996 in an individual case report, it was only recently that a mutation in MPO gene was recognized as a background for GPP [82,83]. Vergnano et al. performed a whole-exome sequencing of 19 unrelated individuals with GPP and identified a subject harboring a homozygous splice-site mutation in MPO. MPO screening in diseases phenotypically related to GPP uncovered further disease alleles in one patient with acral pustular psoriasis and in two subjects with AGEP [83]. Importantly, all three MPO gene variants that were observed in that study have a well-established impact on protein function, as they have been repeatedly observed in individuals with MPO deficiency [84,85]. Moreover, the phenotypic effects of MPO mutations were explored using a phenome-wide association study (PheWAS), which allowed identification of important relationships between genetic variants and a wide range of phenotypes. In vitro functional analysis revealed that mutations in the MPO gene cause an increase in neutrophil accumulation and activity, as well as a reduction in the number of apoptotic neutrophils. This observation further supported the role of this gene in neutrophil hemostasis and indicated its role in GPP pathogenesis [83]. These important findings regarding the significance of MPO gene variants in GPP were further confirmed by Haskamp et al., who discovered that 15 out of 74 patients affected by GPP carried eight variants in MPO gene that were all validated as loss-of-function mutations. They also performed a downstream analysis, which subsequently found that the activity of neutrophil elastase (NE), CTSG, and proteinase 3 (PR3), serine proteases that cleave IL-36 precursors into very active pro-inflammatory IL-36 cytokines, inversely correlated with MPO activity. This observation demonstrated that MPO deficiency was strongly linked to IL-36 pathway activation. Moreover, MPO deficiency caused defective formation of neutrophil extracellular traps (NETs) in the phorbol myristate acetate-induced pathway and reduced phagocytosis of neutrophils by monocytes (efferocytosis), thereby contributing to the prolonged persistence of harmful neutrophils and the reduced ability to resolve skin inflammation in GPP. Notably, a genotype–phenotype relationship similar to that of IL36RN gene was found in the abovementioned study, as the dosage of abnormal alleles of MPO gene negatively correlated with the age of disease onset [86]. Considering that the results of these studies implicated MPO as an important modulating enzyme of inflammation, MPO itself or MPO-related pathways represent attractive targets for anti-inflammatory therapies in GPP.

The above described mutations underlying GPP and their significance are depicted in Table 1.

Table 1. Summary of mutations associated with generalized pustular psoriasis. (ACH—acrodermatitis continua Hallopeau, GPP—generalized pustular psoriasis, IL-36—interleukin 36, NF-ƙB—nuclear factor kappa-light-chain-enhancer of activated B cells, PPP—palmoplantar pustulosis, PsV—psoriasis vulgaris).

3. Immunopathogenesis

3.1. Autoinflammation and Autoimmunity in GPP

Overexpression of IL-36 inflammatory cytokines in cutaneous lesions and loss-of-function mutations in IL36RN gene, as well as mutations in other genes related to the IL-36 pathway (e.g., CARD14, AP1S3, SERPINA3), have been identified in some patients; indicating that the IL-36 signaling pathway may be pivotal in the pathogenesis of GPP [46,50,52]. It has been discovered that IL36RN, CARD14, and AP1S3 gene mutations activate pro-inflammatory signaling pathways via NF-κB, which further results in an increased expression of CXCL1-3, IL-1, IL-8, and IL-36 pro-inflammatory cytokines. In addition, MPO gene deficiency also promotes the activation of IL-36 signaling by regulating the activity of NE, CTSG, and PR3 serine proteases [32]. In addition, data from gene expression analyses have revealed that the transcriptome of GPP shares many similarities with that of plaque psoriasis, but it is inclined more towards innate immune mechanisms [23]. Thereby, subtypes of psoriasis are thought to exist within a continuum, wherein plaque psoriasis is characterized by an adaptive immunity involving a cluster of differentiation four-positive (CD4+) and CD8+ T cells and the key role of the IL-17/IL-23 immune pathway. Oppositely, in pustular variants of psoriasis, it is the innate immune responses involving IL-36 activation, neutrophil infiltration, and autoinflammation that are central to the pathogenesis [63].

Recent research on the interplay between IL-17- and IL-36-driven inflammation has shed a new light on how individual mediators may modify the spectrum of psoriasis via shifting innate to adaptive immunity or vice versa. The pathogenesis of GPP partly overlaps with the typical pathways of psoriasis vulgaris but exerts a more pronounced activation of the innate immune system. Therefore, cytokines such as IL-17A, IL-22, IL-23, and TNF-α were found to be elevated in both psoriasis vulgaris and GPP; however, GPP lesions yielded significantly higher IL-1 and IL-36, and lower IL-17A and interferon-gamma (IFN-γ) messenger RNA (mRNA) expressions, than plaque psoriasis lesions [23].

The discovery of the IL36RN mutation in GPP provided a rationale for blocking inflammasome, thus inhibiting autoinflammation. Antibodies targeting the IL-1–/IL-36–chemokine–neutrophil axis, including the recombinant IL-1 receptor antagonist anakinra and the anti-IL-1β monoclonal antibodies, canakinumab and gevokizumab, were beneficial in GPP, but the efficacy data comes only from isolated case reports and small case series [87,88,89,90]. More recently, as a result of better understanding of the immunopathogenesis of GPP, specific therapies targeting IL-36 have been developed. Two monoclonal antibodies targeting IL-36R, spesolimab (BI 655130) and ANB019, have shown promising initial results in GPP and have proceeded to phase II clinical trials [91,92,93,94].

3.2. GPP as an Autoinflammatory Keratinization Disorder

The term “autoinflammatory diseases” emerged in 1999, when germline mutations in tumor necrosis factor receptor superfamily 1A (TNFRSF1A) were reported as causative in tumor necrosis factor receptor-associated periodic syndrome (TRAPS) [95]. Autoinflammatory diseases, which are usually monogenic disorders with a systemic inflammatory component, are caused by genetic mutations in the molecules and signaling pathways involved in innate immune responses [95,96]. In order to highlight the major cutaneous manifestations of various autoinflammatory diseases, Akiyama et al. proposed a new term to encompass inflammatory keratinization diseases with a prominent autoinflammatory component, namely autoinflammatory keratinization disorders (AiKDs) [60]. AiKDs involve significant genetic factors causing the hyper-activation of innate immunity, primarily within the epidermis and the superficial dermis, which results in abnormally up-regulated keratinization [60]. Importantly, since AiKDs include conditions with mixed pathological mechanisms of autoinflammation and autoimmunity, they are unique, and in many ways different, from classic autoinflammatory diseases. Initially, AiKDs comprised pustular psoriasis and related entities, including GPP, impetigo herpetiformis, and acrodermatitis continua Hallopeau due to mutations in IL36RN, GPP and palmoplantar pustular psoriasis due to CARD14 variants [72], and pityriasis rubra pilaris caused by CARD14 mutations/variants [73]; the AiKDs spectrum has since been extended and now includes several entities [61,62].

3.3. IL-1/IL-36 Inflammatory Axis

IL36-chemokine–neutrophil axis appears to be central to the pathogenesis of GPP. The most prominent inflammatory response in pustular forms of psoriasis involves activation of IL-1 and IL-36 signaling [23]. IL-36 cytokines are part of the IL-1 family, which consists of 11 members: IL-1 (IL-1α, IL-1β, IL-1RA), IL-18, IL-33, IL-36 (IL-36α, IL-36β, IL-36γ, IL-36RA), IL-37, and IL-38 [97]. IL-36 signals to keratinocytes in an autocrine fashion, inducing the expression and enhancing the synthesis of more IL-36 cytokines. This further promotes the release of pro-inflammatory cytokines, antimicrobial peptides, and neutrophil chemokines, such as the chemokine (C-X-C) motif ligand 1 (CXCL1), CXCL2, and CXCL8, acting through six-transmembrane epithelial antigens of prostate (STEAP)1 and STEAP4 metalloreductases, and hence creating a feedback inflammatory loop in the epidermis that drives the disease [23,39,98,99]. To underline the important contrast between psoriasis vulgaris and pustular variants of psoriasis, STEAP1 and STEAP4 are only upregulated in the latter. This fact further confirms that neutrophil recruitment is preferentially active in pustular psoriasis, whereas plaque-type psoriasis is predominantly characterized by IL-17/IL-23 immune responses [26,100,101,102]. IL-36 acts on both naïve CD4+ T cells and dendritic cells [103]. With respect to dendritic cells, IL-36 activation promotes maturation and increases the expression of major histocompatibility complex class II molecules, along with the co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86), in addition to promoting the secretion of such pro-inflammatory cytokines as IL-1, IL-23, TNF-α, and IL-6 [63,104]. IL-36 leads to the induction of IFN-γ, IL-4, and IL-17 by T cells and has also been shown to promote clonal CD4+ T cell expansion, T-helper type 17 (Th17) cells differentiation, and IL-17A production in GPP [105]. This activation, as well as the contribution of both T cells and dendritic cells in IL-36 responses, may be a justification for the good treatment response to anti-TNF-α, anti-IL-17A, and anti-IL-23 biologics that has been achieved in many patients with GPP [27,30,106].

3.4. IL-17/IL-36 Axis as a Bridge between Innate and Adaptive Immunity

IL-17 is one of the main cytokines produced by Th17/Th1 cells, which play a pivotal role in the immunopathogenesis of plaque psoriasis [107,108]. There are two highly homologous members of the IL-17 protein family, IL-17A and IL-17F [109]. Even though IL-36 is the main pathogenic cytokine in GPP, a strong expression of IL-17A is observed among patients with GPP. Nevertheless, the levels of its expression in the lesional skin of GPP patients are significantly lower than in patients with plaque psoriasis [23]. Due to the IL-36 pathway intertwining with the TNF-α/IL-23/IL-17/IL-22 axis, a positive inflammatory feedback loop is created, as explained above [110,111]. IL-17A promotes the chemotaxis and accumulation of inflammatory cells, such as neutrophils, at the sites of inflammation. However, it is believed that Th17 cells might not be solely responsible for IL-17 overexpression in GPP, with neutrophils being an additional source of IL-17 [26,112,113]. As mentioned previously, the CD4+ T cells, mainly CD4+ Th17 cells, secrete IL-17. Interestingly, the augmented proliferation of IL-17 producing CD4+ T cells is promoted via IL-36 signaling, as was first observed by Arakawa et al. [105]. This interlinking between innate and adaptive immune systems has unexpected consequences and links the IL-17 and IL-36 pathways in GPP pathogenesis (Figure 1) [105].

Figure 1. Pathogenesis of generalized pustular psoriasis and plaque psoriasis—a cross-talk between innate and adaptive immunity (modified from [63]). In GPP, skin injury causes dead keratinocytes to release cathelicidin LL-37, a protein that stimulates surrounding keratinocytes to release IL-36, which further enhances the production of different chemokines and recruitment of neutrophils, T cells, dendritic cells, and monocytes. IL-36 expression is induced by other pro-inflammatory cytokines, such as IL-1, TNF-α, and IL-17A. Additionally, neutrophil proteases process and activate IL-36 family cytokines that escalate the inflammatory process. The serine protease inhibitors SERPINA1 and SERPINA3 can inhibit neutrophil proteases, which have been shown to process full-length secreted IL-36 cytokines to their more active forms, thereby increasing their pro-inflammatory activity. The mutation of the IL36RN gene can lead to IL36Ra deficiency, aggravating the inflammatory response and triggering GPP. Other genes (CARD14, AP1S3, TNIP1) are also known to predispose to GPP. In plaque psoriasis, various triggers can cause activation of keratinocytes and the release of self-nucleic acids and antimicrobial peptides (e.g., cathelicidin LL-37), which, along with type I interferons (e.g., IFN-α and IFN-β), activate plasmacytoid and myeloid dendritic cells. Activated dendritic cells promote differentiation of naïve CD4+ cells into Th1, Th17, and Th22 cells. Cytokines produced by these T cells, such as IFNγ, IL-17, and IL-22, act on keratinocytes and cause hyperproliferation. Keratinocytes release chemokines and attract neutrophils and other leukocytes. In plaque psoriasis, a different cytokine pathway than in GPP subsequently results in the same pathophysiological outcome via chemokine and cytokine secretions from keratinocytes and both IL-17 and IL-22, promoting neutrophil infiltration. (AP1S3—adaptor related protein complex 1 subunit sigma 3, CARD14—caspase recruitment domain-containing protein 14, CD4+—cluster of differentiation four-positive, CXCL1—chemokine (C-X-C) motif ligand 1, CXCL2—chemokine (C-X-C) motif ligand 2, CXCL8—chemokine (C-X-C) motif ligand 8, DC—dendritic cell, IFN-α interferon-alpha, IFN-β—interferon-beta, IFN-γ—interferon-gamma, IL-1—interleukin 1, IL-8—interleukin 8, IL-17—interleukin 17, IL-17A—interleukin 17A, IL-17C—interleukin 17C, IL-17R—interleukin 17 receptor, IL-22—interleukin 22, IL-23—interleukin 23, IL-36—interleukin 36, IL-36R—interleukin 36 receptor, IL-36Ra—interleukin 36 receptor antagonist, MAPK—mitogen-activated protein kinase, mRNA—messenger RNA, NF-ƙB—nuclear factor kappa-light-chain-enhancer of activated B cells, SERPINA3—serpin family A member 3, STAT3—signal transducer and activator of transcription 3, Th1—T-helper 1 cells, Th17—T-helper 17 cells, Th22—T-helper 22 cells, TNF-α—tumor necrosis factor alpha, TNIP1—TNFAIP3 interacting protein 1). Parts of the figure were drawn by using pictures from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/), accessed on 1 Jun 2021.

4. Biologic Therapeutics for GPP in the Light of Novel Genetic and Immunological Findings

Recently published findings of a survey regarding dermatologists’ opinions on the treatment efficacy in GPP revealed interesting and somewhat paradoxical results. While most physicians indicated that GPP flare treatments were adequate, they also stated that the response was slow and that many patients suffered from residual post-flare symptoms. It was indicated that the use of plaque psoriasis medications usually provides some benefits for GPP patients, but unmet needs clearly remain. The better utilization of the currently available therapies and the development of novel molecules will ensure safe long-term flare control [114].

TNF-α inhibitors (infliximab, adalimumab, and etanercept) were the first biologic agents to be used as an off-label treatment of GPP; therefore, the available data comprise a considerable number of GPP patients treated with those drugs [26,115]. The administration of those biologics results in rapid neutralization of TNF-α, which is also upregulated in GPP skin lesions [23]. Infliximab, the most-studied TNF-α blocking agent in GPP, showed a good response rate in 58% of patients and partial response in 28%. Notably, a quick onset of action was observed (pustule clearance in 1-3 days) [26]. Case report data also showed that infliximab can effectively treat juvenile GPP [116,117,118,119]. Treatment with TNF-α blockers was also highly effective in patients having IL-36Ra deficiency [120,121]. Interestingly, adalimumab has been shown to be a potential alternative treatment option in patients who fail infliximab, as Matsumoto et al. demonstrated significant improvement of GPP lesions in all four of their patients who had previously failed numerous systemic treatments, including infliximab, prior to switching to adalimumab [122]. It needs to be noted that most studies of TNF-α blocking agents in GPP are case reports. Therefore, further phase II and III clinical trials are necessary to evaluate the benefits and safety of these biologics in this indication.

Considering the upregulation of IL-17 and the pronounced neutrophilic infiltration in the skin of GPP patients, anti-IL-17 treatment appeared to be a very promising option [33]. Three IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) are currently licensed and approved for the treatment of moderate-to-severe plaque psoriasis [123]. All of the mentioned agents were used in GPP patients, including three open-label phase III clinical trials. Overall, a complete response was demonstrated in approximately two thirds of treated individuals, whereas only one in ten patients exhibited weak to no response [26]. The promising efficacy data for each of those compounds resulted in their approval for the treatment of GPP in Japan.

Since IL-23 plays a significant role in the pathogenesis of GPP, ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, has also been successfully utilized in the management of GPP [124]. Out of a total of seven described patients, complete remission has been achieved in six individuals; however, all but one of them were IL36RN-negative [26,124,125,126]. Risankizumab and guselkumab are both highly effective and safe inhibitors of the IL-23 p19 subunit, and which are approved for the treatment of moderate-to-severe plaque psoriasis [127,128]. Guselkumab was assessed in a phase III open-label study in GPP and was less efficient when compared to IL-17 inhibitors [30]. A phase III clinical trial to evaluate the efficacy and safety of risankizumab in Japanese patients with GPP has been completed but detailed results have to date not been published [129]

Even though blocking of the TNF-α/IL-17/IL-23 axis has resulted in some degree of success in GPP, the IL-1/IL-36-chemokine–neutrophil axis appears to be a more promising therapeutic target, especially in the context of the aforementioned immunopathogenetic findings [23].

IL-1 targeting with biologics has been previously performed in GPP patients using the IL-1α receptor antagonist (IL-1-RA) anakinra and the IL-1β monoclonal antibodies gevokizumab and canakinumab. Anakinra, a recombinant IL-1 receptor antagonist, frequently used in the treatment of other autoinflammatory diseases, was also documented to be successfully used in GPP, including a juvenile case [88,130]. However, further randomized control trials are needed to evaluate the efficacy and safety of anakinra in GPP. Gevokizumab is a monoclonal antibody blocking the pro-inflammatory cytokine IL-1β and its signal transduction in inflammatory cells [131]. Mansouri et al. reported a 79 and 65% reduction in GPP area and severity index scores at weeks 4 and 12 after treatment with gevokizumab in two patients with severe, recalcitrant GPP [90]. Another IL-1β antagonist, canakinumab, induced the complete and long-term clearance of GPP lesions in a patient in whom anakinra had been withdrawn due to hypersensitivity reactions [89].

The novel monoclonal antibody spesolimab (formerly BI 655130), targeting IL-36R, can effectively block the IL-36 signaling pathway, to alleviate inflammatory response in GPP patients [132]. Recently, a phase I clinical trial evaluated the safety and efficacy of this molecule in seven biologic-naïve adult patients with moderate GPP flare. The results showed that all patients carrying a homozygous IL36RN mutation (n = 3) or heterozygous mutation in CARD14 (n = 1) or wild-type alleles (n = 4) significantly responded to a single intravenous dose at week 4 [91,93]. None of these patients, nor any of the 124 healthy volunteers who participated in this study, experienced severe adverse effects [93]. This finding suggested that IL-36R inhibition with a single dose of spesolimab can effectively alleviate the severity of GPP, regardless of the presence of a disease-causing gene mutation, and has great potential for the future clinical treatment of GPP

Results of a healthy volunteer phase I study of another anti-IL-36R drug, imsidolimab (formerly ANB019), also suggested a favorable side effect profile of inhibiting the function of the IL-36 pathway, which supported the advancement of imsidolimab into a phase II trial (GALLOP) [94]. Preliminary results were encouraging, as six out of eight patients treated with imsidolimab monotherapy achieved the primary endpoint of improvement in the clinical global impression scale after 28 days of treatment. Imsidolimab was generally well-tolerated, and most treatment-emergent adverse events were mild to moderate in severity and resolved without sequelae. No infusion or injection site reactions were observed. Detailed information on the identified gene mutations in those patients were not disclosed [133]. More detailed characteristics and data on the efficacy of the abovementioned therapies are summarized in Table 2.

Table 2. Targeted therapies in generalized pustular psoriasis. (CD25—cluster of differentiation 25, CGI-I—clinical global impression of improvement, Fab’—humanized antigen-binding fragment, GPP—generalized pustular psoriasis, IFN-γ—interferon-gamma, IgG—immunoglobulin G, IgG1—immunoglobulin G1, IgG1κ—immunoglobulin G1 kappa, IgG1λ—immunoglobulin G1 lambda, IgG2—immunoglobulin G2, IgG4—immunoglobulin G4, IL-1—interleukin 1, IL-1β—interleukin 1 beta, IL-1R—interleukin 1 receptor, IL-2—interleukin 2, IL-2Rα—interleukin 2 receptor alpha, IL-12—interleukin 12, IL-12/23 p40—p40 subunit of interleukin 12 and interleukin 23, IL-17—interleukin 17, IL-17A—interleukin 17A, IL-17RA—interleukin 17 receptor A, IL-23—interleukin 23, IL-23 p19—p19 subunit of interleukin 23, IL-36—interleukin 36, IL-36R—interleukin 36 receptor, IL36RN—IL-36 receptor antagonist gene, Th1—T-helper 1 cells, Th17—T-helper 17 cells, TNF-α—tumor necrosis factor alpha).

5. Conclusions

GPP is a serious and potentially life-threatening disease that is often difficult to treat. The past decade has witnessed enormous progress in the understanding of the molecular and immunologic basis of GPP. Arguably, one of the most important discoveries leading to a better understanding of the pathogenesis of this exceptional type of psoriasis was the report of the association between IL36RN and GPP, which was shortly followed by other significant genetic findings [70]. However, numerous studies found that a large number of patients with GPP did not carry any known variations in the above described genes, which implies that some novel variants located in introns or regulatory regions and other genetic factors may contribute to GPP’s pathogenesis [53]. Further screening and identification of other genes will therefore complement the current genetic map of GPP and is likely to greatly contribute to novel therapeutic approaches. The last few years have shed some new light on the immunological disturbances behind GPP. As shown by the recent studies, the TNF-α/IL-23/IL-17/IL-22 axis and IL-36 pathway intertwine in GPP pathogenesis [105]. This significant observation allowed the use of biologics, known for being effective in the treatment of plaque psoriasis, to be also used in GPP, regardless of IL36RN mutation status. However, the emerging need for more effective targeted therapies resulted in the development of a novel group of drugs that directly inhibits IL-36R [91].

Therapeutic intervention in GPP is a significant challenge. Given the rarity of GPP, the recruitment of a sufficient number of patients to conduct a large, randomized, controlled clinical trial, to adequately investigate the efficacy and safety of therapeutics, is the main difficulty. Moreover, the variable and unpredictable course of GPP makes it even more difficult to assess the efficacy of any intervention in this indication.

Author Contributions

Conceptualization, D.S., J.S., A.R.; Resources, D.S., J.S.; Writing—Original Draft Preparation, D.S., J.S.; Writing—Review & Editing, D.S., J.S., A.R.; Supervision, A.R. All authors contributed equally to this work. All authors have read and agreed to the published version of the manuscript.

Funding

The publication fee was covered by the grant of the University of Rzeszow: “Analysis of clinical and molecular parameters and studies on new drugs in skin diseases” (Scientific Research of Institute of Medical Sciences University of Rzeszow, 500-3-60-601/2021).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data availability is not applicable to this article, as no new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflict of interest.

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Sigma Male vs. Alpha Male: 10 Differences You Need to Know

1. Assertive vs. Aggressive

Both sigma and alpha males are confident but display it differently.

Sigmas typically assert their opinions and desires in healthy, considerate ways. While they can be assertive, they’re rarely obnoxious about it.

Alphas can be a bit more aggressive and may sometimes cross the line with personal relationships. (But their dominance often comes in handy when negotiating business deals!)

Disclaimer: Some alpha males shed their overly aggressive skin after realizing they get further by toning down the bull-in-a-china-shop persona. 

2. Private vs. Social

Sigma males are a lot more private than alpha males. The alpha derives confidence from being at the top of a social hierarchy, so they must be around other people to feel their best.

In a way, they need other people to see their success and status.

Sigmas, however, are significantly more laid back and self-sufficient.

Disclaimer: Many sigma males have close friend groups, but they’re usually better at “alone time” than their alpha counterparts.

3. Quiet vs. Loud

Common wisdom insists that sigma males are quieter than alpha types. And it’s true. Since sigmas don’t court or crave attention, they tend to be lower-key.

But don’t be fooled by silence. Some of the most skilled, ruthless, domineering alpha men choose their words carefully and know when to shut their mouths.

Disclaimer: Some alpha males can be deceptively quiet when assessing a situation. Conversely, sigma males get loud and proud when passionate about a topic.

4. Easy-Going vs. Competitive

One of the best ways to tell a sigma from an alpha is the person’s competitive quotient.

Sigma men tend to be successful but aren’t ferocious about winning. Furthermore, they’re usually not concerned with taking credit. For sigmas, the work is the thing.

Alpha males, on the other hand, crave competition. For them, there’s nothing quite as satisfying as winning.

Disclaimer: Sigmas can be very competitive when they care about a given project, race, or contest.

5. Independent vs. Group-Oriented

Alpha males typically prefer to work and operate in group situations — not to collaborate, but to dominate. Sigmas usually do fine in groups, but they’re more independent.

Regarding careers, sigmas follow their passions, whether art, computing, medicine, or social work.

On the other hand, Alphas tend to stick to lucrative careers, like finance, law, and medicine — professions people see as high-status.

What about alpha men who don’t have the means to work in those fields? They usually pick jobs that can yield high monetary rewards but require less education (and initial financial investment), like real estate, construction, or craftsmanship.

Disclaimer: Some alphas are great collaborators, recognizing that you can get more bees with honey than vinegar, but that is where sigmas shine, they can assume most any position and play multiple roles with ease, cause grief for all alphas!

6. Confidence vs. Cocksure

Confidence is tricky to master. One step over the line, and people will see you as arrogant.

And yet, cultivating confidence is always worth the effort — because a well-balanced sense of self-esteem does wonders for your mental and physical health.

Sigmas typically strike the right balance between approachable and arrogant, but alphas are more at risk of becoming cocksure instead of confident.

Disclaimer: Self-confidence can be challenging to learn. So everyone, whether alpha, beta, delta, gamma, or omega, goes through periods of confidence and arrogance when learning how to get it right. Sigmas allure of self confidence is always evident.

7. Introverted vs. Extroverted

Sigmas are almost always more introverted than alphas. We’re not saying sigmas are friendless; many maintain deep, long-lasting ties. But they’re usually not the life of the party.

Alphas, on the other hand, are front and center in every situation — professional and personal.

One isn’t better than the other. Sometimes, having an extroverted person around adds energy and positivity to a situation. Other times, spending time with a thoughtful introvert is precisely what the doctor ordered.

Disclaimer: Introversion and extroversion are two other behavioral conditions that can be highly contextual. Nobody, not even alpha males, is always on. Sigmas spend more time in Introversion mode but can easily take on the charming extroversion role any day!

8. Avant-Garde vs. Traditional

Men who fall into the alpha category are usually more traditional and conservative.

They like to fill the knight-in-shining-armor slot. Plus, their worldview is reliant on a top-down hierarchical structure. Without it, they don’t have a pack to lead.

Sigma men may fall more on the avant-garde end of the scale because their passions lie elsewhere, and their interests are their lodestars.

Disclaimer: Sigma and alpha men are represented on all sides of the political spectrum. It’s just that alphas tend to be more aggressive when it comes to their viewpoints. often falling victim to sigmas sheer wit

9. Hierarchical vs. Collaborative

As we’ve stated several times, alpha males thrive in hierarchical environments. They want to be the center of attention. Some may be great leaders, and others can be more bullying.

Sigmas are flexible. While they don’t break down in hierarchical environments, they’re better in collaborative atmospheres.

They know how to encourage teammates and don’t take it personally when someone else may get more credit.

Disclaimer: Sigma males who become team leaders can become more hierarchical in their approach with others while remaining completely outside of the said hierarchical structure they are controlling.

10. Indifferent vs. Engaged

We’re not suggesting that sigma males dislike engaging in situations or building deep relationships with people. They do! But they’re not nearly as concerned about whether they’re popular or not. They’re indifferent to being part of the in-crowd.

On the other hand, Alphas are all about being an essential part of the “gang.” Alphas join fraternities and are the first to sign up for the office kickball league.

Disclaimer: Younger alphas tend to be a tad more concerned with winning short term.  While sigmas easy going ways propel them around many of life’s bumps while pursuing much more lofty goals than just short term success.  

We’re not saying that alpha males don’t have fans, but they’re no longer the undisputed top game in town.

All that said, it’s important to remember that looks aren’t the only thing that makes a person attractive. Other desirable traits include:

• Humor: Being funny may be better than being good-looking. That’s why average-looking comics always have great-looking partners.
• Intelligence: Intelligent men are great company for partners packing impressive gray matter.
• Kindness: It’s not true that nice guys never win. Sometimes, it just takes a little while for some people to overcome their “bad boy” stage.
• Humility: Nobody knows everything, and we all have strengths and weaknesses. People who understand that and have a healthy sense of humility emit great vibes that people find attractive.

A Couple of Final Thoughts

Social-hierarchical categories are fun to consider and can provide a framework for determining a person’s motivations and personality type.

A Sigma Male Versus an Alpha Male

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If you are dating, learn more about what a sigma male is versus an alpha male and how they handle relationships.

Every man has character traits that are unique and sum up the way he acts. Though men make different decisions and seem to go about life normally, their actions can be categorized into particular tendencies and habits. Let’s learn more about what a Sigma Male is as we outline how they handle relationships compared to the alpha males.

Own Pace

Mostly sigma males prefer being alone, but that doesn’t mean they are lonely. They enjoy their own company and prefer to go at their own pace, not following or being led by anyone. A woman has to get ways to not only entice a sigma male into a relationship, but she also has to meet his standards which in most cases are pretty high.

On the other hand, alpha males prefer being leaders. If they are not in any group, they will long to be in one and take the lead as soon as they join. If an alpha male has close connections and feels comfortable with them, he will not feel lonely, but if they are lacking, then he will long to have them. His dominant nature makes him uncomfortable when he is not leading in any relationship.

Rebellious

One outstanding trait of sigma males is the tendency not to want to follow the norm. They want to do what they think, not what they are told. They rebel in their actions, fashion statements, and careers. Their rebellious ways give them the title bad boys. Due to them not conforming to expected standards, they disturb to break the monotony as view it.

Alpha males only act out of the norm if there is a conflict with their values but are more careful not to break the law than a sigma male. Alpha males jump onto new trends. They lead in showing off the new style even if they are not keen on fashion.

Speaking

While sigma men only speak when it’s essential and comfortable keeping to themselves, alpha males readily share what’s on their minds. The silence and knowledge of the sigma males attract people when they speak. It also serves as a sexy and puzzling trait that women want to decipher.

The bold and talkative nature of the alpha males makes women feel protected.

Secretive

Sigma males keep to themselves, making them an attractive challenge to women. Women imagine there must be secrets well hidden, and they intend to get close and uncover them.

The trait of the alpha males of stating what is in their minds openly and boldly is equally attractive to women. Sharing is akin to self-confidence and sexy to women.

Centre of Attention or in the Shadows.

Sigma men would rather stay away from any spotlight unless it’s part of their career. However, this piques people’s curiosity and draws them closer.

Alpha men live for the stage to be the point of attention. They want the world to hear them. Whether a man has a puzzle-like character or is bold and open, they are attractive to women. source

Sigma Male vs. Alpha Male: Both Powerful only one is internally Happy & a Charming Man, the Illusive Sigma

1. Both Are Confident And Powerful And Possess Strong Leadership Qualities.

Young men with the sigma male personality or the personality type of alphas are great at social interaction as they possess high interpersonal social skills. They’re confident when talking to a woman and generally have good social status.

2. They Are Powerful And Protective Of Others.

It is a social norm for them to show a protective side. They’ll stick up for their omega and beta male brothers and will come to the aid of a damsel in distress.

3. Both Are Attractive To Women.

If there is a male personality type that women are attracted to, the alphas and sigmas win. There’s something about the sigma male trait and the alpha personality that naturally oozes attractiveness, masculinity, and charm.

Differences

via: Pexels / Antony Trivet

4. While Alpha Males Tend To Be Outgoing And Loud, Sigma Males Are Naturally Introverts And Loners.

As the epitome of a sigma male, John Wick takes the lead. They’re a lone wolf compared to the alpha male archetype of enjoying being part o

f a crowd. Alphas are loud and like to take control of a room. Sigmas like to watch from the corners.

via: Pexels / Ketut Subiyanto

5. Alphas Lead Others Using Their Dominating Nature And Physical Prowess, While Sigmas Lead Without Exerting Authority.

Both alphas and sigmas stand at the top of social dominance hierarchies, but sigmas lead by example rather than make commands or use an authoritative tone.

https://goodshepherdmedia.net/?p=18745 California can share your baby’s DNA sample without permission, but new bill could force state to publicly reveal who they’re giving it to

The State Owns Your Newborn Blood Spot DNA

Genealogy companies like Ancestry.com and 23andMe have to get your permission before they store, use, or share your DNA, under the Genetic Information Privacy Act. However, the California Department of Public Health doesn’t have to. In fact, the agency has been storing DNA samples from every baby born in California since the 1980s.Researchers can purchase those samples for state-approved studies and law enforcement can access them with a court order, but state agency officials recently refused to provide CBS News California with a list of recent law enforcement and research requests for newborn bloodspots.

After more than a decade of CBS reporting on the biobank, this is the first time California officials have refused to reveal to us who has access to California’s newborn bloodspots. Under previous administrations, the agency regularly provided that information under the California Public Records Act.

Keep in mind, if you’re even related to someone born in California since 1983, thanks to genetic genealogy, portions of your DNA are in the biobank too, and can likely be used to identify you.

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While California’s Newborn Genetic Biobank is undoubtedly saving lives, the appearance of state secrecy is raising concerns. In response, some California lawmakers are pushing for transparency, but they face an uphill battle at the State Capitol. (To learn more about newborn blood storage, and how to opt out, click here.)

For some, newborn DNA testing is a lifesaver

“He was a very cute, very adorable baby,” Ronnie’s dad said, as he described seeing his son for the first time, “and perfectly healthy.”

At the time, the new father (who for medical privacy reasons asked us not to use full names in this report) didn’t think much about what happened next. Like every baby born in the state, Ronnie got a heel prick shortly after birth. That blood filled six spots on a special card used to test babies for dozens of disorders that, if treated early enough, could prevent severe disabilities or death.

A couple of days after taking their seemingly healthy boy home from the hospital, they got a call from the local pediatrician, who said the child was diagnosed with “no immune system at all.” They learned Ronnie’s heel prick revealed that he had a rare genetic disorder called SCID, also referred to as “bubble boy disease” after David Vetter, who lived his life in a bubble in the ’70s before dying at age 12.

Ronnie’s first infection could have killed him, but thanks to research, the disease is no longer a death sentence. Ronnie was rushed to UCSF Medical Center where he received lifesaving gene therapy. That’s where he met Dr. Jennifer Puck, who created the test that saved Ronnie’s life.

“I could never have developed a newborn screening test for SCID if we hadn’t had stored dried blood spots,” Puck said.

Doctors only need a few of the baby’s blood spots for their own lifesaving genetic test, but the rest becomes the property of the state and can be purchased by outside researchers.

While newborn bloodspots had been used in research for years, the SCID test was the first to be developed using extracted DNA from bloodspots stored in California’s massive newborn genetic biobank. The state doesn’t extract or sequence the DNA from bloodspots, they store the physical bloodspot samples, which researchers can purchase for state-approved studies and extract or sequence the DNA themselves.

“You have to go through a scientific review to say, is this a worthwhile project,” Puck explained.

Many parents don’t know the state is collecting  newborn DNA

California has amassed what’s believed to be the largest stockpile of newborn bloodspots in the country. It is one of the few states that is still storing every baby’s bloodspots indefinitely, without first getting parents’ consent.

Therein lies the concern. Back in 2018, CBS News California randomly selected six new moms to ask what they knew about the newborn genetic testing program. When asked whether they knew the state was storing their children’s DNA, all said they did not; when asked if they felt they should have been made aware, they agreed they should have.

“I didn’t know there was repository of every baby born in the state,” one concerned mother said. Another added, “There just should be accountability and transparency.”

Some states allow parents to opt-in to storage or give informed consent. California automatically stores your baby’s genetic material, then sends you home from the hospital with a pamphlet that points you to a website where you can request that they destroy the sample. But first, you’d have to know they were storing it in the first place.

“I feel like that’s something that should have been discussed with us in person,” one concerned mother said.

“Everyone who came into our room gave us another pamphlet,” another added.

A CBS News-Survey USA news poll found three-quarters of new parents had no idea the state was storing their baby’s leftover bloodspots indefinitely or that they had the right to have their child’s sample destroyed.

“Blood is intrinsically personally identifiable,” one mother pointed out.

Could privacy violations, lawsuits threaten California’s biobank?

Public records CBS News California obtained from the California Department of Public Health in 2010 revealed that, in addition to research, newborn genetic bloodspots are also used by law enforcement.

Our reporting found at least five search warrants and four court orders for identified blood spots, and that was before the Golden State killer case made genetic geology a common law enforcement tool.

Since then, we know at least one cold case was recently solved with the help of California’s newborn blood spots.

A lawsuit alleges police subpoenaed a 9-year-old’s newborn samples from New Jersey’s biobank to link his father to a cold case rape before the child was born. And Texas reportedly provided race-specific blood spots to the federal government to build a DNA database.

But when we recently asked California’s health department for an updated list of research and law enforcement requests, the agency denied us, saying it “is no longer tracking” that information like it used to and it’s “not required to create a record” telling us who has access to California’s stored DNA:

“Unfortunately, GDSP is unable to provide you the information as requested. Previously, GDSP provided you with an existing spreadsheet of research studies… GDSP has since moved to a new computer program for collecting this data and is no longer tracking research studies using the spreadsheet and the table. Pursuant to Government Code section 6252, subdivision (e), and established case law, a public agency is not required to create a record that does not exist at the time of the PRA request. (See Haynie v. Superior Court (2001) 26 Cal.4th 1061, 1075; Sander v. Superior Court (2018) 26 Cal.App.5th 651, 665-666.)”

For years everyone from privacy advocates to lawmakers to genetic detectives have warned California’s secrecy could ultimately harm trust in the biobank.

“People have the right to choose how their DNA is used and how their children’s DNA is used,” said Cece Moore, a genetic detective.

Texas is one of several states that had to destroy their bloodspots after being sued for storing them without consent. It was a devastating blow to the research community and many worry that California’s biobank could be next.

“I think we need to find ways that parents can consent without harming research,” Puck said.

Medical community opposed allowing opt-ins in the past

The medical community has historically opposed allowing parents to opt into storage, for a number of reasons.

“If you required consent, a lot of people would say yes, and some people would say no,” explained Puck. “And the people who say no, we don’t know if that’s a biased sample. And so that would skew the biobank.”

Puck adds there is also a possibility that the parent could say no and then later really come to regret that decision.

However, the California Constitution guarantees the right to “pursue and obtain privacy” and state law “prohibits health care providers from sharing, selling, or using patient medical information without consent.”

Legal experts involved in lawsuits in other states tell us that it’s only a matter of time before California’s biobank is taken to court. If the state proactively allowed consent, they say it could ultimately help save the biobank.

Despite support, why has newborn DNA legislation stalled?

The Texas Law Review cited our ongoing reporting on this issue and so did legislative analysts when our reporting led to a bill last year that would have let parents opt out of storage or research before the samples were stored. Even the powerful medical lobby removed their opposition to the bill after the author made significant changes.

The bill passed three different committees, at least one with a near-unanimous vote. Then the bill quietly died in January behind closed doors in the Senate suspense file. Why? Money and politics. Any bill that is estimated to cost more than $150,000 is sent to the “suspense file” where, in a budget deficit year, many bills go to die.

The state health department claimed it would cost roughly $4 million to implement, plus ongoing costs of over $1 million a year, to give parents the right to opt out of storage or research before the state automatically stores their child’s DNA.

An independent appropriations analysis of a similar bill in 2015 estimated $120,000 to implement that bill with half a million in ongoing costs.

Neither California’s health department nor the Senate Appropriations Committee could provide an accounting or evidence of the estimated costs. But maybe more importantly, the bill should not have cost taxpayers anything because research fees are supposed to pay for the program.

Still, the Appropriations Committee chair has the power to kill any bill they want to by holding it in the “suspense file,” where it automatically dies without a vote. Then-chair, Glendale Senator Anthony Portantino, decided to do just that, ultimately killing the bill before the rest of the senate got a chance to vote.

The appropriations analysis of the bill clearly states that CDPH’s estimated costs would be covered by the Genetic Disease Testing Fund (GDTF), not the general fund. State regulation requires the biobank program pay for itself through the (GDTF), by charging researchers to use the bloodspots.

The committee analysis does cite potential additional “(c)osts to local registrars for administration,” however, regulations are clear: “It is the intent of the Legislature that the program… be fully supported from fees collected…”

We asked the CDPH Office of Communications to confirm that any costs related to the bill would have been covered by increased fees charged to researchers. The agency did not respond. However, we did receive an unsolicited notice that a California Public Records Act request had been submitted on our behalf. Under state law, that gives the agency two weeks to decide if it will answer our questions.

We also asked the Appropriations Committee and former chair Asm. Portantino, to clarify why they chose to let the bill die in the suspense if the bill would not have created any additional costs to the state?”

They did not respond to repeated emails.

Two new California bills introduced in 2024

Privacy advocates are at it again with two new bills this year.

Prompted by our recent reporting, SB 1099 would force the state to publicly reveal, among other things, who’s using California’s newborn bloodspots and why.

The other, SB 1250, would amend California’s Genetic Information Privacy Act to require the state government to follow the same rules as consumer genetic testing companies and get consent before using or sharing your genetic data.

“Consent is definitely a good option,” said Ronnie’s dad, who supports the biobank and consent.

Genetic data from those stored blood spots has undoubtedly saved thousands of babies, including Ronnie’s, who is thriving — outside of a bubble. source

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The State Owns Your Newborn Blood Spot DNA

The #ReportersNotebook entry below was first published in 2015. Since then, we’ve identified new concerns. Please also see the updated story here:

If you or your child was born in California after 1983, your DNA is likely being stored by the government, may be available to law enforcement and may even be in the hands of outside researchers.

Like many states, California collects bio-samples from every child born in the state. The material is then stored indefinitely in a state-run biobank, where it may be purchased for outside research.

State law requires that parents are informed of their right to request the child’s sample be destroyed, but the state does not confirm parents actually get that information before storing or selling their child’s DNA.

Reporter Julie Watts has learned that most parents are not getting the required notification. She also discovered the DNA may be used for more than just research.

In light of the Cambridge Analytica-Facebook scandal and the use of unidentified DNA to catch the Golden State Killer suspect, there are new concerns about law enforcement access, and what private researchers could do with access to the DNA from every child born in the state.

Continue Reading at CBS San Francisco…

For more information on how your child’s specimen might have been used for research, email newsmom.com@gmail.com

#ReportersNotebook 2015

Do you know if your child’s  DNA is being stored in a government database? If you live in California, or at least 20 other states, it likely is.

In this report for CBS San Francisco, we took a closer look at the life-saving “Newborn Screening Test.”

No one disputes the need for, or benefits of, the mandatory genetic screening program. However, the controversy stems from the lack of disclosure about what they do with your child’s newborn blood spot DNA after the test.

For decades, state governments have been collecting, storing and “selling” babies’ DNA to private companies for research without parental consent—DNA from a blood test that you pay for.

Newborn Screening Test

Every baby born in the U.S. is pricked on the heel at birth so that their blood can be screened for rare genetic disorders. The test is required by law and is even performed following home births.

The Newborn Screening Program allows babies with rare genetic disorders to receive early diagnosis and treatment, often saving their lives.

SaveBabies.org outlines the screening process and the benefits of the test. It also highlights stories of lives saved because of the test.

Genetic screening really is a miracle of modern science.

However, in at least a couple dozen states, the blood spots that are used for the screening are not destroyed after the test.

Now, storing your child’s DNA is not inherently a bad thing. State researchers use the stored blood spots to come up with new genetic tests for other diseases, ultimately saving more lives.

What They Don’t “Tell” You

The issue for many, however, is the fact that some states store and sell your babies’ DNA without your consent or even knowledge.

In addition to state researchers, law enforcement and lawyers can obtain your child’s DNA, and private companies can purchase it for research.

(Note: The California Newborn Screening Program insists that the state does not profit from the sale of blood spots, rather private companies reimburse the state for costs incurred—often tens of thousands of dollars per blood spot.)

Parents do have the right to ask that the blood spots be destroyed, but did you know they even existed? Most don’t.

We asked the California Department of Public Health how it informs parents their child’s blood spots will be stored after the Newborn Screening Test. The state response made me laugh out loud.

The information for parents about storage and use of blood spots is provided on pages 12 and 13 of the Newborn Screening brochure. In addition to being available on the internet in multiple languages, healthcare providers give the brochure to parents prenatally and at birthing centers and hospitals.

Between trying to figure out how to nurse my newborn, change a diaper, sleep train my baby, learn the “5 S’s,” find time to shower, research vaccines, get to doctors’ appointments, interview nannies and deal with insurers, it never occurred to me to comb through the four folders of forms and information I was sent home from the hospital with to find that brochure so I could flip to page 12 and 13.

You’d better bet I did just that, though, as soon as I started researching this story. You know what I found? A “Newborn Screening Test Request Form (TRF),” filled out in a stranger’s handwriting that didn’t even have a spot for my signature.

Requesting/Destroying Your DNA

California’s genetic testing program began in 1980, so I took advantage of my rights in California to request information about how my DNA had been used.

Turns out the state didn’t begin “storing the DNA” until 1983.

So, I requested the same information about my sister and my daughter, but I was told that their specimens had “not been used for research.”

I then asked to have my daughter’s DNA/blood spot card returned to me so that I could ensure it would not be used without my consent. This is the response I received:

Unfortunately, department policy does not allow for specimens to be released to an individual, “The Newborn Screening Program tests newborn specimens to provide medical results for disorders for which we screen.  The residual specimens may be used for research concerning diseases of women and children.  When requested by parents or an adult who was screened as a child, the California Department of Public Health (CDPH) will destroy newborn screening specimens so that they are not available for research or CDPH will send a portion of the specimen safely to another facility for further medical testing. CDPH does not release individual specimens to members of the public pursuant to requests by those individuals.”

So in short, you should trust that the agency that took your child’s DNA without your consent will destroy it upon request. They will not return that DNA to you even though it’s technically yours. I have not yet asked if they will return it to my pediatrician.

Also, note this disclaimer from the state:

You have a right to ask the Newborn Screening Program not to use or share your or your newborn’s information and/or specimen in the ways listed in this notice. However, we may not be able to comply with your request.

Though, keep in mind that by destroying your child’s sample, you are preventing researchers from using it to come up with new, potentially life-saving, tests. California has one of the largest databases in the country, and as a result can test for more genetic disorders than any other state.

After hearing from parents whose children have been saved by those tests, I opted to request that the state simply mark my daughters “specimen” as “do not use for outside research.”

Privacy

Now, to be clear, the state does not sequence the DNA, so it’s not exactly a “DNA database.” Rather, the state stores your child’s blood spots, which can then be sold for research.

It’s the researchers that extract–and potentially sequence–your child’s DNA.

The state claims the information is “de-identified,” so your baby’s DNA can’t be tracked back to the child. However, Yaniv Erlich of Columbia University and the New York Genome Center says there is no way to guarantee that.

As we point out in our CBS Report:

His research demonstrated how easy it is to take anonymized DNA, cross-reference it with online data and connect it to a name. “You need to have some training in genetics, but once you have that kind of training the attack is not very complicated to conduct,” he said.

Once he realized that there’s no guaranteed privacy when it comes to DNA, Erlich took it a step further and created dna.land. It’s essentially a crowd-sourced database where people voluntarily donate their DNA to share with scientists.

Its motto: “Know your Genome to help science.” Similar to 23 and me, you can also find long-lost relatives at dna.land. However, dna.land is free and run by academics at Columbia University and the New York Genome Center.

Is the state database legal?

Even if researchers couldn’t track your child’s DNA back to your child, the states can. They obviously have to be able to find your DNA if you ask to have it destroyed.

We requested public records and found that the state also hands over that DNA to law enforcement. It can be, and often is, subpoenaed. However, as far as we know, no one has yet been convicted of a crime based on their blood spot DNA in the state’s database.

A fairly new federal law requires that any federally-funded researchers using newborn blood spots must first get parental consent. However, that does not apply to state-funded or privately-funded research.

For now, the legal right to store and sell the dried blood spots is determined by each state. However, Pediatrics reported some states “may be acting outside the scope of their legal authority.”

Parents in Texas sued the state for selling their children’s blood without consent. It was later determined that the state sold blood spots to pharmaceutical companies for research and “loaned” it to the U.S. Armed Forces.

The state settled with the families out of court and subsequently destroyed the DNA taken without parental consent. Texas has now enacted a law allowing parents to “opt in” to the program.

The Minnesota Department of Health (MDH) was also sued for establishing a biobank without parental consent. Samples were allegedly used for research by drug companies and equipment manufacturers.

The Minnesota Supreme Court ruled that written, informed consent is required for storage, use or dissemination of any remaining blood samples or test results after completion of a newborn screening.

Ultimately the state was forced to destroy hundreds of thousands of test samples and results. Minnesota later enacted a law requiring written informed consent before newborn samples can be used for research.

That is something the medical community in California is trying to avoid.

We asked the California Department of Public Health why it does not allow parents to opt in, or at least provide informed consent, before storing and selling a child’s DNA. The state declined an interview and ultimately provided this response after our story aired.

Healthcare providers at California’s many birthing facilities give parents informational brochures about opting-out of blood spot storage. Since parents of newborns have many other concerns shortly after birth, this procedure allows them to make that decision at any time, without pressure. Parents can then contact the California Department of Public Health (CDPH) and learn more about their options from knowledgeable professionals who are directly involved with the Newborn Screening Program.

Again, I had to  point out to the state that neither I, nor any new mother I’ve spoken with, recall ever being informed that our child’s DNA would be stored and/or sold after their genetic test.

I’ve now asked if they keep any records or have any evidence that parents are, in fact, informed. I’ve also asked the state to elaborate on why parents are not offered the opportunity to provide “informed consent for the storage and sale of their child’s blood spots at some point during in the 9 months leading up to the delivery.” I am still awaiting a response.

Lawmakers Trying To “Fix It”

Earlier this year, California Assemblyman Mike Gatto introduced the DNA Privacy Bill that would require the state to get informed consent from parents before storing and selling a child’s DNA.

“Whenever data is stored, data can fall into the wrong hands. Imagine the discrimination a person might face if their HIV status, or genetic predisposition to a mental disorder were revealed to the public,” said Gatto. “Parents should have the right to protect their children and people should have the right to control how their personal medical records are used once they reach adulthood.”

The bill was strongly opposed by the biotech, medical and research communities. However, after five revisions, the only remaining opposition was from the California Hospital Association. CHA declined to comment for our story.

Here are excerpts from the opposition to informed consent:

The California Hospital Association (CHA): 
...this bill would also increase the administrative burdens on hospitals, physicians, and new mothers which, in turn, will increase health care costs.

The University of Southern California (USC):  
California's database is internationally recognized as a critical public health asset and allows for the study of these rare diseases among its diverse communities.

The American Academy of Pediatrics and March of Dimes (CA Chapters):
... oppose any amendments that would link consent for storage and research of newborn screening blood spots with the initial collection and testing of the blood spots.

California Children's Hospital Association (CCHA):
... the current California blood spot database is an internationally recognized public health asset because of its size and diversity.... Implementing an informed consent policy will require significant financial resources...

The University of California (UC): 
... this measure could significantly limit the availability of the valuable data and biosamples collected by the CNSP for research use.

The bill ultimately failed. Gatto says he will re-introduce it next year.

Bottom Line

The bottom line is that newborn genetic testing saves lives. Without access to the stored blood spots from the millions of babies born every year, researchers say they would not have been able to create the life-saving tests to begin with.

The question remains: Should parents have the right to consent/opt in to the state storing and selling their child’s DNA after the test is performed?

Currently, the state admits it does not obtain consent, and the industries that benefit from the program are fighting to keep it that way. The general belief is that many parents would not consent if given the option, and the scientific community would ultimately suffer. source

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DNA of every baby born in California is stored. Who has access to it?

You probably know where your Social Security card, birth certificate and other sensitive information is being stored, but what about your genetic material? If you or your child was born in California after 1983, your DNA is likely being stored by the government, may be available to law enforcement and may even be in the hands of outside researchers, CBS San Francisco’s Julie Watts reports.Like many states, California collects bio-samples from every child born in the state. The material is then stored indefinitely in a state-run biobank, where it may be purchased for outside research.

State law requires that parents are informed of their right to request the child’s sample be destroyed, but the state does not confirm parents actually get that information before storing or selling their child’s DNA.

CBS station KPIX has learned that most parents are not getting the required notification. And the DNA may be used for more than just research.

In light of the Cambridge Analytica-Facebook scandal and the use of unidentified DNA to catch the Golden State Killer suspect, there are new concerns about law enforcement access, and what private researchers could do with access to the DNA from every child born in the state.

Health

DNA of every baby born in California is stored. Who has access to it?

SAN FRANCISCO — You probably know where your Social Security card, birth certificate and other sensitive information is being stored, but what about your genetic material? If you or your child was born in California after 1983, your DNA is likely being stored by the government, may be available to law enforcement and may even be in the hands of outside researchers, CBS San Francisco’s Julie Watts reports.Like many states, California collects bio-samples from every child born in the state. The material is then stored indefinitely in a state-run biobank, where it may be purchased for outside research.

State law requires that parents are informed of their right to request the child’s sample be destroyed, but the state does not confirm parents actually get that information before storing or selling their child’s DNA.

CBS station KPIX has learned that most parents are not getting the required notification. And the DNA may be used for more than just research.

In light of the Cambridge Analytica-Facebook scandal and the use of unidentified DNA to catch the Golden State Killer suspect, there are new concerns about law enforcement access, and what private researchers could do with access to the DNA from every child born in the state.

The Lifesaving Test

It all begins with a crucial and potentially lifesaving blood test.

The Newborn Genetic Screening test is required in all 50 states, and is widely believed to be a miracle of modern medicine.

Nearly every baby born in the United States gets a heel prick shortly after birth. Their newborn blood fills six spots on a special filter paper card. It is used to test baby for dozens of congenital disorders that, if treated early enough, could prevent severe disabilities and even death.

It’s estimated that newborn screening leads to a potentially life-saving early diagnosis each year for 5,000 to 6,000 children nationwide.

The California Department of Public Health reports that from 2015-2017 alone, the Newborn Screening test diagnosed 2,498 babies with a “serious congenital disorder that, if left untreated could have caused irreparable harm or death.”

But, unless you or your child is diagnosed with one of these disorders, the test is often lost in the fog of childbirth.

KPIX randomly selected six new moms and asked what they knew about their child’s genetic test.

Three of the moms remembered the heel prick, while the other three say they think they knew about the test. But, like most parents, none knew what happened to their baby’s leftover blood spots after the test.

They were shocked when KPIX reporter Julie Watts explained it to them.

Your rights after the test

The lab generally only needs a few of the blood spots for the baby’s own potentially lifesaving genetic test. They use to collect five blood spots total from each child in California, they’ve now increased that to six.

Some states destroy the blood spots after a year, 12 states store them for at least 21 years.

California, however, is one of a handful of states that stores the remaining blood spots for research indefinitely in a state-run biobank.

Even though the parents pay for the lifesaving test itself, the child’s leftover blood spots become property of the state and may be sold to outside researchers without the parent’s knowledge or consent.

“I just didn’t realize there was a repository of every baby born in the state. It’s like fingerprints,” new mom Soniya Sapre responded.

Amanda Feld, who had her daughter 15 months ago, was concerned in light of recurring data breaches. “We know that companies aren’t very good at keeping data safe. They try,” she said.

New mom Nida Jafri chimed in, “There should be accountability and transparency on what it’s being used for.”

“Blood is inherently or intrinsically identifiable,”added Sapre.

Some states allow parents to opt-in or give informed consent before they store the child’s sample.

In California, however, in order to get the potentially lifesaving genetic test for your child, you have no choice but to allow the state to collect and store the remaining samples.

You do have the right to ask the biobank to destroy the leftovers after the fact, though the agency’s website states it “may not be able to comply with your request.”

You also have the right to find out if your child’s blood spots have been used for research, but you would have to know they were being used in the first place and we’ve discovered that most parents don’t.

Samples used to save more lives

Dr. Fred Lorey, the former director of the California Genetic Disease Screening Program, explained that blood spot samples are invaluable to researchers.

“They’re important because these samples are needed to create new testing technology,” Lorey said.

He explained that they’re primarily used to identify new diseases and improve the current tests, ultimately saving more babies

With nearly 500,000 births a year, California’s biobank is, by far, the largest and is crucial for research nationwide.

According to the Department of Public Health, more than 9.5 million blood spot samples have been collected since 2000 alone. The state has stored blood spots since 1983.

As a result, California can now test newborns for more than 80 different disorders, more than any other state. The standard panel nationwide is around 30 disorders.

But researchers with the California Genetic Disease Screening Program aren’t the only ones with access to samples stored in the biobank.

Blood spots are given to outside researchers for $20 to $40 per spot.

Regulations require that the California Genetic Disease Screening Program to be self-supporting.

“It has to pay for itself,” Lorey noted. Allowing outside researchers to buy newborn bloodspots helps to recoup costs.

According to biobank records, the program sold about 16,000 blood spots over the past five years, totaling a little more than $700,000. By comparison, the program reported $128 million in revenue during the last fiscal year alone, mostly generated by the fees parents pay for the test. Parents are charged around $130 on their hospital bill for the Newborn Screening Test itself.

Making money off your DNA

But while the state may not be making money off your child’s DNA, Lorey admitted that there is the potential for outside researchers to profit off your child’s genetic material.

“Do any of those studies result in something that the company can make money from?” reporter Julie Watts asked Lorey in a recent interview. “Could they create a test or treatment that they ultimately profit from?”

“Theoretically, yes,” Lorey admitted. “I’m not aware of any cases that that’s happened because virtually all, not all, of these researchers that have made requests are scientific researchers.”

He explained that researchers who request the spots must meet specific criteria. Their studies must first be approved by a review board. They’re also supposed to return or destroy remaining blood spot samples after use.

However, privacy advocates point to the Cambridge Analytica-Facebook scandal where third-party researchers were supposed to destroy data, but instead used it for profit – and untimely to attempt to influence a presidential election.

Watts pressed Lorey on that point.

“So there is no possibility a researcher may request blood spots for a specific research experiment … but then keep blood spots without the department’s knowledge to be used for other purposes?” she asked.

“I want to say no” he said. “But I’m not ready to say no because I know how humans can be sometimes.”

“De-identified DNA”

However, Lorey stressed that the blood spots cards, stored in the state biobank, are “de-identified.” There is no name or medical information on the card, just the blood spots and a number.

Lorey explained the identifying information is stored in a separate building and after a few years is microfiched so it’s not even kept on a server. Samples do need to be re-identified for various reasons, but Lorey says, in those cases, parents are notified.

And to be clear, he stressed, there is also no genome database. The state does not sequence or extract the DNA from the blood spots collected, although a researcher might, depending on the study.

Privacy advocates, like Consumer Watchdog’s Jamie Court insist DNA is inherently identifiable.

“There is no such thing as de-identified DNA,” Court said. “The very nature of DNA is that it identifies you and your genetic code specifically.”

Court points to the recent case of the Golden State Killer. Investigators used public ancestry sites to identify a murder suspect using decades-old unidentified DNA from a crime scene.

And we’ve learned, researchers aren’t the only ones with access to the blood spots.

Law enforcement access

A public records request revealed coroners often use blood spots to identify bodies, and at least one parent requested blood spots to prove paternity.

Law enforcement also can — and does — request identified blood spots. We found at least five search warrants and four court orders, including one to test a child’s blood for drugs at birth.

According to the Department Of Public Health, “Only a court order can provide a third-party (including law enforcement) access to an identified stored specimen without parental consent.”

“I think the storage of DNA for purposes other than medical research without informed consent clearly is violating a duty and a trust that the state has to the public,” Court said. “What are they trying to hide?”

State law says parents should know – but they don’t

According to the Department of Public Health, it’s not hiding anything. The agency points to page 13 of the Newborn Screening brochure which does disclose that the blood spots are stored.

“In addition to being available on the Internet in multiple languages, healthcare providers give the brochure to parents prenatally and at birthing centers and hospitals,” the Department of Public Health stated.

We asked the six new moms to bring in all the paperwork they collected from the hospital. Only one of the six women actually had the required newborn screening pamphlet and she admitted that between delivering a baby and learning to raise a tiny human, she hadn’t found the time to flip to page 13.

“I feel like that’s something that should have been discussed with us in person, not on whatever page in a document,” another new mom, Lesley Merritt, responded.

Argelia Barcena added that they were not told the pamphlet was crucial or mandatory reading material.  “I saw it as reference material, to refer to if needed, they dont tell you ‘you must read it,'” she pointed out.

Keep in mind new parents are generally sent home with folders full of paperwork including a variety of medical testing forms and pamphlets with information ranging from breastfeeding and vaccines, to sudden infant death and CPR.

“Everyone who came into our room gave us another pamphlet,” New Mom Amanda Feld pointed out.

In the case of the Genetic Screening Pamphlet, the moms agreed they wouldn’t have thought it was relevant to read after the fact unless their child was actually diagnosed.

And they’re not alone. We conducted an exclusive Survey USA news poll of parents with kids born in California over the past five years.

While a majority of parents reported that they did know about the life-saving test, three-quarters said they didn’t know the state would store the leftover blood spots indefinitely for research, and two-thirds weren’t sure they ever got the newborn screening information.

When we read the six moms that portion of page 13 that disclosed the blood spots could be used for outside research, they noted that it’s not clear the blood spots are stored indefinitely, available to law enforcement, nor that using blood spots for “department approved studies” means giving them to outside researchers.” P.13 states:

“Are the stored blood spots used for anything else? Yes. California law requires the NBS program to use or provide newborn screening specimens for department approved studies of diseases in women and children, such as research related to identify-ing and preventing disease.”

Lorey helped draft previous versions of the pamphlet. He agreed that the portion on page 13 “could be clarified,” but he said he believed the information included provides “adequate disclosure.”

He was surprised, however, when Watts showed him all the forms she was sent home from the hospital with and he acknowledged it could be difficult for parents to digest it all while also learning to care for a newborn.

He was also surprised to see the version of the newborn screening brochure that Watts was given.

Instead of the required 14-page pamphlet with the storage disclosure on page 13, she had a one page, tri-fold hand-out with no mention of storage, or a parent’s right to opt out of it. Instead there was a web link where parents could go “For more information…”

Required disclosure

State regulations say that parents are supposed to get the full 14 page pamphlet twice, once before their due date, and again in the hospital before the heel prick test.

But in practice, most parents say they didn’t even see the pamphlet until after the test, if they got it at all.

While the state says it “distributes more than 700,000 copies of the booklets to health providers each year,” it admits that it doesn’t track whether doctors are giving them out. It also does not confirm parents are informed of their rights to opt out of storage before storing or selling the child’s DNA.

Federal law

Under federal law, blood spots are currently defined as human subjects, and therefore require informed consent for federal research. But, that doesn’t apply to private researchers, and even that protection is about to expire when a new federal policy, known as the Common Rule, takes effect this year.

Following strong opposition from the research community, proposed protections for unidentified bio-specimens were stripped from the final rule. This means researchers won’t need consent to use de-identified blood spots, and, in some cases, can even use identified blood spots without consent.

It’s ultimately up to each state to develop their own policies on disclosure. Parents in  Texas successfully sued the state, ultimately forcing their biobank to destroy samples taken for research without consent or disclosure.

State law

In California, the newborn screening law doesn’t actually authorize the state to store a child’s leftover blood spots after the test, or give it to outside researchers, it only authorizes the life-saving genetic test itself.

However, the newborn screening law does say that state may store samples of the mother’s prenatal blood, which is taken early in the pregnancy, but only if the mother opts in.

Parents don’t get to opt in to storing their baby’s DNA however and that was not decided by voters or lawmakers.

While the newborn screening law was enacted by the state legislature, the authorization to store every child’s DNA and sell it to researchers is actually in a separate regulation enacted by the Director of California Department of Public Health. It says that a child’s “blood specimen and information,” collected during a test paid for by the child’s parents, becomes “property of the state.”

“Any tissue sample that is given in a hospital or any medical facility, once it’s given, is no longer your property,” Lorey explained. “You can agree with that or disagree with that, but it happens to be the law.”

In 2015, former California Assemblyman Mike Gatto introduced a law that would have initially made both the test and storage opt-in. It was strongly opposed by the powerful hospital and research lobbies, and after several revisions, it died in the Senate Health Committee.

Health advocates said their primary opposition at the time was due to the fact that Gatto’s bill would have made both the test and storage opt in, and since the test itself is crucial to saving lives, they said the test should not be optional.

Researchers, on the other hand, oppose letting parents opt in to the storage too because they believe they would get fewer samples if parents had a choice.

But, that doesn’t seem to be the case in California.

Calif. moms opt in to prenatal

Along with newborn blood spots, the California Genetic Disease Screening Program also tests mothers’ blood in the first and second trimesters, and they’re allowed to opt in.

About 90 percent of pregnant women do opt in to letting the state store their own blood for research. And, unlike the newborn screening test, a majority of moms said they do remember the disclosures and pamphlets about their own genetic test, because they got them early in the pregnancy.

Eighty four percent of parents surveyed said they think they should get information about their child’s genetic screening at the same time they learn about their own. That would give them time — several months without the distraction of a newborn — to process the information and understand their rights before the child is born.

Many said they also should have the right to opt out of storage before their child’s DNA is stored, or at least give informed consent before it is sold for research.

The problem with opting in

Critics of the opt-in option point to Texas. Following a lawsuit by parents, the biobank was forced to destroy blood spots that were taken without consent to store them for research. Now Texas allows parents to opt-in to storage.

When the potentially life-saving screening test is given in Texas, a storage consent form with a matching ID number is given to the parents to take home from the hospital and review. Blood spots are not stored in the biobank unless parents sign and return the consent form. As a result, a significant percentage of samples are destroyed.

Critics note that many parents never return the form, likely in part due to the distractions of a new baby.

Ultimately, that hurts the biobank and researchers because they get fewer samples, and more importantly, fewer samples from certain communities.

This means that research performed with those samples may not be valid for the entire population. In contrast, research performed with samples from California’s biobank is considered very strong and applicable to all babies.

A Calif. opt-in solution

Parents and advocates we spoke with in California would like to see the informed consent given out early in the pregnancy, long before the due date, which may lead to a higher opt-in rate than in Texas.

An opt-in early in the pregnancy would require a system in place to match the mothers’ consent forms, collected in the first trimester, with the babies’ blood spots, collected months later by hospital staff.

Lorey said California already has a similar matching system in place for the prenatal genetic test so it does seem feasible.

Court believes parents should have the right to opt-in before their baby’s genetic material is collected and stored indefinitely by the state, though that would be fought hard by the powerful hospital and research lobbies in Sacramento.

“Informed consent basically means we should know what we’re donating a sample for,” Court said. “If hospitals and the medical complex is so concerned that if we knew that we might not donate our samples, than we absolutely need to know what they’re doing with them because it suggests there is a purpose beyond what we know.”

Meanwhile, a majority of parents surveyed said they would have opted-in to storage if given the chance.

Additionally, they said they’re more likely to destroy their child’s sample now than they would have been if they had been notified of their rights to begin with.

Both the California Hospital Association and the March of Dimes, which opposed previous legation that would have allowed parents to opt-in, say they are now open to improving the way the state informs parents that their child’s samples will be stored and “may be used to advance research.”

However, neither has an official position on allowing parents to opt-in to storage.

Short of an opt-in, Court said he thinks there should at least be a tracking mechanism to ensure every parent is getting complete and accurate information about the storage early in the pregnancy, before the DNA samples are stored.

Since state law already requires prenatal doctors to provide the information, Court notes, it wouldn’t be a stretch to require they also get a signature from moms, allowing the state to track whether or not parents are actually getting the information.

What next?

So the questions remain: Should parents have the right to know that their child’s DNA will be stored indefinitely in a state-run biobank and may be available to law enforcement? Should the state have to confirm that parents are informed of their rights before it stores and sells the child’s DNA? Who has the power to make that happen?

Karen Smith, appointed by Governor Brown, is the current Director of the Department of Public Health. She has the power to adopt new regulations.

Though, for a more permanent fix, lawmakers in Sacramento would need to pass new legislation.

We’ve shared our findings with several state lawmakers on the Assembly Privacy Committee.  Many were shocked to learn that the state was storing DNA samples from every baby born in the state and selling them to outside researchers without parents’ knowledge or consent.

So far, however, none have shown any interest in giving parents the right to opt out of storage before the child is born, or even requiring the state to confirm parents are informed before storing their baby’s blood indefinitely. source

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California collects, owns and sells infants’ DNA samples

The DNA data is supposedly anonymized, but one expert says the de-identification is easy to see through.If you were born in California since 1983, the state owns your DNA.

The data of every Californian born since that year is kept in a bland office building in Richmond, a city located in the eastern section of the San Francisco Bay Area.

That data’s not just passively kept, mind you: it’s also being sold, to third parties, for research purposes, according to CBS local station KPIX.

That biometric data, taken by a heel prick at birth to screen for 80 hereditary diseases, represents a wealth of information on an individual, from eye and hair color to pre-disposition to diseases such as Alzheimer’s and cancer.

Besides being sold – in purportedly de-identified form – to third parties, it’s also available for law enforcement requests.

None of this is new, mind you.

Dr. Jeffrey Botkin of the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, which advises the Department of Health and Human Services on newborn screening, in June 2014 told Newsweek that this is a “long-standing issue and a controversy to a certain extent in the newborn screening field.”

The screening tests are generally mandatory under state law. When the program was first developed in the 1960s, Botkin said that the thinking behind it was that …

...the advantages for newborn screening were so compelling, it was appropriate or acceptable to have states simply mandate screening.

As of July 2014, 43 states allowed parents to decline the screening process based on religious beliefs or philosophical reasons, but the option is rarely exercised.

That’s probably due in no small part to the fact that parents only hear about the program during the hectic time when a mother in labor enters the hospital.

As Newsweek has reported, in most states, the blood spots are transferred to long-term storage banks run by state departments of health and retained for at least a few years.

In 12 states, they’re kept for 21 years or longer.

But California is one of just four states where dried blood samples become the property of the state: along with Iowa, Michigan and New York, it participates in a virtual repository, government-owned and -operated, that enables researchers to access the data and sometimes the blood spots themselves.

It’s not that the screening doesn’t help families. A prime example is the family of Luke Jellin, whose heel prick at birth led doctors to diagnose a rare metabolic disease.

KPIX quotes Luke’s mother, Kelly Jellin, a member of the Save Babies Through Screening Foundation:

Had he not been tested he would have been severely brain damaged, possibly would have had heart and kidney problems. If blood spots hadn’t been saved, they wouldn’t have been able to make the test that saved my child’s life.

Why isn’t this opt-in?

This all may surprise parents of the newborns, given that the tests are administered without parents’ informed consent.

Cases such as that of Luke Jellin notwithstanding, the question remains: why doesn’t the California Department of Public Health (CDPH) obtain permission before taking, saving, sharing and selling these blood spots?

When KPIX asked the CDPH for an interview on the issue, the request was denied.

In denying the interview request, the CDPH also failed to answer the question of why consent isn’t required for the test.

It turns out that information about the tests is buried on page 12 of the brochure about the Newborn Screening Program that hospitals give parents of newborns before they go home.

KPIX interviewed one mother, Danielle Gatto, who says she scarcely remembers the nurse mentioning tests performed at her two daughters’ births.

And she certainly didn’t turn away from her newborn to instead focus on a ream of paperwork, she noted:

I don’t think that any woman is in a state of mind to sit down and start studying up on the literature they send you home with.

The CDPH says that parents have the option of having the DNA samples destroyed: here’s the form to get that done.

Are the blood spots really de-identified?

The CDPH’s premise that DNA samples have been de-identified is questionable, one expert said.

Yaniv Erlich with Columbia University and the New York Genome Center told KPIX that there’s no way to guarantee that the samples can be rendered anonymous.

He’s actually found it quite easy to cross-reference anonymized DNA with online data and connect it to a name, he said:

You need to have some training in genetics, but once you have that kind of training the attack is not very complicated to conduct.

Erlich is, in fact, a supporter of sharing genomic information, for the sake of advancing biomedical research:

This is the only way that we can help families with kids that are affected by these devastating genetic disorders.

For her part, Gatto is unnerved by the unknowns of what could be done with the treasure trove of information stored in DNA samples and thinks that the state should at least ask for consent before storing and selling DNA:

We are at the beginning of a frontier of so much genetic research, there is no knowing at this point in time what that info could be used for. The worst thing as a parent is to think that a decision that you are making today may negatively affect your children down the road.

Her husband, Assemblyman Mike Gatto, introduced a DNA privacy bill this year that would have required signed consent on newborn screening.

The bill was killed after opposition – such as this letter from the University of California – from the state and the industry. source

Danielle Gatto has requested that her daughters’ blood spots be destroyed.

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Bills to shed light on newborn DNA storage in California quietly killed or gutted

If you’re related to someone who was born in California since 1983, a portion of your DNA is likely in the state’s massive Newborn Genetic Biobank. In response to our decade-long investigation, lawmakers have introduced several bills intended to shed light on how the state is amassing and using California’s newborn DNA stockpile.

Only one of those bills is still alive, and while privacy advocates say it is a step in the right direction, recent amendments raise new questions about the appearance of state secrecy.

If you’re related to someone who was born in California since 1983, a portion of your DNA is likely in the state’s massive Newborn Genetic Biobank. In response to our decade-long investigation, lawmakers have introduced several bills intended to shed light on how the state is amassing and using California’s newborn DNA stockpile.Only one of those bills is still alive, and while privacy advocates say it is a step in the right direction, recent amendments raise new questions about the appearance of state secrecy.

(To learn more about newborn bloodspot storage and how to opt out of storage or research, click here.)

A life-saving test

Every baby born in California gets a heel prick shortly after birth. Their newborn blood fills six spots on a special card which is used to test them for genetic disorders that, if treated early enough, could prevent severe disabilities – even death.

Doctors only need a few of the baby’s newborn bloodspots for their own life-saving genetic test. The leftovers become the property of the state and are stored indefinitely in California’s massive Newborn Genetic Biobank.

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What happens next has become a state secret.

California State Secrets

According to the state, there has never been an outside audit of how California’s stored newborn DNA samples are being used by the state, law enforcement, or independent researchers.

Throughout our decade-long investigation, CBS New California has reported on multiple law enforcement requests for identified newborn bloodspots, and the thousands of de-identified DNA samples that are sold each year to independent researchers.

For years, we’ve obtained those records from the state under California’s Public Records Act. The records have enabled us to show the public how our DNA is being used and highlight the program’s lifesaving benefits.

However, following the pandemic, the California Department of Public Health suddenly started refusing to disclose who is requesting California’s stored newborn DNA samples and why.

The agency told CBS News California that it “is no longer tracking” that information like it used to and is “not required to create a record” revealing who has access to our DNA.

Playing Politics with Newborn DNA

In response to our reporting, SB 1099 would have required the California Department of Public Health to publicly identify “each entity performing a research project, the specific nature of the research they are performing, and the potentially substantial public health benefit from the research.”

With no formal opposition or significant cost, the bill has sailed through the legislature with widespread support, and it is expected to head to the governor’s desk.

However, after the bill passed the Assembly, it was recently amended in the state Senate where lawmakers agreed to remove the part of the bill that requires the state to reveal who is using our DNA for research and why.

Instead, the bill now only requires the state to reveal the number of published studies and the number of California DNA samples used for research.

Privacy advocates say that is a small step in the right direction, but they question the continued state secrecy.

Calls for transparency

While California’s Newborn Genetic Biobank program has undoubtedly saved lives, the appearance of state secrecy raises concerns.

For years, everyone from privacy advocates to lawmakers has called for more transparency.

“People (should) have the right to choose how their DNA is used and how their children’s DNA is used,” said Cece Moore, a genetic detective, in a previous interview.

“What are they trying to hide?” asked Consumer Watchdog’s Jaime Court.

ALSO READ: Lawmakers could force California to stop storing your DNA without permission

Parents are in the dark

California has been storing newborn blood spots since 1983 and has amassed what’s believed to be the largest stockpile of newborn DNA samples in the country because it’s one of only a handful of states that stores the bloodspots indefinitely without parents’ permission.

You can ask to have your child’s DNA sample destroyed or opt out of storage for research after your DNA is collected and stored. However, you’d have to know the state was storing your child’s bloodspot in the first place, and most parents don’t know.

(To learn more about newborn blood storage and how to opt-out of storage or research, click here.)

California’s Genetic Information Privacy Act requires consumer companies like 23andMe to get your permission before they store, use, or sell your DNA. However, your state government is exempt from that law, and there has never been an outside review or audit of how your DNA is being used.

In 2015, former Assemblyman Mike Gatto was the first to author a bill intended to increase transparency related to the Newborn Genetic Biobank. The bill would have allowed parents to opt out of bloodspot storage for research before the bloodspots were stored. It passed the Assembly and died in the Senate.

“There is no reason to be doing experiments on a child’s blood without informed consent,” Gatto said.

Over the years, the powerful medical lobby killed several bills that would have allowed parents to consent to storage and research. They argued that if given the choice, too many parents would opt out of storage, which could ultimately harm potentially life-saving research.

However, earlier this year, the medical lobby appeared to change its stance following amendments to another newborn genetic transparency bill, SB 625.

When the author agreed to amend the bill to allow parents to “opt-out” of storage instead of allowing them to “opt-in,” the medical lobby removed its opposition and changed its stance to “neutral.”

Three different state Senate committees passed the bill to let parents opt out of storage before the DNA is collected.

However, it was quietly killed behind closed doors without a vote in the Senate Appropriations suspense file because California’s Health Department argued it would cost too much to give parents that right.

Privacy advocates plan to try again next year.

Find out if researchers have requested your child’s newborn bloodspot

Parents do have the right to find out if their own child’s bloodspots are being used for research and they can request the state destroy their child’s sample after it is stored.

You can find more information about your rights here.

source

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Los Angeles, CA: California Biobank Stores Every Baby’s DNA; Parents Had No Idea

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]]> https://goodshepherdmedia.net/pupil-size-is-a-marker-of-intelligence/ Wed, 04 Sep 2024 08:01:27 +0000 https://goodshepherdmedia.net/?p=18590 Pupil Size Is a Marker of Intelligence

There is a surprising correlation between baseline pupil size and several measures of cognitive ability.

It has been said that “the eyes are the window to the soul,” but new research suggests that they may be a window to the brain as well.

Our pupils respond to more than just the light. They indicate arousal, interest or mental exhaustion. Pupil dilation is even used by the FBI to detect deception. Work conducted in our laboratory at the Georgia Institute of Technology suggests that baseline pupil size is closely related to individual differences in intelligence. The larger the pupils, the higher the intelligence, as measured by tests of reasoning, attention and memory. In fact, across three studies, we found that the difference in baseline pupil size between people who scored the highest on the cognitive tests and those who scored the lowest was large enough to be detected by the unaided eye.

We first uncovered this surprising relationship while studying differences in the amount of mental effort people used to complete memory tasks. We used pupil dilations as an indicator of effort, a technique psychologist Daniel Kahneman popularized in the 1960s and 1970s. When we discovered a relationship between baseline pupil size and intelligence, we weren’t sure if it was real or what it meant.

Intrigued, we conducted several large-scale studies in which we recruited more than 500 people aged 18 to 35 from the Atlanta community. We measured participants’ pupil size using an eye tracker, a device that captures the reflection of light off the pupil and cornea using a high-powered camera and computer. We measured participants’ pupils at rest while they stared at a blank computer screen for up to four minutes. All the while, the eye tracker was recording. Using the tracker, we then calculated each participant’s average pupil size.

To be clear, pupil size refers to the diameter of the black circular aperture in the center of the eye. It can range from around two to eight millimeters. The pupil is surrounded by the colorful area known as the iris, which is responsible for controlling the size of the pupil. Pupils constrict in response to bright light, among other things, so we kept the laboratory dim for all participants.

In the next part of the experiment, participants completed a series of cognitive tests designed to measure “fluid intelligence,” the capacity to reason through new problems, “working memory capacity,” the ability to remember information over a period of time, and “attention control,” the ability to focus attention amid distractions and interference.

As one example of an attention control test, participants had to resist glancing toward a bold, flickering asterisk on one side of a computer screen and instead rapidly look in the opposite direction to identify a letter. The letter would disappear within moments, so even a brief eye movement toward the flickering asterisk could result in missing it. Humans are primed to react to objects passing through their peripheral vision—it’s what once allowed us to spot a predator or prey—but this task required participants to redirect their focus from the flicking asterisk to the letter.

We found that a larger baseline pupil size was correlated with greater fluid intelligence, attention control and, to a lesser degree, working memory capacity—indicating a fascinating relationship between the brain and eye. Interestingly, pupil size was negatively correlated with age: older participants tended to have smaller, more constricted, pupils. Once standardized for age, however, the relationship between pupil size and cognitive ability remained.

But why does pupil size correlate with intelligence? To answer this question, we need to understand what is going on in the brain. Pupil size is related to activity in the locus coeruleus, a nucleus situated in the upper brain stem with far-reaching neural connections to the rest of the brain. The locus coeruleus releases norepinephrine, which functions as both a neurotransmitter and hormone in the brain and body, and it regulates processes such as perception, attention, learning and memory. It also helps maintain a healthy organization of brain activity so that distant brain regions can work together to accomplish challenging tasks and goals. Dysfunction of the locus coeruleus, and the resulting breakdown of organized brain activity, has been related to several conditions, including Alzheimer’s disease and attention deficit hyperactivity disorder. In fact, this organization of activity is so important that the brain devotes most of its energy to maintain it, even when we are not doing anything at all—such as when we stare at a blank computer screen for minutes on end.

One hypothesis is that people who have larger pupils at rest have greater regulation of activity by the locus coeruleus, which benefits cognitive performance and resting-state brain function. Additional research is needed to explore this possibility and determine why larger pupils are associated with higher fluid intelligence and attention control. But it’s clear that there is more happening than meets the eye.

Jason S. Tsukahara is a Ph.D. student in cognition and brain science at the Georgia Institute of Technology, where he does research in the Attention & Working Memory Lab.

Alexander P. Burgoyne earned his Ph.D. in cognition and cognitive neuroscience at Michigan State University in 2019. He is currently a postdoctoral research fellow in the Attention & Working Memory Lab at the Georgia Institute of Technology.

Randall W. Engle is a professor at the Georgia Institute of Technology and a member of the National Academy of Sciences. 

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]]> https://goodshepherdmedia.net/what-sigma-men-hate-the-ultimate-guide-to-sigma-males/ Tue, 27 Aug 2024 16:11:36 +0000 https://goodshepherdmedia.net/?p=13320 What Sigma Men Hate! – The Ultimate Guide to Sigma Males

The Ultimate Guide to Sigma Males

You’ve heard of alpha males, but have you heard of sigma males?

You know you’re not an Alpha, you don’t see yourself as Beta, but you’re curious if you’re a Sigma and you want to know more about this type.

Maybe you think it will help you meet more girls. Or that it will help you in your current relationship.

Or your just curious about who these Sigma males are.

Sigmas are an elusive type. They are brooding and mysterious; it’s hard to define them. They like their own space and don’t follow others. They don’t necessarily want to lead or to follow and are independent, neither belonging to nor standing against a crowd.

But this gives them advantages.

https://youtu.be/hyXxA8CapDA

The Real King of the Jungle

For a long time now, popular psychology has described men as either Alpha or Beta, deriving the terms from studies of animals and their social hierarchies. Ethologists describe Alpha males as the more dominant, aggressive members in mammalian groups where the animal’s position in the group social hierarchy determines mating rights.

In these groups, typical of dogs, lions, horses, apes, chimpanzees and gorillas, the stronger, more aggressive males would fight and dominate the other males. As a leader, they retain rights to mate with all the females in the group, but must continuously defend their position. Fights in the wild are often vicious and can lead to death.

Betas are the secondary males, all those who are less healthy and able and of secondary rank.

Nowadays, the general public translates these concepts over to Homo sapiens.

Although our mating system is different and we don’t operate in winner takes all groups like the animals above, our society is still somewhat hierarchical, and those at the top do gain more access to wealth and status.

Translated into human terms, Alpha males are aggressive, dominating, confident, and extroverted. They like to lead and take charge, and they don’t seem to suffer self-doubt. We tend to think of them as loud and belligerent, a little obnoxious. Quite often, Alpha males will work out and will be happy to show off their muscles.

Beta males are more submissive and collaborative. They are introverts and like to follow instructions. They don’t want to stand out of the crowd and are afraid of their more dominant peers. No one wants to be a Beta. They suffer insecurity and stress from being near the bottom of the pack.

Sigmas are Introverted Alphas

The Urban dictionary describes Sigma males as:

“The introverted Alpha male. They stand outside society’s guidelines and are independent thinkers. In many respects, they are like Alpha males. Although they can appear quiet to those who do not know them, they are outgoing once you speak to them. Sigmas are on a similar level to Alphas, but they are less loud and are more in tune with themselves.”

Here are 17 traits of Sigma Males that you need to know. Learning these will give you insight into how to become one:

1. Independent

Sigma males are direct. They rely on themselves. Company is ok, but they don’t need too much. They may have a couple of close friends, but they don’t need a large social circle. They are content with their own company and don’t like wasting time.

2. Illusive

The words mysterious, elusive and hard to reach, are often used to describe a Sigma male. It’s not that they are particularly secretive, it’s just that they don’t engage in banalities. They don’t like to overshare their life.

3. Off the Grid

Because of their character traits, Sigma males are less likely to be on the web. They recognise its benefits but rarely see the need to engage social media all the time. They see all media as helpful tools to connect, but also understand they can drain time.

4. Deep Thinkers

Sigma males ponder the deep questions in life. They wonder why we are here, what the purpose of life is, and how to live a good life. Because of their depth, they often reject much of what society says and does.

https://youtu.be/dsV6yMCNVnE

5. Detest Shallowness

Sigma males detest superficiality and shallowness, that’s usually why they dislike groups and small talk and why they keep themselves to themselves. They take life far too seriously to engage in life’s trivialities.

6. Charismatic

Because of their elusiveness, quietness and independence, many people find them quite charismatic. Sigmas are silently confident, and that has power. They are ‘dark horses’, and their lack of desire for social approval makes them stand out.

7. Differently Dominant

While Alphas dominate through their loud behaviour, hostility, and showing off, Sigmas dominate differently. They often get what they want without others noticing. They can be excellent at networking as people respect what they say.

8. Brooding

Some people say Sigmas are brooding. They are undoubtedly quiet and rarely speak unnecessarily. Their moods are often darker. It’s not that they are not happy or optimistic, just that they are not superficial. They favour practicality over positivity.

9. Critical Thinking

Sigma males think critically about what others tell them whether this is from teachers, parents, or co-workers. And even stuff that they read on the web. They recognise critical thinking skills are crucial to getting by in the world.

10. Embrace Ambiguity

Sigma males are happy with uncertainty; they don’t need the world to be black and white. They recognise that this applies to many spheres, including what is real and what is right. They still have preferences like anyone else, but don’t hold onto them too tightly.

11. No Slave to Fashion

Sigma males don’t care too much about what is fashionable. They are far too independent and practical to care. They like to look good, but they embrace their style and pay no mind to what is popular.

12. Don’t Fit In

Sigma males rarely find themselves as part of groups. They can take part in them if it suits their needs, but they will never be a full-time member. Something about the dependence of a clique puts them off.

13. Adaptable

Sigma males can adapt to different circumstances. Because they reject much of what society says everyone should do, they often don’t follow the same path as everyone else. Yet Sigma’s don’t like to stand out and attract attention to themselves, so they learn to adjust and blend in.

14. Dislike Rules

Sigma males are not anarchists and they do obey the rules. But where the rules are not transparent, or the rules seem trivial and pointless, and no one is getting harmed, then they may choose to sidestep them.

15. Dislike Constraints

Sigmas detest it when others try to control them, and this is why others often see them as rebels. Many see society’s rules as a subtle form of control and so choose not to follow blindly. Thus Sigmas celebrate freedom and fight things that hold them back.

16. Travel Lightly

Sigmas are not impressed by material wealth. While an Alpha may be striving for money and status to show off their power, the Sigma male is content with what he has. He prefers his wit, his intellect and his cunning to any material possession.

17. Have No Plans

Sigma males find it hard to dedicate themselves to one thing for any length of time. They have many things that interest them and like to be involved in different activities. Often they have a varied and exciting life but don’t always have the single-minded success dedication brings.

 

Adopt the Best Traits of This Popular Personality

Do you identify with any of these traits?

lets not fool yourself. Your IQ plays a big part and IQ and raw intelligence in all areas of intelligence is not easily obtained and is obtained through DNA and proper training combined! Intelligence is more than an IQ test, creative intellect, hierarchy intellect, emotional intellect, scholarly intellect, scientific approach intellect, physics intellect intellect is undefinable to those that have it and definable by those that do not poses much of it!

that said enjoy your day God bless your and treat all people like you want to be treated, your schooling means nothing as does intelligence if you cannot be civil or temperate  

The Sigmas’ ability at understanding personalities and thought processes of a vast majority of people allow the Sigma maintain superior analytics and over others that rely on mainly power and control. Sigma does not need a powerful position but often gets one handed to them. Sigmas do not need to control others but often find their way to the top where it must be done creatively.

what you can do if you encounter an sigma is be kind, listen, work with them never against them.

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Learn more about the Sigma Males …..

Alpha vs Sigma: The Dominant Sigma Male

What Sigma Men Hate! – The Ultimate Guide to Sigma Males

How To Become A High Value Man

Why is a sigma male so irresistible to women?

The Sigma Male Explained: Understanding the Lone Wolf

Sigma Males Destroy Controlling and Manipulative People

Why Are Sigma Males So Confident its Intimidating?

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Learn More About on Stoicism – The Stoic Man An Unstoppable Force to Reckon With…..

Want An Unconquerable Mind? Try Stoic Philosophy

What is Stoicism? A Definition & Stoic Exercises To Get You Started

9 Principles of Stoicism which will Improve your Life

A Complete Guide to Stoicism: How You Can Use this Ancient Philosophy to Live a Better Life

Stoicism, Virtue, and Mental Health

The Stoic Man – Indifference is a power – Stoicism 101

What is Stoicism and How Can it Turn your Life to Solid Gold?

Stoic Quotes on Control – The Absolute Man

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Other Men’s Health Topics Below

Good Habits That Will Help You Become Rich

How To Become A High Value Man

What every woman loves in a man?

 

]]> https://goodshepherdmedia.net/scientists-turn-words-into-matter-the-neuroscience-behind-our-words/ Thu, 18 Jul 2024 07:11:43 +0000 https://goodshepherdmedia.net/?p=18164

How A Scientist Proved Water Has Feelings Too

Proverbs 18:21 “Death and life are in the power of the tongue, And those who love it and indulge it will eat its fruit and bear the consequences of their words.”

Okay, I know, I know… Water doesn’t have feelings, right? Actually, Dr. Masaru Emoto says otherwise.

Dr. Emoto theorizes that human consciousness actually has an effect on the molecular structure of water. In other words, water reacts to positive and negative words accordingly.

In 1994, Dr. Emoto conducted a study which included exposing different samples of water to different words for a period of time. Some samples were exposed to the word “love”, some to the words “thank you”, and others to the phrase, “I hate you”. Then, he would freeze the water to observe the effects.

Here’s what he found:

These results are pretty amazing on their own, but it gets even more amazing when we consider that our bodies are made up of anywhere between 50% and 75% water.

If words impact a single droplet of water so drastically, can you imagine how much they affect the human body? Can you imagine how much they can affect you and me?

Of course, Dr. Emoto’s findings drummed up a lot of skepticism, and if I’m honest, I was one of the skeptics. That’s why, a few years ago I decided to conduct my own research with the help of my kids.

How We Used Rice to Test the Power of Words

We filled three jars with cooked rice and assigned each jar to a category of words. The first jar was labelled “love”, which meant we had to say kind and encouraging words to this jar every day.

The second jar was labelled “hate”, which meant we had to say mean and discouraging words to this jar every day.

The last jar remained unlabelled. We ignored this jar all together.

After 21 days, here’s what we found:

We were completely blown away by the results. The jar exposed to kind words flourished, while the jar exposed to mean words didn’t fare as well, and the jar we completely ignored turned out to be the mouldiest of all.

It really makes me wonder how important it is to give attention and love to ourselves (and how detrimental it can be if we don’t).

Honestly, I think Mother Theresa said it best:

“Spiteful words can hurt your feelings but silence breaks your heart.”

source

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The Neuroscience Behind Our Words

Sticks and Stones

“Sticks and stones may break my bones, but words can never hurt me.”

This phrase is reminiscent of childhood recess when we didn’t want others to know how hurtful their words truly were. However, the belief that physical injury is more painful than psychological or emotional injury is not necessarily true.

Scientific studies actually show that positive and negative words not only affect us on a deep psychological level, but they have a significant impact on the outcome of our lives.

It’s a phrase we hear all the time, but it makes me wonder if it’s actually true. For some people, words like “crazy”, “ugly” or “stupid” might not mean a lot. To others, it can leave a really negative impact on their self-esteem.

If you’re someone who has ever felt the detrimental effects of these negative words, you know what I mean.

But guess what — water feels that way too!

Words Can Hurt Me

In their neuroscience experiment, “Do Words Hurt?”, Maria Richter and collaborating scientists monitored subjects’ brain responses to auditory and imagined negative words. During this process, they discovered painful or negative words increase Implicit Processing (IMP) within the subgenual anterior cingulate cortex (sACC).

Put frankly, their study proved that negative words release stress and anxiety-inducing hormones in subjects.

Additionally, a study found increased levels of anxiety in children associated with higher rates of negative self-talk. According to the study’s abstract,

“These results suggest negative self-talk plays a role in the generation or maintenance of anxiety in normal children.”

Ultimately, negative words, whether spoken, heard, or thought, not only cause situational stress, but also contribute to long-term anxiety.

Think Happy Thoughts

 Naturally, the recognition that holding negative thoughts in our mind is enough to induce stress and anxiety hormones begs the question, “What effect do positive thoughts have?”

In their jointly written book, Words Can Change Your Brain, Dr. Andrew Newberg, a neuroscientist at Thomas Jefferson University, and Mark Robert Waldman, a communications expert state, “a single word has the power to influence the expression of genes that regulate physical and emotional stress.”

Furthermore, according to these two experts in their field, exercising positive thoughts can quite literally change one’s reality.

“By holding a positive and optimistic [word] in your mind, you stimulate frontal lobe activity. This area includes specific language centers that connect directly to the motor cortex responsible for moving you into action. And as our research has shown, the longer you concentrate on positive words, the more you begin to affect other areas of the brain.”

~Newburg, Waldman

Over time, given sustained positive though, functions in the parietal lobe start to change. Consequently, this changes our perception of the self and those around us. Essentially, holding a positive view of ourselves helps train our brain to see the good in others.

Thus, by exercising consistent positive thoughts and speech, we not only change our self-perception, but how we perceive the world around us. Ultimately, this grants us the ability the shape our reality and change the world for the better.

BRMs: Using Positive Language to Drive Value

Evidently, as humans, our thought patterns directly shape our perception of the world and those around us. Our thoughts become our words, and therefore our language.

This holds true for humans individually, as well as organizationally. A strong company culture is one derived from a shared positive language based on organizational core values.

As BRMs, we know that relationships lie at the core of our role, and that language shapes our human interactions. So, how can we make a shift in the language we use in our daily work lives to reduce the negative associations with traditional “corporate lingo”?

In his article, “Language Matters”, Aaron Barnes, CEO of BRM Institute, dives deeply into the importance of positive language in elevating your business communications to drive value.

Take a look at a few examples of how you can shift towards positive language. As you do, really think about how each of these words or phrases make you feel, remember, or associate.

BRM Positive Language Shifts

• Capability instead of Process
• Convergence instead of Alignment
• Shared Ownership instead of Accountability
• Demand Shaping instead of Demand Management
• Business Capabilities instead of Services

Making these small changes in the words we use to express ideas creates a culture that doesn’t single out or place blame on any department or individual within the organization. Rather, it aims to promote transparency, elevate communications, and appreciate individual value.

In the end, shared positive language will promote effective communication and collaboration; breeding innovation, success, and organizational value.

“Language Matters” contains a comprehensive list of all the positive language shifts you can implement to drive effective communication across your enterprise. source

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Scientists turn words into matter

Machine learning translates human language into materials

Is our consciousness, thoughts, and words a state of matter or the result of our neurons creating a material reality? It’s a phenomenon of discovery that MIT scientists explored using a variety of machine learning tools to understand the connection between human language and matter. What they found is that human language can create a physical object which has materialized in the exact way our words describe.

At the American Physics Society’s March Meeting, materials scientist Markus Buehler, the Jerry McAfee Professor of Engineering at the Massachusetts Institute of Technology, will present new research conducted by him and his team that uncovers a text-to-material design approach of multi-material composite designs based on human readable language and 3D printing.

“Human language contains the rules of grammar that form phrases and sentences together to convey meaning. It’s equivalent to the self-assembly process in materials science, where a molecule forms into larger scale structures by itself,” said Buehler.

Another correlation is the importance of order in language. Different words produce different meanings and the same is true for molecules and the building blocks of materials. “If you assemble them in different order, they are going to have a very different function,” adds Buehler.

The researchers experimented with this concept using deep learning and transformer models to translate human language into describing the assembly of material building blocks. “We developed this system where we can ask computers to help us assemble materials that don’t exist yet,” said Buehler.

The system allows a person to type text into the computer that describes anything their imagination wants to create, and a couple hours later, you have a physical three-dimensional replica in your hands that resembles everything you just typed.

Using machine learning tools to understand and translate human language into multi-dimensional materials is a cumbersome and computationally expensive problem to solve.

Buehler’s lab has been working to solve this problem to design bio-based materials and for many years used analytical methods like category theory.

“The power of machine learning allows us to solve complex problems computationally that are not tractable using any of the analytical pen and paper methods,” said Buehler

Buehler adds, this form of materialization wouldn’t be possible without deep learning models. “It’s building a relationship between language and our thoughts. We can now explore, what are the physical properties of our thoughts?”

Simulation of our thoughts to describe an architectural material printed on flexible black TPU filament

 

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Your Words Do Matter

Negative, angry and critical words cause emotional and physical damage, not only to the listener, but to the speaker. A single negative word, whether spoken to a stranger, a friend or a family member, can leave a lasting impression that might never be erased. Negative words create negative attitudes, destroy relationships and block communication. For children, the effects are more serious. Studies have found that connections between the left and right sides of the brain are underdeveloped in adults who were verbally abused as children by their parents or by peers.

Some people justify angry behavior by claiming that they need to express feelings of being frustrated, stressed, or under pressure. In fact, speaking negative words to others causes physical changes in your own brain that can affect your well-being. Neurologists have found that vocalizing a negative word such as “no” immediately releases a flood of stress-producing hormones that interrupt normal brain function and impair your ability to think logically, reason, process language and communicate. This is believed to be linked to a “flight response” that helped our ancestors survive by reacting instantly to dangerous situations.

Thinking and speaking negative thoughts over and over can permanently damage parts of your brain that regulate your memory, emotions, appetite, and sleep patterns. Feelings of anxiety and sadness increase, and the ability to experience long-term satisfaction decreases. Unfortunately, thinking and saying positive words does not have the same dramatic effect on your brain. You need to speak a positive word multiple times to counteract the effect on your brain of one negative word.

Controlling or eliminating negative words and actions has a positive effect on your overall health. Research shows that a positive attitude reduces the occurrence of heart disease, improves immune responses, and is associated with making healthier lifestyle choices. Here are some tips;

Understand yourself. Ask yourself why you feel so angry or negative. Are you hungry, tired, disappointed, late, or upset by something that happened at work? Instead of saying unkind words to the person in front of you, look for a positive way to alleviate the source of your distress.

Smile (even a fake smile). A study by the University of Kansas showed that the physical act of smiling lowers blood pressure and slows the heart rate during times of stress.

Be polite. Everyone likes to be treated with courtesy and respect. Showing consideration for others creates a positive environment.

Be aware of the whole situation. An employee serving a long line of customers at the deli counter or post office is under a lot of pressure. A waiter who forgets your order could be new on the job. Remember when you might have been in a similar situation. By being tolerant and understanding, you make it easier for them to do their job.

Try an attitude adjustment and turn negatives into positives. Instead of fuming because you have to commute in heavy traffic, use the time to listen to music or podcasts. If you are short on money, appreciate the good things you have, such as the company of friends and family.

Learning to control negative thoughts and avoid negative actions will result in more rewarding relationships and have a positive effect on your health and well-being. source

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Positive thinking: Stop negative self-talk to reduce stress

Positive thinking helps with stress management and can even improve your health. Practice overcoming negative self-talk with examples provided.

Is your glass half-empty or half-full? How you answer this age-old question about positive thinking may reflect your outlook on life, your attitude toward yourself, and whether you’re optimistic or pessimistic — and it may even affect your health.

Indeed, some studies show that personality traits such as optimism and pessimism can affect many areas of your health and well-being. The positive thinking that usually comes with optimism is a key part of effective stress management. And effective stress management is associated with many health benefits. If you tend to be pessimistic, don’t despair — you can learn positive thinking skills.

Understanding positive thinking and self-talk

Positive thinking doesn’t mean that you ignore life’s less pleasant situations. Positive thinking just means that you approach unpleasantness in a more positive and productive way. You think the best is going to happen, not the worst.

Positive thinking often starts with self-talk. Self-talk is the endless stream of unspoken thoughts that run through your head. These automatic thoughts can be positive or negative. Some of your self-talk comes from logic and reason. Other self-talk may arise from misconceptions that you create because of lack of information or expectations due to preconceived ideas of what may happen.

If the thoughts that run through your head are mostly negative, your outlook on life is more likely pessimistic. If your thoughts are mostly positive, you’re likely an optimist — someone who practices positive thinking.

The health benefits of positive thinking

Researchers continue to explore the effects of positive thinking and optimism on health. Health benefits that positive thinking may provide include:

• Increased life span
• Lower rates of depression
• Lower levels of distress and pain
• Greater resistance to illnesses
• Better psychological and physical well-being
• Better cardiovascular health and reduced risk of death from cardiovascular disease and stroke
• Reduced risk of death from cancer
• Reduced risk of death from respiratory conditions
• Reduced risk of death from infections
• Better coping skills during hardships and times of stress

It’s unclear why people who engage in positive thinking experience these health benefits. One theory is that having a positive outlook enables you to cope better with stressful situations, which reduces the harmful health effects of stress on your body.

It’s also thought that positive and optimistic people tend to live healthier lifestyles — they get more physical activity, follow a healthier diet, and don’t smoke or drink alcohol in excess.

Identifying negative thinking

Not sure if your self-talk is positive or negative? Some common forms of negative self-talk include:

• Filtering. You magnify the negative aspects of a situation and filter out all the positive ones. For example, you had a great day at work. You completed your tasks ahead of time and were complimented for doing a speedy and thorough job. That evening, you focus only on your plan to do even more tasks and forget about the compliments you received.
• Personalizing. When something bad occurs, you automatically blame yourself. For example, you hear that an evening out with friends is canceled, and you assume that the change in plans is because no one wanted to be around you.
• Catastrophizing. You automatically anticipate the worst without facts that the worse will happen. The drive-through coffee shop gets your order wrong, and then you think that the rest of your day will be a disaster.
• Blaming. You try to say someone else is responsible for what happened to you instead of yourself. You avoid being responsible for your thoughts and feelings.
• Saying you “should” do something. You think of all the things you think you should do and blame yourself for not doing them.
• Magnifying. You make a big deal out of minor problems.
• Perfectionism. Keeping impossible standards and trying to be more perfect sets yourself up for failure.
• Polarizing. You see things only as either good or bad. There is no middle ground.

Focusing on positive thinking

You can learn to turn negative thinking into positive thinking. The process is simple, but it does take time and practice — you’re creating a new habit, after all. Following are some ways to think and behave in a more positive and optimistic way:

• Identify areas to change. If you want to become more optimistic and engage in more positive thinking, first identify areas of your life that you usually think negatively about, whether it’s work, your daily commute, life changes or a relationship. You can start small by focusing on one area to approach in a more positive way. Think of a positive thought to manage your stress instead of a negative one.
• Check yourself. Periodically during the day, stop and evaluate what you’re thinking. If you find that your thoughts are mainly negative, try to find a way to put a positive spin on them.
• Be open to humor. Give yourself permission to smile or laugh, especially during difficult times. Seek humor in everyday happenings. When you can laugh at life, you feel less stressed.
• Follow a healthy lifestyle. Aim to exercise for about 30 minutes on most days of the week. You can also break it up into 5- or 10-minute chunks of time during the day. Exercise can positively affect mood and reduce stress. Follow a healthy diet to fuel your mind and body. Get enough sleep. And learn techniques to manage stress.
• Surround yourself with positive people. Make sure those in your life are positive, supportive people you can depend on to give helpful advice and feedback. Negative people may increase your stress level and make you doubt your ability to manage stress in healthy ways.
• Practice positive self-talk. Start by following one simple rule: Don’t say anything to yourself that you wouldn’t say to anyone else. Be gentle and encouraging with yourself. If a negative thought enters your mind, evaluate it rationally and respond with affirmations of what is good about you. Think about things you’re thankful for in your life.

Here are some examples of negative self-talk and how you can apply a positive thinking twist to them:

Putting positive thinking into practice

Negative self-talk	Positive thinking
I’ve never done it before.	It’s an opportunity to learn something new.
It’s too complicated.	I’ll tackle it from a different angle.
I don’t have the resources.	Necessity is the mother of invention.
I’m too lazy to get this done.	I couldn’t fit it into my schedule, but I can re-examine some priorities.
There’s no way it will work.	I can try to make it work.
It’s too radical a change.	Let’s take a chance.
No one bothers to communicate with me.	I’ll see if I can open the channels of communication.
I’m not going to get any better at this.	I’ll give it another try.

Practicing positive thinking every day

If you tend to have a negative outlook, don’t expect to become an optimist overnight. But with practice, eventually your self-talk will contain less self-criticism and more self-acceptance. You may also become less critical of the world around you.

When your state of mind is generally optimistic, you’re better able to handle everyday stress in a more constructive way. That ability may contribute to the widely observed health benefits of positive thinking. source

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Sticks and Stones: Hurtful Words Damage the Brain

Verbal abuse in childhood inflicts lasting physical effects on brain structure.

Sticks and stones may break my bones, but words will never hurt me.

We all know how untrue that childhood incantation is. Words do hurt. Ridicule, disdain, humiliation, and taunting all cause injury, and when it is delivered in childhood from a child’s peers, verbal abuse causes more than emotional trauma. It inflicts lasting physical effects on brain structure.

The remarkable thing about the human brain is that it develops after birth. Unlike most animals whose brains are cast at birth, the human brain is so underdeveloped at birth that we cannot even walk for months. Self-awareness does not develop for years. Personality, cognitive abilities, and skills take decades to develop, and these attributes develop differently in every person. This is because the development and wiring of the human brain are guided by our experiences during childhood and adolescence. From a biological perspective, this increases the odds that an individual will compete and reproduce successfully in the environment the individual is born into, rather than the environment experienced by our caveman ancestors and recorded in our genes through natural selection. Developing the human brain out of the womb cheats evolution, and this is the reason for the success of our species.

When that environment is hostile or socially unhealthy, development of the brain is affected, and often it is impaired. Early childhood sexual abuse, physical abuse, or even witnessing domestic violence, have been shown to cause abnormal physical changes in the brain of children, with lasting effects that predispose the child to developing psychological disorders. This type of brain scarring is well established now by human brain imaging studies, but prior to the recent study by Martin Teicher and colleagues at Harvard Medical School, taunting and other verbal abuse experienced by middle school children from their peers was not thought to leave a structural imprint on the developing brain. But it does, according to their new study published online in advance of print in the American Journal of Psychiatry.

Young adults, ages 18-25, with no history of exposure to domestic violence, sexual abuse, or parental physical abuse, were asked to rate their childhood exposure to parental and peer verbal abuse when they were children, and then they were given a brain scan.

The results revealed that those individuals who reported experiencing verbal abuse from their peers during middle school years had underdeveloped connections between the left and right sides of their brain through the massive bundle of connecting fibers called the corpus callosum. Psychological tests given to all subjects in the study showed that this same group of individuals had higher levels of anxiety, depression, anger, hostility, dissociation, and drug abuse than others in the study.

Verbal abuse from peers during the middle school years had the greatest impact, presumably because this is a sensitive period when these brain connections are developing and becoming insulated with myelin. (Myelin is formed by non-neuronal cells, brain cells that are also known as “the other brain”, or glia.)

The environment that children are raised in molds not only their mind, but also their brain. This is something many long suspected, but now we have scientific instruments that show us how dramatically childhood experience alters the physical structure of the brain, and how sensitive we are as children to these environmental effects. Words–verbal harassment–from peers (and, as a previous study from these researchers showed, verbal abuse from a child’s parents) can cause far more than emotional harm.

Early childhood experience can either nourish or stifle brain development, and the consequences are physical, personal, and societal. Childhood taunting and verbal bullying have always been a problem, but many feel that civility, courtesy, polite social interactions, have declined markedly from the environment that today’s adults experienced as children. Many schools are more hostile places than schools once were, and new technologies, such as the internet, offer more opportunities for taunting and humiliation of children. If this is true, modern conditions or attitudes that tolerate verbal abuse of children by their peers are an incubator for developing brains with abnormalities in the corpus callosum and an elevated risk of psychiatric problems. The critical concern for ridding our environment of neurotoxins must also include “neurotoxins” children are exposed to in their social environment. source

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Why This Word Is So Dangerous to Say or Hear

This word can damage both the speaker’s and listener’s brain.

KEY POINTS

• Research shows that seeing the word “no” causes the sudden release of dozens of stress-producing hormones and neurotransmitters in the brain.
• Fear-provoking words—like poverty, illness, and death—also stimulate the brain in negative ways.
• To overcome bias toward negativity, one needs to generate at least three positive thoughts and feelings for each negative expression.

If I were to put you into an fMRI scanner—a huge donut-shaped magnet that can take a video of the neural changes in your brain—and flash the word “no” for less than one second, you’d see a sudden release of dozens of stress-producing hormones and neurotransmitters. These chemicals immediately interrupt the normal functioning of your brain, impairing logic, reason, language processing, and communication.

In fact, just seeing a list of negative words for a few seconds will make a highly anxious or depressed person feel worse, and the more you ruminate on them, the more you can actually damage key structures that regulate your memory, feelings, and emotions. [1] You’ll disrupt your sleep, your appetite, and your ability to experience long-term happiness and satisfaction.

If you vocalize your negativity, or even slightly frown when you say “no,” more stress chemicals will be released, not only in your brain but in the listener’s as well. [2] The listener will experience increased anxiety and irritability, thus undermining cooperation and trust. In fact, just hanging around negative people will make you more prejudiced toward others. [3]

Any form of negative rumination—for example, worrying about your financial future or health—will stimulate the release of destructive neurochemicals. The same holds true for children: The more negative thoughts they have, the more likely they are to experience emotional turmoil. [4] But if you teach them to think positively, you can turn their lives around. [5]

Negative thinking is also self-perpetuating, and the more you engage in negative dialogue—at home or at work—the more difficult it becomes to stop. [6] But negative words, spoken with anger, do even more damage. They send alarm messages through the brain, interfering with the decision-making centers in the frontal lobe, and this increases a person’s propensity to act irrationally.

Fear-provoking words—like poverty, illness, and death—also stimulate the brain in negative ways. And even if these fearful thoughts are not real, other parts of the brain (like the thalamus and amygdala) react to negative fantasies as though they were actual threats occurring in the outside world. Curiously, we seem to be hardwired to worry, perhaps an artifact of old memories carried from ancestral times when there were countless threats to our survival. [7]

To interrupt this natural propensity to worry, several steps can be taken. First, ask yourself: “Is the situation really a threat to my personal survival?” Usually, it isn’t, and the faster you can interrupt the amygdala’s reaction to an imagined threat, the quicker you can take action to solve the problem. You’ll also reduce the possibility of burning a permanent negative memory into your brain. [8]

After you have identified the negative thought (which often operates just below the level of everyday consciousness), you can reframe it by choosing to focus on positive words and images. The result: Anxiety and depression decrease and the number of unconscious negative thoughts declines. [9]

The Power of Yes

When doctors and therapists teach patients to turn negative thoughts and worries into positive affirmations, the communication process improves and the patient regains self-control and confidence. [10] But there’s a problem: The brain barely responds to our positive words and thoughts. [11] They’re not a threat to our survival, so the brain doesn’t need to respond as rapidly as it does to negative thoughts and words. [12]

To overcome this neural bias for negativity, we must repetitiously and consciously generate as many positive thoughts as we can. Barbara Fredrickson, a founder of positive psychology, discovered that if we need to generate at least three positive thoughts and feelings for each expression of negativity. If you express fewer, personal and business relationships are likely to fail. This finding correlates with Marcial Losada’s research with corporate teams, [13] and John Gottman’s research with marital couples. [14]

Fredrickson, Losada, and Gottman realized that if you want your business or personal relationships to flourish, you’ll need to generate at least five positive messages for each negative utterance you make. (“I’m disappointed” or “That’s not what I had hoped for” count as expressions of negativity, as does a facial frown or nod of the head.)

It doesn’t matter if your positive thoughts are irrational; they’ll still enhance your sense of happiness, well-being, and satisfaction. [15] In fact, positive thinking can help anyone build a better and more optimistic attitude toward life. [16]

Positive words and thoughts propel the motivational centers of the brain into action [17] and help us build resilience when we are faced with problems. [18] According to Sonja Lyubomirsky, a leading happiness researcher, if you want to develop lifelong satisfaction, you should regularly engage in positive thinking about yourself, share your happiest events with others, and savor every positive experience. [19]

Our advice: Choose your words wisely and speak them slowly. This will allow you to interrupt the brain’s propensity to be negative, and, as recent research has shown, the mere repetition of positive words like love, peace, and compassion will turn on specific genes that lower your physical and emotional stress. [20] You’ll feel better, live longer, and build deeper and more trusting relationships with others, at home and at work.

As Fredrickson and Losada point out, when you generate a minimum of five positive thoughts for each negative one, you’ll experience “an optimal range of human functioning.” [21] That is the power of Yes.

References

[1] Some assessments of the amygdala role in suprahypothalamic neuroendocrine regulation: a minireview. Talarovicova A, Krskova L, Kiss A. Endocr Regul. 2007 Nov;41(4):155-62.

[2]HaririAR, Tessitore A, Mattay VS, Fera F,Weinberger DR.. The amygdala response to emotional stimuli: a comparison of faces and scenes. Neuroimage. 2002 Sep;17(1):317-23.

[3] Duhachek A, Zhang S, Krishnan S. Anticipated Group Interaction: Coping withValence Asymmetries in Attitude Shift. Journal Of Consumer Research. Vol. 34. October 2007.

[4] The Role of Repetitive Negative Thoughts in the Vulnerability for Emotional Problems in Non-Clinical Children. Broeren S, Muris P, Bouwmeester S, van der Heijden KB, Abee A. J Child Fam Stud. 2011 Apr;20(2):135-148.

[5] Protocol for a randomised controlled trial of a school based cognitive behaviour therapy (CBT) intervention to prevent depression in high risk adolescents (PROMISE). Stallard P, Montgomery AA, Araya R, Anderson R, Lewis G, Sayal K, Buck R, Millings A,Taylor JA. Trials. 2010 Nov 29;11:114.

[6] What is in a word? No versus Yes differentially engage the lateral orbitofrontal cortex. Alia-Klein N, Goldstein RZ, Tomasi D, Zhang L, Fagin-Jones S, Telang F, Wang GJ, Fowler JS, Volkow ND. Emotion. 2007 Aug;7(3):649-59.

[7] Wright, R. The Moral Animal: Why We Are, the Way We Are: The New Science of Evolutionary Psychology. Vintage, 1995.

[8] Erasing fear memories with extinction training. Quirk GJ, Paré D, Richardson R, Herry C, Monfils MH, Schiller D, Vicentic A. J Neurosci. 2010 Nov 10;30(45):14993-7.

[9] Generalized hypervigilance in fibromyalgia patients: an experimental analysis with the emotional Stroop paradigm. González JL, Mercado F, Barjola P, Carretero I, López-López A, Bullones MA, Fernández-Sánchez M, Alonso M. J Psychosom Res. 2010 Sep;69(3):279-87.

[10] [Negative and positive suggestions in anaesthesia : Improved communication with anxious surgical patients]. Hansen E, Bejenke C. Anaesthesist. 2010 Mar;59(3):199-202, 204-6, 208-9.

[11] Kisley MA, Wood S, Burrows CL. Looking at the sunny side of life: age-related change in an event-related potential measure of the negativity bias. Psychol Sci. 2007 Sep;18(9):838-43.

[12] May I have your attention, please: electrocortical responses to positive and negative stimuli. Smith NK, Cacioppo JT, Larsen JT, Chartrand TL. Neuropsychologia. 2003;41(2):171-83.

[13] Losada, M. & Heaphy, E. (2004). The role of positivity and connectivity in the performance of business teams: A nonlinear dynamics model. Losada M, Heaphy E. Am Behav Scientist. 2004 47 (6):740–765.

[14] Gottman J. What Predicts Divorce?: The Relationship Between Marital Processes and Marital Outcomes. Psychology Press, 1993.

[15] On the incremental validity of irrational beliefs to predict subjective well-being while controlling for personality factors. Spörrle M, Strobel M, Tumasjan A. Psicothema. 2010 Nov;22(4):543-8.

[16] The value of positive psychology for health psychology: progress and pitfalls in examining the relation of positive phenomena to health. Aspinwall LG, Tedeschi RG. Ann Behav Med. 2010 Feb;39(1):4-15.

[17] What is in a word? No versus Yes differentially engage the lateral orbitofrontal cortex. Alia-Klein N, Goldstein RZ, Tomasi D, Zhang L, Fagin-Jones S, Telang F, Wang GJ, Fowler JS, Volkow ND. Emotion. 2007 Aug;7(3):649-59.

[18] Happiness unpacked: positive emotions increase life satisfaction by building resilience. Cohn MA, Fredrickson BL, Brown SL, Mikels JA,Conway AM. Emotion. 2009 Jun;9(3):361-8.

[19] Pursuing Happiness in Everyday Life: The Characteristics and Behaviors of Online Happiness Seekers. Parks AC, Della Porta MD, Pierce RS, Zilca R, Lyubomirsky S. Emotion. 2012 May 28.

[20] Genomic counter-stress changes induced by the relaxation response. Dusek JA, Otu HH, Wohlhueter AL, Bhasin M, Zerbini LF, Joseph MG, Benson H, Libermann TA. PLoS One. 2008 Jul 2;3(7):e2576.

[21] Positive affect and the complex dynamics of human flourishing. Fredrickson BL, Losada MF. Am Psychol. 2005 Oct;60(7):678-86.

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