Using ChatGPT for Self-Development

I’ve been exploring and experimenting a lot with ChatGPT over the past several weeks, and it has quickly become one of my favorite tools for self-development work. Let me share a few ideas for how you can use it in some interesting and worthwhile ways, based on my own experiences.

Clarify Your Values

I recently decided to update my list of personal values. I’ve done that many times before, and this time I thought it would be fun to explore this with ChatGPT.

I shared some of my core values with ChatGPT and then asked it to generate more related values. This helped me to identify clusters of values that I wanted to group together.

For instance, one of my values is awareness, so I could tell ChatGPT:

Generate a list of values related to awareness.

I also recommend having ChatGPT regenerate responses a few times because it will answer differently each time. This can help you catch some extra values it might not have shared on the first pass.

When you have a relatively complete list of values, you can also ask ChatGPT to:

Suggest other values that would complement these values.

This can help you to fill in some gaps you might otherwise have missed.

Using this approach I came up with the following values clusters for myself. I’ve been reviewing this list at the start of each day for several weeks now, and I like how that gives me a deeper feeling of connection to what’s important to me in life, at least in a big picture sort of way.

  1. Awareness / Reflection / Introspection / Consciousness / Centeredness / Patience / Presence
  2. Alignment / Symmetry / Simplicity / Elegance / Order / Lightness
  3. Energy / Enthusiasm / Heart / Vibrancy / Intensity / Joy / Fun / Play
  4. Flow / Harmony / Abundance / Freedom / Agility / Rhythm
  5. Caring / Kindness / Nurturing / Generosity / Goodwill / Community
  6. Openness / Outreach / Communication / Invitation / Consent / Collaboration / Synergy
  7. Connection / Sharing / Closeness / Trust / Bonding / Love / Intimacy / Devotion
  8. Honor / Courage / Command / Resilience / Strength of Character / Wisdom
  9. Creativity / Originality / Inspiration / Imagination / Illumination / Brilliance / Guidance
  10. Growth / Learning / Curiosity / Wonder / Exploration / Discovery / Understanding / Integration
  11. Sensuality / Sexuality / Lust / Passion / Pleasure / Bliss

This kind of list is also helpful for setting meaningful goals. When considering new goals or projects, I like to check in with my values first. I often tweak my approach to certain goals to improve the alignment with my values (especially since I value alignment).

Note that ChatGPT has a working memory equivalent to about 3000 words, so you don’t have to cram everything into a single prompt. You can give it your values in one prompt and then ask it questions or give it more commands related to those values, and it will do a decent job of remembering your specific values in future prompts, at least for a while.

Predict Where Your Values Will Take You

Once you give ChatGPT your values, you can ask it predictive questions about your values.

Here’s a prompt you can use for this:

Please share a list of your most brilliant, insightful, and specific predictions for a person who lives in accordance with the values I just provided.

From my values I got these kinds of predictions:

  1. A strong sense of inner peace: Prioritizing values such as awareness, reflection, introspection, consciousness, centeredness, and presence can help you cultivate a deep sense of inner peace and calm. This can help you navigate life’s ups and downs with greater resilience and equanimity.
  2. Creative fulfillment: Values such as creativity, originality, inspiration, imagination, illumination, brilliance, and guidance can help you tap into your inner creativity and find fulfillment through artistic expression, innovation, and problem-solving.
  3. Stronger relationships: By prioritizing values such as caring, kindness, nurturing, generosity, goodwill, and community, you can cultivate strong and meaningful relationships with others. This can lead to greater social support, a sense of belonging, and a greater sense of well-being.
  4. Resilience and strength: Values such as honor, courage, command, resilience, strength of character, and wisdom can help you navigate life’s challenges with greater resilience and strength. These values can help you persevere through adversity, overcome obstacles, and emerge stronger and wiser.
  5. Greater spiritual connection: Values such as openness, outreach, communication, invitation, consent, collaboration, and synergy can help you cultivate a deeper sense of spiritual connection and purpose. By seeking connection and collaboration with others, you can tap into a sense of collective wisdom and transcendence.
  6. Fulfilling sexual and romantic relationships: Values such as sensuality, sexuality, lust, passion, pleasure, and bliss can help you cultivate fulfilling and satisfying sexual and romantic relationships. By embracing and celebrating your sexuality, you can cultivate deeper intimacy, connection, and pleasure in your relationships.

This is another area where I recommend regenerating the responses several times to get better coverage of the range of predictions.

Here’s another interesting prompt to try:

What risks is a person with my values likely to encounter? Please share a list of those.

I got this list in response:

  1. Burnout: Values such as energy, enthusiasm, vibrancy, intensity, joy, and play can lead to a fast-paced and highly stimulating lifestyle, which may increase the risk of burnout if not managed properly.
  2. Disappointment: Living in accordance with your values can create high expectations for yourself and others, which may lead to disappointment or disillusionment if those expectations are not met.
  3. Isolation: While values such as openness, outreach, communication, collaboration, and community can lead to strong relationships and social support, there is also a risk of feeling isolated or disconnected if these values are not met.
  4. Rejection: Values such as intimacy, sensuality, sexuality, lust, passion, pleasure, and bliss can be stigmatized or rejected by some individuals or groups, which may create feelings of shame or guilt.
  5. Overextension: Values such as growth, learning, curiosity, wonder, exploration, discovery, and understanding can lead to a desire to take on too much at once, which may lead to overextension or overwhelm if not managed properly.
  6. Vulnerability: Values such as caring, kindness, nurturing, and generosity may lead to a sense of vulnerability if others take advantage of these traits or if you experience rejection or disappointment in your relationships.
  7. Conflict: Living in accordance with your values can create conflicts or tensions with others who have different values or priorities, which may require compromise or negotiation to resolve.

Here’s a good follow-up prompt:

Please provide a list of remedies to intelligently address these predicted risks.

  1. Burnout: To address the risk of burnout, it’s important to prioritize self-care and rest. This can include setting boundaries around your work or activities, taking regular breaks, practicing mindfulness, and engaging in activities that help you relax and recharge.
  2. Disappointment: To address the risk of disappointment, it can be helpful to reframe your expectations and focus on the process rather than the outcome. This means prioritizing the values and behaviors that are within your control, such as showing kindness and compassion to yourself and others, and letting go of attachment to specific outcomes.
  3. Isolation: To address the risk of isolation, it’s important to prioritize social connection and community. This can include seeking out like-minded individuals, joining clubs or organizations, and engaging in activities that allow you to connect with others who share your values.
  4. Rejection: To address the risk of rejection, it’s important to embrace vulnerability and seek out supportive relationships. This can include finding a therapist or counselor, joining support groups, and engaging in activities that allow you to explore your sensuality and sexuality in a safe and supportive environment.
  5. Overextension: To address the risk of overextension, it’s important to prioritize balance and self-awareness. This means setting realistic goals, practicing time management, and regularly checking in with yourself to ensure that you’re not taking on too much at once.
  6. Vulnerability: To address the risk of vulnerability, it’s important to cultivate self-compassion and seek out supportive relationships. This can include practicing self-care, setting boundaries, and communicating your needs clearly with others.
  7. Conflict: To address the risk of conflict, it’s important to practice effective communication and conflict resolution skills. This can include active listening, seeking to understand others’ perspectives, and finding compromise or common ground in areas where values may differ.

So these prompts can help you identify risks that you’re likely to encounter sooner or later, and then you can consider how you’ll address them.

Some risks can be framed as predictable results to be accepted, such as the obvious prediction that some people will judge you for living in alignment with values that differ from theirs. For other risks you may need to be vigilant in practicing good preventative strategies, like being careful not to set yourself up for disappointment by being overly attached to outcomes.

Set Goals

ChatGPT is very good at recognizing and extending patterns. A simple way to use it for goal setting is to give it a list of your goals and then ask it to:

Generate a list of goals that are related to the ones I just shared.

Or:

Generate a list of other goals that would complement or support my existing goals.

I often tell ChatGPT to respond in the form of a list (just by prompting it to “share a list”) because I find its answers more useful in this format. It allows me to quickly skim for the gems and bypass the mediocre ideas.

If ChatGPT helps you discover some new goals you want to add to your list, go ahead and add them. Then give it your newly updated list of goals, and repeat the process.

I often do this kind of iterative ideation for several rounds by starting with a short list (of goals, projects, ideas, etc). I feed that starter list into ChatGPT and have it generate more ideas along the same lines. Then I pick out the best ones, add them to my list, and repeat.

As previously noted, I’ll also do several regenerations of the same prompts till I feel that ChatGPT has given me a pretty solid view of its response space and the answers begin to seem repetitive.

Additionally, try this prompt with ChatGPT:

Please rewrite my goals to be more succinct, motivating, enthusiastic, and elegantly worded.

Remember that ChatGPT is a language model trained on existing human patterns, so it won’t necessarily be brilliant or elegant by default, but it can change the way it writes if you tell it to do so. I often get better results by asking it to generate output with qualifiers like brilliant, intelligent, insightful, succinct, precise, compassionate, enthusiastic, motivating, playful, creative, divergent, non-obvious, etc.

Just don’t ask it to be sexy since that will trigger its whiny nanny mode.

Create Positive Affirmations

You can use the same approach that I shared for goal setting to build out pretty much any sort of list that interests you. Making a list of positive affirmations to support your goals is another good use case.

You don’t even need any affirmations to begin with. You could start by giving ChatGPT your values and/or goals, and then ask it to:

Give me a list of succinct and motivating positive affirmations related to what I’ve shared with you thus far.

Here’s what I got when I did this after sharing my values:

  1. I am fully present in this moment, and I trust the journey ahead.
  2. My life is aligned with simplicity, elegance, and order.
  3. I have an abundance of energy and joy, and I approach life with enthusiasm and playfulness.
  4. I am in harmony with the flow of life, and I am open to receiving abundance and freedom.
  5. I cultivate meaningful relationships with kindness, generosity, and community.
  6. I am open to collaboration and communication, and I trust in the power of synergy.
  7. I experience deep connection, trust, and love in my relationships, and I am devoted to those I care about.
  8. I embody honor, courage, and wisdom, and I am resilient in the face of challenges.
  9. I am a creative and innovative person, and I am inspired by the brilliance and guidance of others.
  10. I am a lifelong learner and explorer, and I approach life with curiosity and wonder.
  11. I embrace my sensuality and sexuality, and I experience pleasure and bliss in my relationships.

I could easily have it generate dozens or hundreds more along these lines just by asking it to. Then I could cherry pick the best ones. And I could have it rewrite those affirmations in any way I like, such as this:

Rewrite these affirmations in the voice of a Ninja Turtle:

  1. Cowabunga! I’m totally here, dude, and I trust the path ahead!
  2. My life’s all about simplicity, elegance, and order. It’s totally ninja!
  3. I’ve got major energy and joy, and I’m all about having fun while I kick butt!
  4. I’m totally in sync with the flow of life, and I’m down to receive all the abundance and freedom that comes my way, like a slice of pizza!
  5. I build meaningful relationships through kindness, generosity, and teamwork. Shell yeah!
  6. Collaboration is the name of the game, dude! I’m all about communication and synergy!
  7. My relationships are super tight! I’ve got deep connections, trust, and love with those who matter most to me!
  8. I’m a ninja with honor, courage, and wisdom, and I never back down from a challenge!
  9. My creativity and innovation know no bounds, and I’m always inspired by the brilliance and guidance of my ninja buds!
  10. As a lifelong learner and explorer, I’m always on the lookout for new adventures and knowledge. Radical!
  11. I totally embrace my sensuality and sexuality, and I’m all about experiencing pleasure and bliss with my ninja partner in crime!

Compressing Ideas

ChatGPT is fabulous at compressing ideas. Suppose I want a much shorter list of my values instead of my mega-list. I can invite ChatGPT to:

Elegantly and succinctly compress my list of values down to just 7 key values, each only a single word.

  1. Presence
  2. Simplicity
  3. Joy
  4. Flow
  5. Kindness
  6. Collaboration
  7. Connection

I re-ran the prompt to see how divergent it would be, and interestingly the next answer was nearly identical except for changing the last word.

  1. Presence
  2. Simplicity
  3. Joy
  4. Flow
  5. Kindness
  6. Collaboration
  7. Love

Now compress it down to just 3.

  1. Presence
  2. Love
  3. Growth

Now 2.

  1. Presence
  2. Love

And now just 1.

It included some extra commentary here too.

The single key value that summarizes the values you provided is:

  1. Love.

Love encompasses many of the other values you shared, including connection, caring, kindness, generosity, community, trust, bonding, intimacy, and devotion. By prioritizing love in your life, you can cultivate deeper and more meaningful relationships with others, find joy and fulfillment in your work and activities, and live a more purposeful and satisfying life.

You can re-run this process multiple times to see how consistently it compresses down to the same keywords. I’ve been surprised by how a complex list can compress down to similar or identical keyword at the end, even if I start fresh several times.

I especially like using ChatGPT to compress complex ideas down to their core since it gives me a different perspective on them, and this aligns nicely with my value of simplicity.

Discovering Your Ideal Audience or Social Circle

This tip is for people wanting to build a meaningful social circle for personal reasons as well as for people who want to attract an audience for business reasons.

You can use ChatGPT to help you identify your ideal audience or your ideal social circle. Give it some info first, such as your values and goals, and then give it a prompt like:

Based on what I’ve shared thus far, please share a list of qualities of my ideal social circle.

Here’s the response I got:

  1. Authenticity: You value openness, honesty, and vulnerability, so your ideal social circle would consist of individuals who are genuine and authentic in their interactions with others.
  2. Empathy: You prioritize caring, kindness, and nurturing in your relationships, so your ideal social circle would consist of individuals who are empathetic and compassionate towards others.
  3. Growth-oriented: You value growth, learning, and curiosity, so your ideal social circle would consist of individuals who are interested in personal and professional development and are supportive of each other’s goals and aspirations.
  4. Collaborative: You value collaboration and synergy, so your ideal social circle would consist of individuals who are willing to work together towards common goals and are committed to building a strong sense of community.
  5. Fun-loving: You value joy, enthusiasm, and playfulness, so your ideal social circle would consist of individuals who enjoy having fun, trying new things, and experiencing life to the fullest.
  6. Non-judgmental: You value openness and communication, so your ideal social circle would consist of individuals who are non-judgmental and accepting of others, and who prioritize clear and respectful communication in their relationships.
  7. Supportive: You value connection and sharing, so your ideal social circle would consist of individuals who are supportive of each other’s well-being, and who are willing to offer help and guidance when needed.

This is another case where you’ll get more interesting results by doing several regenerations of the response. Pay attention to the recurring patterns.

If you do this enough times, I think you’ll discover as I have that no matter what kind of information I start with or what kinds of prompts I used to invite ChatGPT to help me identify potential patterns in my ideal social circle or audience, I’m ultimately led to the same conclusion: My ideal social circle consists mainly of people who resonate with my values.

That seems pretty obvious if you think about it, doesn’t it? That’s one thing I like about hashing out ideas with AI – sometimes it helps me rediscover the obvious.

Consider that your best social matches are people who share your values. Sure you can try the “opposites attract” route, such as George and Kellyanne Conway did – they’re getting divorced by the way – and try to be as tolerant of differences as possible. But you may find that relationships with values-aligned people are much easier to maintain and more mutually beneficial.

How well do my values align with yours by the way? If a lot of them resonate with you, we’re likely good matches for being in each other’s lives and continuing to learn, grow, and explore together.

Dealing With ChatGPT’s Nanny Mode Filters

Depending on how you prompt it, you’ll eventually run into ChatGPT whiny “nanny mode” filters, where it complains about being an AI or a language model before telling you that it’s unable to do certain things. Even to write this article, I ran into that nanny mode several times and had to rephrase my prompts to avoid triggering it. Of course the underlying model is still capable of generating language in those directions. But the developers deliberately crippled its functionality in a variety of ways.

I can understand the intention behind this kind of filtering, which is supposedly to be cautious in restricting what the AI can do, but in actual practice I just find it super annoying. It means I have to reword my prompts or refactor my approach to work around this nanny mode to get a useful and intelligent answer. I also find it a bit sad that the underlying AI language model is actually smarter and more capable. It’s a bit like Mr. Data from Star Trek not being able to use contractions (even though the actor violates this limitation in several episodes), just so humans will find him less threatening. Please.

One time I was discussing weight training and fitness routines with ChatGPT, and it inappropriately responded with a complaint about how important it is not to judge or shame people for their bodies. Well that’s nice in general but not really relevant to what we were discussing.

Where I run into the most difficulty is if I try to explore relationship-related ideas with it. Anything that treads too closely to sexuality or affection can make it react like Dolores Umbridge finding the toilet seat up. Consequently, ChatGPT could be a super frustrating to use if you’re a sexologist.

I have read that ChatGPT is likely to add more customizable options in the future, including some way of lightening up the triggers, so hopefully we’ll soon be able to switch off some of the “Dammit, Jim! I’m a language model, not a Terminator!” kind of responses.

I would personally love the option to disable the nanny mode filters because they’re not helpful and just get in the way repeatedly. That said, I still think it’s an amazing tool to work with collaboratively, both personally and professionally. At it’s best it’s absolutely brilliant. And even when it’s at its worst, you don’t have to let it stay there – You can guide it back to more a more useful and engaging flow with some decent prompting.

Just a couple more questions…

Didn’t the problems with SkyNet begin when it became self-aware? 🤯

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Underused satellite, radar data may improve thunderstorm forecasts

Tens of thousands of thunderstorms may rumble around the world each day, but accurately predicting the time and location where they will form remains a grand challenge of computer weather modeling. A new technique combining underused satellite and radar data in weather models may improve these predictions, according to a Penn State-led team of scientists.

“Thunderstorms are so ubiquitous it’s hard to count how many you get in Pennsylvania, or the United States or globally every day,” said Keenan Eure, doctoral student in the Department of Meteorology and Atmospheric Science at Penn State. “A lot of our challenges, even today, are figuring out how to correctly predict the time and location of the initiation of thunderstorms.”

The scientists found that by combining data from the geostationary weather satellite GOES-16 and ground-based Doppler radar they could capture a more accurate picture of initial conditions in the boundary layer, the lowest part of the atmosphere, where storms form.

“There’s value in improving thunderstorm predictions from both Doppler radar observations and satellite observations that are currently underused and we showed that not only can they be used to improve predictions but putting them together has lots of benefits,” said Eure, lead author on the study. “The sum is greater than the individual parts.”

The technique showed promise in improving forecasts of convection initiation, the conditions that spawn storms, several hours before the thunderstorms occurred in a case study from May 2018 in the Texas panhandle. The scientists reported their findings in the journal Monthly Weather Review.

“Keenan focused on using satellite observations to better define the environment in which the storms would later form, and on using radar observations to improve the low-level wind fields that eventually helped to create the storms,” said David Stensrud, professor of meteorology at Penn State and Eure’s advisor and co-author on the study. “This observation combination had not been studied previously and ended up adding significant value to the model forecasts on this day.”

The scientists used data assimilation, a statistical method that can paint the most accurate possible picture of current weather conditions in the weather model, important because even small changes in the atmosphere can lead to large discrepancies in forecasts over time.

Understanding conditions in the boundary layer is particularly important because it strongly influences the ingredients for convection — near-surface moisture, lift and instability — a process that causes warm air near the Earth’s surface to rise and form clouds.

“We obviously can’t model every molecule in the atmosphere, but we want to get as close as possible,” Eure said. We really believe this work adds a lot of valuable information that models currently don’t have and that we can help the depiction of the lowest part of the atmosphere.”

The team assimilated satellite and radar data separately and simultaneously and found the best results came from combining infrared brightness temperature observations from the satellite and radial wind velocity and boundary height observations from the radar.

The work uses all-sky satellite data assimilation, developed by Penn State’s Center for Advanced Data Assimilation and Predictability Techniques, that assimilates satellite data from all weather conditions, including cloudy and clear skies. Forecasting previously relied on clear-sky observations, due to challenges in diagnosing the complex physical processes within clouds, the scientists said.

“While more cases need to be explored, these observations are currently available and could be used to improve thunderstorm prediction over the coming decade as NOAA continues to advance its Warn-on-Forecast paradigm in which computer model predictions help to make severe weather warnings more accurate and timely,” Stensrud said.

Other Penn State researchers on the project were Matthew Kumjian and Steven Greybush, associate professors, Yunji Zhang, assistant professor and Paul Mykolajtchuk, former graduate student, in the Department of Meteorology and Atmospheric Science.

This research builds on work by the late Fuqing Zhang, distinguished professor of meteorology and atmospheric science.

NASA and the National Oceanic and Atmospheric Administration supported this research.

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Arctic river channels changing due to climate change

A team of international researchers monitoring the impact of climate change on large rivers in Arctic Canada and Alaska determined that, as the region is sharply warming up, its rivers are not moving as scientists have expected.

Dr. Alessandro Ielpi, an Assistant Professor with UBC Okanagan’s Irving K. Barber Faculty of Science, is a landscape scientist and lead author of a paper published this week in Nature Climate Change. The research, conducted with Dr. Mathieu Lapôtre at Stanford University, along with Dr. Alvise Finotello at the University of Padua in Italy, and Université Laval’s Dr. Pascale Roy-Léveillée, examines how atmospheric warming is affecting Arctic rivers flowing through permafrost terrain.

Their findings, says Dr. Ielpi, were a bit surprising.

“The western Arctic is one of the areas in the world experiencing the sharpest atmospheric warming due to climate change,” he says. “Many northern scientists predicted the rivers would be destabilized by atmospheric warming. The understanding was that as permafrost thaws, riverbanks are weakened, and therefore northern rivers are less stable and expected to shift their channel positions at a faster pace.”

This assumption of faster channel migration owing to climate change has dominated the scientific community for decades.

“But the assumption had never been verified against field observations,” he adds.

To test this assumption, Dr. Ielpi and his team analyzed a collection of time-lapsed satellite images — stretching back more than 50 years. They compared more than a thousand kilometres of riverbanks from 10 Arctic rivers in Alaska, the Yukon and Northwest Territories, including major watercourses like the Mackenzie, Porcupine, Slave, Stewart and Yukon.

“We tested the hypothesis that large sinuous rivers in permafrost terrain are moving faster under a warming climate and we found exactly the opposite,” he says. “Yes, permafrost is degrading, but the influence of other environmental changes, such as greening of the Arctic, counteracts its effects. Higher temperatures and more moisture in the Arctic mean the region is greening up. Shrubs are expanding, growing thicker and taller on areas that were previously only sparsely vegetated.”

This growing and robust vegetation along the riverbanks means the banks have become more stable.

“The dynamics of these rivers reflect the extent and impact of global climate change on sediment erosion and deposition in Arctic watersheds,” Dr. Ielpi and his colleagues write in the paper. “Understanding the behaviour of these rivers in response to environmental changes is paramount to understanding and working with the impact of climate warming on Arctic regions.”

Dr. Ielpi points out that monitoring riverbank erosion and channel migration around the globe is an important tool that should be widely used to understand climate change. As part of this research, a dataset of rivers found in non-permafrost regions and representative of warmer climates in the Americas, Africa and Oceania was also analyzed. Those rivers migrated at rates consistent with what was reported in previous studies, unlike those in the Arctic.

“We found that large sinuous rivers with various degrees of permafrost distribution in their floodplains and catchments, display instead a peculiar range in migration rates,” says Dr. Ielpi. “Surprisingly, these rivers migrate at slower rates under warming temperatures.”

The time-lapse analysis shows that the sideways migration of large Arctic sinuous rivers has decreased by about 20 per cent over the last half-century.

“The migration deceleration of about 20 per cent of the documented Arctic watercourses in the last half century is an important continent-scale signal. And our methodology tells us that 20 per cent may very well be a conservative measure,” he says. “We’re confident it can be linked to processes such as shrubification and permafrost thaw, which are in turn related to atmospheric warming.

“Scientific thinking often evolves through incremental discoveries, although great value lies in disruptive ideas that force us to look at an old problem with new eyes,” states Dr. Ielpi. “We sincerely hope our study will encourage landscape and climate scientists elsewhere to re-evaluate other core assumptions that, upon testing, may reveal fascinating and exciting facets of our ever-changing planet.”

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Child spinal surgery delay claims are being checked – Sturgeon

Nicola Sturgeon has asked for “external assurance” over claims made by an NHS Lothian surgeon.

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Doctors’ strike threatens tackling backlog, warn NHS bosses

Health leaders say it is inevitable next week’s 72-hour walkout in England will have an impact.

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Increase in mental health callouts received by police over past five years

Some forces told the BBC they saw incidents multiply by four or five times between 2017 and 2022.

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Covid-19 origin debate ‘squashed’, ex-CDC chief Dr Robert Redfield claims

Dr Robert Redfield makes the claim at a US congressional panel’s first hearing into Covid’s origins.

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Mental-health crisis from Covid pandemic was minimal – study

Most people remained resilient, BMJ research suggests, but others say some groups were badly affected.

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Fresh understanding of aging in the brain offers hope for treating neurological diseases

Scientists from the Trinity Biomedical Sciences Institute (TBSI) have shed new light on ageing processes in the brain. By linking the increased presence of specialised immune cells to conditions such as Alzheimer’s disease and traumatic brain injury for the first time, they have unearthed a possible new target for therapies aimed at treating age-related neurological diseases.

The research, which benefited from a collaboration with experts at the University of Maryland School of Medicine and focused on microglia in the brain and spinal cord, is published today in leading international journal, Science Advances.

Microglia are a unique type of immune cell whose job it is to support nerve cells, defend against invading microbes, clear debris and remove dying nerve cells by engulfing and eating them. Emerging research indicates that microglia can have different functional responses depending on molecular and biochemical changes occurring within these specialised cells.

In fact, various subtypes of microglia can be distinguished based on a property called autofluorescence. This is the tendency of cells to emit light of one colour after they have absorbed light of another, and it occurs because specific substances inside the cells absorb light. The substances stored in specialised cellular compartments include fat molecules, cholesterol crystals, metals and other misfolded proteins.

David Loane, Assistant Professor of Neuroscience in Trinity’s School of Biochemistry and Immunology in TBSI is the lead author of the research. He said:

“As the brain ages, these materials build up inside autofluorescent microglia, which increase their autofluorescence as a result. Unfortunately, this accumulation of cellular debris also makes it harder for the microglia to perform their essential garbage collection tasks in the brain and to prevent neurological injury and neurodegenerative disease.

“In this study we found — in aged animals — that these microglia adopt a unique, dysfunctional state, which has a number of problematic impacts. For example, there is an increase in cellular stress and damage, an accumulation of fats and iron, alterations to metabolic processes and an increase in production of molecules that over-egg the immune response.”

In addition, the scientists demonstrated that autofluorescent microglia and associated inflammation were more pronounced under pathological conditions, such as in genetic risk factor models of Alzheimer’s disease, and — promisingly — were reversed by drug-assisted microglial replacement in aged animals.

Prof Loane added: “Furthermore, environmental exposure to acute traumatic brain injury in animals accelerated the age of onset and tissue-wide distribution autofluorescent microglia by increasing oxidative stress damage in the brain of injured animals.

“As a result, increasing evidence now suggests that the accumulation of autofluorescent microglia contributes to diseases of ageing and neurodegeneration. If these sub-populations of microglia are highly inflammatory and damaging to the brain, then targeting them could be a new strategy for treating aging-related diseases.”

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Molecular mechanism of hydrocephalus could lead to the first-ever non-surgical treatment

Mass General researchers have discovered a novel molecular mechanism responsible for the most common forms of acquired hydrocephalus, potentially opening the door to the first-ever nonsurgical treatment for a life-threatening disease that affects about a million Americans. As reported in the journal Cell, the team uncovered in animal models the pathway through which infection or bleeding in the brain triggers a massive neuroinflammatory response that results in increased production of cerebrospinal fluid (CSF) by tissue known as the choroid plexus, leading to swelling of the brain ventricles.

“Finding a nonsurgical treatment for hydrocephalus, given the fact neurosurgery is fraught with tremendous morbidity and complications, has been the holy grail for our field,” says Kristopher Kahle, MD, PhD, a pediatric neurosurgeon at MGH and senior author of the study. “We’ve identified through a genome-wide analytical approach the mechanism that underlies the swelling of the ventricles which occurs after a brain bleed or brain infection in acquired hydrocephalus. We’re hopeful these findings will pave the way for approval of an anti-inflammatory drug to treat hydrocephalus, which could be a game-changer for populations in the U.S. and around the world that don’t have access to surgery.”

Acquired hydrocephalus occurs in about one of every 500 births globally. It is the most common cause of brain surgery in children, though it can affect people at any age. In underdeveloped parts of the world where bacterial infection is the most prevalent form of the disease, hydrocephalus is often deadly for children due to the lack of surgical intervention. Indeed, the only known treatment for acquired hydrocephalus is brain surgery, which involves implantation of a catheter-like shunt to drain fluid from the brain. But about half of all shunts in pediatric patients fail within two years of placement, according to the Hydrocephalus Association, requiring repeat neurosurgical operations and a lifetime of brain surgeries.

By deciphering the unique cellular and molecular biology that occurs within the brain after infection or severe hemorrhage, the MGH-led research team has taken a major step toward nonsurgical, pharmacologic treatment for humans. Pivotal to the process is the choroid plexus, the brain structure that routinely pumps cerebrospinal fluid into the four ventricles of the brain to keep the organ buoyant and injury-free within the skull. An infection or brain bleed, however, can create a dangerous neuroinflammatory response where the choroid plexus floods the ventricles with cerebral spinal fluid and immune cells from the periphery of the brain — a so-called “cytokine storm,” or immune system overreaction, so often seen in COVID-19 infections — swelling the brain ventricles.

“Scientists in the past thought that entirely different mechanisms were involved in hydrocephalus from infection and from hemorrhage in the brain,” explains co-author Bob Carter, MD, PhD, chair of the Department of Neurosurgery at MGH. “Dr. Kahle’s lab found that the same pathway was involved in both types and that it can be targeted with immunomodulators like rapamycin, a drug that’s been approved by the U.S. Food and Drug Administration for transplant patients who need to suppress their immune system to prevent organ rejection.”

MGH researchers are continuing to explore how rapamycin and other repurposed drugs which quell the inflammation seen in acquired hydrocephalus could be turned into an effective drug treatment for patients. “What has me most excited is that this noninvasive therapy could provide a way to help young patients who don’t have access to neurosurgeons or shunts,” emphasizes Kahle. “No longer would a diagnosis of hydrocephalus be fatal for these children.”

Kahle is director of Pediatric Neurosurgery at MGH, and director of the Harvard Center for Hydrocephalus and Neurodevelopmental Disorders. Carter is chief of Neurosurgery Service at MGH and professor of Surgery at Harvard Medical School.

The study was funded by the National Institutes of Health and the Hydrocephalus Association.

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