Pittsburg secondary problem prompt: OK to talk about an intellectual problem?

[OdysseanUnderdog]

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[PA_dud3]

You didn't resolve it, though.

 

[gyngyn]

It's more likely that they are looking for a personal experience...

 

[gonnif]

I have a question about the Pittsburgh secondary for the first prompt ("Tell us about a challenging problem you faced and how you resolved it").

A challenging problem I faced is, amyloid-beta causes Alzheimer’s disease (AD) experimentally and in familial AD patients (who hyper-produce amyloid-beta due to mutations), yet all phase-III RCTs targeting amyloid-beta have failed. I resolved it by reviewing decades’ neuropathology and imaging studies, reinterpreting them in light of novel mechanistic studies, and reasoning from evolution, physiology, and cell/molecular biology first principles.

Resolution? Amyloid-beta is….

Then the rest of it is a short summary of my big-picture resolution to the problem (my explanation for why that is the case I think), then a few examples of interventions that may be required to prevent, arrest, and reverse AD. Is this an appropriate answer to the question? It's about an intellectual problem, more than a practical problem, I guess. Is that OK? I'd appreciate any input.

Absolutely positively NO!!!!! They are looking for a non-intellectual issue. Show me some personal growth

 

[Moko]

I guess if this was rephrased in terms of a challenging situation that you encountered in research that would be fine. The essay should be focused on how you overcame the challenge though.

However, have you actually studied these and published about them? Or is this all theory-crafting? If it's the latter, I would choose a more conventional topic. The purpose of this question is to display resilience and coping mechanisms, not to show off your intellectual chops.

 

[Goro]

I have a question about the Pittsburgh secondary for the first prompt ("Tell us about a challenging problem you faced and how you resolved it").

A challenging problem I faced is, amyloid-beta causes Alzheimer’s disease (AD) experimentally and in familial AD patients (who hyper-produce amyloid-beta due to mutations), yet all phase-III RCTs targeting amyloid-beta have failed. I resolved it by reviewing decades’ neuropathology and imaging studies, reinterpreting them in light of novel mechanistic studies, and reasoning from evolution, physiology, and cell/molecular biology first principles.

Resolution? Amyloid-beta is….

Then the rest of it is a short summary of my big-picture resolution to the problem (my explanation for why that is the case I think), then a few examples of interventions that may be required to prevent, arrest, and reverse AD. Is this an appropriate answer to the question? It's about an intellectual problem, more than a practical problem, I guess. Is that OK? I'd appreciate any input.

It's a secondary prompt for medical school, not a grant proposal.

Introspection is a required trait for a doctor.

 

[ciestar]

This fails to answer the prompt.

 

[OdysseanUnderdog]

Got it, thank you very much for the feedback, @gonnif, @ciestar, @gyngyn, @Doktor_dud3, @Moko, and @Goro! I'll talk about a personal experience that shows personal growth, resilience, coping skills, and introspection.

Thank you, @Goro! I'll do some introspection. I find what's in there much less interesting than what's out there in terms of medicines, diseases, patients, etc., but I take your point.

That message will self-destruct in 3, 2, 1...

 

[OdysseanUnderdog]

You didn't resolve it, though.

@Doktor_dud3, thanks for your feedback. Could you expand on that possibly?

 

[PA_dud3]

@Doktor_dud3, thanks for your feedback. Could you expand on that possibly?

Sorry, i just reread my post and it sounds kinda rude and short, didnt mean it that way. I was trying to say that you personally did not resolve the actual problem. You dissected it in your mind and thought about it. But you didnt resolve a problem which affected you "in the real world" so to speak. I hope that makes sense.

 

[OdysseanUnderdog]

Sorry, i just reread my post and it sounds kinda rude and short, didnt mean it that way. I was trying to say that you personally did not resolve the actual problem. You dissected it in your mind and thought about it. But you didnt resolve a problem which affected you "in the real world" so to speak. I hope that makes sense.

Yes, it does. It's not like I treated patients with AD and got results, which would mean actually solving the problem.

 

[ciestar]

Got it, thank you very much for the feedback, @gonnif, @ciestar, @gyngyn, @Doktor_dud3, @Moko, and @Goro! I'll talk about a personal experience that shows personal growth, resilience, coping skills, and introspection.

Thank you, @Goro! I'll do some introspection. I find what's in there much less interesting than what's out there in terms of medicines, diseases, patients, etc., but I take your point.

That message will self-destruct in 3, 2, 1...

Don’t forget that schools want so see there is more to you than science and medicine

 

[OdysseanUnderdog]

I have another option that I think might work well enough, but I feel like I'm having trouble thinking of a problem that I resolved that's impressive and that also is a personal experience that shows personal growth, resilience, coping skills, and introspection. Any examples?

 

[mmchick]

I have another option that I think might work well enough, but I feel like I'm having trouble thinking of a problem that I resolved that's impressive and that also is a personal experience that shows personal growth, resilience, coping skills, and introspection. Any examples?

You can’t think of anything challenging in your life that required alternative problem-solving via some sort of introspective effort? You’ll have to do this a lot as a doctor...

 

[OdysseanUnderdog]

You can’t think of anything challenging in your life that required alternative problem-solving via some sort of introspective effort? You’ll have to do this a lot as a doctor...

Absolutely. I did eventually think of a good option for that.

 

[cj_cregg]

I have another option that I think might work well enough, but I feel like I'm having trouble thinking of a problem that I resolved that's impressive and that also is a personal experience that shows personal growth, resilience, coping skills, and introspection. Any examples?

It doesn't have to be an impressive problem. It can be a conflict on a group project, a disagreement with a roommate, a challenge you faced in your personal life or ECs. What they're looking for is not how interesting your problems are but how you respond to them. You should be the focus of your essay, not the problem.

 

[OdysseanUnderdog]

Could you guys possibly take a look at this? It started as a secondary about intellectual diversity or life-long learning, but it's become my first attempt to write what I would say to the doctors if I rushed an Alzheimer's disease (AD) patient to the ER. I had this idea because I wrote somewhere that AD and pancreatic cancer are emergencies, and I received the difficult feedback that what I had written before was too intellectual. I realized I have a unique opportunity to tell doctors the most important highlights, and I have a duty to make use of that opportunity to benefit patients as best I can. What do you think? Keep in mind this is an extremely abridged, simplified summary of summaries. Let me know if you would like references or more of an explanation about anything. Constructive feedback is welcome!


I have spent >2,000 hours reading and writing about Alzheimer’s disease (AD). Amyloid-beta plaques sequester metals, exosomes, and pathogens relatively harmlessly in the extracellular space. Amyloid-beta oligomers are antimicrobial, killing neurons and pathogens alike. Diverse viruses, bacteria, and fungi accumulate in AD patients’ brains due to immunosuppression. Immunosuppression occurs via many mechanisms and mediators, including endogenous retroviruses, cortisol, interferon/IL-1beta mutual suppression, etc. The innate immune system cannot distinguish between oxidatively damaged former-self biomolecules and pathogens, so both drive neuroinflammation and compensatory anti-inflammatory immunosuppression, e.g. interferons respond to viral DNA and cytoplasmic oxoDNA found in AD patients’ brains via cGAS, and interferons suppress IL-1beta immunity.

Familial AD is caused by mutations in genes that cause excessive amyloid-beta production, but sporadic AD, which 95% of AD patients suffer from, is not caused directly by mutations. Amyloid-beta is a regulated second-signal propagating most aspects of AD, but it is not the distal cause of sporadic AD. The root causes of sporadic AD, amyloid-beta genesis and immunosuppression are specific founder pathogens, DNA damage, and oxidative stress. All-cause oxidative stress is contributed to by aging, most diseases, biopsychosocial stress, unhealthy lifestyle habits, and common environmental toxins, such as aluminum, iron, mycotoxins, and combustion-derived carbon nanoparticles from pollution. Yumoto and colleagues found iron and aluminum accumulated in the DNA of AD patients’ hippocampal neurons, which generate hydroxyl radicals that directly oxidatively damage DNA. Oxidative stress activates TRPM2s, which allow calcium and zinc to flux into the neural cytoplasm, effluxing potassium and driving excitotoxicity and mitochondrial dysfunction. Activated by oxidative DNA damage, PARP1/PARG/TRPM2 metabolite AMP blocks ANT translocators, starving mitochondria of ADP—the final phosphate acceptor—inhibiting ATP synthase.

AMP, oxidative stress, and DNA damage activate AMPK, an ancient kinase rheostat of oxidative/genotoxic/starvation stress responses that hyper-activates autophagy and lysosomal digestion of mitochondria, mitophagy. Phospho-tau enables surviving mitochondria to evade mitophagy, but also disconnects synapses, “holding the door” against further uptake of exosomes and pathogens. Glucose hypo-metabolism/insulin resistance ensues, which promotes evasion of PARP1-induced parthanatotic cell death and sepsis. To survive, selected-for AD neurons catabolize proteins with AMPK-driven autophagy, catabolizing liberated amino acids, e.g. L-Alanine with upregulated GPT2/ALT. ALT converts L-Alanine to pyruvate, which keeps the Krebs cycle running to avoid starvation, but also to glutamate, which excitotoxically kills neurons and synapses. Hesperidin, an ALT inhibitor, has been found in multiple preclinical AD models to treat the disease well, though this has been attributed primarily to its antioxidant capacity. ADP and PARP1 inhibitors promote axon elongation.

Aberrantly cycling, p53-deficient, hypoxic hippocampal neurons secrete trans-synaptic exosomes, extracellular vesicles bearing amyloid-beta, phospho-tau, ceramides, and likely IL-1beta, zinc and oxoDNA functioning as sterile pseudo-viruses inflaming, immunosuppressing, and hyper-exciting the neocortex, spreading the disease.

From this diverse perspective, it makes sense how decades of phase III clinical trials of amyloid-targeting therapies have not met their primary endpoints. Trying to treat a disease as complex as AD with any single monotherapy is like trying to prevent and reverse the damage of WWII by preventing a single kind of bullet from being fired. Only rationally-designed up-to-date multicomponent treatment protocols will ever prevent, arrest, and reverse AD. A minimum viable set of likely indicated approaches would include antioxidant molecular hydrogen, I-CAM1-catalase fusion peptide, nucleus-penetrating iron/aluminum chelators, TRPM2 antagonists, DNase, PARP inhibitors, ADP, potassium, hesperidin, extracellular vesicle uptake inhibitors (EVUIs), anti-amyloid-beta-oligomers, anti-retrovirals, anti-herpes drugs, anti-fungals, biofilm disruptors, gingipain inhibitors, lipopolysaccharide-targeting agents, interferon lambda, etc. all administered intranasally to reach the brain directly, plus whole-body hyperthermia or sauna and Mediterranean diet. Oxidative stress-promoting risk factors should be addressed individually with personalized medicine as needed.

 

[ciestar]

Please say you’re not planning on putting all of that in a secondary.

 

[Moko]

No. Just no. Answer the prompt.

 

[KD's burner account]

The prompt is indirectly asking you about a personal adversity you have faced - not necessarily one faced by millions of people. Take a step back and relax; you are overthinking this. This adversity does not have to be something as intense as overcoming being homeless and working five jobs at once to be able to support your family, or not being able to solve Alzheimer's disease. Any conflict you have had with other people and showing how you resolved such conflict can be one thing to write about. Take the advice of everyone else in this thread and ditch the science; show your humanistic side.

 

[Bonne Nuit]

Could you guys possibly take a look at this? It started as a secondary about intellectual diversity or life-long learning, but it's become my first attempt to write what I would say to the doctors if I rushed an Alzheimer's disease (AD) patient to the ER.

I'm confused, is this an attempt to answer a Pitt secondary?

ETA: I'm not trying to be snarky or unkind; I genuinely do not understand if this an attempt to answer a secondary prompt or if you're just spitballing ideas. I don't understand the "what I would say to doctors" angle. What prompt is this in reference to?

 

[AnMDtoB]

Could you guys possibly take a look at this? It started as a secondary about intellectual diversity or life-long learning, but it's become my first attempt to write what I would say to the doctors if I rushed an Alzheimer's disease (AD) patient to the ER. I had this idea because I wrote somewhere that AD and pancreatic cancer are emergencies, and I received the difficult feedback that what I had written before was too intellectual.

I feel like you're stuck on this idea of submitting a book report on a challenging disease, and don't realize Pitt is looking for a challenge that you ****personally**** have dealt with that affected **you** personally.

Remember, the secondary is supposed to be about helping them understand who you are, not what Alzheimers is and how it works.

 

[OdysseanUnderdog]

Please say you’re not planning on putting all of that in a secondary.

No. Just no. Answer the prompt.

The prompt is indirectly asking you about a personal adversity you have faced - not necessarily one faced by millions of people. Take a step back and relax; you are overthinking this. This adversity does not have to be something as intense as overcoming being homeless and working five jobs at once to be able to support your family, or not being able to solve Alzheimer's disease. Any conflict you have had with other people and showing how you resolved such conflict can be one thing to write about. Take the advice of everyone else in this thread and ditch the science; show your humanistic side.

I'm confused, is this an attempt to answer a Pitt secondary?

I feel like you're stuck on this idea of submitting a book report on a challenging disease, and don't realize Pitt is looking for a challenge that you ****personally**** have dealt with that affected **you** personally.

Remember, the secondary is supposed to be about helping them understand who you are, not what Alzheimers is and how it works.

To clarify, this is not for a Pitt secondary. I might use fragments of it where appropriate to answer prompts asking about life-long learning, intellectual diversity, or research. Apart from that, I might use it as a summary of my research for purposes other than secondaries.

 

[Moko]

None of what you wrote (apart from the very first sentence) should go remotely close to any application to medical school. Period.

Even if someone asks you about examples of life-long learning or research, vomiting up a bunch of random facts does not answer the question.

Much like introspection, having common sense is also a required trait to become a physician.

 

[Bonne Nuit]

To clarify, this is not for a Pitt secondary. I might use fragments of it where appropriate to answer prompts asking about life-long learning, intellectual diversity, or research. Apart from that, I might use it as a summary of my research for purposes other than secondaries.

Thank you for the clarification. That makes a lot more sense.

What you've written would work best as summary of your research, though appropriate only for audiences with an established understanding of the science. It's way too dense for a lay audience, and I don't think the tone and style is very appropriate for secondaries.

I know a couple EM docs, and they wouldn't stick around past the first few sentences of that explanation. Your summary does not effectively communicate "the most important highlights" of what a EM doctor would need to know about the AD patient.

 

[OdysseanUnderdog]

None of what you wrote (apart from the very first sentence) should go remotely close to any application to medical school. Period.

Even if someone asks you about examples of life-long learning or research, vomiting up a bunch of random facts does not answer the question.

Much like introspection, having common sense is also a required trait to become a physician.

Thank you for the feedback, @Moko. I am working on expanding on the introspection and reflection part, focusing more on the process and less on the findings.

 

[OdysseanUnderdog]

Thank you for the clarification. That makes a lot more sense.

What you've written would work best as summary of your research, though appropriate only for audiences with an established understanding of the science. It's way too dense for a lay audience, and I don't think the tone and style is very appropriate for secondaries.

I know a couple EM docs, and they wouldn't stick around past the first few sentences of that explanation. Your summary does not effectively communicate "the most important highlights" of what a EM doctor would need to know about the AD patient.

That's a fair point, @StayWandering. I took some creative license with my own premise in order to include findings about the basic biology of AD that most people, even people who are experts in AD, would find surprising, and that I think are important to know in order to understand how to treat the disease. It is very dense. It's definitely meant for doctors, not for a lay audience.

 

[JustAUser]

To clarify, this is not for a Pitt secondary. I might use fragments of it where appropriate to answer prompts asking about life-long learning, intellectual diversity, or research. Apart from that, I might use it as a summary of my research for purposes other than secondaries.

What you wrote will not answer any prompt. It looks like you took out a page from a textbook over AD. It doesn't tell me anything about what you've done (besides what you wrote in the first sentence but there's nothing to back it). It doesn't tell me what you've done in research, or how you're a life-long learner.

I realized I have a unique opportunity to tell doctors the most important highlights, and I have a duty to make use of that opportunity to benefit patients as best I can.

The secondary is not a place to educate doctors on a disease. Also, many of the adcoms might not be doctors and they are more interested in learning about you and not AD.

Adcoms care more about what you've learned from the experience and what you took away. This is what Goro means by introspection. Everyone will have some volunteering, and many will have some research under their belt. However, what did you gain from it? Did you have to overcome some challenges? Did you learn some new skill? The essays have to be about YOU. Adcoms want to glean more about you as a person to see if you would make a good medical student and what you will bring to their school.

Remember, the main part is answering the question the prompt asks you. Do they want you to give them an example of you overcoming a failure? Or what you learned from a failure? Or a creative solution you had to a challenge? Or about a time you almost gave up but ultimately stayed through?
There are small nuances so make sure to read the prompt and answer it accordingly.

 

[ThrowawayShmoaway]

what I would say to the doctors if I rushed an Alzheimer's disease (AD) patient to the ER

I realized I have a unique opportunity to tell doctors the most important highlights, and I have a duty to make use of that opportunity to benefit patients as best I can

even people who are experts in AD, would find surprising, and that I think are important to know in order to understand how to treat the disease

This may be a little off-topic in terms of secondaries/this thread, but somewhat related to the points about introspection: if you do decide to touch upon your DIY thesis in secondaries, or are fortunate enough to get any interviews, you should probably rethink how you describe your research and its impact on the field/treatment of AD. Your above quotes sound a little too “full-of-yourself.” It’s tough to tell from your quotes what type of research background you have, but since you referenced your thesis as “DIY,” I’m assuming it is not through a Ph.D. program, and it also sounds like it is not published work. Therefore, although it’s admirable that you’ve put in so much time & effort researching this on your own, you should realize that, as of right now, your work is not that groundbreaking, and you should not describe it as something that would “surprise” experts in AD, or even state that you have some sort of duty/opportunity to educate physicians about this (I’m not even sure what you mean...). In fact, nothing you wrote in that one post would be necessary for an ED physician to triage and emergently treat an AD patient, so your assessment of your own work sounds a bit unrealistic and self-important. I don’t mean any of this in an insulting manner, but it’s just something to think about when speaking about your work.
(I apologize in advance if your work actually is published and/or if you actually do have a Ph.D. in this line of research.)

 

[Goro]

That's a fair point, @StayWandering. I took some creative license with my own premise in order to include findings about the basic biology of AD that most people, even people who are experts in AD, would find surprising, and that I think are important to know in order to understand how to treat the disease. It is very dense. It's definitely meant for doctors, not for a lay audience.

OP, I have read over this thread 2x. I have a to give you a warning. Being unteachable is a reason why some residents get fired from residency.

Reread the posts from the wise Moko very carefully.

 

[differentiating]

Could you guys possibly take a look at this? It started as a secondary about intellectual diversity or life-long learning, but it's become my first attempt to write what I would say to the doctors if I rushed an Alzheimer's disease (AD) patient to the ER. I had this idea because I wrote somewhere that AD and pancreatic cancer are emergencies, and I received the difficult feedback that what I had written before was too intellectual. I realized I have a unique opportunity to tell doctors the most important highlights, and I have a duty to make use of that opportunity to benefit patients as best I can. What do you think? Keep in mind this is an extremely abridged, simplified summary of summaries. Let me know if you would like references or more of an explanation about anything. Constructive feedback is welcome!


I have spent >2,000 hours reading and writing about Alzheimer’s disease (AD). Amyloid-beta plaques sequester metals, exosomes, and pathogens relatively harmlessly in the extracellular space. Amyloid-beta oligomers are antimicrobial, killing neurons and pathogens alike. Diverse viruses, bacteria, and fungi accumulate in AD patients’ brains due to immunosuppression. Immunosuppression occurs via many mechanisms and mediators, including endogenous retroviruses, cortisol, interferon/IL-1beta mutual suppression, etc. The innate immune system cannot distinguish between oxidatively damaged former-self biomolecules and pathogens, so both drive neuroinflammation and compensatory anti-inflammatory immunosuppression, e.g. interferons respond to viral DNA and cytoplasmic oxoDNA found in AD patients’ brains via cGAS, and interferons suppress IL-1beta immunity.

Familial AD is caused by mutations in genes that cause excessive amyloid-beta production, but sporadic AD, which 95% of AD patients suffer from, is not caused directly by mutations. Amyloid-beta is a regulated second-signal propagating most aspects of AD, but it is not the distal cause of sporadic AD. The root causes of sporadic AD, amyloid-beta genesis and immunosuppression are specific founder pathogens, DNA damage, and oxidative stress. All-cause oxidative stress is contributed to by aging, most diseases, biopsychosocial stress, unhealthy lifestyle habits, and common environmental toxins, such as aluminum, iron, mycotoxins, and combustion-derived carbon nanoparticles from pollution. Yumoto and colleagues found iron and aluminum accumulated in the DNA of AD patients’ hippocampal neurons, which generate hydroxyl radicals that directly oxidatively damage DNA. Oxidative stress activates TRPM2s, which allow calcium and zinc to flux into the neural cytoplasm, effluxing potassium and driving excitotoxicity and mitochondrial dysfunction. Activated by oxidative DNA damage, PARP1/PARG/TRPM2 metabolite AMP blocks ANT translocators, starving mitochondria of ADP—the final phosphate acceptor—inhibiting ATP synthase.

AMP, oxidative stress, and DNA damage activate AMPK, an ancient kinase rheostat of oxidative/genotoxic/starvation stress responses that hyper-activates autophagy and lysosomal digestion of mitochondria, mitophagy. Phospho-tau enables surviving mitochondria to evade mitophagy, but also disconnects synapses, “holding the door” against further uptake of exosomes and pathogens. Glucose hypo-metabolism/insulin resistance ensues, which promotes evasion of PARP1-induced parthanatotic cell death and sepsis. To survive, selected-for AD neurons catabolize proteins with AMPK-driven autophagy, catabolizing liberated amino acids, e.g. L-Alanine with upregulated GPT2/ALT. ALT converts L-Alanine to pyruvate, which keeps the Krebs cycle running to avoid starvation, but also to glutamate, which excitotoxically kills neurons and synapses. Hesperidin, an ALT inhibitor, has been found in multiple preclinical AD models to treat the disease well, though this has been attributed primarily to its antioxidant capacity. ADP and PARP1 inhibitors promote axon elongation.

Aberrantly cycling, p53-deficient, hypoxic hippocampal neurons secrete trans-synaptic exosomes, extracellular vesicles bearing amyloid-beta, phospho-tau, ceramides, and likely IL-1beta, zinc and oxoDNA functioning as sterile pseudo-viruses inflaming, immunosuppressing, and hyper-exciting the neocortex, spreading the disease.

From this diverse perspective, it makes sense how decades of phase III clinical trials of amyloid-targeting therapies have not met their primary endpoints. Trying to treat a disease as complex as AD with any single monotherapy is like trying to prevent and reverse the damage of WWII by preventing a single kind of bullet from being fired. Only rationally-designed up-to-date multicomponent treatment protocols will ever prevent, arrest, and reverse AD. A minimum viable set of likely indicated approaches would include antioxidant molecular hydrogen, I-CAM1-catalase fusion peptide, nucleus-penetrating iron/aluminum chelators, TRPM2 antagonists, DNase, PARP inhibitors, ADP, potassium, hesperidin, extracellular vesicle uptake inhibitors (EVUIs), anti-amyloid-beta-oligomers, anti-retrovirals, anti-herpes drugs, anti-fungals, biofilm disruptors, gingipain inhibitors, lipopolysaccharide-targeting agents, interferon lambda, etc. all administered intranasally to reach the brain directly, plus whole-body hyperthermia or sauna and Mediterranean diet. Oxidative stress-promoting risk factors should be addressed individually with personalized medicine as needed.

Serious question: have you actually done any research in this area (as in, in a lab, not just reading papers)? As someone who's been involved in AD research, this would make me side-eye pretty significantly - your first version, in addition to not addressing the prompt at all, also made some incorrect statements about the disease pathogenesis. This version almost reads like you were trying to cram as many scientific terms in as you possibly could, and I'm honestly unsure what your point is - what question would this supposedly answer? I have a hard time seeing how this could apply even to the examples you later listed.

If you're interested in studying AD, talk about *your interest* in a secondary that asks what particular areas of medicine appeal to you. Leave out the papers and the references - let people know why you find it so fascinating and what you hope to do in the field. If you've done actual research on AD, great - mention it briefly to emphasize your passion. If a doctor wanted to learn about the biology of AD, they'd go to the primary literature, not a med school application.

 

[OdysseanUnderdog]

Serious question: have you actually done any research in this area (as in, in a lab, not just reading papers)? As someone who's been involved in AD research, this would make me side-eye pretty significantly - your first version, in addition to not addressing the prompt at all, also made some incorrect statements about the disease pathogenesis. This version almost reads like you were trying to cram as many scientific terms in as you possibly could, and I'm honestly unsure what your point is - what question would this supposedly answer? I have a hard time seeing how this could apply even to the examples you later listed.

If you're interested in studying AD, talk about *your interest* in a secondary that asks what particular areas of medicine appeal to you. Leave out the papers and the references - let people know why you find it so fascinating and what you hope to do in the field. If you've done actual research on AD, great - mention it briefly to emphasize your passion. If a doctor wanted to learn about the biology of AD, they'd go to the primary literature, not a med school application.

I'm going to reply later to people here, but for now, what incorrect statements did I make about the disease pathogenesis?

 

[differentiating]

I'm going to reply later to people here, but for now, what incorrect statements did I make about the disease pathogenesis?

You wrote that beta-amyloid causes AD, which is inaccurate- it’s certainly a contributing factor, but studies have shown that healthy individuals can have beta-amyloid deposition in their brain despite being asymptomatic, so it’s not as simple as you’d made it seem. You’d also made no mention of tau, and some in the field think of AD as a tauopathy because phosphorylates tau correlates more with symptoms in studies than beta-amyloid, so that seems like an odd omission.

There’s also some debate about whether RCT failure has more to do with the fact that we’re treating individuals who already have symptoms or beta-amyloid on imaging - suggesting that beta-amyloid has already has had its effect- rather than individuals who are younger and without any evidence of disease, so preventing/reversing symptoms is unlikely to begin with. That’s why the studies with APP families are so exciting, and why some groups are working on drugs that are focused more on phosphorylated tau.

 

[OdysseanUnderdog]

You wrote that beta-amyloid causes AD, which is inaccurate- it’s certainly a contributing factor, but studies have shown that healthy individuals can have beta-amyloid deposition in their brain despite being asymptomatic, so it’s not as simple as you’d made it seem. You’d also made no mention of tau, and some in the field think of AD as a tauopathy because phosphorylates tau correlates more with symptoms in studies than beta-amyloid, so that seems like an odd omission.

There’s also some debate about whether RCT failure has more to do with the fact that we’re treating individuals who already have symptoms or beta-amyloid on imaging - suggesting that beta-amyloid has already has had its effect- rather than individuals who are younger and without any evidence of disease, so preventing/reversing symptoms is unlikely to begin with. That’s why the studies with APP families are so exciting, and why some groups are working on drugs that are focused more on phosphorylated tau.

I agree with you. I wrote that because I was trying to take out too many words. AD contributes to most but not all aspects of AD. Fun fact: sporadic AD patients have BMI1 downregulation in their frontal cortices, but amyloid-beta cannot reproduce this effect. I didn't mention tau also because of the word limit. What you said is the current most common interpretation of why RCTs have failed, and that's probably true--treating asymptomatic people or patients with MCI is always going to be more doable than treating patients with full-blown AD--but my view is, we shouldn't just give up on patients with AD. We should adapt our approach, using multicomponent treatment protocols, which I and others think might be enough to make a difference if we select our targets well. FYI though, as far as the last time I checked, all phase III trials of anti-tau therapies have also not met their primary efficacy endpoints.

 

[differentiating]

I agree with you. I wrote that because I was trying to take out too many words. AD contributes to most but not all aspects of AD. Fun fact: sporadic AD patients have BMI1 downregulation in their frontal cortices, but amyloid-beta cannot reproduce this effect. I didn't mention tau also because of the word limit. What you said is the current most common interpretation of why RCTs have failed, and that's probably true--treating asymptomatic people or patients with MCI is always going to be more doable than treating patients with full-blown AD--but my view is, we shouldn't just give up on patients with AD. We should adapt our approach, using multicomponent treatment protocols, which I and others think might be enough to make a difference if we select our targets well. FYI though, as far as the last time I checked, all phase III trials of anti-tau therapies have also not met their primary efficacy endpoints.

What targets do you have in mind? It’s all well and good to say “multicomponent treatment protocols”, but unless you have an actual plan for what that entails, you’re not suggesting anything novel. Of course we’d love to treat AD, but our treatments need to be evidence-based and specific. I wouldn’t knock the idea of preventative treatments when they could potentially decrease the amount of AD we’re seeing in general. I agree that none of the trials so far have made breakthrough discoveries, but that’s why so much research is still in process.

There’s also the question of what treating someone with AD means to you. Neural death isn’t reversible, so the most we can hope for is halting progression of the disease in these cases. Is that still “giving up on” AD patients?

Lastly- I’d work on bettering your summaries of your reading, because misinformation goes counter to your stated goals and AD experts would read that summary and conclude that you have a very shallow understanding of AD. Neither of which would represent you well. Be concise but accurate.

 

[OdysseanUnderdog]

OP, I have read over this thread 2x. I have a to give you a warning. Being unteachable is a reason why some residents get fired from residency.

Reread the posts from the wise Moko very carefully.

Consider me taught and teachable!

As a general reply to everybody, thank you for your feedback.

I realized that I was being too focused on the hypotheses because I hadn't submitted a paper for publication about the metabolic hypotheses yet. I was planning to do that after finishing secondaries, but since I'm travelling for a couple days, I decided to write a new draft of that paper and submit it to get it out of my system, which I just did.

I guess if this was rephrased in terms of a challenging situation that you encountered in research that would be fine. The essay should be focused on how you overcame the challenge though.

However, have you actually studied these and published about them? Or is this all theory-crafting? If it's the latter, I would choose a more conventional topic. The purpose of this question is to display resilience and coping mechanisms, not to show off your intellectual chops.

I am in the submission and revision process for publishing, which is part of where this is coming from, because I don't yet have a published paper in a journal I can point to, just a thesis (which I'm very proud of, but it lacks the same cachet). Like I said though, I just wrote and submitted another paper, so I'm working on it. I'm hoping I might get something officially published in time for an update letter at least.

This advice is very helpful. I can talk about resilience, challenging situations, not giving up despite absurd odds and situations, coping skills, reaching out to professional researchers for feedback and to get to the next level with a couple of especially challenging topics, etc. I've had plenty of those experiences.

 

[OdysseanUnderdog]

What targets do you have in mind? It’s all well and good to say “multicomponent treatment protocols”, but unless you have an actual plan for what that entails, you’re not suggesting anything novel. Of course we’d love to treat AD, but our treatments need to be evidence-based and specific. I wouldn’t knock the idea of preventative treatments when they could potentially decrease the amount of AD we’re seeing in general. I agree that none of the trials so far have made breakthrough discoveries, but that’s why so much research is still in process.

There’s also the question of what treating someone with AD means to you. Neural death isn’t reversible, so the most we can hope for is halting progressing of the disease in these cases. Is that still “giving up on” AD patients?

Lastly- I’d work on bettering your summaries of your reading better, because misinformation goes counter to your stated goals and AD experts would read that summary and conclude that you have a very shallow understanding of AD. Neither of which would represent you well. Be concise but accurate.

I included a few targets and interventions in that summary at the end. I'll copy and paste them here: "A minimum viable set of likely indicated approaches would include antioxidant molecular hydrogen, I-CAM1-catalase fusion peptide, nucleus-penetrating iron/aluminum chelators, TRPM2 antagonists, DNase, PARP inhibitors, ADP, potassium, hesperidin, extracellular vesicle uptake inhibitors (EVUIs), anti-amyloid-beta-oligomers, anti-retrovirals, anti-herpes drugs, anti-fungals, biofilm disruptors, gingipain inhibitors, lipopolysaccharide-targeting agents, interferon lambda, etc. all administered intranasally to reach the brain directly, plus whole-body hyperthermia or sauna and Mediterranean diet. Oxidative stress-promoting risk factors should be addressed individually with personalized medicine as needed." This is not an exhaustive list, just a few of the main things I think are needed! Please feel free to ask about why I have included any of these. Also, note that a few are medication categories that have not been invented yet, such as EVUIs.

It is possible that another monotherapy could make a significant difference for AD patients on its own. Donepezil and memantine have been shown to slow the progression significantly, but only temporarily. But realistically, AD is just too complex to treat with any single monotherapy alone to any satisfactory extent. Would you try to prevent or reverse the damage of WWII by preventing a single kind of bullet from being fired? No, right? That would be absurd, because WWII was too complex for that. Same for AD. We need comprehensive treatment strategies, not any single wonder drug.

No bad summaries--got it. I appreciate your feedback!

I'm not knocking prevention at all. An ounce of prevention is worth a pound of treatment. You're right, neural death is not reversible, and that is a thorny problem I've been thinking about. One thing to keep in mind is that adult neurogenesis does occur, though it seems to taper off with age. Another problem is that this adult neurogenesis contributes to oxidative stress, and abortive neural cell cycle reentry is core feature of AD, so we'd have to resolve the oxidative stress and injury before this neurogenesis could be beneficial. Another possibility is, dare I say it, neural stem cells, again, after resolving the underlying oxidative stress, immunosuppression, and poly-pathogen infections, but to be honest I don't know much about stem cell therapies so I don't really know how well that might work. I'm open to ideas.

 

[differentiating]

I included a few targets and interventions in that summary at the end. I'll copy and paste them here: "A minimum viable set of likely indicated approaches would include antioxidant molecular hydrogen, I-CAM1-catalase fusion peptide, nucleus-penetrating iron/aluminum chelators, TRPM2 antagonists, DNase, PARP inhibitors, ADP, potassium, hesperidin, extracellular vesicle uptake inhibitors (EVUIs), anti-amyloid-beta-oligomers, anti-retrovirals, anti-herpes drugs, anti-fungals, biofilm disruptors, gingipain inhibitors, lipopolysaccharide-targeting agents, interferon lambda, etc. all administered intranasally to reach the brain directly, plus whole-body hyperthermia or sauna and Mediterranean diet. Oxidative stress-promoting risk factors should be addressed individually with personalized medicine as needed." This is not an exhaustive list, just a few of the main things I think are needed! Please feel free to ask about why I have included any of these. Also, note that a few are medication categories that have not been invented yet, such as EVUIs.

It is possible that another monotherapy could make a significant difference for AD patients on its own. Donepezil and memantine have been shown to slow the progression significantly, but only temporarily. But realistically, AD is just too complex to treat with any single monotherapy alone to any satisfactory extent. Would you try to prevent or reverse the damage of WWII by preventing a single kind of bullet from being fired? No, right? That would be absurd, because WWII was too complex for that. Same for AD. We need comprehensive treatment strategies, not any single wonder drug.

No bad summaries--got it. I appreciate your feedback!

I'm not knocking prevention at all. An ounce of prevention is worth a pound of treatment. You're right, neural death is not reversible, and that is a thorny problem I've been thinking about. One thing to keep in mind is that adult neurogenesis does occur, though it seems to taper off with age. Another problem is that this adult neurogenesis contributes to oxidative stress, and abortive neural cell cycle reentry is core feature of AD, so we'd have to resolve the oxidative stress and injury before this neurogenesis could be beneficial. Another possibility is, dare I say it, neural stem cells, again, after resolving the underlying oxidative stress, immunosuppression, and poly-pathogen infections, but to be honest I don't know much about stem cell therapies so I don't really know how well that might work. I'm open to ideas.

That sentence is what I meant by it honestly looking like you just listed every molecule you've heard of - note that, of course, many of those same treatments would have other effects, as they're not specific to AD or even neurons. You'd have to try therapies against all these agents to see if they have any effect whatsoever on AD - many may not, even when combined together. I also wouldn't generally consider intranasal a route that would lead to the brain directly (especially since it'd spread systemically from there) - you'd probably need to do intrathecal injections if that was really your goal.

I'd just hesitate before making bold claims like educating experts in the field when, looking at prior posts, you haven't done any actual research on these topics yourself. Many things are easier said than done, and I suspect that research experience - especially clinical research - would open your eyes to how much more complicated it truly is to try and put these things into practice (especially when you're suggesting medications that don't exist). It's always good to be thinking of ways of approaching a problem, but keep in mind that your knowledge of AD is going to be much less than those who have spent decades researching AD and treating those patients. Be humble and acknowledge that you, too, still have much to learn. That's what adcoms are going to be looking for in applicants, not people who feel that they have medicine all figured out as pre-meds.

 

[Moko]

I can talk about resilience, challenging situations, not giving up despite absurd odds and situations, coping skills, reaching out to professional researchers for feedback and to get to the next level with a couple of especially challenging topics, etc. I've had plenty of those experiences.

To echo what others have said, I would also recommend considering the use of a non-academic challenge for this essay. This would give a more well-rounded picture of who you are as a person. Presumably your primary application already had your research activities there. If you don't have a better topic, overcoming a research challenge is fine too. Just remember to demonstrate the characteristics and qualities that you possessed or have gained that would make you a better classmate, colleague, and doctor. Good luck

 

[OdysseanUnderdog]

That sentence is what I meant by it honestly looking like you just listed every molecule you've heard of - note that, of course, many of those same treatments would have other effects, as they're not specific to AD or even neurons. You'd have to try therapies against all these agents to see if they have any effect whatsoever on AD - many may not, even when combined together. I also wouldn't generally consider intranasal a route that would lead to the brain directly (especially since it'd spread systemically from there) - you'd probably need to do intrathecal injections if that was really your goal.

I'd just hesitate before making bold claims like educating experts in the field when, looking at prior posts, you haven't done any actual research on these topics yourself. Many things are easier said than done, and I suspect that research experience - especially clinical research - would open your eyes to how much more complicated it truly is to try and put these things into practice (especially when you're suggesting medications that don't exist). It's always good to be thinking of ways of approaching a problem, but keep in mind that your knowledge of AD is going to be much less than those who have spent decades researching AD and treating those patients. Be humble and acknowledge that you, too, still have much to learn. That's what adcoms are going to be looking for in applicants, not people who feel that they have medicine all figured out as pre-meds.

Intranasal is the administration method for the brain of the future! I got the idea from Dr. Craft at Wakefield, who's used it in her intranasal insulin trials. Another group intranasally administered a TLR2-MyD88 interaction inhibiting peptide to AD mice (a smart approach I did not include in that list for brevity but arguably should have), and it reached the hippocampus. Why do you think people snort illicit drugs? It's not because they like the nosebleeds. If you're interested in treating the medial temporal lobe especially, intranasal is the way to go.

EDIT: Also, consider that there's evidence that AD may be caused primarily in most patients by inhalation of oxidative-stress-driving pollutants, such as iron-enriched combustion derived carbon nanoparticles and mycotoxins. So intranasal treatments are just using the same process for positive purposes.

Absolutely. I did not intend to say anything about educating experts. What I have left to learn dwarfs what I know.

Every single one of those approaches is carefully selected for multiple reasons. Pick that one you're the most skeptical could possibly be important in AD, and I'll share why I included that. Trust me, I have reasons for everything.

 

[OdysseanUnderdog]

To echo what others have said, I would also recommend considering the use of a non-academic challenge for this essay. This would give a more well-rounded picture of who you are as a person. Presumably your primary application already had your research activities there. If you don't have a better topic, overcoming a research challenge is fine too. Just remember to demonstrate the characteristics and qualities that you possessed or have gained that would make you a better classmate, colleague, and doctor. Good luck

Yes sir/ma'am! Thank you.

 

[differentiating]

Intranasal is the administration method for the brain of the future! I got the idea from Dr. Craft at Wakefield, who's used it in her intranasal insulin trials. Another group intranasally administered a TLR2-MyD88 interaction inhibiting peptide to AD mice (a smart approach I did not include in that list for brevity but arguably should have), and it reached the hippocampus. Why do you think people snort illicit drugs? It's not because they like the nosebleeds. If you're interested in treating the medial temporal lobe especially, intranasal is the way to go.

EDIT: Also, consider that there's evidence that AD may be caused primarily in most patients by inhalation of oxidative-stress-driving pollutants, such as iron-enriched combustion derived carbon nanoparticles and mycotoxins. So intranasal treatments are just using the same process for positive purposes.

Absolutely. I did not intend to say anything about educating experts. What I have left to learn dwarfs what I know.

Every single one of those approaches is carefully selected for multiple reasons. Pick that one you're the most skeptical could possibly be important in AD, and I'll share why I included that. Trust me, I have reasons for everything.

People snort illicit drugs because it enters the blood stream quickly through the thin nasal mucosa, thus having a faster on-time than other methods of administration. It doesn't go directly to the brain.

It's nice that it may work in mice, but do we have high enough concentrations to work in humans, considering the majority will likely either act locally or go into the blood stream and act systemically? If we're affecting things like ADP/K/etc., are the systemic side effects even worth it? Those are things you have to consider. I haven't heard anything about intranasal being anywhere near viable enough to be our administration method for neurological drugs anytime soon.

 

[OdysseanUnderdog]

People snort illicit drugs because it enters the blood stream quickly through the thin nasal mucosa, thus having a faster on-time than other methods of administration. It doesn't go directly to the brain.

It's nice that it may work in mice, but do we have high enough concentrations to work in humans, considering the majority will likely either act locally or go into the blood stream and act systemically? If we're affecting things like ADP/K/etc., are the systemic side effects even worth it? Those are things you have to consider. I haven't heard anything about intranasal being anywhere near viable enough to be our administration method for neurological drugs anytime soon.

Here's the part where your medical knowledge and experience trump my knowledge of papers about AD. I know that Dr. Craft has had good results giving patients intranasal short-acting insulin, a peptide. Those are good points you raise about ADP and K+ and potential side effects in the bloodstream that I do not know the answers to. I hope to go to medical school so that I can start to get on your level about understanding the physiology of different administration methods!

 

[OdysseanUnderdog]

People snort illicit drugs because it enters the blood stream quickly through the thin nasal mucosa, thus having a faster on-time than other methods of administration. It doesn't go directly to the brain.

It's nice that it may work in mice, but do we have high enough concentrations to work in humans, considering the majority will likely either act locally or go into the blood stream and act systemically? If we're affecting things like ADP/K/etc., are the systemic side effects even worth it? Those are things you have to consider. I haven't heard anything about intranasal being anywhere near viable enough to be our administration method for neurological drugs anytime soon.

What about this? We test every hour blood electrolyte levels to make sure potassium doesn't increase too much. (By the way, what would that cause again? Atrial fibrillation, or something? Please excuse my ignorance. Again, this is one reason why I want to go to med school.)

I don't know of any particular reason why excess blood ADP would be a problem.

In case you are wondering why on earth I included potassium as one suggested treatment, here are a few reasons: vascular risk factors, namely hypertension, are important risk factors for AD, and treating hypertension is an important preventative strategy. A low Na and relatively high K diet can help control hypertension. AD patients' brains have significantly less potassium in them than those of control individuals. In a murine model of AD, increased K+ intake led to "a change in the aggregation pattern of the Aβ peptide, a partial decrease in some epitopes of tau phosphorylation and improvement in the cognitive performance. The recovery in cognitive performance was correlated with a significant improvement in the generation of long-term potentiation. We also observed a decrease in markers related to inflammation and oxidative stress such as glial fibrillary acidic protein (GFAP), interleukin 6 (IL-6) and 4-hydroxynonenal (4-HNE)."

ADP is more complicated and would involve me sharing a lot of sources I've used for the thing I just submitted, so I'll omit that for now. Just for the final piece though, ADP has been shown to promote axon elongation.

 

[differentiating]

What about this? We test every hour blood electrolyte levels to make sure potassium doesn't increase too much. (By the way, what would that cause again? Atrial fibrillation, or something? Please excuse my ignorance. Again, this is one reason why I want to go to med school.)

I don't know of any particular reason why excess blood ADP would be a problem.

In case you are wondering why on earth I included potassium as one suggested treatment, here are a few reasons: vascular risk factors, namely hypertension, are important risk factors for AD, and treating hypertension is an important preventative strategy. A low Na and relatively high K diet can help control hypertension. AD patients' brains have significantly less potassium in them than those of control individuals. In a murine model of AD, increased K+ intake led to "a change in the aggregation pattern of the Aβ peptide, a partial decrease in some epitopes of tau phosphorylation and improvement in the cognitive performance. The recovery in cognitive performance was correlated with a significant improvement in the generation of long-term potentiation. We also observed a decrease in markers related to inflammation and oxidative stress such as glial fibrillary acidic protein (GFAP), interleukin 6 (IL-6) and 4-hydroxynonenal (4-HNE)."

ADP is more complicated and would involve me sharing a lot of sources I've used for the thing I just submitted, so I'll omit that for now. Just for the final piece though, ADP has been shown to promote axon elongation.

Hyperkalemia can cause fatal arrhythmias - classically you're taught to look for peaked T waves, then QRS widening, which eventually becomes a sine wave on EKG, which is bad news bears for a patient. But ideally you'd never let it get anywhere near that stage. You can also get muscle weakness from hyperK, It's also worth noting that q1h labs are hard enough to get in a hospital, never mind in an outpatient setting, and the lab takes time to process them as well, so it's probably not a particularly viable strategy.

Of note, I generally haven't seen K recommended in HTN patients - I can't say whether it'd have a beneficial effect or not, but there are other strategies for controlling blood pressure that are probably more effective. Certainly, there are a number of comorbidities in which a high K diet would be contraindicated (renal failure, congestive heart failure), which AD patients may have by virtue of being older adults with prior medical histories. I'd think there are probably also differences in our body's ability to regulate K intake through the diet vs intranasal administration, so it'd be important to titrate the dose carefully even in those who aren't at risk.

This is what I mean when I say there are a lot of complexities involved - and I'm an intern myself, so I certainly don't know everything! Not only do things found in vitro not always translate to in vivo, but they often come with other considerations. It's perfectly reasonable to be interested in AD treatment and express that interest! It's just going to take many years (med school, residency, etc.) to really hone the knowledge base needed to come up with the next big AD drug.

I'd pay a particular interest to schools with strong AD/dementia clinics - my med school had a well-renowned Memory and Aging Center which treated AD amongst other diseases, and the clinicians there were passionate about the field and very eager to teach students who rotated through. They also had many research projects and trials ongoing. Settings like that may be up your alley.

 

[OdysseanUnderdog]

Hyperkalemia can cause fatal arrhythmias - classically you're taught to look for peaked T waves, then QRS widening, which eventually becomes a sine wave on EKG, which is bad news bears for a patient. But ideally you'd never let it get anywhere near that stage. You can also get muscle weakness from hyperK, It's also worth noting that q1h labs are hard enough to get in a hospital, never mind in an outpatient setting, and the lab takes time to process them as well, so it's probably not a particularly viable strategy.

Of note, I generally haven't seen K recommended in HTN patients - I can't say whether it'd have a beneficial effect or not, but there are other strategies for controlling blood pressure that are probably more effective. Certainly, there are a number of comorbidities in which a high K diet would be contraindicated (renal failure, congestive heart failure), which AD patients may have by virtue of being older adults with prior medical histories. I'd think there are probably also differences in our body's ability to regulate K intake through the diet vs intranasal administration, so it'd be important to titrate the dose carefully even in those who aren't at risk.

This is what I mean when I say there are a lot of complexities involved - and I'm an intern myself, so I certainly don't know everything! Not only do things found in vitro not always translate to in vivo, but they often come with other considerations. It's perfectly reasonable to be interested in AD treatment and express that interest! It's just going to take many years (med school, residency, etc.) to really hone the knowledge base needed to come up with the next big AD drug.

I'd pay a particular interest to schools with strong AD/dementia clinics - my med school had a well-renowned Memory and Aging Center which treated AD amongst other diseases, and the clinicians there were passionate about the field and very eager to teach students who rotated through. They also had many research projects and trials ongoing. Settings like that may be up your alley.

Thank you! I have one more question. What are q1h labs? I didn't find a definition on Google.

I definitely accept that there are a lot of complexities in the reality of medicine that I'm not used to thinking of yet, and there's so much that I just don't know yet. That's part of why I'm excited to learn. I kind of like thinking of possible side effects and what could go wrong and coming up with contingency plans, as weird as that sounds.

I will look for schools with strong dementia clinics. On the other hand though, I'm interested in other diseases too, particularly metabolic and autoimmune diseases, so I don't feel tied down to only schools that are known for that. Part of why I like medicine is that I like variety, I just haven't given myself that the past year because I was trying to produce something useful, and I figured I needed to focus on one disease for a little while in order to do that.

 

[Moko]

What are q1h labs?

medical abbreviation for "every hour".

 

[TelemarketingEnigma]

Nothing you write for a secondary response should require academic citations. You should be able to be introspective about your own experiences without regurgitating facts. Others have given you great responses about why you should avoid this AD discussion, as well as some of the ways you seem to be misinformed about certain details, so please take their advice to heart! If this is something you’re truly passionate about researching, you should try to find a mentor with expertise in the subject who can guide your future research.

I have another option that I think might work well enough, but I feel like I'm having trouble thinking of a problem that I resolved that's impressive and that also is a personal experience that shows personal growth, resilience, coping skills, and introspection. Any examples?

The problem you resolved doesn’t need to be “impressive.” What should be impressive is the effort you put into resolving the problem and learning from the experience. Here’s a few questions you can try answering to see if it guides you in a better direction:

1. Have you ever had a serious disagreement with someone significant (a boss, a mentor, someone you were collaborating with on an important project)? How did you resolve it?
2. Were you ever in a position of authority (club president, TA, RA, team captain), and had someone come to you with a problem? How were you able to help them?
3. Were you ever given responsibility for something (class project, club event, etc), that fell through/didn’t go as planned? What did you do?
4. Have you ever been prevented from achieving your personal goals by any sort of obstacle (medical, financial, circumstance, other) which you were ultimately able to circumvent through your own initiative? How did you do that?

Those are just a few ideas for your specific prompt (talk about a challenging problem you resolved). Some of these questions can also be used, with some variation, for an adversity prompt or similar. in my personal opinion, a “challenging problem” prompt can be something smaller/more discrete, while an adversity prompt can often be tied into bigger-picture things.

 

[OdysseanUnderdog]

Does this Kaiser secondary prompt offer any opportunity to talk about what I learned or hypothesized in addition to everything else it asks about? It instructs specifically to "Tell us about an area of intellectual exploration you are passionate about and have sustained over time." That sounds like it's asking applicants to describe the area of intellectual exploration a little, no? And maybe to give a flavor for why you're so passionate about it and have sustained it over time? Below is the full prompt, and then how I've begun my second attempt, attempting to integrate everyone's excellent feedback:

"Lifelong learning is an essential process for continued professional development in physicians that includes reflection and being open and responsive to constructive feedback. Tell us about an area of intellectual exploration you are passionate about and have sustained over time. What means have you used to explore this area? (250 Words)"

"I’ve read, written, and integrated findings and feedback from researchers about Alzheimer’s disease (AD) for >2,000 hours. I wrote a thesis, and then a paper. Reviewers requested revisions. I found the feedback helpful and used it to revise that paper and write a new one. Both await peer review. As evidence of my passion and sustained exploration, here’s what I’ve learned or found:...."


I feel like I've already answered all the other parts of the prompt with this opening. Could I use the rest to summarize some novel hypotheses I've developed based on other people's empirical findings, as evidence of passion and sustained exploration like the prompt asks about? Here's an updated version of what I could write for the rest, integrating feedback from @differentiating and others. Sorry if I'm being thick-headed! Just double checking, since I think this prompt is quite a bit different than the Pitt one and therefore worth asking about.


"As evidence of my passion and sustained exploration, here’s what I’ve learned/found: AD’s distal drivers are pathogens and oxidative stress. Viruses, bacteria, fungi accumulate in AD brains via immunosuppression. Amyloid-beta is antimicrobial. Innate immunity cannot distinguish between oxidized biomolecules and pathogens: interferons respond to viral DNA and cytoplasmic oxoDNA via cGAS. p53-deficient neurons secrete trans-synaptic exosomes bearing amyloid-beta, phospho-tau, and likely oxoDNA, sterile pseudo-viruses destroying synapses.

Oxidative stress is contributed to by diseases, stress, unhealthy lifestyle, pollutants, including combustion-derived nanoparticles, iron, aluminum. Activated by oxidative DNA damage, PARP1/PARG/TRPM2-produced AMP blocks ANTs, starving mitochondria of ADP—inhibiting ATP synthase. To survive, remaining AD neurons catabolize amino acids liberated from proteins via autophagy. Upregulated ALT1/2 convert L-Alanine to pyruvate and glutamate, fueling the Krebs cycle but promoting excitotoxicity, killing neurons and synapses.

Reflecting on this, it makes sense decades’ phase III clinical trials of amyloid-targeting therapies have failed. Only multicomponent treatment protocols will prevent, arrest, and reverse AD. A minimum viable set of likely indicated approaches includes antioxidant hydrogen, iron/aluminum chelators, DNase, PARP inhibitors, ADP, ALT-inhibiting hesperidin, extracellular vesicle uptake inhibitors (EVUIs), anti-retrovirals, anti-herpes drugs, anti-fungals, biofilm disruptors, gingipain inhibitors, lipopolysaccharide-targeting agents, interferon lambda, etc. administered intranasally to reach the brain."

Where possible, for those who are curious, I've added links to papers that give you one of many reasons why each approach might be indicated.

 

[ThrowawayShmoaway]

Sorry if I'm being thick-headed!

You are being thick-headed. Reread Goro’s post about being unteachable...
Stop. Putting. Your. “Hypotheses”. In. Secondary. Answers.
The question does not ask what your hypotheses were, it just asks for a time when you demonstrated lifelong learning. A (revised) version of the first paragraph you wrote about conducting your research would suffice.