12 ms·

Proteins That May Restore Damaged Sound-Detecting Cells in the Ear

510 points by laurex 7y ago

woliveirajr 7y ago
I'm curious if this will enable not only the recovery of those cells but also allow us to extend our hearing range
- hprotagonist 7y ago
  it cannot. The frequency limits of hearing are set by the length (and material properties) of the basilar membrane, not the density of innervation.
- alecst 7y ago
  Well, functionally speaking your range is set by the cells that you have that are alive, which die slowly over time, starting with the higher frequency ones which tend to be more fragile. If you could restore all the cells you had when you were a child you'd have a larger range than you have now. But you couldn't extend the range beyond what you had when you were born AFAIK.
Beltiras 7y ago
My wife has premature hearing loss of an unknown cause. Doctor kind of shrugged when asked what could be done about it. This was some 15 years ago. I'll push her to make an appointment with a doc again to see if something new has been discovered.
- hprotagonist 7y ago
  wait another 15 years, sorry: this is very early-stage work.
  - Beltiras 7y ago
    I'm not hoping that this specifically will remedy her problems. But general understanding of hearing loss might have advanced since her non-diagnosis.
- alecst 7y ago
  I try to keep up to date on this sort of thing as it affects me as well. There are a few companies that are doing clinical trials in humans using drugs that may restore hearing. They've done a good job of keeping the results under lock and key so far but one of them (Frequency Therapeutics) might announcing some preliminary results next month. I've linked a press release from a few months ago.[1] As there are several companies attacking this problem from different angles, and an explosion in clinical trials, you wouldn't be crazy to be optimistic. If by luck any one of these drugs turns out to improve hearing by 10db or so, you might see the it on the market in no more than a few years. [1] https://www.frequencytx.com/news-events/news-events-press-release-04-09-2019.php https://www.frequencytx.com/news-events/news-events-press-re...
  - hprotagonist 7y ago
    decibel therapeutics https://decibeltx.com https://decibeltx.com is also interesting.
- openureye1s28 7y ago
  "Unknown" is often code for "vaccines"
- michaelbuckbee 7y ago
  My dad has severe hearing loss (hearing aids, etc.) but we made an interesting discovery: bone-conduction headphones bypass the portion of his ear that's damaged. When he first put them on he literally said: "That's better than I've heard anything sound in a decade". YMMV but it might be something useful to try with your wife.
  - alecst 7y ago
    That's weird. I wonder what the physical reason could be, if (e.g.) it's the eardrum that's acting up on top of the damaged cochlea. (Could there be wax buildup?)
    - jrace 7y ago
      Not weird, but a 'conductive' hearing loss. In this case the sound that arrives at the eardrum does not conduct through the middle ear bones to the cochlea. Wax will only cause a slight drop in hearing thresholds. This can be determined with a standard hearing exam.
  - wanderfowl 7y ago
    For what it's worth, this only works if the source of hearing loss is conductive (e.g. eardrum or the ossicles). If your cochlea or any sub-element (e.g. inner hair cells) are damaged, bone conduction will be no different. In fact, the comparison between acoustic and bone-conduction hearing tests is a key element of audiological testing.
    - alecst 7y ago
      True. The classic tuning fork test: hit the fork, hold it up in front of your ear. Can you hear it? Then gently press the end of the (still vibrating) fork against your skull. Can you hear it now? If no/yes, the loss is conductive. If no/no, it's sensorineural.
  - oddsockmachine 7y ago
    Do you have a source for any good bone conduction headphones? I have a damaged eardrum that stops me hearing low frequencies. Recently tried a demonstration at SF's Exploratorium which involved biting a metal bar, and the result was incredible! Most bone conduction headphones I find when searching (eg AfterShokz) appear to rest against the bones around the ear, so I'm not sure if they're as effective.
- mentat 7y ago
  Modern hearing aids work pretty well at least for moderate loss. I tried previous ones and they were not helpful. Have had Oticon OPN and now OPN S for the last 4 years and it's been transformative. Still, it's software which you can't manage yourself. Any Oticon people on here, handling of the release of S w/ feedback shield issues with high pitched voices was done quite poorly. There are some large and fairly extensive genetic panels that can be run within months now for a few thousand if insurance doesn't cover. Unfortunately they don't have the variants causing my loss. Looking at full exome sequencing at Stanford but insurance is balking and it's 10k.
  - synaster 7y ago
    Depending on your model, it’s possible to obtain fitting software and hardware and fit the hearing aids by yourself. It really isn’t that difficult and the results can be very impressive.
- commandlinefan 7y ago
  Since most of us are required to work cacophonous open offices and have to drown out the insanity with hearing-destroying headphones just to concentrate well enough to get our jobs done, this is (I guess) good news for everybody.
scarygliders 7y ago
I was hoping to read that it might also help people like myself who suffer from tinnitus. Sadly, no. Still, if it can restore hearing to the deaf, this is a good thing.
- alecst 7y ago
  Even though it wasn't mentioned in the article, a lot of researchers in this field believe that a cure for hearing loss will take care of tinnitus and hyperacusis too, at least for a patient subgroup. There's tinnitus caused by muscle tension/dysfunction (?) which is of an entirely different etiology apparently, but the good news is that that kind seems more treatable than the kind caused by permanent hearing dysfunction.
  - heyoni 7y ago
    Tinnitus being caused by muscle tension could explain why ADHD medications have that as a side effect?
- hprotagonist 7y ago
  Restoration of hair cells may have knock-on effects for tinnitus. If tinnitus is a maladaptive neuroplasticity (your brain "needs" to hear something so if it can't because you're deaf at that frequency it'll invent things for you to hear instead) that makes sense to model as some stable limit cycle of a nonlinear system -- which is one of the leading hypotheses for tinnitus right now -- then it's not totally implausible that restoration of function would change your tinnitus percepts. It's not clear that it'd help, but I'm pretty confident that if we can restore hair cell function, someone's going to try.
  - alecst 7y ago
    Yes -- although there are lots of folks with hearing loss who don't have tinnitus. There must be more to the story than just the ghost ringing that you're talking about. But I do think that the hypothesis you quote makes intuitive sense, at least as much as these hypercomplex things can be intuitive.
dankohn1 7y ago
I have early hearing loss. If you haven't checked out hearing aids in the last few years, they've improved significantly, although they remain appallingly expensive. Wired wrote up a short piece about my hearing aids at the bottom of https://www.wired.com/story/why-we-love-tech-better-humans/ https://www.wired.com/story/why-we-love-tech-better-humans/ Of course, some drops to regain perfect hearing would be far better.
chiefalchemist 7y ago
Slightly off topic but (nearly) two years ago my father had a bad stoke. They keep him in a drug-induced coma for a week. Prior to the stroke his hearing was pretty bad. Loud TV, etc. In any case, after the stroke I swear his hearing wasn't as bad. I didn't have to talk as loud. He would hear more of what was said even when it wasn't directed at him. I have no idea if his hearing is better but all the signs that said it was bad don't say that as much as often.
- Medicalidiot 7y ago
  There are some conditions, like cranial nerve VII (facial nerve) palsy, where hyperacousis is a symptom. You have a couple muscles in your ear that attenuate sound, so it's not out of the realm of possibility that something happened to your father and his hearing improved.
MS90 7y ago
I'll be interested to see how this pans out. I have significant hearing loss in both ears from infections as a baby, and the doctors always said it was because the hairs in my cochlea are dead. I was denied a few opportunities when I was younger due to my hearing, and I still can't hear most higher frequency sounds (whistles, some cymbals, smoke detectors, fire alarms...etc). It would be nice to be able to hear what everyone else hears and not have to say "what?" so often. Though, as a bald man, I've learned not to get too hopeful about scientific advancements in regrowing hairs ;)
- technofiend 7y ago
  Yours is worse than mine but same root cause and probably exacerbated by power tools and loud music (and loud music at a bar called power tools) later on. There's a huge dip in the middle of my hearing range so I can hear the clink-clink-clink of pint glasses in a pub but people speaking to me over it is a struggle.
  - MS90 7y ago
    Yeah, hearing people over background noise is probably the thing that I struggle with the most. It's been a pretty big social hindrance, especially when I was in college. In crowded social areas like bars and restaurants it's very difficult for me to understand what people are saying. As a result, I ended up being the weird guy just sitting there not saying anything all night because I was unable to carry on a conversation. Hearing aids never seemed to help, because they amplified the background noise too.
    - posix_compliant 7y ago
      I don’t have hearing loss and this is a challenge for me.
    - RankingMember 7y ago
      As someone with full spectrum hearing, a lot of those environments are awful for me too. Just miserable to be practically yelling to be heard and then needing to cup your hand over your ear to make out what they're saying, often just giving up and nodding and hoping that a "nod" response makes sense in the context of whatever they said.
whalesalad 7y ago
I would love the opposite... some kind of medical treatment to make my ears less sensitive to sound. I feel constantly bombarded by noise to a point where now I got this dorky little thing on my keychain with ear plugs in it for loud places. Curious if anyone here has experience w/ this and any advice.
- sdfasdfsafasf 7y ago
  I can't hear all that great, but I am also very annoyed by noises. I think earplugs are the best solution. I keep a box of earplugs where I am likely to get annoyed, office, bedroom, but I also keep a box in the car so I am likely to have them close at hand (say I go on vacation and the hotel has rowdy neighbors). I also keep a pair in my backpack.
- dave84 7y ago
  Noise sensitivity is common in individuals on the autism spectrum so there might be some therapies in that field that could help with noise sensitivity.
- triMichael 7y ago
  I don't have experience with it, but I have heard of what you are saying and I believe the technical term for it is "hyperacusis". If you haven't already done so, search that term and I'm sure you will find people with similar experiences. I would also suggest trying to find communities on Reddit, it looks like they even have a subreddit with a few hundred people subscribed, "https://www.reddit.com/r/hyperacusis/" https://www.reddit.com/r/hyperacusis/"
proyb2 7y ago
I was diagnosed with Sudden Sensorineural Hearing Loss years ago and haven’t found any cures despite some kind of Chinese acupuncture wasn’t of help.
- socen 7y ago
  I as well was diagnosed with SSH about a year and a half ago. This was shortly after I fell on my head in a yoga handstand class. I went to an Audiologist/ENT and was classified as having Meniere's and ultimately there was nothing I could do according to the doctors. I accepted this as truth because that's what the experts say and my Meniere's wasn't so bad at the time. Over time, the symptoms got worse and it was unbearable. My quality of life was at the lowest point of my existence and I had to do something. I did some research and found an article documenting people with Meniere's and how a specific niche of Chiropractic has helped them. This isn't the original article, but it's a copy of it: https://drthomasforest.com/menieres-disease-treatment/ https://drthomasforest.com/menieres-disease-treatment/ I did my research and started going to this doctor and within weeks I was getting relief. Now it's been about 6 months since I started treatment and I would say my hearing is back to normal for about 2 months now. I'm not saying this would resolve your SSH issues, but it's an avenue worth looking at especially if the article makes sense to you.
  - alecst 7y ago
    Yea same, correcting my posture and doing some mind-body work has made my symptoms go away basically. I'm still improving to this day almost a year later.
deleted 7y ago
[deleted]
torgian 7y ago
Hell yeah. I have tinnitus from my time in the military, and this would be a huge thing. I hope it comes to fruition in the next several years.
newsreview1 7y ago
I have read other studies by Dr. Angelika Doetzlhofer, and she is brilliant. I am heavily involved with disability law, and have had two very close associates who have received treatment aimed at inner-ear hair stimulation for balance issues. The study of molecular impediments to mammalian hair cell regeneration could not only change lives for those who have hearing loss, but also for those who suffer from balance issues. Thank you for the share!
fouc 7y ago
Quite a few hearing impaired people had their cochlea hairs "burnt" by audiotoxic drugs. More specifically, they caught a serious infection in the meninges when young, and aggressive drugs were needed to save their lives. It would be amazing if these cochlea hairs could be repaired.
stefs 7y ago
i remember about a call for volunteers for an experiment treating hearing loss with some proteins and/or adenoviruses (not a specialist). this was a couple of years ago and it sounded pretty much exactly like what this article describes. a 90% success rate was expected. as this was in the u.s. (washington dc, iirc?) and i'm not a citizen i didn't apply. i thought it to be a game changer, but found no follow up articles. the original search even was on HN, but i have little hope of finding it again. edit, after a little bit of googling: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464776/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464776/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225386/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225386/

510 points by laurex 7y ago

woliveirajr 7y ago

I'm curious if this will enable not only the recovery of those cells but also allow us to extend our hearing range

hprotagonist 7y ago
it cannot. The frequency limits of hearing are set by the length (and material properties) of the basilar membrane, not the density of innervation.
alecst 7y ago
Well, functionally speaking your range is set by the cells that you have that are alive, which die slowly over time, starting with the higher frequency ones which tend to be more fragile. If you could restore all the cells you had when you were a child you'd have a larger range than you have now. But you couldn't extend the range beyond what you had when you were born AFAIK.

Beltiras 7y ago

My wife has premature hearing loss of an unknown cause. Doctor kind of shrugged when asked what could be done about it. This was some 15 years ago. I'll push her to make an appointment with a doc again to see if something new has been discovered.

hprotagonist 7y ago
wait another 15 years, sorry: this is very early-stage work.
- Beltiras 7y ago
  I'm not hoping that this specifically will remedy her problems. But general understanding of hearing loss might have advanced since her non-diagnosis.
alecst 7y ago
I try to keep up to date on this sort of thing as it affects me as well. There are a few companies that are doing clinical trials in humans using drugs that may restore hearing. They've done a good job of keeping the results under lock and key so far but one of them (Frequency Therapeutics) might announcing some preliminary results next month. I've linked a press release from a few months ago.[1] As there are several companies attacking this problem from different angles, and an explosion in clinical trials, you wouldn't be crazy to be optimistic. If by luck any one of these drugs turns out to improve hearing by 10db or so, you might see the it on the market in no more than a few years. [1] https://www.frequencytx.com/news-events/news-events-press-release-04-09-2019.php https://www.frequencytx.com/news-events/news-events-press-re...
- hprotagonist 7y ago
  decibel therapeutics https://decibeltx.com https://decibeltx.com is also interesting.
openureye1s28 7y ago
"Unknown" is often code for "vaccines"
michaelbuckbee 7y ago
My dad has severe hearing loss (hearing aids, etc.) but we made an interesting discovery: bone-conduction headphones bypass the portion of his ear that's damaged. When he first put them on he literally said: "That's better than I've heard anything sound in a decade". YMMV but it might be something useful to try with your wife.
- alecst 7y ago
  That's weird. I wonder what the physical reason could be, if (e.g.) it's the eardrum that's acting up on top of the damaged cochlea. (Could there be wax buildup?)
  - jrace 7y ago
    Not weird, but a 'conductive' hearing loss. In this case the sound that arrives at the eardrum does not conduct through the middle ear bones to the cochlea. Wax will only cause a slight drop in hearing thresholds. This can be determined with a standard hearing exam.
- wanderfowl 7y ago
  For what it's worth, this only works if the source of hearing loss is conductive (e.g. eardrum or the ossicles). If your cochlea or any sub-element (e.g. inner hair cells) are damaged, bone conduction will be no different. In fact, the comparison between acoustic and bone-conduction hearing tests is a key element of audiological testing.
  - alecst 7y ago
    True. The classic tuning fork test: hit the fork, hold it up in front of your ear. Can you hear it? Then gently press the end of the (still vibrating) fork against your skull. Can you hear it now? If no/yes, the loss is conductive. If no/no, it's sensorineural.
- oddsockmachine 7y ago
  Do you have a source for any good bone conduction headphones? I have a damaged eardrum that stops me hearing low frequencies. Recently tried a demonstration at SF's Exploratorium which involved biting a metal bar, and the result was incredible! Most bone conduction headphones I find when searching (eg AfterShokz) appear to rest against the bones around the ear, so I'm not sure if they're as effective.
mentat 7y ago
Modern hearing aids work pretty well at least for moderate loss. I tried previous ones and they were not helpful. Have had Oticon OPN and now OPN S for the last 4 years and it's been transformative. Still, it's software which you can't manage yourself. Any Oticon people on here, handling of the release of S w/ feedback shield issues with high pitched voices was done quite poorly. There are some large and fairly extensive genetic panels that can be run within months now for a few thousand if insurance doesn't cover. Unfortunately they don't have the variants causing my loss. Looking at full exome sequencing at Stanford but insurance is balking and it's 10k.
- synaster 7y ago
  Depending on your model, it’s possible to obtain fitting software and hardware and fit the hearing aids by yourself. It really isn’t that difficult and the results can be very impressive.
commandlinefan 7y ago
Since most of us are required to work cacophonous open offices and have to drown out the insanity with hearing-destroying headphones just to concentrate well enough to get our jobs done, this is (I guess) good news for everybody.

scarygliders 7y ago

I was hoping to read that it might also help people like myself who suffer from tinnitus. Sadly, no. Still, if it can restore hearing to the deaf, this is a good thing.

alecst 7y ago
Even though it wasn't mentioned in the article, a lot of researchers in this field believe that a cure for hearing loss will take care of tinnitus and hyperacusis too, at least for a patient subgroup. There's tinnitus caused by muscle tension/dysfunction (?) which is of an entirely different etiology apparently, but the good news is that that kind seems more treatable than the kind caused by permanent hearing dysfunction.
- heyoni 7y ago
  Tinnitus being caused by muscle tension could explain why ADHD medications have that as a side effect?
hprotagonist 7y ago
Restoration of hair cells may have knock-on effects for tinnitus. If tinnitus is a maladaptive neuroplasticity (your brain "needs" to hear something so if it can't because you're deaf at that frequency it'll invent things for you to hear instead) that makes sense to model as some stable limit cycle of a nonlinear system -- which is one of the leading hypotheses for tinnitus right now -- then it's not totally implausible that restoration of function would change your tinnitus percepts. It's not clear that it'd help, but I'm pretty confident that if we can restore hair cell function, someone's going to try.
- alecst 7y ago
  Yes -- although there are lots of folks with hearing loss who don't have tinnitus. There must be more to the story than just the ghost ringing that you're talking about. But I do think that the hypothesis you quote makes intuitive sense, at least as much as these hypercomplex things can be intuitive.

dankohn1 7y ago

I have early hearing loss. If you haven't checked out hearing aids in the last few years, they've improved significantly, although they remain appallingly expensive. Wired wrote up a short piece about my hearing aids at the bottom of https://www.wired.com/story/why-we-love-tech-better-humans/ https://www.wired.com/story/why-we-love-tech-better-humans/ Of course, some drops to regain perfect hearing would be far better.

chiefalchemist 7y ago

Slightly off topic but (nearly) two years ago my father had a bad stoke. They keep him in a drug-induced coma for a week. Prior to the stroke his hearing was pretty bad. Loud TV, etc. In any case, after the stroke I swear his hearing wasn't as bad. I didn't have to talk as loud. He would hear more of what was said even when it wasn't directed at him. I have no idea if his hearing is better but all the signs that said it was bad don't say that as much as often.

Medicalidiot 7y ago
There are some conditions, like cranial nerve VII (facial nerve) palsy, where hyperacousis is a symptom. You have a couple muscles in your ear that attenuate sound, so it's not out of the realm of possibility that something happened to your father and his hearing improved.

MS90 7y ago

I'll be interested to see how this pans out. I have significant hearing loss in both ears from infections as a baby, and the doctors always said it was because the hairs in my cochlea are dead. I was denied a few opportunities when I was younger due to my hearing, and I still can't hear most higher frequency sounds (whistles, some cymbals, smoke detectors, fire alarms...etc). It would be nice to be able to hear what everyone else hears and not have to say "what?" so often. Though, as a bald man, I've learned not to get too hopeful about scientific advancements in regrowing hairs ;)

technofiend 7y ago
Yours is worse than mine but same root cause and probably exacerbated by power tools and loud music (and loud music at a bar called power tools) later on. There's a huge dip in the middle of my hearing range so I can hear the clink-clink-clink of pint glasses in a pub but people speaking to me over it is a struggle.
- MS90 7y ago
  Yeah, hearing people over background noise is probably the thing that I struggle with the most. It's been a pretty big social hindrance, especially when I was in college. In crowded social areas like bars and restaurants it's very difficult for me to understand what people are saying. As a result, I ended up being the weird guy just sitting there not saying anything all night because I was unable to carry on a conversation. Hearing aids never seemed to help, because they amplified the background noise too.
  - posix_compliant 7y ago
    I don’t have hearing loss and this is a challenge for me.
  - RankingMember 7y ago
    As someone with full spectrum hearing, a lot of those environments are awful for me too. Just miserable to be practically yelling to be heard and then needing to cup your hand over your ear to make out what they're saying, often just giving up and nodding and hoping that a "nod" response makes sense in the context of whatever they said.

whalesalad 7y ago

I would love the opposite... some kind of medical treatment to make my ears less sensitive to sound. I feel constantly bombarded by noise to a point where now I got this dorky little thing on my keychain with ear plugs in it for loud places. Curious if anyone here has experience w/ this and any advice.

sdfasdfsafasf 7y ago
I can't hear all that great, but I am also very annoyed by noises. I think earplugs are the best solution. I keep a box of earplugs where I am likely to get annoyed, office, bedroom, but I also keep a box in the car so I am likely to have them close at hand (say I go on vacation and the hotel has rowdy neighbors). I also keep a pair in my backpack.
dave84 7y ago
Noise sensitivity is common in individuals on the autism spectrum so there might be some therapies in that field that could help with noise sensitivity.
triMichael 7y ago
I don't have experience with it, but I have heard of what you are saying and I believe the technical term for it is "hyperacusis". If you haven't already done so, search that term and I'm sure you will find people with similar experiences. I would also suggest trying to find communities on Reddit, it looks like they even have a subreddit with a few hundred people subscribed, "https://www.reddit.com/r/hyperacusis/" https://www.reddit.com/r/hyperacusis/"

proyb2 7y ago

I was diagnosed with Sudden Sensorineural Hearing Loss years ago and haven’t found any cures despite some kind of Chinese acupuncture wasn’t of help.

socen 7y ago
I as well was diagnosed with SSH about a year and a half ago. This was shortly after I fell on my head in a yoga handstand class. I went to an Audiologist/ENT and was classified as having Meniere's and ultimately there was nothing I could do according to the doctors. I accepted this as truth because that's what the experts say and my Meniere's wasn't so bad at the time. Over time, the symptoms got worse and it was unbearable. My quality of life was at the lowest point of my existence and I had to do something. I did some research and found an article documenting people with Meniere's and how a specific niche of Chiropractic has helped them. This isn't the original article, but it's a copy of it: https://drthomasforest.com/menieres-disease-treatment/ https://drthomasforest.com/menieres-disease-treatment/ I did my research and started going to this doctor and within weeks I was getting relief. Now it's been about 6 months since I started treatment and I would say my hearing is back to normal for about 2 months now. I'm not saying this would resolve your SSH issues, but it's an avenue worth looking at especially if the article makes sense to you.
- alecst 7y ago
  Yea same, correcting my posture and doing some mind-body work has made my symptoms go away basically. I'm still improving to this day almost a year later.

deleted 7y ago

[deleted]

torgian 7y ago

Hell yeah. I have tinnitus from my time in the military, and this would be a huge thing. I hope it comes to fruition in the next several years.

newsreview1 7y ago

I have read other studies by Dr. Angelika Doetzlhofer, and she is brilliant. I am heavily involved with disability law, and have had two very close associates who have received treatment aimed at inner-ear hair stimulation for balance issues. The study of molecular impediments to mammalian hair cell regeneration could not only change lives for those who have hearing loss, but also for those who suffer from balance issues. Thank you for the share!

fouc 7y ago

Quite a few hearing impaired people had their cochlea hairs "burnt" by audiotoxic drugs. More specifically, they caught a serious infection in the meninges when young, and aggressive drugs were needed to save their lives. It would be amazing if these cochlea hairs could be repaired.

stefs 7y ago

i remember about a call for volunteers for an experiment treating hearing loss with some proteins and/or adenoviruses (not a specialist). this was a couple of years ago and it sounded pretty much exactly like what this article describes. a 90% success rate was expected. as this was in the u.s. (washington dc, iirc?) and i'm not a citizen i didn't apply. i thought it to be a game changer, but found no follow up articles. the original search even was on HN, but i have little hope of finding it again. edit, after a little bit of googling: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464776/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464776/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225386/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225386/