Archive for: August, 2017

Knowing what you know and knowing what you don’t know

Aug 23 2017 Published by under Uncategorized

One of the most valuable things in the world is knowing what you know and knowing what you don’t know. One of the most inadvertently self-destructive is making a mistake about what you know: Not knowing what you don’t know, and not realizing what you do know.

It is easy to think you know something. Sometimes it’s a big thing and sometimes a little thing. I remember, as a grad student, visiting Manhattan, with another grad student. We did it cheap – a bus ride crashing with a friend who was a postdoc at Columbia, a splurge for theater tix but walking and walking and taking the subway. On the last day, walking through Central Park, I had a feeling: I know New York. It felt good, and comfortable and exciting all at once. And my immediate next thought: idiot, of course not.

Sometimes when you are in a place, as a student, or a postdoc, or even a junior faculty you think you know it. Remember your undergrad institution? You thought you Really Knew It. Actually, US Universities try and promote that feeling, it encourages a sense of belonging and ultimately, donations. Of course, you did know things, about the major, about the classes, which bars were good for conversation, and which coffee houses were the most generous with real cream. Or quiet. Or glamorous.

You knew the profs. Who taught a good class, and who was an ass, at least the undergrads in their lab. You knew who had money, and who had power. Or at least you thought you did. Years later, you sometimes learned how superficial that knowledge was.

That’s the trouble with figuring out what you don’t know. You know a little bit and it’s easy to mistake that for knowing more. Sometimes you don’t have a clue about the neighborhood a block away from the subway stop. Or, you may have a sense that there was some place you only looked at, standing on the corner, glancing or studying, or even trying to memorize, down the block. But if you don’t get off the subway at the five stops between Here and There, you wouldn’t have a clue whether it’s one or 10 neighborhoods that you missed. You didn’t know if there were even stores, or restaurants, or dance studios in the neighborhoods you didn’t know existed.

In doing research, there are lots of places and things we’ve not seen. There are the content parts. In the olden days, one could major in biology, and taken a series of first or second year classes and get a sense of th breadth of biology. Now, I gather that half of the majors never had a botany class, or even evolution or ecology. Clinicians may have seen down the block to see the neighborhood called “research”. Smart ones say, ah, lots of buildings there. Irritating ones say, yup, big buildings of brick and I know what’s in them, because they’re just down the block from the place where I’ve been hanging. Good ones actually walk down the block.

[aside: yeah, yeah, Not All Clinicians, not all scientists, everyone knows an example or counter example. Folks, we are talking trends here].

My twenties-ish step-ish children think there is nowhere to live but New York. I admire them because they have built lives that they want to live. They work hard, and play hard and love life. And they think there is nowhere to live but New York City. When I pointed out that they had never lived, as adults, anywhere BUT New York, they said “yes, but I know”.

So take a moment and question what you know. It’s hard, but. I’ve written the concluding “but” here and erased about 16 things. But, you will have a richer life. But it will save your from being embarrassed. But you will make better decisions about the things you do know. What the heck. Yes those  "buts" are important, and justifications for trying to figure out what you don't know.

Me, I’d always rather know. Period.  Even if it’s ugly and embarrassing and points out my mistakes. Long held and long repeated mistakes. I’d always rather know.

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One more marvelous thing about my postdoc

Aug 22 2017 Published by under Uncategorized

I was off giving a talk elsewhere (and lots of thoughts about that to follow in the next few days). I came home to an ugly paper rejection from a mid-tier journal (don't bother resubmitting and don't give up your day job). It was a paper I thought was tight, and short, and good. It was the first paper of the new project.

And... of course followed the inevitable thought: I am a lousy scientist and They all know it.

Then I talked with my postdoc. Who looked at the reviews and his first comment was: I already hate reviewer one. And then he said: "these are silly comments". And then "hey, reviewer two liked it. And obviously the editor didn't." and finally "what shall we do next?"

And my spirits lifted and we shall resubmit.


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Measurement Error

Aug 18 2017 Published by under Uncategorized

Anyone who does animal-based research, or heck, human-based research has measurement error as a close and intimate companion. Variation is a fact of life. [Aside, one of the best organized volumes to help you think about variation is this book by Hall and Hallgrimsson, Variation: A Central Concept in Biology. You can download the pdf's. I am sorry that it is Elsevier. But also buy a cheap version here. The first chapter is why variation is an important concept in all of biology, and why it is not just "noise".]

Amid the brouhaha about reproducibility in the social sciences, one voice of reason that I follow is Andrew Gelman who often has interesting & informative things about data analysis that actually help me in my work. Erik Loken (who do not know, or know of) and Gelman had an article in Science titled "Measurement error and the replication crisis".

I was drawn to it because of the sub-title: "The assumption that measurement error always reduces effect sizes is false.". I think effect size is one of the most neglected concepts in biomedical/neuroscience/evolutionary studies. When I got asked to give an "honorary" (hahah) talk at one of my home societies, I did not talk about the exact science of what I do. They are clinical. I am animal models, and I by and large get neither traction nor respect for my work from those folks. So I talked about significance and the difference between clinical significance and statistical significance and what the heck effect size means in general. When the editor in chief of the society's journal did stand up and say "I don't care, I won't publish without p-values", I knew I had actually scored and said something reasonable.

Back to Loken & Gelman. Measurement error is often used as the (pick your socially insensitive alternative metaphor, if you wish) scapegoat of studies with large variation amongst subjects. One of their theses in this article is that if you can find an effect size of meaning (there are ways to measure this), and your data are noisy, that means that the effect size is probably better, stronger and more apt to be "true", because you are seeing the effect size despite the noise.

Yet, L&G are saying that no, this is not the case. In fact, noisy data can make the effect size seem bigger (better?) than might be "true". I keep putting true in quotes, and using it as shorthand for what we want to know - what is it that we want to know. Do not bust my chops over this word. here. later, maybe.

They are explicit as to why this bias exists:

It seems intuitive that producing a result under challenging circumstances makes it all the more impressive.

They have two reasons that this is not valid.

The first is what they term researcher degrees of freedom. These are the decisions that any scientist makes from design through final analysis. All of these choices, given our human nature, tend to bias us towards significance. The second is that statistical significance is not necessary a good indicator of the effect, especially if the sample size is small. The article contains cites to studies supporting these points and Gelman blogged about it here. Part of their argument is that in small samples with noise, the standard errors will be higher, which in turn will make the estimates higher, which will magnify effects. When I read these first through, it was confusing. I will come back to this, and try and explain better, in a subsequent post.

Part of what is important, IMO, is advice on what to do to avoid this. Some parts of noise are unavoidable, so what can be done to offset the issue?

One of the papers cited, Simmons & Nelson, had actual concrete steps for authors. Here are their "Requirements for authors"

1. Authors must decide the rule for terminating data collection before data collection begins and report this rule in the article.

This is a level of self-discipline that is hard to add to one's work. For me, sometimes, it feels unrealistic. I'm still figuring out exactly what it is that can be measured. I've got ideas and plans and designs going into it, but quite often things fail, and fail spectacularly, both in physical disaster as well as intellectual/data/design disaster. Still, it is worth trying to do, and worth adding to the work.

2. Authors must collect at least 20 observations per cell or else provide a compelling cost-of-data-collection justification.

Now we get back to my diatribes on what is your unit-of-analysis. Is it the three bunnies you watch, the 10 trials per bunny, or the 40 hops per trial per bunny?

3. Authors must list all variables collected in a study.

This one is easy. Why aren't we doing it? Because we sometimes don't know what can be extracted from the data. If you've filmed your bunny hopping, there is a lot more than frequency of footfall that you could measure.

4. Authors must report all experimental conditions, including failed manipulations.

Again easy. Again why not? Hmmm..

5. If observations are eliminated, authors must also report what the statistical results are if those observations are included.

There is part of me that says: you have to be told to do this? Nu?

6. If an analysis includes a covariate, authors must report the statistical results of the analysis without the covariate.

Yes. But this is one we often don't think about, because that covariate often makes the results stronger, why report lesser results? Yet, there is a good point here.

I think this stuff is very important, and wanted to add more, but this has already gotten quite long. So, plow through, and I will try and pick up on this again. Soon. Real Soon.

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We've forgotten (if we ever knew) what dead means

Aug 15 2017 Published by under Uncategorized

On August 12th, a woman, a woman named Heather Heyer was killed. Murdered. She was young and was doing something she believed in, something which someone else decided she did not have the right to do and he was going to stop her.

She is now "the woman who was killed when...". And you read about all the other terrorists who had incidents of domestic violence in their pasts, and you remember all those other incidents you try to forget. All the people killed because someone else didn't think they had the right to live.

There is injury that maims, inside and out. There are scars and ugliness and things that are very hard to fix, if at all. Those are in people who are alive. We help them, we try to stop it from happening again.

But a woman is dead, and that cannot be changed. fixed. undone.

We'll move on, except for the people in her life.

Dead. Gone. Not coming back.

Sometimes, when it is your elderly, ill mother, you can do a little rationalizing dance in your head about it being her time, or better off now. You miss the person, and remember the life full of good and bad and try to stay on the good.

But when you lose a child or a partner or a best friend, there is a hole in your heart. Sometimes hot hot burning pain pours out of that hole. Sometimes its just cold and grey and filled with the I don't want anything of depression.

Gone. Never coming back.

Somewhere, many wheres, there is a mother, a father, a lover, saying: I just want to hear my child, my partner, my sister laugh one more time. I just want to tell her that I love her, one more time. There's so much I didn't get to say. There's so much we didn't get to do. Please.

I just want to hold my baby one more time.

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Everything does NOT happen for a reason

Aug 15 2017 Published by under Uncategorized

I do not believe that everything happens for a reason. At best, that is post-hoc rationalization and type I error. At worst, it is magical thinking to protect one's self from reality.

The world, for the most part, presents itself to us as a large random number / event generator. Other people, other actors, other agents, have reasons and rationales and justifications for their acts. And we do not, cannot, control them. And frequently when we try to control them, it backfires. Often spectacularly and horribly.

Whether we control our actions and feelings is quite open to debate. That's another rabbit hole that people of religion are quite willing to go down.

Why is this worth pondering? Because, one can't control that random universe, but one can position oneself to take advantage of it. One can be in a place where more and good random things are more likely to come your way.

Take for example staying in place vs. leaving the region/city/whatever you grew up in. I call this the Patty Duke effect (ah, certain people of a certain age will remember Patty and Cathy and the rest of you, just don't worry about it). There is a comfort and support for being in a community, and being in the same  community. My partner is Patty, who, with the exception of 3 years has lived in a 10 mile radius of the parental house. When we go out to dinner, we are inevitably approached by people saying hi. My partner is deeply imbedded in this community and it is a joyful thing.

I am more of a Cathy and while I haven't lived most everywhere, I've done a lot of moving for all sorts of reasons, including better jobs, other partners, parental units. I think its helped me grow, and become much more than I would have been had I stayed in place.  There are inevitably more opportunities to do different things with one's life, if one is willing to move and seek them out. It's increasing your sample size, and being less likely to make a type II error in life.

Yesterday, I had a marvelous young person in my office talking about her future. Or her perception that she is "stuck" and doesn't know what to do with her life. Grad school? Follow a partner? Work and earn some real money? She had a friend, she said, who is a school teacher, married, and just bought a house. All at the tender (to me) age of 23. It made her feel unaccomplished, and well, stuck. I tried to give a different perspective. "You're not stuck" I said. "You are free and flexible". I wish I had said "you are a bird on a branch and getting ready to fly."

It was relatively easier for me at 22, to be a Cathy and move. My parents had. While they put down roots to raise a family, and found community in middle age, they are also helped push me and my sibs to go see the world. I am grateful for that. My partner's children are Cathys too, which I admire in my partner, for pushing these kids to go out into the world. One child is queer, and would have been bitterly closeted and unhappy in the small local Patty-community. I love my partner's kids, and while they can be infuriating (they are in their 20s), that's part of the charm, and part of their strength, and part of why I love them so very much.

So, to the incredible young person, debating life: You are a minnow and the ocean is wide, and this is a good thing and a scary thing. Enjoy, revel in the fact that you do have a choice. That hasn't always been true for young women in our society, and there are still many places where it is not. Swim and Fly and grab life with both hands.



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quote of the day: dreams edition

Aug 15 2017 Published by under Uncategorized

This is the thing of which I am most scared.

“There are people who put their dreams in a little box and say, 'Yes, I've got dreams, of course I've got dreams.' Then they put the box away and bring it out once in awhile to look in it, and yep, they're still there. These are great dreams, but they never even get out of the box. It takes an uncommon amount of guts to put your dreams on the line, to hold them up and say, 'How good or how bad am I?' That's where courage comes in.” ― Erma Bombeck

I'd like to say this is only since I've become an olde farte, but that's not true.

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Change in NIH human subjects policy

Aug 14 2017 Published by under Uncategorized

From Mike Lauer. Comments & thoughts later:


Message to NIH grant applicants/awardees, contractors, researchers and research administrators:

If you are conducting NIH-funded research that involves human subjects, or are considering applying to NIH for support of such research, we want to call your attention to important changes that may affect how you:

  • select the right NIH funding opportunity announcement
  • write the research strategy and human subjects sections of your application
  • comply with appropriate policies and regulations

First, familiarize yourself with the new PHS Human Subject and Clinical Trial Information form. For application due dates of January 25, 2018, and beyond, you will be required to use an updated application forms package (FORMS-E), which includes the new human subject and clinical trial form. This form requests human subject and clinical trials information at the study level using discrete form fields, which is a change from current practice. Contract proposals will also require this information. Learn about the new form here.

Second, take a moment to answer these four questions about your current or proposed research:

1) Does the study involve human participants?

2) Are the participants prospectively assigned to an intervention?

3) Is the study designed to evaluate the effect of the intervention on the participants?

4) Is the effect that will be evaluated a health-related biomedical or behavioral outcome?

If the answer to all four questions is yes, then your proposed research meets the NIH definition of a clinical trial. Clarified and broadened in 2014, the definition encompasses a wide range of trial types: mechanistic, exploratory/developmental, pilot/feasibility, behavioral, and more. NIH expanded the clinical trial definition in response to widespread calls from diverse stakeholders for improved reporting of research milestones and outcomes, and for assuring maximal transparency.

Need help determining whether your study would be considered by NIH to be a clinical trial? See our webpage on the definition that includes case studies, FAQs and other resources that can help. Still unsure?  Contact your NIH program official or the scientific point of contact listed on the funding opportunity announcement to which you are applying.

Third, familiarize yourself with NIH policy changes related to enhancing stewardship of clinical trials.

NIH made a number of policy changes to improve the stewardship of clinical trials across the life cycle of the trial. We encourage you to familiarize yourself with all that is changing, including:

  • the requirement to apply to an FOA that specifically allows for the submission of clinical trial applications for due dates beginning January 25, 2018.
  • Good Clinical Practice training expectations for NIH staff, grantees, and contractors that went into effect January 2017.
  • updated peer review criteria that will be included in FOAs for clinical trial applications and solicitations for due dates on/after January 25, 2018.
  • new Human Subject Information form requirements for clinical trials that will be included in updated application forms (FORMS-E) for due dates on/after January 25, 2018, and contract solicitations published as of January 25, 2018.
  • use of a single IRB for non-exempt, multi-site clinical trials for application due dates on/after January 25, 2018.
  • expanded registration and reporting to include all NIH supported clinical trials.

Improving the design, efficiency, and transparency of clinical trials is important because it:

  • respects our ethical obligation to participants to maximize the use of the knowledge from the trials in which they participate
  • facilitates design of clinical trials while reducing unnecessary duplication
  • promotes broad, timely, and responsible dissemination of research information and results
  • fosters responsible stewardship of the public’s investment in biomedical research


We have developed a new Clinical Trial Requirements for NIH Grantees and Contractors web page to bring together all the information you need to know.  Please review this information carefully.  Your attention to detail will be critical to ensuring successful funding of your clinical trial awards.

We will be putting out a series of reminder policy notices, training opportunities, and other resources in the NIH Guide to Grants and Contracts, in the NIH Extramural Nexus, and on my blog.

The success of clinical trials relies on the public trust in scientific rigor and ethical oversight.  We all play a critical role in this process.  We are most grateful to you for your help and support.




Michael S. Lauer, MD

Deputy Director for Extramural Research, NIH

One Center Drive, Building 1, Room 144

Bethesda, MD 20892


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Finding Joy in Life

Aug 14 2017 Published by under Uncategorized

I am sitting here in my apartment, with morning sun falling in through the large east windows. I am joyful, and remembering just how damn good it is to be alive. Yes, there are problems in my life right now, though, no, I don't feel like sharing them here. One reason is that they seem so distant in the sun. I feel like I can do anything.

I saw the movie Moana, and finally, a disney princess in which I can believe. It's important to have hero/role models that look like one, but its also important to see heroes in people who do not look like one This latter is true for me, as I am not Polynesian/Maori/Hawaiian. No, the movie is not deep, and it wears its message on its sleeve. But I cried during the scenes where she stamps her foot and says her name.

I have known terrible depressions, externally generated or internally opaque to me. But I have always managed to find my way back to joy and the beauty of the world. I know there are others who do not, cannot, will not.

Then there are the friends and colleagues who rejoice in dwelling in dark places. Some of these folks fancy themselves witty and erudite for seeing the world through grey or brown or dull blue glasses. Some of these wear not just skepticism, but negativity like a cloak to protect themselves from something they fear, but cannot name. There are reasons: problems in the past, abuse, emotional neglect, the list is as long as the Canon. Some of these friends, people I know well, and love, and embrace, can no more change this outlook then I can stop being inappropriately goofy with the happiness inside of me.

But one of the things that makes me sad is the inability to shed that drab blue and faded brown outlook. I've had students and techs and collaborators who are cynical and ironic and see disaster at every turn. Hell, I've had partners I lived with like that. They are people who cannot look at a piece of work, something they did, and see the beauty in it. "Here's another stupid thing I finished".

There are many kinds of lack of support and encouragement. You can be critical and a perfectionist and see people as failing to meet your standards. But there is the one where it all seems pointless. This isn't mentor failing to support mentee. This is friend not seeing the beauty in friend. This is reading a paper and nit-picking your way through it, and not being able to say to the first author: Wow, I took a step back and you've done something really, really good here.

I was talking to my summer medical students who have another week or so in my lab. This year's batch was one of the best ever, if not the best ever. When they interviewed with me, and then again when they started I promised them that they would work harder than any of their peers in the same program. That the hours, because of the experiments, would be longer, and that they would be more challenged. I said this is because they would be partners in the work, and the work is hard. Yesterday, I asked them if they though it was true, and they all said yes, but, ... but.... what they got out of it was worth it. We talked about how to write the first draft of their letter of recommendation (from me, for their future projects). And they started listing what they learned: surgery, electrophysiology, and then they went beyond techniques and talked about working together and compassion for the animals and their co-workers. Their faces held joy.

Life is short. Being happy is better than being miserable. Making the world happy and better for someone else is one of the greatest accomplishments we can have. We can choose. I do not believe I can make those ironic and unhappy friends better. I can't. You can't. But I can set the space, create the place where it CAN happen.

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Two perspectives on "dis"-ability

Aug 11 2017 Published by under Uncategorized

WaPo just had two op-eds with  interesting perspectives by people that if one is not a clinician taking care of people with achrondoplasia or stroke survivors, one would not meet or work with every day. One is by Rebecca Cokley, a former exec director of National Council on Disability, who has achrondoplasia,  a disease that reduces bone growth, and as she says "the most common form of dwarfism".  The other is by Robert Fowler who had an ischemic stroke (blood clot in the brain). These two are different perspectives, and dealing with different issues. What united them in my mind was yet another reminder to me about the world out there. We, I, get so wrapped up in life that I can easily lose track of other people and their stories. People with physical challenges, people with "dis-abilities" often more so than people who just look different, are easily swept under the rug, and locked in a mental closet out of site.

Surviving a stroke is difficult, and Mr. Fowler is wrestling not only with  different physical capabilities, but with the shame of asking for help. He didn't intend to be ill or poor but has been dealt a rather bum hand. Not his fault that his parents weren't rich and that he can't afford the best health care that private insurance can buy.

There are good reasons, defensible reasons to promote a culture of "a hand up not a handout", and we are all or should be Clint Eastwood and Chuck Norris and totally self-reliant. Except, of course when we are not. And then it's hard. We are supposed to battle cancer, and be warriors in our own life. The metaphors of illness are of war and battle and fight. When I was very ill, I was just too damn tired of being sick to explore metaphor. And the asking for emotional and psychological help carries a stigma that makes the physical burden even more. Mr. Fowler paints this picture clearly.

Ms. Cokley has had achrondoplasia since birth, and is the third generation in her family. Her concerns are based on the announced breakthrough in gene editing and represent a much more difficult ethical dilemma. She makes the strong point that this announcement came on the anniversary of the ADA (Americans w/ Disabilities Act), a landmark piece of legislation that our current president has yet to understand. Ms. Cokley rightly points out that the language in many of the press releases talks about "unfit" and editing out mutations as "progress" and "remediation".  Her language is beautiful in describing the pain that "adult little people" felt when the gene was discovered:

I remember clearly when John Wasmuth discovered fibroblast growth factor receptor 3 in 1994. He was searching for the Down syndrome gene and found us. I remember my mother’s horrified reaction when she heard the news. And I remember watching other adult little people react in fear while average-height parents cheered it as “progress.”

How, if you are an average-height parent, do you explain to children whom you’ve spent years telling are beautiful the way they are, that if you could change them — fix them in a minute — you would?

Her discussion of the community and culture of little people is similar to what my Deaf friends, and my friends who sign, talk about for their life and community. They do not want cochlear implants at birth, they do not want their culture and their society, rich and complex, taken away. I freely admit to struggling with this. Music is so central to my life, how could I trade anything for that? But I try and listen, and Ms. Cokley's story is a good listen.

Her argument against gene-editing has two parts. Firstly, again, she talks about the beauty and the potential and the culture of being different. What is lost if every "imperfection" is corrected? What is lost if we all became perfect. This may seem to us, able-bodied as a reducto ad absurdum. How can we fix everything? But it is not for people within that culture.  Her other point is the ugliness of, as she says "society’s fear of the deviant — that boogeyman of imperfection'. It is what people, maybe too old for gene-editing, hear when normal-height (and that word sticks as I type it) say "fixing". In some ways physical differences, that are not skin color, or body size, are things we apply "dis" and "non" and "anomaly" and other words that mean "less" and "ugly".

Ms. Cokley implies that she wants to pass this culture, her culture,  on to her children, and does not want "fixes". She talks about how the vague language of the scientists and clinicians who talk about fixing "serious disease" avoids pinpointing what needs to be, or ought to be, or should be, fixed, once the "can be fixed" is done. There are discussions that have no occurred, part of her point. The articles about gene-editing do not talk to the people who might or might not be fixed and edited.

What is a parent to do in this situation? A parent who has not grown up in the culture of little people or Deafness might only want the best for their child. And one issue is that some of these "fixes" might likely have to be done at birth, or in utero, well before the human being who bears the gene can make a decision for him/her/xe self. If teenagers can rage about "why didn't you make me practice the piano" as much as "why did you torture me so much to practice piano", how much more rage will there be over the choice to edit or not edit one's genes? Is gene editing like gender fixing surgery of years gone by, when decisions were made about ambiguous genitalia at birth, something we now rightly regard with horror? Or is it like vaccines, where the ultimate good, to the individual is so strong, we want to mandate it (and yes, I recognize there is societal good to vaccines that may not apply here)?

I am grateful for these voices that make me think, once again, about the problems I do not understand.

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Really? Screw that ... (interviews with more brilliant tech break-through types)

Aug 10 2017 Published by under Uncategorized

Ozy, which I try not to read, had a profile of James Park, who heads up FitBit. How does he stay ahead? The tagline from the article is:

In a behind-the-scenes interview from OZY Fest 2017, James Park shares his tips for success: sleeping five hours a night and always preparing for the worst.

When you delve into the article (and I don't necessarily recommend that), it's a bit more complex.

Park: I only get five hours of sleep a night. I  know that’s bad and I need to work at it, but it’s gotten even harder as I’ve gotten older. I just find it difficult to settle my brain at night.

Damn straight its bad.

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