Questions and answers from this week’s weekly Q&A session are here:
Questions and answers from this week’s weekly Q&A session are here:
The foundation of science is this: that we can determine how adding or removing something changes a scenario by comparing it to what happens when we do not nothing.
Sunblock is a very simple example of this. In order to see what sunblock does, or does not do, we first keep track of what happens when a person doesn’t use sunblock, and then replicate that situation with the only change being that person now using sunblock. It is important to keep everything else the same: if the person we are testing normally drinks three cups of coffee before noon, wears make up, and doesn’t get enough sleep, we want that person to keep doing those things while we study what the sunblock does.
The reason we want this is because if lots of things change at once, how can we know that the sunblock causes any changes we see? For example, let’s say this person often has an upset stomach. If she suddenly stops drinking coffee when she starts using sunblock, and this improves her upset stomach, the data might indicate that wearing sunblock helps with upset stomach even though that’s not really the case.
Most people think that clinical trials do what I just described: that they compare the effect of a therapy to people who think they are getting the therapy but are actually getting the placebo. While this does sometimes happen, that is almost never the case for people with advanced life threatening diseases or rare diseases. This is a complex topic so I’m going to unpack this in a series of posts so that I can answer questions as they come up.
The first thing to understand is that there are phases of clinical trials. Understanding the phases will help you to know what the data means when the results are released.
For trials that are supervised by the American FDA, there are four phases. They are cleverly called Phase I, Phase II, Phase III, and Phase IV.
Phase I is the first and most preliminary. Phase I trials are safety and dosing trials. I have never seen a phase I trial with more than fifty people. Most of the ones I see involve 10-20 people. This is the first real contact a new treatment (drug or biologic) has with patients that the therapy is intended to treat. It is literally to see how the human body reacts when it is given any amount of this substance.
Phase I trials are to see what adverse events present with this therapy. Adverse events are basically side effects and complications. They are the risks you accept when using the therapy. Some are serious, and some are not.
Dosing trials are just what they sound like: they give different people different doses in order to figure out the lowest effective dose. This is because we want to give as little of this substance as possible because this usually gives the lowest risk for complications. So we will split our phase I group into smaller groups called cohorts. Cohort is just the science term for a group of patients that have things in common that we are studying.
For example, let’s say we have a phase I study for Klimasonium, a drug that is taken once daily and cures mast cell disease. (I super wish for Klimasonium.) Let’s say I gather up 30 patients with MCAS for Klimasonium. (Please do not think this is real thing.) In order to determine what doses we should use to treat patients, I would break up my 30 patients into 3 groups, also called cohorts. Cohort 1 would take one tablet a day. Cohort 2 would take two tablets a day. Cohort 3 would take three tablets a day.
At the end of the trial, I would look at what side effects and complications patients had, and if their disease got worse or better, and in what ways. Based upon this information, I will pick a dose that helps the disease while causing the fewest complications. I will also have to report any and all side effects or complications to the FDA so that the risks of this therapy are recorded and patients who take this drug at any time will be made aware.
We are going to take a short break from the 107 series to address a topic I get asked about constantly: which drugs are best for advanced systemic mastocytosis and how they compare to one another.
Before we get started, there are some things we need to get out of the way. While my second life revolves around educating about mast cell disease and helping patients (and my third life involves having mast cell disease and living with it), my first life and real world job is as a senior scientist for the biomedical research division of a large pharma organization. My job is to figure out ways to test for things that will tell us if a patient is likely to get benefit from the therapies we are testing in studies and clinical trials to treat diseases. While my job largely focuses on supporting trials for cancers like lung cancer and melanoma, I also contribute to trials for rare diseases. One of the rare diseases we have trials for is systemic mastocytosis.
Nothing I say here or in my capacity as Lisa Klimas from MastAttack or Lisa Klimas, a human with systemic mastocytosis, should be taken as representing the organization I work for. I do not ever speak as an employee about the things I just mentioned unless I am at work working. Ever.
Obviously, I have systemic mastocytosis. Everyone knows that. This is not a secret. Systemic mastocytosis is the center of the Venn Diagram of my three lives: they all touch there. For this reason, I avoid talking about certain things about my health because it triggers questions about things that relate closely to my job. For the same reason, I am also very restricted in what I can say about certain therapies for systemic mastocytosis. Specifically, I am very restricted in what I can say about therapies for advanced systemic mastocytosis, like tyrosine kinase inhibitors and multitarget kinase inhibitors.
However, I can talk about how to compare two therapies to one another using science, and you can apply that however you wish. So for the next several posts, I’m going to give a crash course in drug development, clinical trials and data interpretation for laypeople. If you have specific questions, please comment on this post. I will answer any question in a post provided it does not violate my obligations I mentioned above. First post goes up tomorrow night and covers how clinical trials work, what the phases mean, and how people with no science background can understand what the results mean.
Hope this helps clear things up. This will be fun.
People with severe mast cell disease are at risk of losing all foods due to reactivity and anaphylaxis. These patients are often dependent upon elemental formulas for nutrition. These formulas are incredibly expensive but lifesaving for many.
Recently, one of these elemental formulas, Elecare Jr, was re formulated. Some patients who have failed EVERY OTHER nutrition option rely upon this formula to stay alive.
The mom of one of my little masto buddies graciously agreed to explain the importance of this elemental formula to her son, Ollie:
“Hi Lisa, here’s a little on why keeping formula the same for Ollie is
Ollie was sick on day one of his life. We started nursing and he was a
“puker” on day one. By 2 weeks old I thought he was MSPI and cut dairy
and soy from my diet. At 4 weeks old he was gaining weight, but not
fast enough, covered in rashes, throwing up nearly constantly and just
screamed for hours. We did this for a total of 4 months. Changing my
diet, with no change in him. At 4 months old his pediatrician
diagnosed him as failure to thrive. She gave us a can of Elecare
infant. Within 2 weeks, he was a whole new kid. No rashes, no more
vomiting, his stools looked phenomenal and for the first time, he was
gaining appropriately! He was diagnosed with Fpies around 5 months
old. Oliver then continued to fail all solid foods. Elecare infant was
his sole source of nutrition. We tried switching him to Elecare Jr and
Neocate Jr. He reacted to those as well. At 18 months old, Oliver was
diagnosed with MCAS. Thanks to medication, he gained his first food,
Eggs about this same time. He still relied primarily on Elecare
Infant. By 18 months it had helped him get to 50th percentile in
weight! When Oliver was 2.5, he gained his second safe food, broccoli.
He’s added 8 more foods since then. Today, he’s 6 weeks from his third
birthday. He has 10 safe foods and relies on Elecare Infant for 90% of
his nutrition still.
Abbott has changed their labels and the names of some of their
ingredients. They claim they didn’t actually change anything in the
formula, but one change, one minor change could mean a reaction for
him. If he loses this formula, he has no other options. He will slowly
become nutrient deficient causing many other problems that he doesn’t need.
We need Abbott to leave their formularies alone!”
I know lots of kids (and adults) just like Ollie. They need our support right now. If you are so inclined, please consider adding your name to a petition asking Abbott to reconsider their new formulation of Elecare Jr. Mast cell patients (and other patients with significant nutritional difficulties) need your support.
Hope everyone had a safe and happy weekend! Can’t wait to see everyone at the weekly Q&A this Wednesday at 7-9pm, EST.
I have a sunburn. Today, I embarked upon that most quintessential New England autumn venture: apple picking. It was supposed to be about 70 degrees with a breeze and some clouds. Instead it was almost 90 degrees with a little breeze and a sun beaming directly down upon us. I always wear sunblock on my face and cover a lot of my skin, even in the summer, so it wasn’t too bad.
The sunburn is on my chest and shoulders. It’s not serious. It won’t blister. It looks red and angry and kind of hurts. Not a lot of pain, but there. Persistent. Stinging.
I have been sick a long time. And that means have been in pain a long time, too. There are lots of different pains and I know them all. I know the loose instability of stretching a joint too far. I know the burning of flushing skin and the stinging that remains after the flush is gone. The abdominal neuropathy that spreads like lightning across my midsection, electric fractals emanating from a central point. The hard swelling of my colon when fluid is trapped in the tissue. The way it feels like broken glass when my GI tract reluctantly moves things through its lower portions. The white hot fire of something passing over an open wound. The acid throbbing of vasculitis. The beating against the back of my skull of a terrible headache. The pressure of food that will not move as my stomach swells around it.
I have needed pain medication of one kind of another for several years. I have lived a very privileged life and I have been very lucky to have a medical team that has been largely the same for several years. My doctors know me pretty well. And because they have seen me screaming in pain and seen the damage that caused the pain, they are willing to help me manage my pain. It is a never ending process of adjusting medications and behaviors and foods but I have options that many people do not. I am lucky. Very lucky.
Drug addiction is a hell I wish on no one and one that has affected me personally in many ways. Heroin abuse is often a complication of opiate abuse: it renders a similar high but is cheaper and easier to get (as I understand it – I do not have personal experience with heroin). Sometimes people who are prescribed opiates for legitimate reasons become addicted and are forced to buy pills illegally or resort to other products, like heroin. Often, people with addiction come to heroin or pills another way, without ever having had a medical reason for using them.
Last year, the CDC made broad recommendations regarding prescriptions for opiates, probably the most well known drug class of pain killers. I had anticipated their recommendations with dread and I was not disappointed. In brief, their recommendations were that every other avenue for pain management be thoroughly exhausted before use of opiates, which would almost certainly render pain relief. The quantities to be prescribed were small and the courses short, irrespective of whether or not this was appropriate to the pain condition or realistic in any way.
Patients would all be drug tested frequently so that we could prove over and over again that we are not drug addicts. Our medication would not be filled without us proving over and over again that we are not drug addicts.
And for those patients like me who have debilitating, chronic pain, there were provisions for trialing removal of pain meds so that they could determine whether or not we actually needed them and if it was possible to reduce the dose at all. Most alarmingly, in my state, they adopted guidelines that could people like me to be evaluated by a doctor who knows nothing about me or my rare disease in order to determine whether or not I really needed these drugs. I am not an addict. I take my medication as directly. I fully comply with any and all guidelines and am happy to pee in a cup every time they instruct me to. But I am still afraid. I am afraid that I will do everything right and still end up in severe pain with no drugs to manage it because government agencies are conflating the epidemic of drug addiction with the necessary pain management of chronic pain patients. And that fear is getting larger and larger as time passes.
This past week, a large pharmacy chain in the US announced that they would only dispense seven days of opiates for “new” patients. There is already a lot of debate about what exactly this means but I guarantee it means more trouble and stress and fear for people like me. I cannot imagine a system in which a pharmacist can know my personal health and pain situation better than my provider of many years. What if the pharmacy decides I’m a new patient and just won’t give me more than seven days? What happens then? There are no answers yet on what will happen, but I don’t need to specifics to know that the people who will be most affected are people like me.
There are many practical reasons why this particular practice is a terrible idea. For one, it requires patients to be seen again to get a new prescription after seven days. For a pain situation in which a patient might need pain meds for a month, this would translate to four office visits instead of one. That’s four copays. That’s four trips with associated expenses. And that’s four copays at the pharmacy. That’s four office visits that already overextended provider’s office now needs to find time for. And when they can’t find the time, those patients may be left without any pain medications until the next appointment.
But these are not the reasons that literally keep me up at night so that I am writing this post at 12:50am despite being absolutely exhausted. What keeps me up is that no matter what, no matter what the intentions are for all these restrictions, and who they are supposed to affect, me and people like me will suffer. We already know what it is like to be treated like a junkie. We already know that we have to convince every provider we interact with that we use pain medication responsibly as directed at appropriate doses for our pain condition. We already know that we’re never totally convinced that those providers believe that.
But most of all, we know pain. And we know that in the current climate of increasing restrictions on pain management, we will have more pain than we used to. Pain that could be treated effectively if there was not such a stigma upon using opiates for chronic pain when everything else has failed. Pain we remember and are afraid of.
Pain is such an abstract quality to those who don’t live with it. People who don’t have it often do not empathize with those of us who do. We are often painted as lazy or attention seeking. Some day, those people will know about pain, and they will feel guilty then. But it will be too late at that point. People like me can’t wait for that day.
Pain is a monster with many faces that haunts every moment of your life. It eats our sore muscles and swollen joints and ruined organs and twisted bones. It eats and eats and eats until there is nothing left that suggests a person lived in this vessel. That there was once a life here, and dreams, and aspirations. That beautiful things lived here before they were destroyed.
Pain is not something you can overcome as a society by pretending the people who have it will be able to figure out another way to manage it when you rob them of their best tools. Chronic pain kills people. We know this fact. It is not disputed. Pain causes inflammation that can cause strokes, heart attacks, cancer. It causes despair and loneliness. It causes suicide.
I am afraid that we will not be remembered as the generation that overcame opiates. I am afraid that we will be remembered as the generation that pain destroyed. If we are remembered at all.
After a several month hiatus, I am back answering questions in the MastAttack Facebook group. A new thread is posted weekly where people can comment with their questions. Questions are answered on Thursday nights from 7p-9p EST. Once the session is over, the thread is locked but will stay visible so it is available for reference.
The lovely Mikal Mowdy, mother of Yssabelle Eddlemon, who is disease free and living a normal life after a bone marrow transplant, made a PDF with all the questions and answers from last night. You can read it here: Week One PDF
Anyone who wants to participate is welcome. Request to the join the MastAttack FB group and an admin will approve you.
For this coming week only, the Q&A session will be on Wednesday from 7p-9p.
Hope to see you all there!
I have two best friends named Allison and Alyson who are both very, very into music. With few exceptions, all of my musical influences arrived to my ears via one or both of them. Alyson lives in Seattle. Alli and I went to visit her there in 2014 when I had a PICC line and 40 lbs of steroid weight and a constant flirtation with anaphylaxis.
While we were visiting, the three of us went to Portland, Oregon for the weekend. It was a really amazing and cathartic experience for me. It feels like that was when I began to reclaim myself and my body and my life. It was an experience I will never forget.
Alyson has always been the type of person who follows bands around the country because she is much cooler than I am. In the last few years, she has been obsessed with Kasabian, a British rock band. She flew into Boston for less than 48 hours to see them in Boston two days after seeing them in New York and a few days before following them to Chicago.
I hadn’t really heard much Kasabian before but tonight I went to the Kasabian with Alli, Alyson and Alyson’s mom, Charlene. We were having some hairy health care moments in the line outside, waiting to get in, so I wasn’t really sure how things were going to go. But I decided that if we got into the venue that I was going to be a huge Kasabian fan for the duration of the show. It didn’t matter that I knew virtually nothing about them. I knew I loved the people I was with. I was happy to be well enough to even go to a concert. So I was a Kasabian fan. Sometimes it’s enough to just believe something, even when there’s no good or logical reason for it. Believing is enough.
We stood right up front and jumped up and down and screamed at the band. I really shouldn’t have sang along since I knew literally no words but that has never stopped me before. I jumped and bounced and screamed for two and a half hours. The energy in the crowd was amazing and the show was great.
I said to Alli tonight that I think that concert years are like dog years. I am therefore 132 concert years old. It sure as hell feels like it. I’m going to need a cane to walk tomorrow. No thigh blaster workouts necessary.
I have a Wall of Hopeful Things in my home office space, where I do most of my MastAttack work. It is covered with things patients or parents have sent me. There is a trinket dish on my Wall of Hopeful Things that says, “It is not enough to put your heart and soul into something, the really important things require much more than that.” I think of this as the MastAttack motto. You can’t build something without leaving pieces of yourself among the blocks.
In the last few weeks, I have painstakingly mapped out the next year of my personal, professional (work) and professional (MastAttack) worlds. I have monster goals for MastAttack for the next year. I have started putting together the materials for the course videos for the spring. I have been networking a lot to work towards some other MastAttack goals. I have professional development and program goals at work. I have lots of personal things that I have forced myself to find time for. It is an intimidating amount of life I am trying to fit into these time constraints. But I decided that I could do it, and as soon as I did, I became capable of it. You have to believe it and hold your nerve. So here goes nothing.
Hope you all are having a super weekend. Be on the lookout for some MastAttack announcements this week.
It is not enough to put your heart and soul into something. The really important things require much more than that.
74. Is mast cell activation the cause of many other diseases?
No, but it is involved in many other diseases.
I write a lot about mast cells and the way they are involved in various other conditions. Mast cells live throughout the body in many tissues. Because they are in so many tissues, their role in many diseases is well researched.
Mast cell activation is not the same as mast cell activation syndrome. I have written about this here. Basically, there are tons of things in the body that cause mast cell activation. These are conditions where we want or need mast cells to become activated because then the mast cells help keep our body working the way it is supposed to. For example, during a woman’s menstrual cycle, if mast cells could not become activated the way they normally do, a woman’s period could become very irregular. This in turn could affect the amounts and types of hormones in a person’s body, causing symptoms and problems.
Situations where mast cells normally become activated include labor and delivery, during any type of infection, during situations where the GI tract is inflamed, when your body is growing new blood vessels, any time your body is healing, and when you have cancer or a tumor. In these situations, the mast cells activate to send signals to other cells in the body to help regulate what is happening. Mast cell activation is not always bad. It is, in fact, a normal and necessary process that happens in the body of everyone every day. Mast cell activation is necessary to stay alive.
Now let’s look at the role of mast cells in diseases that are not mast cell diseases.
When I was little, I was a Girl Scout for three weeks before I got kicked out. (This is true and not related to mast cell activation.) There was a game that we used to play called “Telephone.” During this game, everyone would sit in a big circle. One person would think up a short sentence and whisper it into the ear of the person next to her, who would in turn whisper into the ear of the person next to them, and so on. Often, people misheard the sentence and so it was completely wrong by the time it got back to the person who started it.
Diseases in the human body are like a very complex game of Telephone. In every disease, many cells that did not cause the disease can cause symptoms even though they are not the cause. The way to know if a disease is a true mast cell disease is to know which cell first messed up the sentence in the game of Telephone.
Here’s what this sounds like in people:
Lisa says to Pari: Puff the magic dragon
Pari says to Dana: Puff the magic dragon
Dana says to Celeste: Puff’s magic is dragging
Celeste says to Lisa: Puff’s magic is dragging
So in this situation, Dana changed the sentence. Because she changed it, Celeste also had the sentence wrong. So Dana caused the problem. Celeste did not. (In real life, Dana is lovely and not a problem.)
When your body has a disease, the symptoms and damage are caused by cells giving or receiving messages incorrectly. Instead of using words to talk to each other, cells use molecules. Even though they use molecules to talk to each other, it is very much like a language. If the message is “said” wrong in this cell language, then all the cells after the mistake are doing things that are unhelpful or dangerous. However, they are NOT the cause of the disease because they are not the one that changed the message.
Now let’s look at this with cells in the human body during a disease. I’m going to use a very simplified explanation of rheumatoid arthritis as an example.
T cell says to B cell: I think our body is dangerous to us!
B cell says to T cell: Oh, snap! Let’s get the word out!
B cell needs to tell the body about this danger. It makes a message that says, “Danger right here! Danger!”
B cell says to mast cell: WE ARE IN GRAVE DANGER! ATTACK! ATTACK!
Mast cell to other cells: KILL THIS INVADER KILL IT TO DEATH
Except there is no invader. It is just your regular joints being regular and not dangerous.
Other cells: *trying to kill your joints*
Joints: Uh, guys, I’m actually supposed to be here –
Mast cell: I CAN’T HEAR YOU OVER THIS SCREAMING B CELL
T cell gives the B cell bad information. This causes B cell to alert other cells of “danger.” But this wasn’t the B cell’s fault. It was the fault of the T cell which gave the B cell bad information. And that means that everything that comes after the T cell giving the B cell the bad information makes the problem worse but is not really the cause of the problem.
I used rheumatoid arthritis as an example because a lot of treatment of rheumatoid arthritis revolves around blocking those danger signals from mast cells. But is the mast cell the cause of the rheumatoid arthritis? No, it is not. It is not the cause because mast cells have to respond to commands from B cells in order to help protect us against infection and do other helpful things. The mast cell did not decide the joints were dangerous. The B cell told the mast cell this so the mast cell is working with bad information that it doesn’t realize is bad.
If the mast cell isn’t the cause of the rheumatoid arthritis, why do we bother blocking mast cell signals instead of telling the T cell and B cell to be quiet? Because quieting the mast cell signal will help with symptoms and we know how to quiet the mast cell signal and we don’t always know how to quiet the other signals. Stopping the mast cell signal can make symptoms much better but it does NOT cure rheumatoid arthritis. Why? Because mast cells do not cause rheumatoid arthritis.
So mast cells are involved in many diseases without causing most of them. The way you can tell they are not the cause is that they did not start the wrong “message” that caused the symptoms and damage.
Now, I would like to address the fact that there are some diseases that have some research to suggest that they may genuinely be a form of mast cell activation disease. Fibromyalgia is one of these diseases. However, at this time, there is not enough evidence for it to be classified as a mast cell disease.
I tried to be as clear as possible about a very complicated topic. If I didn’t do it well, tell me and I’ll have another go at it.
(Author’s note: This is a SUPER simplified version of rheumatoid arthritis. RA is an autoimmune disease and it is still not clear exactly how the T cells and B cells start sending the wrong messages in an autoimmune disease. I just simplified it here to make it easier to see my point.)
Yesterday was a quintessential New England fall day. It was warm and sunny with a little bite to the wind coming off the ocean. Astoria and I walked four miles. I got a bunch of normal people errands accomplished. I drove to go get coffee. It was really lovely.
It was especially lovely because September is tricky for me. The change of seasons hits my mast cells pretty hard. The falling leaves often have mold on them and mold is a huge trigger for me. I always contend with a pretty significant flare in September but it usually wraps up in a week or two. Last year, I deteriorated rapidly in September, ultimately needing months of medical leave. September is making me apprehensive this year.
On top of the physical issues, my last few Septembers have been pretty wrought with emotional stress. I will always associate this time of year with the fever pitch terror of someone you love almost dying and the horror of what happened to Kristina. I imagine I will have difficult Septembers for the rest of my life.
It’s the middle of the night here and I’m awake because I’m in a lot of pain. My abdomen is really swollen and painful. I’m not sure what happened but it’s the same thing that required hospitalization in June. I was sitting at my parents’ house, talking to my dad, and suddenly I was having killer abdominal pain. Like just this side of screaming pain. I took pain meds and extra steroids and mast cell meds but they didn’t do much. So I’m sitting here with a heating pad on my abdomen, waiting.
I am trying to remind myself that eventually it will stop and then I’ll just be in normal pain. That I’ve been in pain a long time but there are days when it is better. But every new pain is an echo of the first one, a lesser shadow that follows closely, a half step behind me. And if it’s all just one unending pain, a red path burned through my life, it doesn’t really ever stop. It might always be like this. I’m hopeful that it won’t but when you are in a lot of pain, it consumes everything. It consumes your happiness and optimism. It consumes your future.
I’m trying to pack my September full of fun plans to get me through. I’m going to a concert this Saturday with my Portland Soul Sisters, Alli and Alyson. I am going apple picking with my nephew. I am going apple picking again with my nieces the weekend after. My nephew’s birthday party is coming up.
Once I get through September, it will be October and I love October. I love Halloween. I watch a different scary movie every night and decorate my house and get a costume together for trick or treating with the kids. Halloween is always the gift I get for surviving September.
I pulled out all my Halloween decorations and decorated my apartment three weeks early. Even if I am in pain forever, I will still get Halloween. So it’s Halloween in my home.
The university I went to had a nuclear reactor. A real one, underground. The radiation source was an unstable isotope of cobalt that glowed an eerie and otherworldly blue at the bottom of a huge pool.
I was a student there a few years before I found out. I walked over it on almost a daily basis. I had no reason to know it was there until I did and so I didn’t. Naturally, as soon as I found out about the (really woefully and shockingly insecure) nuclear source under my campus, I became very paranoid that it would meltdown or be hijacked by terrorists. I wonder how many hours I have spent worrying about this.
I found out today that a friend of mine has cancer. She told me about her recent appointments and test results. We talked about the grieving process when you receive seriously health news. She hadn’t been having symptoms and the diagnosis took her completely by surprise.
We make a lot of the connection between our minds and bodies. We feel that this linkage is not only real but deeply spiritual, that it is the basis for our awareness of our very selves. We expect there to be signs when something is wrong with our bodies. We feel that we will intuitively known something is off when our bodies harbor such significant health issues. When we don’t, the betrayal is even more searing. We feel that we have failed ourselves in some way and that we have no one to blame but ourselves.
It is harder to reconcile your reality with your experience when the physical state of your body is at odds with your experience of living in it. It makes you wonder what would have happened if you just didn’t know. How many things do we notice only because we know this thing? How many things are significant only because we know this secret hidden inside ourselves? When would you have started to feel sick? Would you ever have noticed otherwise?
I am a scientist and the currency of science is inherently facts and truth. I have always felt it is better to know the facts both in my work and in my health. But it does make me wonder how much time I have lost to perseverating about unlikely worst case scenarios because I demand that knowledge. How much time I have spent being afraid of these things that never came to pass and probably never will? How long have I looked at this shimmering blue and convinced myself of a danger that was never real?