One More Dream…..

 

One More Dream…

The purpose of this post is an illustration of a strategy I use to improve my sleep.  I am currently an old man and have had sleep problems since I was a toddler. I had night terrors at an early age and still remember the hallucinations.  I wrote about them in a previous post.  Night terrors as a kid generally predicts sleep problems and risk for psychiatric difficulty as an adult. I also inherited obstructive sleep apnea and that contributes to poor sleep quality. For most of my career, I practiced in a high stress environment and with my personality factors that also lead to significant sleep disruption in situations where there was no clear solution to the problems I was trying to treat. A good example would be catatonic patients who were not eating, drinking, or responding to treatment. I would find myself laying in bed at night and reviewing the current treatment plan and that person’s medical status – sometimes for hours. Since retiring 2 years ago that type of nocturnal stress is gone – but your life is never completely stress free.

When I do fall asleep – I generally like dreaming. I tend to dream about medical centers and anxiety provoking situations. A common dream is being in residency and realizing that I just stopped going to biochemistry class as a first-year medical student. I never took the exams or confirmed whether I got a grade or not. Instead, I find myself near the end of residency and wondering if I am going to graduate.  I am not sure if there is a black mark against my name or not. At the same time, I am engaged with many doctors – doing what we did in residency training. I wake up somewhat anxious until I realize it is just a repetitive dream. I am always amazed at the content of the dream in terms of the architecture and landscape – all manufactured from incidental memory. None of the institutions in my dreams exist in real life. The same is true of most of the people in my dreams, but occasionally there is a friend, family member, or celebrity.

I try to practice the lucid dreaming that I discovered in childhood. If I am stressed or anxious in a dream, especially to the point of bodily sensations like feeling flushed, like my heart is pounding, or shortness of breath I try to wake myself up by rehearsing what to do ahead of time.  Those bodily sensations can be associated with strenuous activity in the dream like skating or biking – but not always.  I have tried a lot of the relaxation and CBT techniques for falling asleep but did not find them very effective. I also have not used any medications for sleep.  My primary care MD gave me 3 zolpidem tablets once.  They were moderately effective but he did not prescribe any more.  I take medication that is toxic and has drug interactions so I did not try other options that might affect cardiac conduction.

What I did come up with was a technique that I call “One more dream.”  Before I get into the details – let me emphasize that this is not an instruction manual or guide for people to use this technique.  It has not been shown to be effective in clinical trials and doubt it will ever be studied. This is just a technique that I personally have found to be effective and it is not medical advice for anyone else.  And like everything on this blog I am not promoting it to make money.  The discussion is strictly educational – nothing more.

Here is an outline of the basics beyond the typical sleep hygiene measures:

1: Recall the somatic sensations just before you fall asleep:  These sensations vary widely from person to person.  In my case, I get a feeling that I am sinking and I start to lose sensation in my arms and hands – they start to feel very light. I am also aware of any stiffness in the chest and abdominal wall.  I will typically do a few breathing exercises to get rid of that stiffness.  I actively try to recall that sequence of events and the actual feeling.  I have had several instances of general anesthesia in the past 5 years and recalling that state can also be helpful. 

2:  Recreate 'sleep reverie' transition state (usually just waiting for it is enough):  Sleep reverie is the transitional state from wakefulness to sleep. There is typically a period where conscious thoughts start to run together.  If you are good at mental imagery – an image might start out with a person walking down a stairway and change in an instant to a different person engaged in a different activity.  Noticing when this occurs is typically associated with transitional images. It is also a sign that sleep is rapidly approaching.  Focusing on those instances is helpful. 

3:  The conscious goal is one more dream:  I typically try to focus on an image of something that I want to dream about but having that dream is extremely rare. These images often dissolve in the sleep reverie stage. It is also a time to rehearse endings to problematic dreams. A common theme for me is strenuous physical activity. I am overexerting myself in a dream and wake up to rapid heartbeat, palpitations, rapid breathing, and sweating. If I can recognize that in a dream – my usual rehearsed ending is to wake up and start over.   

Those are the basic steps and the mile high view. They are not completely original since there are elements of lucid dreaming and dream/imagery rehearsal – both of which have been studied, tested and used clinically (1). In clinical practice I have had good results advising people about sleep hygiene; the pharmacology of caffeine, alcohol, and addictive drugs; whether their dreams were interpretable; and how to stop unpleasant dreams or nightmares using dream rehearsal. The decision to use these techniques generally depends on the amount of autonomic arousal the person is experiencing.  For example, people with high levels of anxiety all day long who experience associated nightmares and nocturnal arousal including panic attacks, rapid heartbeat, palpitations, sweating, and ongoing sleep deprivation are much more likely to need pharmacotherapy in addition to the above measures.  Standard insomnia therapies may be useful, but more specific therapy targeting heightened adrenergic output is more likely to work, especially in the case of post traumatic nightmares.

The biology of sleep transitions remains at the theoretical stage at this point with several interesting classical and newer hypotheses (2,3).  While the hypotheses are interesting and becoming more sophisticated it is also apparent that pluralistic interventions are effective including the measures described in this post.  In other words, astute clinicians have been able to design self-help, structured, and psychotherapeutic interventions that can reduce or eliminate both primary and trauma-based nightmares and improve sleep quality and general health.  Like many other interventions in psychiatry - they work irrespective of whether a biological mechanism of action is known or not. They also do not depend on a prescribed medication or medical test. They are dependent on a skilled sleep assessment and training in these techniques.

 

George Dawson, MD, DFAPA

 

References:

1:  Yücel, D. E., van Emmerik, A. A. P., Souama, C., & Lancee, J. (2020). Comparative efficacy of imagery rehearsal therapy and prazosin in the treatment of trauma-related nightmares in adults: A meta-analysis of randomized controlled trials. Sleep Medicine Reviews, 50, https://doi.org/10.1016/j.smrv.2019.101248

2:  Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010 Dec 22;68(6):1023-42. doi: 10.1016/j.neuron.2010.11.032. PMID: 21172606; PMCID: PMC3026325.

3:  Osorio-Forero A, Cardis R, Vantomme G, Guillaume-Gentil A, Katsioudi G, Devenoges C, Fernandez LMJ, Lüthi A. Noradrenergic circuit control of non-REM sleep substates. Curr Biol. 2021 Nov 22;31(22):5009-5023.e7. doi: 10.1016/j.cub.2021.09.041. Epub 2021 Oct 13. PMID: 34648731.

 

Likely and Unlikely Causes of Mass Shootings

     

The pace of mass shootings and school shootings in the United States continues unabated at this time. I am writing this like I have written many posts in the past – a few days after a mass shooting in a school.  I just heard a news reports saying that this was the 167^th school shooting since Columbine on April 20, 1999.  NPR posted a story saying that there is a shooting or a potential for shooting in schools every day (1) – based either on a gun discharge of someone brandishing a firearm in school. They reference the K-12 School Shooting Database stating that this is the 39^th incident this year that involved gunfire on school grounds.

The media descriptions of the current incident follow much of the coverage in the past about unclear motive, shocking circumstances, unpredictability, questions of an “emotional disorder” and counseling, and the devastating impact on families and the community. I saw a forensic psychiatrist interviewed speculating on the aggressive dynamics based on the detail that the shooter recently disclosed a transsexual orientation.  A clergyman was interviewed and suggested the shooter was really looking for the school minister who was providing counseling.  One of the shooter’s fiends was interviewed.  She was contacted immediately prior to the incident and promptly notified authorities – but by then it was too late. The video of the SWAT team running through the hallways and eventually running toward gunfire and killing the shooter keeps playing.  In some cases that video is compared directly to the Uvalde, Texas video  and comments are made about this is a much better example of how law enforcement should respond. I saw some of these reports where they put up the response time on the screen.  

There are the usual expressions of “enough is enough” and “we don’t send our kids to school for this to happen.”  Republican Representative Tim Burchett came right out and said what most people were thinking: “ We’re not gonna fix it….” But then to make it more palatable he added: “criminals are gonna be criminals.”  He thought we needed a “revival” to “change peoples’ hearts in this country.” Later he disclosed he was home schooling his daughter (3).

I am already on record on this blog writing about the real cause of mass shootings and gun violence in general and it is the politics of gun extremism.  The Republican party has figured out that gun extremism works for them along with several other easily demagogued social issues like abortion, voter suppression, education, anti-science, anti-climate change, and more recently “wokeism”. That has led to a series of initiatives to drastically reduce gun regulations.  There has been an undeniable increase in deaths due to gun violence.  Mass shootings, suicide, homicide, and accidental deaths are all routinely ignored as calls for regulations that were effective for decades until Republican advocates rolled them back – even though gun regulations in the past were never a problem.

The typical rhetoric used is a gun extremist interpretation of the Second Amendment.  In the case of voters, it was the usual emotional appeal that “they” were coming to take their guns.  Anyone familiar with the distribution of guns in the United states realizes this is an impossibility, but it is a rallying point for emotional rather than rational appeals.  In recent years we have seen the rhetoric extended to mental illness as a cause of mass shootings.  There is some confluence with antipsychiatry factions who falsely equate psychiatry with the pharmaceutical industry and suggest that antidepressant drugs cause the mass shooting phenomena.  This post will provide clear evidence to the contrary.

On the issue of common psychiatric disorders in comparing the countries that utilize the most antidepressant prescriptions – the prevalence of those disorders is consistent among the United States and the other countries at the top of the list.  These disorders include depression, anxiety disorders, and substance use disorders – conditions that antidepressants are all commonly prescribed for. English speaking and European countries had similar prevalence (4) with possibly lower prevalence in Asia. There are similar variations in the estimated prevalence of schizophrenia and mood disorders in different areas of the world (5, 6).  

A good summary document on the research about mental illness and mass shooting incidents is available from the Treatment Advocacy Center (10).  They summarize the results of several studies as indicating that at least one third of the perpetrators had "serious untreated mental illness."  Their review is remarkable for a wide range of methodologies and selection biases that probably overestimates the number of cases of severe mental illness in mass shootings.  Smaller sample sizes generally showed a greater number of cases of severe mental illness.  In the case of a study by Stone (11) he found that 32% of 228 mass killers had severe mental illness but during the sampling period there were 1,000 incidents.  The variation is often considered due to methodological differences in the surveys but as previously illustrated– even significant differences in incidence and prevalence of these disorders is unlikely to account for the huge differences in gun deaths between the USA and other countries.  The main difference is that people with the same mental illnesses have much easier gun access in the US.

Several studies of people involved as shooters have shown that some of them have psychiatric diagnoses and in some cases they are being treated by psychiatrists.  Some are prescribed medications but the toxicology at the time of the incident is typically not available. In a related study of murder-suicide by the New York City Medical Examiner’s office that of 127 cases over a 9-year period only 3 (2.4%) were taking antidepressants (7).  Two were taking amitriptyline and 1 was taking sertraline. The authors made the point that antidepressant use in this case series was much lower than the expected population rate.  In a series of 27 elderly men who killed their spouse and then died by suicide – more disease conditions and depression were seen as possible predisposing factors – but none tested positive for antidepressants (8).  When considering the prescribing of antidepressants in general,  epidemiological studies suggest that most of these medications are prescribed by non-psychiatrists. With the proliferation of non-physician prescribers, managed care strategies designed to accelerate antidepressant prescribing based on limited assessments, and widely advertised televisit prescribing it is likely that gap between psychiatrist and other prescribers has increased substantially and will continue to grow.

The argument has been made that people become agitated, suicidal, and homicidal on antidepressants. This is a recurrent theme that is often related to medicolegal considerations, criticism of the pharmaceutical industry, and psychiatric criticism.  There is often a suggested scenario of the antidepressants (especially selective serotonin reuptake inhibitors or SSRIs) causing agitation or activation making suicidal or aggressive behavior more likely.  After reviewing the existing evidence the FDA has placed a black box warning for suicidality in "children, adolescents, and young adults".  There are also warning and counseling bullet points on clinical worsening as evidence by: "emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down".  Standard medical and psychiatric practice advises the patient of these potential risks and what the plan should be if they occur.  In 35 years of clinical practice my observations were that these symptoms were rare and most likely to occur if an antidepressant was discontinued and the patient experienced significant sleep disturbance. The patients I treated with severe aggressive behavior were generally untreated for psychiatric disorders and often had substance use disorders.  A recommendation I have not seen is that all of these incidents should be studied from a prospective comprehensive psychiatric standpoint as they occur with no selection bias.  That study should include toxicology, detailed collateral information, analysis of available medical records, and post mortem analysis if relevant.

In choosing a reference (9) for international comparison of mass shooting phenomenon it is important to consider how the database is constructed. In choosing reference 9, the author described a clear rationale and methodology.  The basic criteria include an incident where there are at least 4 shooting deaths and the shooter is acting alone and not due to criminal or terroristic motivations. Since mass shootings in the US have been motivated by neither – there would be no equivalent comparison with incidents in the US. The author also compares the US to the 35 United Nations definition economically developed countries (see Supplement 1). The time frame of 1998-2019 was chosen.  On that basis half of the countries did not have a single mass shooting incident, ten had more than one, five had more than 20 fatalities, and the US had 12 times as many incidents as the country with the second most mass shootings. Much greater detail is included in the original reference.

I prepared two reference tables based on this data (click on either table for a better view).  The graphic at the top of this page does not include suicide and homicide rates for each country.  The table below includes both of these rates.  Data sources are referenced in the tables.  

 

The countries are arranged by defined daily doses (DDD) of antidepressant medications.  DDD is a World Health Organization (WHO) defined metric for medication utilization. It looks at the total amount of a defined class of medication using the Anatomic Therapeutic Chemical (ATC) classification based on the usual prescribed dose of medication. In that system antidepressants are listed as a class.  US data are highlighted in the table because they represent the focus of this post.

What are some likely and unlikely observations from the Table.  First, it is unlikely that antidepressant prescriptions are a proximate cause of mass shootings.  The countries bracketing the US in antidepressant utilization (Iceland and Portugal) each had no mass shooting during the period of interest (1999-2018).  Second, gun availability stands out as an obvious factor in mass shootings, gun related suicides, and gun related homicides.  Third, gun availability in the US (120.5 firearms per 100 person) nearly equals gun availability in every other country in the table (128.4 firearms per 100 persons).  Fourth, no country had homicide rates similar to the US, but 3 of the countries had similar suicide rates but much lower rates of gun suicides. The reference study looks at locations, relationships, and firearms as relevant points but no comments on mental illness or toxicology at the time of the incident. The author also points out that in many countries mass shootings trigger government intervention focused on decreasing the likelihood of future shootings.  Except for a time limited assault rifle ban that does not happen in the United States.  The gun regulatory landscape is headed in the opposite direction with a movement to permitless access to handguns.

In summary, the gun violence landscape in the United States is bleak. Despite rationalizations that this is really a mental illness or mental illness treatment problem there is no real supporting evidence, since the distribution of mental illnesses in the US is the same as comparable countries with no to few mass shootings. There is low quality evidence that mental illness may be a factor in 15-30% of incidents - but the only way to explain why that is a factor is those people have much easier access to firearms.  The overwhelming evidence is that this is a problem of gun extremism, gun access, and sociocultural factors like subcultural acceptable violence, media notoriety, and politically reinforced messaging about gun use. The only way to address the problem based on international examples is to decrease gun access.  That is unlikely as long as one major party and their appointed judges need to activate their base with false messaging and flood the country with easy to access firearms.  They bear the ultimate responsibility.

George Dawson, MD, DFAPA

 

Supplementary 1:  UN Classified Developed Countries (total of 36) for reference 3 in Table and reference 9 below:  Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Japan, Latvia, Lithuania, Luxembourg, Malta, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom, and the United States.

 

 References:

1:   Florido A, Summers J. By one measure, the U.S. has had a shooting on school grounds almost every day.  https://www.npr.org/2023/03/28/1166630346/by-one-measure-the-u-s-has-had-a-shooting-on-school-grounds-almost-every-day

2:  K-12 School Shooting Database:  https://k12ssdb.org/all-shootings

3:  Winter J.  After the Nashville shooting a faithless remedy for gun violence. New Yorker.  Amrch 29, 2023:  https://www.newyorker.com/news/daily-comment/after-the-nashville-school-shooting-a-faithless-remedy-for-gun-violence

4:  Steel Z, Marnane C, Iranpour C, Chey T, Jackson JW, Patel V, Silove D. The global prevalence of common mental disorders: a systematic review and meta-analysis 1980-2013. Int J Epidemiol. 2014 Apr;43(2):476-93. doi: 10.1093/ije/dyu038. Epub 2014 Mar 19. PMID: 24648481; PMCID: PMC3997379.

5:  Goldner EM, Hsu L, Waraich P, Somers JM. Prevalence and incidence studies of schizophrenic disorders: a systematic review of the literature. Can J Psychiatry. 2002 Nov;47(9):833-43. doi: 10.1177/070674370204700904. PMID: 12500753.

6:  Waraich P, Goldner EM, Somers JM, Hsu L. Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can J Psychiatry. 2004 Feb;49(2):124-38. doi: 10.1177/070674370404900208. PMID: 15065747.

7:  Tardiff K, Marzuk PM, Leon AC. Role of antidepressants in murder and suicide. Am J Psychiatry. 2002 Jul;159(7):1248-9. doi: 10.1176/appi.ajp.159.7.1248. PMID: 12091219.

8:  Malphurs JE, Eisdorfer C, Cohen D. A comparison of antecedents of homicide-suicide and suicide in older married men. Am J Geriatr Psychiatry. 2001 Winter;9(1):49-57. PMID: 11156752.

9:  Silva JR. Global mass shootings: Comparing the United States against developed and developing countries. International Journal of Comparative and Applied Criminal Justice. 2022 Mar 21:1-24.

10: Treatment Advocacy Center.  Serious Mental Illness and Mass Homicide. June 2018,  https://www.treatmentadvocacycenter.org/key-issues/violence/3626-serious-mental-illness-and-mass-homicide

11:  Stone, M. F. (2015). Mass murder, mental illness, and men. Violence and Gender. 2015; 2, 51-86.

 

 

 

How I ended up in a high-risk pancreatic cancer screening clinic

Pancreatic cancer is a scary disease. The pancreas (like the brain) is in a difficult to access space.  It is removed from other anatomical structures so that it does not produce symptoms that lead to early detection.  In medical school they taught us two presentations – waking up with painless jaundice and depression.  The painless jaundice is more of a specific give away than the depression. In either case, prognosis at the time of diagnosis is poor and has not improved significantly in the past decades (1,2,7).

I think about discussions I used to have over lunch with several specialists. Our typical group consisted of 3 GI docs, 1 or 2 Infectious Disease docs, a nephrologist and me.  We usually talked about movies but one day it turned to pancreatic cancer.  The question became – if you could screen for it would you?  This discussion happened back in the 1990s and the consensus at that time was no.  One of the pieces of evidence offered was the poor prognosis after surgical intervention – irrespective of the time of diagnosis.

I personally know 10 people who were diagnosed with pancreatic cancer. Four of them are on the paternal side of my family and one is a first degree relative – my sister. My earliest recollection of the disease was visiting my paternal aunt who lived a few blocks from my family.  Back in the 1950s, there was no useful imaging and diagnoses typically depended on exploratory surgery and direct tissue sampling. People who lived in remote areas did not travel to large referral centers to see specialists. You lived and died based on the skill of local physicians – some who had surgical training but were not technically general surgeons. Blood banking also did not exist and my father and uncle had to donate blood for my aunt. Nine of the 10 people I have known with pancreatic cancer are deceased some of them within weeks to months of the diagnosis.  My sister has been a trail blazer.  After a fortuitous diagnosis while being scanned for gallbladder disease, pancreatic cancer was diagnosed and she underwent radiation therapy, chemotherapy, a Whipple procedure, and maintenance therapy with a poly (ADP-ribose) polymerase (PARP) inhibitor.  She saw an oncologist who recommended genetic testing and discovered she had an ATM gene variant. The genetic counselor she was seeing at the time recommended that all her siblings get tested for the same gene and to see if their children also needed to be tested.

ATM stands for “ataxia telangiectasia mutated.”  Ataxia telangiectasia (AT) is a hereditary degenerative ataxia that occurs in 1 in 20K to 100K live births (3,4).  Gait problems and truncal instability occurs in the first decade of life followed by progressive ataxia. Telangiectasias starts at about age 5 and are most evident in the conjunctive but can occur at various sites on the body. Immunodeficiency is noted with frequent respiratory infections.  Humoral and cell mediated immunity are affected as evidenced by decreased immunoglobulins and lymphocytopenia. AT is also associated with an increased frequency of cancers beginning with hematological malignancies in childhood and different malignancies as adults (6).  Lifespan with AT is decreased but is now more than 25 years with supportive measures. 

The mutations causing AT were discovered as mutations in the ATM gene in the late 20^th century.  The ATM gene is located on chromosome 11, and the gene product is a serine-threonine kinase involved in DNA repair (5). Like most human genes there are a large number of mutations and single nucleotide polymorphisms (SNPs).  Those mutations associated with AT are insertions, deletions, missense, and truncations.  These mutations can lead to absence or loss of function ATM protein.  In my case the lab report read:

 

Variant Details:

ATM, Exon 10, c.1564_1565del (p.Glu522Ilefs*43), heterozygous, PATHOGENIC

This sequence change creates a premature translational stop signal (p.Glu522Ilefs*43) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872).

This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9000145, 9463314, 10330348, 10817650, 12497634, 21965147, 27083775).

In order to appreciate how the ATM protein works – a brief review of cell biology is in order.  Cells reproduce according to a cell cycle with various components. The protein components and cell signaling of that cycle were discovered in the past 40 years.  The cell cycle has checkpoints designed to stop the cycle and repair any DNA that is discovered as defective along the way. ATM is one of the proteins that modulates that process.  Functional ATM protein means that it is less likely that damaged DNA is passed along in new cell lines and that reduces the risk of cancer.  ATM mutations are associated with increase risk for pancreatic, ovarian, breast, and prostate cancer and as previously noted – malignancies associated with AT.  That is the mile high version of checkpoint and checkpoint proteins.  If you want a more detailed explanation, put it in the comments section and I will add more.

This mechanism is interesting to consider when thinking about genomic versus environmental effects. Peak incidence for new diagnoses of pancreatic cancer occurs during the 70s. If you have a defective DNA repair mechanism – is this the time where those defects accumulate to the point of creating malignancy?  How is your history of avoiding carcinogens like alcohol and tobacco smoke relevant to that probability?  What about the protective effects of antioxidants and exercise? At some point does a partially functional ATM protein protect against cancer or is the fully functional protein required?

The referral process in my own primary care clinic went smoothly when I told my internist about my sister’s diagnosis. I got an online appointment with a genetic counselor and when the results came back – she told me there was a 10-15% chance of pancreatic cancer and one clinic that did risk surveillance at Mayo.  She asked me if I was interested and why.  She also advised me that there are currently loopholes in the law that allow some companies to discriminate against you based on genetic testing. After discussing what those companies did – I told her I was not concerned about it and she made the referral.  I met with the gastroenterologist who headed the clinic, signed up for additional research protocols, had an MRI scan and just completed an upper GI endoscopy with ultrasound (US).  The ultrasound device is in the head of the gastroscope and it needs to be positioned in various areas of the stomach and duodenum to visualize the entire pancreas. The US procedure was also set up to proceed with a fine needle biopsy of the pancreas – but no lesions were noted and no biopsy was necessary. If a biopsy is required it is done through the wall of the stomach or duodenum.  Current screening is on an annual basis and the orders have already been placed for next year.

Getting back to the answer to the question posed in the title - it comes down to genes. One of the cultural myths in the US is that you always bear some level of responsibility for your disease. Recall any discussion about this with friends or family: “Did you hear that your classmate died last week from X?”  The next question or comment is likely to be – “well he (smoked, drank, never exercised, was obese, didn’t take care of himself, never saw a doctor, etc.”). There always must be an explanation for your old classmate dying prematurely and it is rarely biological.  Even though everybody in town with the same risk factors – outlived him by 20 years.  The stark reality is that it does not take a risk factor-based analysis. All it takes is a gene (or many genes) that code for the disease either directly or indirectly.

 

George Dawson, MD, DFAPA

 

References:

1:  Armstrong SA, Schultz CW, Azimi-Sadjadi A, Brody JR, Pishvaian MJ. ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications. Mol Cancer Ther. 2019 Nov;18(11):1899-1908. doi: 10.1158/1535-7163.MCT-19-0208. PMID: 31676541; PMCID: PMC6830515.

2:  Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021 Jul;18(7):493-502. doi: 10.1038/s41575-021-00457-x. Epub 2021 May 17. PMID: 34002083; PMCID: PMC9265847.

The risk of death from pancreatic cancer rises dramatically with age from <2 deaths per 100,000 person-years for individuals in the USA aged 35–39 years to >90 deaths per 100,000 person-years for individuals aged >80 years.

3:  Subramony SH, Xia G. Disorders of the cerebellum, including the degenerative ataxias.  In:  Neurology in Clinical Practice (7^th edition). RB Daroff, J Jancovic, JC Mazziotta, SL Pomeroy (eds). Elsevier, London, 2016.  p: 1468-1469.

4:  Rothblum-Oviatt, C., Wright, J., Lefton-Greif, M.A. et al. Ataxia telangiectasia: a review. Orphanet J Rare Dis 11, 159 (2016). https://doi.org/10.1186/s13023-016-0543-7

5:  ATM serine/threonine kinase [ Homo sapiens (human) ]

Gene ID: 472, updated on 12-Mar-2023

https://www.ncbi.nlm.nih.gov/gene/472

6:  Hsu F, Roberts NJ, Childs E, et al. Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene. JAMA Oncol. 2021;7(11):1664–1668. doi:10.1001/jamaoncol.2021.3701

“The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95%CI, 0.8%-1.3%) by age 50 years; 6.3%(95%CI, 3.9%-8.7%) by age 70 years; and 9.5%(95%CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95%CI, 4.5-9.5) in ATM variant carriers compared with noncarriers.”

7:  Trikudanathan G, Lou E, Maitra A, Majumder S. Early detection of pancreatic cancer: current state and future opportunities. Curr Opin Gastroenterol. 2021 Sep 1;37(5):532-538. doi: 10.1097/MOG.0000000000000770. PMID: 34387255; PMCID: PMC8494382.

8:  Oh SY, Edwards A, Mandelson MT, Lin B, Dorer R, Helton WS, Kozarek RA, Picozzi VJ. Rare long-term survivors of pancreatic adenocarcinoma without curative resection. World J Gastroenterol. 2015 Dec 28;21(48):13574-81. doi: 10.3748/wjg.v21.i48.13574. PMID: 26730170; PMCID: PMC4690188.

9:  Overbeek KA, Goggins MG, Dbouk M, Levink IJM, Koopmann BDM, Chuidian M, Konings ICAW, Paiella S, Earl J, Fockens P, Gress TM, Ausems MGEM, Poley JW, Thosani NC, Half E, Lachter J, Stoffel EM, Kwon RS, Stoita A, Kastrinos F, Lucas AL, Syngal S, Brand RE, Chak A, Carrato A, Vleggaar FP, Bartsch DK, van Hooft JE, Cahen DL, Canto MI, Bruno MJ; International Cancer of the Pancreas Screening Consortium. Timeline of Development of Pancreatic Cancer and Implications for Successful Early Detection in High-Risk Individuals. Gastroenterology. 2022 Mar;162(3):772-785.e4. doi: 10.1053/j.gastro.2021.10.014. Epub 2021 Oct 19. PMID: 34678218.

10:  Søreide K, Ismail W, Roalsø M, Ghotbi J, Zaharia C. Early Diagnosis of Pancreatic Cancer: Clinical Premonitions, Timely Precursor Detection and Increased Curative-Intent Surgery. Cancer Control. 2023 Jan-Dec;30:10732748231154711. doi: 10.1177/10732748231154711. PMID: 36916724; PMCID: PMC9893084.

"The overall poor prognosis in pancreatic cancer is related to late clinical detection. Early diagnosis remains a considerable challenge in pancreatic cancer. Unfortunately, the onset of clinical symptoms in patients usually indicate advanced disease or presence of metastasis."

11:  National Center for Biotechnology Information. ClinVar; [VCV000127340.60], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000127340.60 (accessed March 19, 2023).

Graphics:

I drew that genogram of my immediate family using EDraw Max.  I am one of the two siblings that tested positive for the ATM variant. My other siblings have not been tested. 

Endemic ≠ Benign

 

“There is a widespread, rosy misconception that viruses evolve over time to become more benign. This is not the case: there is no predestined evolutionary outcome for a virus to become more benign, especially ones, such as SARS-CoV-2, in which most transmission happens before the virus causes severe disease…”

Aris Katzourakis
Professor of Evolution and Genomics
University of Oxford

 

I typically don’t like to post on a non-psychiatric topic immediately after posting one.  But the current level of misinformation on the pandemic necessitates this. That is obviously not because I am a big influencer with widespread readership – but I like responding to the sea of right wing misinformation on Twitter. And today it was all about how the response to the pandemic was an overreaction with far reaching effects. Nothing about how the virus has killed 1.1 million Americans, the impact of that mortality on families and businesses, the impact on the healthcare system and its workers, and the enduring disability of millions with long COVID.  The evidence is clear that the pandemic was mishandled early on as the Trump administration denied the degree of the problem and then falsely reassured the public that everything was under control. The only way the right wing can rewrite that history is to push a false narrative that there was a conspiracy theory to prevent any investigation of the lab leak theory, that face masks and public health measures don’t work, that school children are irrevocably damaged from online learning, and that all of these unnecessary measures were really an unnecessary infringement on freedom. Unfortunately, pandemic viruses don’t work that way. They do not really care about your political affiliation or what you read on Twitter.

One of the popular myths during the early to mid-pandemic was the idea of herd immunity and how by ignoring all of the public health suggestions up to and including the immunizations (or “jabs” as they are referred to by the right wing) the entire population would build up immunity and the pandemic would fade away. The way that argument was typically presented minimized any death or disability along the way.  Herd immunity would happen and it would happen quickly to resolve the problem.  It also implicitly assumed that writing off the elderly and the 10% of the population that is immunocompromised was morally acceptable.  Not much discussion of how herd immunity would happen without immunizations – since many of the proponents were ideologically sympathetic to the idea that public health measures and immunization were unnecessary.

An associated concept of endemic disease cropped up at one point. The popular usage was  to say: “This is no longer a pandemic, there are no more large outbreaks, therefore we can declare it is an endemic like the common cold viruses.”  Since this was also an ideological rather than scientific argument – it was also a rationale for stopping all of the suggested public health measures and getting things back to normal as soon as possible,

That brings me to a brief essay on endemics written by evolutionary virologist Aris Koutzourakis in Nature (1).  The title speaks for itself.  His definition of endemic is straightforward -  endemic infections mean that the infection rate is static – not rising or falling. The best intuitive example is common cold viruses – there are predictable seasonal fluctuations but the number of viruses and the composition of the pool of common respiratory viruses stays about the same and no one outcompetes the others. Nobody is too worried about common cold viruses because they are not too deadly and don’t commonly overwhelm the healthcare system.  Influenza viruses are somewhat different.  Whether and epidemic or pandemic occurs depends on an elaborate system of guessing the correct components for the influenza vaccine and measures taken to prevent zoonotic transmission of potentially more lethal influenzas viruses – like avian influenza. That backdrop of common cold versus influenza viruses seems like a way to understand endemicity.  It leaves out one important point and that is endemic pathogens can also be lethal and create disability.

Dr. Koutzourakis lists several examples of endemic, but lethal pathogens including malaria, polio, and tuberculosis.  They are all significant causes of mortality and morbidity.  He successfully predicted that unless the pandemic was stopped quickly subsequent evolving variants could be more transmissible and difficult to treat.  That occurred with the subsequent 4 SARS-CoV-2 variants. Viral evolution has also been observed with other pandemic viruses and the occurrence of more dangerous variants. He analyzes the current behavioral situation correctly in the United States.  Even if people are not using the word endemic – they are generally stating that the pandemic is over and that it is time for a return to normal.  Normal typically means no public health measures like masking, social distancing, or even deciding to stay home if you are ill.  The only place that those measures are acceptable is in a medical or dental facility and even then they are no longer universal. To compound the problem, the anti-public health ideologues are either bragging that they were correct all along or actively spreading misinformation about masks, vaccines, or the origin of the virus.

The graphic at the top of this page (click to enlarge) is taken from the CDC web site today.  Even though the area in the red rectangle looks fairly static going back to May of 2022 – the actual number of cases per week ranges from 170 to 900K.  That corresponds with weekly deaths 1,795 to 3,697.   Dr. Katzourakis suggests that there is the potential to see additional spikes of infection and suggests that the direction this pandemic will take at this point depends a lot on continued public health measures, immunizations, antiviral medication, and individual behavior.  One of the critical aspects of science as I explained in my previous post is that scientists look at data supporting or refuting hypotheses in terms of probabilities and also speculate with probability statements. Viral epidemiologists and evolutionary virologists know how viruses work and evolve. Their predictions are much more likely to be accurate than someone with no expertise and no data.  The next time you hear politicians or news personalities talking like this pandemic is over take it as an unfounded opinion. Do the same thing when your neighbor tells you that you don’t need to get any more vaccinations or wear a mask in crowded places.

Don’t let ideology blind you to science.

 

George Dawson, MD, DFAPA

 

References:

1:  Katzourakis A. COVID-19: endemic doesn't mean harmless. Nature. 2022 Jan;601(7894):485. doi: 10.1038/d41586-022-00155-x. PMID: 35075305.

2:  Centers for Disease Control and Prevention. COVID Data Tracker. Atlanta, GA: US Department of Health and Human Services, CDC; 2023, March 12. https://covid.cdc.gov/covid-data-tracker  accessed on 03/12/2023

3:  Callaway E. Beyond Omicron: what's next for COVID's viral evolution. Nature. 2021 Dec;600(7888):204-207. doi: 10.1038/d41586-021-03619-8. PMID: 34876665.