Vol. 199 September 15, 2018 Nature vs. Nurture . . . an update

September 15, 2018

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“The closer scientists get to understanding the impact of individual genes,
the smaller that impact seems to be.”
– Evan Horowitz, Boston Globe, 9/11/18,C1

The discussion about what influences our upbringing the most, the environment (“nurture”) or our genes (“nature”), has been going on for decades. Sets of twins, particularly comparison of fraternal twins (two genetically different people born at the same time) and identical twins (two genetically identical people born at the same time), have been the subjects of much research trying to tease out the answer to which has the most influence. Why is one twin smarter than the other? Why does one love football and the other the violin? Why do they have the same walk, the same tastes in clothing, and the same gestures, but one has no sense of humor and the other is the class clown?

Despite the revelations in the recent movie, “Three Identical Strangers, many ethical and scientifically-rigorous twin studies have added a great deal of insight into the nature vs. nurture conundrum, and the discussion continues in the absence of consensus. The completion of the human genome project in 2003 was heralded as an historic step in finally settling this question. The hope was that, at last, we would be able to correlate a specific gene, or maybe just two or three genes, with a human characteristic, a human condition, and even a human disease.

In a recent study of the human genome, researchers found 1,271 different genes that seemed to improve educational outcomes. However, the cumulative effect of these educationally significant genes explained only about 11-13% of real world, actual educational attainment. (1) In a separate study by other researchers, the role of inherited genes in height, obesity, and education seemed to have much less influence than previously estimated . . . and a drastically much smaller role than suggested by twin studies. The influence of genes was highest for height (55%) and lowest for years of schooling (17%). The gene effect on cholesterol level was about 31% and the gene effect on determining your body mass index (BMI) was 29%.(2) There is no single “fat gene.”

One group of researchers suggested that perhaps the genes of the parents that are NOT passed to their offspring are important. What if the parents’ genes made them “slightly more attentive to kids and more willing to sacrifice their own happiness for the benefit of the kids”? Perhaps that could result in those children receiving a richer education. They suggested calling this influence of the parents’ genes on the children’s environment “genetic nurture”. (Thanks a lot for mudding the waters some more!)

There is no doubt that the genes we inherit from our parents influence our health and longevity. The adage, “To enjoy a long life, pick your parents right”, was dramatically brought home to me one day in the hospital cafeteria many years ago. A dozen of us physicians were discussing over lunch the pros and cons of a new study that daily baby aspirin could prevent some heart attacks, and different opinions about this brand new data were being voiced. A cardiologist espousing the strong genetic influence on heart disease interrupted our lively discussion with the question, “How many of you can call your father on the phone right now?” Only three could.

So the discussion of nature vs. nurture continues despite our growing knowledge of the human genome, but we have nothing to worry about as long as we have picked our parents right.

References
1. Nature Genetics, July 2018, as reported in Boston Globe, September 11, 2018
2. Ibid

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Vol. 198 September 1, 2018 A RX for Play

September 1, 2018

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“Unfortunately both the value and the meaning of play are poorly understood in our hurried society.”
The Hurried Child, 1981

“Play for children buffers toxic stress, builds parental relationships,
and improves executive functioning.”
-The Power of Play,  2018

This month the American Academy of Pediatrics (AAP) recommended that all clinicians write a “prescription for play” for all children at each well child visit. The AAP first touted the benefits of play in 2007.  What’s new about this 2018 report, “The Power of Play”,  is 1) the compilation of 139 scientific studies supporting the benefits of childhood play, 2) the specific recommendation that clinicians give a “prescription to play” to the parents of children at every well child visit in the first two years of life, and 3) the inclusion of a list of specific parental actions and behaviors to help parents actually “fill the prescription”.

What is not new is the knowledge that play is very important for children’s cognitive (academic), social, language, and emotional development. In 1981 (almost 40 years ago!) David Elkind, Ph.D. in The Hurried Child, Growing Up Too Fast Too Soon (1) catalogued how play was one of the antidotes to the toxic stresses on our children at that time. His 1981 list of the sources of that stress on children sound still familiar to us in 2018:

  • early pressure to gain academic skills
  • early intervention to help learning in the early years (concept of “readiness” was disputed)
  •  media presentations of adult clothing and behavior as models for children
  •  changes in the traditional family model (dual-career couples, increased single parent families, single parent dating, increased divorce rate )
  • summer camps (and after school programs) becoming competitive training sites for specific skills
  • Cutting of recess, physical education (“gym period”), art, music and drama from school curriculum
  • increasing modes of passive play (no real-time human interaction; media play is passive).

“Play has been transformed into work. Perhaps the best evidence of the extent to which our children are hurried is the lack of opportunities for genuine unstructured play available to them. Genuine play involves human interaction, mostly child to child but also child to adult. Play is nature’s way of dealing with stress for children as well as adults.” – All written in 1981 by Dr. Elkind.

What are some of the specific ingredients listed by the AAP to fill the 2018 “prescription for play”? (2)

Newborn- 6 months

  • talk to your infant, mimic his or her sounds
  • make various faces at the infant so he or she can mimic you
  • let him or her put safe objects in their mouth

7-12 months

  • put infant in different positions so that he or she can view the world from different angles (“tummy time”)
  • use a mirror to show different faces to your infant
  • Peek a boo is a BIGGIE !
  • give him or her more toys to drop (teaches that actions have effects)
  • let infant safely crawl and explore freely

1-3 years

  • give paper, crayons, etc. to encourage scribbling
  • play make-believe with the child
  • read regularly to the child
  • sing and play rhythms to the child

4-6 years

  • allow child to move between make-believe and reality (pretend making biscuits and then tolerate the “spreading of flour all over the kitchen table”; if you can’t tolerate the mess, maybe change this play into ‘actions have effects’?)
  • tell stories and ask your child what she or he remembers about it
  • encourage a variety of safe physical movements (climbing, somersaults, etc.)

“Play with parents and peers is fundamentally important for developing a suite of 21st century skills in a competitive world that requires collaboration and innovation.”(3)

Dr. Elkind won me over completely when he explained why young children are entranced by dinosaurs; something that has perplexed me for years.
“Dinosaurs provide children with a symbolic and safe way of dealing with the giants in their world, namely adults.” (pg. 196)

Refernces:
1. Also “The Power of Play, Learning What Comes Naturally”, 2007, David Elkind, Ph.D
2. from www.pathways.org
3. Michael Yogman, MD, lead author of The Power of Play, AAP, 2018


Vol. 197 August 1, 2018 GMO Tomatoes?

August 1, 2018

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“ The sad reality is that industry is not really committed to making a better tasting tomato.”
– Harry J. Klee, Ph.D., University of Florida

 

It’s August on Cape Cod, and I have yet to taste a big red luscious locally grown tomato! How long do I have to settle for the bland, tasteless, but very red (they gas green tomatoes with ethylene to turn them red) commercially grown ones?! Is there any hope for a better tasting commercial tomato?

GM (genetic modification) has been going on for centuries through selective breeding and artificial selection by the hands of mankind to improve plants and animals. Pre-Columbian natives, by selecting and re-planting those wild scrubby plants that had bigger, redder, and more fruits, started the development of the beefsteak heirloom tomato we know today. There is probably no vegetable or fruit that we eat today, including corn, soybean, and potatoes, that is not the result of mankind’s genetic selection over thousand of years.

But now those initials, GM or GMO, spark great controversy because scientists can do the genetic selections in a much shorter time in the laboratory. The initial GMO crops introduced by Monsanto in the 1990’s were “transgenic” products;. foreign DNA, even from other species, was introduced or “spliced” into the genes of plants to make them more resistant to Monsanto’s herbicides. Corn and soybean which could thrive in the rain of a new, “more effective” herbicide ignited wide-spread concern and speculation about the long-term effects of the “foreign DNA” GMO crops.

In the same year of 2012 the Tomato Genome Project completed its listing of the 900 million DNA base pairs on 12 chromosomes of the tomato AND a gene-cutting technique dubbed CRISPR  was first described.  Scientists from three universities  published their CRISPR research separately in the same year. UC Berkley , MIT, and Harvard continue the legal battles over the patent rights which will be worth billions. CRISPR is basically a pair of biological scissors that allow scientists to precisely snip and delete part of a gene. It is referred to as “gene-editing”. It is not “transgenic”. No “foreign DNA” is involved or inserted.

For example, for the past 60 years growers have been trying to develop a “jointless” tomato. The classic tomato plant develops a swollen knuckle of tissue in its stem just above the fruit. When the tomato is ripe, the stem knuckle gets a signal from the plant for its cells to die, the stem breaks at this “joint”, and the tomato falls to the ground to happily spread its seeds and make new plants. The problem for the tomato grower who is mechanically harvesting tons of tomatoes is that the residual long stem pierces lots of other tomatoes in the picking process. The damage makes them unsellable. By CRISPRing the gene responsible for the knuckle and deleting it, a “jointless” tomato plant results in a bigger, undamaged crop, and more money for the grower.

Other CRISPR experiments are aimed at developing “self-pruning” tomato plants that are half as tall, less bushy, and with more fruits. Some experiments hope to develop plants that flower earlier, that ignore daylight clues, that require a smaller footprint, and that space their fruit on a stem like an accordion. If you discern that these efforts are all aimed at improving the tomato’s financial return in the market place, you are right. One cynic has stated that the “perfect tomato will be one that exactly matches the size of a MacDonald hamburger… A better tasting tomato always plays second fiddle to market economics.”

CRISPR is great at knocking out or deleting genes. It edits genes. The US Department of Agriculture has determined that crops developed with gene editing mutations are “indistinguishable” from those produced by traditional breeding and “do not require regulatory oversight”. It is a long way from the research lab to the market place via the three agricultural mega-conglomerates, but a variety of start-up companies are developing CRISPR-like technologies for getting cheaper, and maybe better tasting, gene-edited produce to market.

So, just when you hoped that life would be getting simpler and choices might become fewer, you now have to ask yourself a new question, “If it’s GMO, is it transgenic (jury is still out) or just gene-edited (approved)?” Although we may be a long way from getting commercially grown tomatoes that taste as good as our locally grown beefsteak heirlooms, do not fear, CRISPR may soon produce a gluten-free wheat!

Reference: “Tomorrow’s Tomato”, Stephen S. Hall, WIRED, August 2018, pg.053-061


Vol. 196 July 15, 2018 Consequences of Separating Children From Their Parents

July 15, 2018

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“Home Security and Family Values –
Is that an oxymoron?”

 

 

Hundreds of children in immigrant families wishing to enter the U.S. from Mexico have been separated from their parents by U.S. policy. The administration has not released the actual number, but the number of unaccompanied children held in U.S. detention centers jumped up by 20% from 8,000 to a little over 10,000 children after implementation of the “zero tolerance policy”.

In 2016 the Secretary of Home Security John Kelly began to talk about such a separation policy as a deterrent to families seeking entrance either illegally or even if legally seeking asylum on our Mexican border. In response to that proposed policy a coalition of pediatricians, psychiatrists, and social scientists published “Separating Families at the Border – Consequences for Children’s Health and Well-Being” in the New England Journal of Medicine (NEJM) June 15, 2017 and founded the Child Advisory Network   to advocate against the “zero tolerance policy”.

Now, nobody really believes that separating children from their parents, unless the children are being maltreated or abused, is good for the children. Our own legal system has a very high threshold for removing children from their parents. And maybe, administration policy makers were probably counting on this universal belief (in all languages, of course) to make their action an effective deterrent to immigration.

The NEJM article summarized the many studies that document the deleterious effects of separating children from parents; all based on the over-activation of the stress response system of the child’s brain and specific hormone producing organs. Proper balance of that system is necessary for normal physical growth, proper and appropriate regulation of emotions, and maintenance of good health. In fact, such stress and anxiety is apparently cumulative and can ever result in an earlier-than-expected death!

The high costs of separating and detaining the children, especially the costs of finding and supporting foster care for U.S.-citizen children of parents who have already been deported, was cited in this review. In many states the foster care system for American children is overwhelmed and an occasional source of horror stories of maltreatment by foster parents.

Perhaps you’re thinking that these are moot points after the announcement of the reversal of the “zero tolerance policy”, but NPR reported on July 12 that in a response to a court order deadline only 57 of the 100 under the age of 5 years had been reunited with their parents (49 other were not). NPR also reported that the total number of separated children is 3000. The next court order deadline in about two weeks calls for 2000 families to be reunited. Both court orders stem from suits brought by the ACLU against the U.S. Department of Home Security.

Reason cited by the Home Security Department for some “failures to reunite” include criminal charges against a parent(s), parent not available since already deported, and a lack of match between the child’s DNA and the parents’ DNA. Wow, talk about opening up another Pandora’s box for the U.S. border staff, Home Security Department, and our judicial system, already creaking under “zero tolerance policy” consequences. Resolution of those instances of DNA “mismatch” will become another nightmare for already stressed-out families and children who were seeking sanctuary from the stress of living in their own country in the first place; a uniquely modern negative consequence of political policy once again trumping science.


Vol. 195 July 1, 2018 BIG DATA and a whiff of AI in health care

July 1, 2018

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“When it comes to health data, Watson hasn’t been much help.”
-STATNEWS, Ross and Swetlitz. Bos Globe 6/18/18

This week all the newspapers (at least in Massachusetts) have been abuzz with the announcement that Atul Gawande, MD has been picked by three moneyed titans of innovation to head their new company to revolutionize health care. Optimism, promise, and hope is in the air! Kind of like when IBM presented Watson, its supercomputer, in 2015 as the tool to provide workable insights into the financial and clinical dilemmas of U.S. hospitals in 2015 via Watson Health.

How is that working out? Watson Health has access to data on tens of millions patients, in part by spending $9 billion to acquire other companies. It’s initial focus was on developing workable products in oncology, designed to help physicians individualize cancer treatments. “With these acquisitions, IBM will be one of the world’s leading health data, analytics, and insights companies, and the only one that can deliver the unique cognitive capabilities of the Watson platform”, said the general manager of Watson Health in 2015.

They (the newly merged companies) struggled with the basic step of learning about the different forms of cancer and the rapidly changing landscape of treatments. Last week Watson Health laid off people partly because, according to some, even Watson had difficulty in digesting all that data. “…They also don’t understand the generation of information, and how it is used, and whether they can do something different with it,” said Robert Burns, professor of health management at U Penn Wharton School. You can almost hear every primary care physician that is struggling to get their new EMR system to give him/her more information and less data cheering loudly in the background, “We couldn’t have said it better!”

The goal of a great deal of innovative technology in health care is “ “zero patient harm”. if Atul can’t do it all with his surgical checklists and Watson can’t do it all with data from tens of millions of patients , what/who can? How about Artificial Intelligence (AI), aka “machine learning”? AI and machine learning is the converting of data into information without the need for human programmers. For instance, if the computer views enough pictures of different dogs, it will learn to correctly identify a cocker spaniel. I think a real test of AI would be to see if it can recognize a Labradoodle,  or any other of the many poodle cross breeds. (Don’t you sometimes worry about the moral standards of poodles that seem to be eager to mate with any kind of passing breed?)

The building of knowledge from patterns in data, both visual and language, is labeled “computer vision”. In some medical studies “computer vision” is used to monitor actual bedside events and identify omissions or non-compliance in procedures. It has apparently improved rapidly beyond just identifying dogs or skin rashes because of “deep learning”: a type of machine learning that uses “multilayered neural networks whose hierarchical computational design is partly inspired by biologic neutron’s structure.” (1)  Got that? Think Google’s self-driving cars. “Computer vision may soon bring us closer to resolving a seemingly intractable mismatch between the growing complexity of intended clinician behavior and human vulnerability to error.” (2)

So, the effort to cut the Gordian knot of patient safety and cost-effective medicine continues. I suspect that the three titans of innovation have turned to Atul Gawande, a health care innovator who successfully uses clinical insight and re-education to effect change, because they recognize the limitations that are becoming more apparent in big data.

  1.  NEJM April 5, 2018 378:14; 1271-2
  2. Ibid.

Vol. 194 June 1, 2018 Some DOs and DON’Ts

June 1, 2018

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Avoid fried meats which anger up the blood.
-Satchel Paige’s Guide to Good Living

 


DON’T drink alcohol
 Really?? I thought red wine prolonged your life by preventing certain types of heart disease. That IS the current wisdom. It is thought to be the compound reservatrol that provides that benefit. If you believe that then eat lots of grape skins, peanuts, and blueberries for their reservatrol.

A Lancet Journal study of 600,000 current  high-income European drinkers suggests that the threshold for an increased risk of cardiovascular disease is LESS than previously thought. The U.S. Dietary Guidelines, based on previous studies, state that one glass of wine daily for women and two glasses daily men is carries no risk and might even be beneficial. This Lancet study suggests that the threshold of increased risk of death from cardiovascular disease is just one glass a day, regardless of gender. Reviewers of the study remark that such guidelines are not very helpful for individuals. Remembering that obesity kills more people than alcohol is helpful for the context. But, alcohol deaths are still more common than opioid deaths. About one-third of driving fatalities involve alcohol-impaired drivers. In one study 40% of convicted killers said they were under the influence of alcohol when they committed homicide. About 25% of suicides are alcohol related. So, again, as they say on Fox radio news, “We report. You decide.”

DO measure your PAS (Prostate-Specific-Antigen) if your 55-69 years old.
DON’T measure it if you’re 70 or older.
This is a more neutral update of the 2012 U.S. Preventative Services Task Force recommendation against PAS testing because of studies showing overly aggressive diagnostic testing and treatment of low risk patients based on the PAS level. Nowadays “active surveillance” rather than “aggressive treatment” has become the norm as has “shared decision-making” ( the fancy label for discussing the results and management options with your primary physician).

DON’T smoke marijuana if breast-feeding.
A very small study (8 women from Denver, … from where else but?) had their breast milk analyzed for THC at different times after smoking a standard joint. Calculations showed that about 2.5% of the inhaled dose was ingested by the infants. The THC levels in the breast milk were highest in the 1 and 2-hour post-joint breast milk samples . The 20 minute and 4 hour post-joint samples were one-half that. Those breast milk levels are very low, would not cause any apparent change in the infant’s behavior, but the effect of any exposure of cannabis to the developing brain is unknown. No THC metabolites were found in the breast milk.

DO consider liquid nicotine for e-cigarettes as dangerous for toddlers.
One quarter of the nearly 9000 children under 6 years old that got into liquid nicotine meant for e-cigarettes during 2012-2017 had significant clinical effects from the ingestion. Many states, but not all, have legislated child-proof packaging of the liquid nicotine as a result.

DO use the right words for childhood obesity.
Apparently Latino children are more apt to be obese than non-Latino children. A study has shown that those children and parents prefer the words,”unhealthy weight” and “too much weight for the child’s health”. DON’T use “chubby”, “fat”, gordo”, or “muy gordo”. The words “high BMI” and “overweight” were judged to be not motivating in BOTH languages. I guess words DO matter.

DO ignore baby formula marketing pitches.
If you don’t breast feed your infant, then DO use any cow’s milk formula. All the cow’s milk formula’s with added iron are the same nutritionally. DON’T be led astray by marketing ploys like “added amino acids”, “probiotics added”, ” more digestible protein”, etc. The global baby milk formula market is close to $62.5 billion. The only beneficial added ingredient to formula is iron.  Most babies do very well on whatever cow’s milk formula you give them.  Some special infants may need special formulas, but it is a small number. Vegetarians and babies with galactosemia can use soy-milk formula. Otherwise, all infants are “of course, above average” and can thrive on what ever cow’s milk with iron formula you buy for them.

DO reconsider your child’s allergy to penicillin.
Formal allergy testing of 100 children making an ER visit and labeled as “allergic to penicillin” revealed that 0% (nada) of those children with previous low-risk symptoms of penicillin allergy were actually allergic to penicillin. In a follow-up of those children one year later, 60% of them had been given penicillin treatment without incident or allergic reaction symptoms. The estimated savings from using penicillin instead of the higher priced non-penicillin antibiotics for all of the 6700 patients who visit that ER annually with a diagnosis of penicillin allergy was $192,000.

DON’T spend your money for SPF over 30 in sunscreens.
An SPF of 15 blocks 94% of UVB rays. SPF 30 blocks 96%. SPF 40 blocks 97%. None of the usual sunscreens available in the U.S. block the UVA rays which penetrate deeper in the skin and cause aging of the skin. The FDA continues its years-long study of UVA blocking sunscreens already available in Europe. DO put on the sunscreen 30 minutes before going out in the sun to allow its ingredients to activate the skin, and re-apply 20 minutes after exposure to the sun.

and finally . . .

 Avoid running at all times.
DON’T look back. Something might be gaining on you.
– Satchel Paige’s Guide To Good Living


Vol. 193 May 15, 2018 Antibiotics are Beneficial: A Reminder

May 15, 2018

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A disease outbreak anywhere is a risk everywhere.”
-Dr. Tom Frieden, Director U.S. CDC

 

We read a lot about the dangers of using too many antibiotics. The popularity of “organic foods” is due in part to their claim to be from “antibiotic-free” animals and plants. Concern about the increasing antibiotic resistance of germs due to antibiotic overuse is real as is frequently described in scientific journals as well as the general press. Why, then, would the New England Journal of Medicine publish an article describing the benefits of random, mass distribution of an oral antibiotic to nearly 100,000 children who had no symptoms or diagnosis! Maybe because that effort reduced the death rate of children aged 1-5 months by 25%!

As you’ll remember in my last blog,  I was impressed by Bill Gate’s knowledge of the medical literature because during his presentation he cited this antibiotic clinical trial which had been published that very same week. Well, full disclosure, he knew about the study because his foundation funded it! This study is the kind of innovative medical study related to global health that the Bill & Melinda Gates Foundation supports. I think it is worthwhile to review the details of the study, if just to remind us that antibiotics are good, that medical science advances on the shoulders of previous work, and that sometimes simple answers, like putting iodine into salt or fluoride into water, can prevent a whole lot of disease.

Previous studies in sub-Saharan Africa showed that blindness caused by trachoma, an infectious disease, could be reduced markedly through the mass distribution of an oral antibiotic, azithromycin. Other studies suggested that the same antibiotic could prevent other infectious deaths like malaria, infectious diarrhea, and pneumonia. It is known that azithromycin affects the transmission of infectious disease, so that treatment of one person might have benefits on others in the same community. The data in two of these studies of trachoma prevention in Ethiopia suggested that mass distribution of azithromycin “might” reduce childhood deaths. Since death (after the neonatal period) is a relatively rare event, even in these settings, the trial had to be conducted in a large population. Hence the need for a large grant to carry it out.

A single dose of oral azithromycin was given to 97,047 children aged from 1 month to 5 years in three African countries during a twice-yearly census. 93,191 children in different communities of the same countries were given a placebo. Over the two-year study the “treated” children received 4 oral doses of azithromycin, each about 6 months apart. Children were identified by the name of the head of the household and GPS coordinates of their location for subsequent censuses. Approval for the study was obtained from 9 ethics committees in 6 countries (3 in the US, 1 in the UK, and 2 in Africa).

The average reduction of annual death rates of children receiving a single dose of the antibiotic every 6 months was 13.5% . Children aged 1 month to 5 months receiving the antibiotic had a mortality rate reduction of 25%. At the conclusion of the trial all the children in the communities of Niger, which has one of the highest child mortality rates in the world and a mortality rate reduction of 18% for all ages in this study, were offered treatment with azithromycin.

This study is a beautiful example of the testing of a simple hypothesis, generated by the results of previous work, using innovative methods, requiring a large population for validity,  and implemented by a multi-national team of medical scientists with a large grant from a private foundation that resulted in clear benefits for better global health.

I, for one, am happy to trumpet some good news about antibiotics and this example of “medical research for all” at its best.

Reference:
Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa, NEJM 378;17, April 26, 2018

 

 

 

 


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