Data Science in Medicine – Part I

Only a few years ago Health Care practitioners would methodically write down their clinical impressions during a face to face interview with patients and then pass the chart to a waiting nurse or aide that would proceed to the next stage. The piece of paper was the final trustworthy depositary for all the clinicians’ opinions and recommendations. Then the chart would eventually be shared with other professionals, technicians, administrators, payors’ functionaries, etc., and ultimately find its home in an archive.

The advent of Electronic Record-keeping has dramatically upended that quaint era and changed all the paradigms of care delivery for all the involved parties. As most practitioners sit in front of their terminals and type along the patients’ narrative, once the face to face clinical encounters are finished and the patients leave the medical office, a torrent of medical information also rushes out of the door with them too. Then it proceeds to feed several endpoints related to consulting offices, studies’ referrals, control and audit, pharmacies’ inboxes, administrative oversight, etc.

We are living in an era when every time we click on our computers or smartphones, every time we send any messages, every time we manifest any preferences in the social media, there is a quick sharing of information that escapes our control and becomes manipulated by total strangers as we have described in a previous article. However, this technological tsunami can become very useful for the smart medical researchers who can analyze and interpret  humongous amounts of data sets. Using ever changing algorithms and powerful computers, they can mine gold from it.

The classical tenets of medical research are changing dramatically as breakthroughs are achieved by biomedical researchers, mathematicians, computer programmers, statisticians and several others that contribute specific skills for the task at hand; together they can “read” from the enormous amount of data to find significant correlations between seemingly disconnected facts to swiftly inform practitioners. The biggest gains from Data Science have occurred in the field of genomics, thus enabling to tailor treatments to the patients’ unique characteristics in Oncology, Hematology, Cardiovascular diseases, Neurological diseases, Ophtalmological disorders, etc.

At present the first priority of the research community is to figure out multiple ways to share clinical, laboratory and technical data in real-time with their peers all over the country and beyond in order to use it to find innovative, revolutionary cures. The Observational Health Data Sciences Informatics program (OHDSI) has designed a data- sharing network of medical investigators of multiple institutions in twenty-five countries to study the medical records of almost 400 million (yes, million) people. The Department of Biomedical Informatics at the Columbia University Irving Medical Center (CUIMC) has the responsibility of coordinating this research; they are already actively mining the data and producing outstanding results in racial disparities of health care access and equity, cross-national differences, hidden side effects of drugs, etc. We will discuss many of them in future installments of our next blogging season.

What do you think? Please tell us.

Don’t leave me alone.

Artificial Intelligence (AI) in Medicine –part I

There are some things or issues that we eagerly discuss in the public forum with the certainty that it dramatically concerns us all and should be addressed forthrightly. While we waste time in endless intellectual discussions about their different aspects, that thing or issue is silently seeping through into the own fabric of our societies. We have the illusory comfort that our civic concerns might modify and/ or mollify their progress. Those fetishist vagaries give them the time to invade our personal spaces and seize our lives. The use of Artificial Intelligence (AI) is a case in point. It is already here with us.

Awake or asleep, we are already sharing a significant part of our lives with various machines that process humongous loads of data to deliver specific, tailored services for us all. When we join a chat or dating group, when we load up pictures in our platforms, when we program appliances in our techie-laden homes, when we plan a vacation, etc., we provide a lot of information to computers and programs that efficiently process it. The arrival of AI in the medical realm has been fostered by the need to process vast amounts of data for precise diagnoses and treatment protocols to get good outcomes.

In an April 2019 position paper, Dr. Scott Gottlieb, the outgoing director of the Food and Drug Administration (FDA), designed the basis for the regulatory framework to authorize and supervise the medical devices infused with the Artificial Intelligence. Dr. Gottlieb emphasized that there was a critical need to build guardrails to protect the development of new techniques and algorithms without stifling the innovation or restricting the access to breakthrough treatments for patients in critical need. He said that: “Artificial Intelligence and machine learning have the potential to fundamentally transform the delivery of health care…As technology and science advance, we can expect to see earlier disease detection, more accurate diagnosis, more targeted therapies, and significant improvements in personalized medicine.”

In the past, the FDA has been acerbically criticized by scientist, physicians, patients and almost all the professional cadres of the Health Care realm because of its slow, step-by-step review of any major technology, drug or treatment to assure the efficacy and safety of any new product that aspires to swiftly enter the commercial market. Acknowledging that its traditional approach is unfit for rapidly evolving treatment algorithms that are constantly being updated using the field data, the FDA is devising novel ways to allow the software to evolve and adapt to changing circumstances while at the same time steadily meeting the stringent safety requirements of the institutional regulator.

We celebrated our birthday with our son by sharing a nice dinner and a night out at the movies. What film did we see? Terminator Dark Fate, of course. It won’t be long before any of you us would be relaxing at the operating table with the early effects of a total anesthesia when we will suddenly notice a familiar figure approaching us in green scrubs:

-“Hi, my name is Dr. Arnold,” he would say with a hoarse Teutonic accent. “I will be performing your surgery today. Any questions?” Let us confess that his mechanically smiling face will not appear as that re-assuring to us in that moment.

What do you think? Please tell us.

Don’t leave me alone.

Love and Libido after a Total Mastectomy

Women have a strong sense of self and body that helps them visualize themselves at all times. A small physical defect will hardly ever pass unnoticed and unacknowledged by the dear women. In a mirror image, they will perceive “what the other sees” in her, especially the other women. Then it should come as no surprise that the utterly traumatic surgical event of a Total Mastectomy for Breast Cancer often has a devastating physical and psychological tally on their minds and moods.  In order to experience libido or “the desire for sexual company”, women have to feel at ease from the physical and emotional standpoints, which is hardly the case in post-surgical patients. This is one of the least discussed issues in our medical practices, compounded by the fact that it is almost never addressed in medical schools’ curriculums, even in the supposedly “enlightened” countries. Physicians and other health care personnel are left with the extremely bad option of learning sur-le-champ, often quasi-alone.

After forty years of medical practice, we have collected a few nuggets of wisdom for these patients, even though we never practiced Gynecology and we have always avoided doing any Gyn exams ever since we were in medical school. However, talking to patients and friends after undergoing that procedure, we found these challenging issues:

  1. Toxicity of associated medication.
  2. The unwise hurry to have a Prosthesis.
  3. The lack of an honest discussion between partners
  4. The absence of a proper bereavement process

A – Toxicity of associated medication

In 1998 the Food and Drug Administration (FDA) approved the use of Tamoxifen for the use in both men and women that were diagnosed with hormone-receptor-positive early-stage Breast Cancer to avoid the recurrence of the disease after surgery; similarly it is being used for patients with advanced-stage of the disease and had metastases of a hormone-receptor-positive neoplasia. The pharmacological activity is dependent on its conversion to its active metabolite, endoxifen, by the enzyme CYP2D6, which acts as an estrogen modulator to competitively inhibit the binding of endogenous estrogens. It is available in a pill form (Nolvadex) or  a liquid from, easier to swallow (Soltamox) Almost ten percent of Breast Cancer patients have a slow-functioning CYP2D6, which can hamper the effectiveness of the drug and several medications, most notably the selective serotonin re-uptake inhibitors (SSRIs) like the anti-depressants, can block its activity. This drug has serious side effects like blood clots, Stroke and Endometrial Cancer but also less prominent ones like vaginal bleeding, dryness of vagina and loss of libido that affect the quality of life.

B – The unwise hurry to have a Prosthesis

Many surgeons precipitously offer the possibility of having a prosthesis installed right after the resection, in a kind of “two-for-one” deal to supposedly expedite the healing process of women. Unfortunately, most women would surely miss “the part that was taken away” and consider that prosthesis as an alien object that does not have the necessary seal of approval by her hormonal and psychological self. If there was an honest discussion with her family and sexual partner about the traumatic aftermath of the procedure, why rush through the protocols and insert the prosthesis?

C – The lack of an honest discussion between partners

There is not a hint of sexual enticement or libidinal drive in a woman that feels nausea and pain after the surgical act, compounded by the psychological stigma of “being uglier’ than before. Patients have to take charge of the physical and emotional distress to slowly research and find the pharmacological, hormonal, psychological and sociological interventions to ease her burden. One of the most damaging approaches consist of “sticking the head in the ground’ like an ostrich to avoid facing the dark undertones of this radical procedure. Nothing will be the same after it. Patients, partners and family members must honestly deal with the reality and find ways to heal. Women should make clear to their partners that they cannot recover the same kind of sex life. There will be times of physical discomfort, depressive states, untoward side effects and frustration. The patient, partner and family should carefully consult the caring professionals to find the proper pharmacological solutions and psychological help to overcome the trauma post-mastectomy.

D – The absence of a proper bereavement process

When we lose a loved one, we must sadly go through one the worst human processes: bereavement. After the initial shock and denial stages, we progressively start accepting that most tragic fact. Only after we methodically go through each and every stage, will we be able to overcome grief. Similarly, a woman, that was aesthetically and psychologically attached to her own body before,  must go through the same stages until she can find a way (or ways) to cope with the stark reality. In those circumstances, the sustained support of her partner and family play a pivotal role.

After a Total Mastectomy, a savvy woman will learn the new parameters of her new physical and psychological coordinates and, eventually, she will recover her lost desire for sex and company. She will need the continued assistance, tolerance and patience of all those who love her dearly. Piercing through her dense fog of dire despair, we should be a beacon of hope and encouragement so she can resume her life journey in earnest.

What do you think? Please tell us.

Don’t leave me alone.

 

Epigenetics

(This article was adapted from our new book Emotional Frustration-the hushed plague.)

After the Darwinian revolutionary writings[i] enshrined the concept that natural selection and evolution were the major mechanisms to modify our bodies, some alternative hypotheses were summarily discarded for the sake of clarity. Jean Baptiste Lamarck, a French naturalist, proposed that all the species have strived to attain the perfect state, for which there are multiple variations; the living organisms not only evolved but they did it slowly, little by little and successively.[ii]

In 1800 Lamarck gave his first lecture in the prestigious Musée National d’ Histoire Naturelle where he discussed the mutability of species—later developed in a book.[iii] According to Lamarck, life becomes diversified due to these factors:

  1. The Power of Life: tends to make organizations increasingly complex.
  2. Effects of the Environment: modifying influence of circumstances.

When the molecular structure of the human DNA was discovered by Watson and Crick in 1953[iv], scientists determined that its coded information could not be altered in any significant way by the environment or the person’s lifestyle choices. In 1975 Robin Holliday and John Pugh, English biologists, and Arthur Riggs, an American, found that methylation—an inherited chemical change of the DNA strand—can be modified by the environmental factors.[v] Epigenetics.[vi]

Studying laboratory animals, they discovered that severe environmental stress can have long-term effects in the information provided by the genes, i.e. epigenesis. The genetic material stays untouched but its “expression” or “reading” is greatly altered; this biological alteration can be transmitted in some instances to future generations that have not experienced the initial triggering factor in their lifetimes. Rat or mouse pups are subjected to maternal separation and then their behavior is studied for signs of depression; their genetic material is analyzed for alterations.

Rudolph and Adrian Bird published a seminal paper in 2003 where they said: “stable alterations of this kind are ‘epigenetic’ because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years have focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histones modifications.”[vii]  As part of our reaction to stress, we secrete a hormone called glucocorticoid that mediates certain immune mechanisms like inflammation; when the offending agent disappears, the glucocorticoids bind to some brain receptors and its production in the adrenal cortex stops in a feedback loop. [viii]In 2106 Gustavo Turecki and Michael Meaney published a paper where they show that the gene that codifies this glucocorticoid receptor is inactive in animals that had experienced great stress in their early days, thereby limiting their ability to shut off its production.[ix] Even after the cause for stress has disappeared, they keep producing the stress hormone.

The epigenetic mechanism consists of a physical barrier of methyl markers in the DNA, which prevents the proper reading of the stored information in genes. Can this epigenetic trait be transmitted from a mother to her children? Scientists are still debating this issue but there are indications that when the DNA replicates during the cell mitosis, the methyl markings can be introduced in the new genetic material.

Scientific studies have shown that when women are subjected to undue stress during pregnancy, they give birth to children with impaired responses to stress. After the Allied landing in Normandy in August 1944, there was a prolonged stand-off between the opposing armies in the Lower countries, Belgium and Holland.[x] In order to force the population into not helping the Resistance and the advancing armies of Montgomery and Patton, the German Army rationed food supplies.[xi] The women who were pregnant at the time of the tragic Dutch Hunger winter, eventually gave birth to children with a higher rate of obesity and schizophrenia.  Nadine Burke Harris says that the origin of many of our societal problems may arise from the exposure to undue stress in childhood that leave a genetic marking.[xii]

Did our mothers and grandmothers possess the right intuition before science confirmed it?

What do you think? Please tell us.

Don’t leave me alone.

References

[i] Charles Darwin, “On the origin of species”, Mass Market Paperback, New York, 2003.

https://www.amazon.com/Origin-Species-150th-Anniversary/dp/0451529065

[ii] Encyclopedia Britannica, “Jean-Baptiste Lamarck”, https://www.britannica.com/biography/Jean-Baptiste-Lamarck

[iii] Jean Baptiste de Monet de Lamarck, « Recherche sur l’organisation des corps vivants : précédé du discours d’ouverture du cours de zoologie donne dans le Musée d’Histoire Naturelle » Fayard, Paris, 1986.

https://www.amazon.com/Recherches-sur-lorganisation-corps-vivants/dp/2213017018

[iv] Leslie A. Pray, “Discovery of DNA structure and function: Watson and Crick” Nature Education, 1(1):100, 2008.

[v] Nelson Cabej, “Building the most complex structure on Earth: an epigenetic narrative of Development and Evolution of animals”, Elsevier, February 2013.

https://www.elsevier.com/books/building-the-most-complex-structure-on-earth/cabej/978-0-12-401667-5

[vi] Israel Rosenfield, Edward Ziff. “Epigenetics: The Evolution Revolution”, The New York Review of Books, June 7, 2018. https://www.nybooks.com/articles/2018/06/07/epigenetics-the-evolution-revolution/

[vii] Jaenisch R., Bird A., “Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals” Natural Genetics, 2003 March, Supplement 245-54.1

https://www.ncbi.nlm.nih.gov/pubmed/12610534

[viii] Robert M. Sapolsky, L. Michael Romero, Allan U. Munck, “How do Glucocorticoids Influence Stress responses? Integrating Permissive, Suppressive, Stimulatory, and Preparative Actions” Endocrine Reviews, Volume 21, Issue 1, February 2000, pages 55-89. https://doi.org/10.1210/edrv.21.1.0389

[ix] https://www.utsc.utoronto.ca/~pmcgowan/documents/McGowanBrainRes08.pdf

[x] William Shirer, “The rise and fall of the Third Reich, Fiftieth Anniversary edition”, Barnes and Noble, 2018.

https://www.barnesandnoble.com/w/rise-and-fall-of-the-third-reich-william-l-shirer/1100214065#/

[xi] Ibidem as above.

[xii] Nadine Burke Harris, “The deepest well: healing the long-term effects of childhood adversity” January 2018.

https://www.amazon.com/Deepest-Well-Long-Term-Childhood-Adversity/dp/0544828704/ref=tmm_hrd_swatch_0?_encoding=UTF8&qid=&sr=

The SPRINT-MIND study – Control of BP to reduce risk of Dementia

The randomization for the clinical trials of the SPRINT-MIND study was started on November 8, 2010, in 102 sites in the USA and Puerto Rico under the guidance of Dr. Williamson et al. Out of the 9361 randomized participants—mean age of 67.9 years and a female participation over 35%— approximately 91% of them completed one year of follow-up cognitive evaluation. The participants were randomized into two groups: in the first one, half were treated to maintain a systolic blood pressure of less than 120 mm of HG—the intensive group—and the other half was treated to maintain one of less than 140m mm HG—the standard treatment group. The median time of interventions was 3.34 years. Initially designed to end in 2018 the study was ended in August 2015 due to bioethical reasons because the researchers found benefits for the first group.

Individuals confined to a nursing home, with a diagnosis and/or treatment of dementia, diabetes or stroke were excluded form this study. The researchers did not explicitly screen participants for a diagnosis of Mild Cognitive Impairment (MCI) in their selection, which raises the possibility that a few of the participants might have already clinical signs of Dementia at the beginning. Moreover, they purposefully did not include the older patients with several co-morbid conditions, which might actually bear the higher risks of aggressive treatment of high blood pressure—orthostatic hypotension, stroke or ongoing cardiovascular failure. Another example of how trials discriminate against older patients and expose them to unknown grave risks with their cookie-cutter approach.

During a median intervention period of 3,34 years, probable dementia occurred in 149 participants of the intensive and care group and 176 in the standard treatment group; intensive BP control reduced the risk of MCI—14.6 versus 18.3 cases per 1,000 person-years—and the combined rate of MCI or probable dementia—20.2 versus 24.1 cases per 1000 person-years. The trial failed to reach statistical significance on its primary cognitive outcome of a reduction in the occurrence of dementia. Some academics claim that the study failed to reach significance because the testing was cut short and more time should be allotted for follow-up of patients; the Alzheimer’s Association has announced the provision of a U$ 800,000 grant to add two more additional years to the study.

In a Neurology Today article on this study, Dr. Emer R. McGrath said that the technique for obtaining blood pressure readings they had utilized—use the average of three automatic readings with no personnel in the room—might give mischievously low readings than the one in practices. The risk of over-treatment and adverse effects in already frail patients is worrisome indeed. Other practitioners point out that researchers do not know which BP medication might work best and at what age. However, the majority of those interviewed were hopeful that the follow-up study might bring statistical significance to the concept of controlling the BP to avoid future onset of dementia.

We already know that a methodical control of one’s blood pressure as of middle age will make a significant difference to avoid cardiovascular and renal diseases in our older years. Similarly, we believe that the same Wellness interventions will help us at least delay the mind ravages of ageing in order to have a better quality of life.

What do you think? Please tell us.

Don’t leave me alone.

Is transfusion of “young plasma” the modern Fountain of Youth?

Baby boomers, long accustomed to the ethos of youth, have a hard time accepting their inevitable ageing, especially when it involves the onset of serious neurodegenerative pathologies like Alzheimer’s Disease. Apart from trying countless, varied drug and Wellness interventions, which include a healthier diet and exercise, some worried adults are spending a lot of money in non-FDA approved therapies like transfusions of plasma. In a February 2019 warning, the Food and Drug Administration (FDA) informed consumers that they should be very wary of those providers and clinics that offer “miracle cures” with young plasma.

The FDA warning did not exclude the possibility that “plasma transfusions” might eventually become a valid therapeutic tool , after conducting carefully designed peer-reviewed clinical trials under the supervision of institutional review boards and strong regulatory oversight. The practice has risks. The use of transfusions can produce infections, allergic reactions, circulatory volume overload and the danger of botched maneuvers.

In the July 2019 issue of AMA Neurology, Dr. Sharon Sha et al, from the prestigious Stanford University, informed the results of a small study that involved 10 participants with Alzheimer’s disease; nine individuals got four weekly infusions of the plasma fraction under a protocol of the double blind crossover and nine other individuals got four weekly infusions under an open label. The researchers found that the plasma infusions were safe and tolerable for all the participants. Dr. Sha found that even though there was not a clinically significant improvement in their mood and cognitive alterations, there was some improvement in their cognitive abilities, which eased the burden of the caregivers.

This pioneering Stanford trial was funded by Alkahest, a California biotechnology company that was co-founded by Dr. Tony Wyss-Coray, a Stanford neuroscientist who invented a technique. Parabiosis is the study of the circulatory changes when a young mouse is connected to an old one; the surgical technique allowed the exchange of blood and its derivatives in both directions. Alexander Eggel and Wyss-Coray found that the old mice that received the plasma improved their ratings in the memory testing using the maze techniques and the histochemical studies of their brains showed increased plasticity, which is a hallmark for good synaptic activity in learning and memory.

Are all the components of young plasma responsible for these results or is it produced by fractions? Alkahest has designed a “selected plasma fraction” from the processing of pooled plasma and at present is testing two of those in three Phase 2- clinical trials for chronic diseases; it is also testing a small molecule-inhibitor in the treatment of macular degeneration, which produces blindness. In a scientific meeting in Barcelona about Clinical Trials in Alzheimer’s Disease, Grifols, another biotechnology company, showed encouraging results of a clinical trial using plasma products.

Obtaining the necessary safety data about these techniques will eventually pave the way for the use of plasma fractions in many neurodegenerative diseases; however, many scientists warned that, even with the benefit of efficacy and safety features, there might not be not a “magical cure” as the nefarious components in old blood might ultimately prevail in the protracted clinical process. In a January 2018 article, Bjorn Hofmann wrote: “eternal youth and endless bliss have always been vital human dreams. Although parabiosis may brings us closer to the fountain of youth than ever, it is still too early to provide full-fledged assessments of its implications or to foresee how it will change health, aging, medicine and society.”

What do you think? Please tell us.

Don’t leave me alone.

The nutritional value of Moringa

After resoundingly defeating King Darius III at the battle of  Gaugamela, near modern-day Mosul in Irak,  Alexander the Great conquered the Achaemenid Empire of Persia which stretched to the Indian sub-continent in the East. Believing that the world ended in India, he then led his impressive Macedonian Army in 326 B.C. into its Easternmost frontier, which corresponds to the present-day Punjab in Pakistan. His army faced the forces of King Porus in the battle of Hydaspes and defeated them; however, there were many casualties in the conquering army, including Bucephalus, Alexander’s dear horse. When the conqueror decided to continue his march, his army, exhausted and homesick, rebelled at Hyphasis and obliged him to give up his dream, turning southward instead.

The Macedonians were surprised by the stamina and fighting capacity of Porus’ soldiers, which they attributed to the healing and wellness faculties of an indigenous plant from a tree: Moringa. It is a native tree of many regions of Africa and Asia, the sole genus in the flowering plant family Moringaceae; the name derives from the Tamil denomination of “drumstick”. The most diffused variant is Moringa oleifera, which grows at the foothills of the Himalayas, in Northeastern India.  For centuries this plant has been used to treat anxiety, stress, asthma, anemia, chronic bronchitis, skin infections, cholera, etc.; its anti-inflammatory, anti-spasmodic, anti-hypertensive, anti-tumor, anti-pyretic, anti-epileptic, diuretic, anti- cholesterol, anti-diabetic properties were known by many cultures.

The modern interest in phytotherapy—the study of the healing power of extracts of natural origin—has rekindled the scientific initiatives to determine the real value of the components of this plant, which has been labelled as “the tree of life” in ancient cultures for its great versatility. The Moringa has vitamins, minerals, beta-carotenes, antioxidants, anti-inflammatory components and omega 3; its leaves have a high content of Vitamins C, calcium, Beta-carotene, potassium and essential proteins. The high concentration of flavonoids, ascorbic acid, carotenoids and phenolics extends the period of usage of fat containing foods, a critical factor to conserve food in the under-developed world.

Recent studies linked the presence of low-grade inflammation to Insulin resistance and Obesity through the presence of cytokines, tumor or necrosis alpha factor, interleukin-1-Beta, etc. Moringa oleifera has significant power as a blood glucose-lowering agent because some of its metabolites—N-Benzyl thiocarbamate, N-Benzyl carbamates, benzyl nitrites and benzyl—trigger the release of Insulin in pancreatic cells in experimental rats. An in-vitro study of a Philippine variant showed that several of its metabolites decreased the size of tumors; abnormal growths treated with methanolic extracts of Moringa fruits and leaves were slowed down. Aqueous extracts of pods’ husks have anti-microbial properties against Gram positive, gram negative and yeasts organisms.

The Moringa leaves can be eaten fresh, cooked or stored as dried powder for many months, without losing any of its nutritional value.  In the tropical areas, the Moringa tree remains in full leaf at the end of the dry season, a critical period for the continued sustenance of the population because most of the trees become leafless. It can be safely used a dietary supplement for children, the elderly and pregnant women as well.  For the above-mentioned reasons, it has been dubbed as the Miracle tree or Mother’s best friend.

What do you think? Please tell us.

Don’t leave me alone.