research Archives - Professor Tony Magaña

What I learned and hope to return to at Mekelle University Ayder Comprehensive Specialized Hospital

Ayder Comprehensive Specialized Hospital campus of Mekelle University

In building neuroscience and neurosurgery at Mekelle University I experienced great happiness in serving the people and training future neurosurgeons and scientists. My seven year experience at Mekelle University serving the people of Tigray and surrounding areas as well teaching neurosurgeons and neuroscience gave me a new perspective on what is true career success. I now recognize there are three phases.

When I first came to Ayder Comprehensive Specialized Hospital in 2015 my initial goal was get a good neurosurgery service going. They were really the only government hospital capable of developing this goal outside Addis Ababa, the capital of Ethiopia, as well as being some distance north so it would offer chances to treat patients who would otherwise go untreated. The University and hospital were committed to building not only quality and quantity of good health care for Tigray and surrounding regions but also to medical education.

Initially I helped teach neuroscience and clinical neurology/neurosurgery to medical students and general surgery residents (young physicians who have graduated from medical school now doing specialty training) basic neurosurgical skills involving mostly traumatic injuries. My goal was to create a neurosurgery training program as well as a neuroscience research team.

Teaching medical students about head injury

After about a year working with Ethiopian Ministries and some good collaboration from the Ethiopian ministries, World Federation of Neurosurgical Societies, and Mekelle University faculty we started a five year training program and a three year fellowship program. Up until the Tigray Ethiopian conflict we had grown to 18 trainees, doing 1,500 operations year, and published internationally recognized research with our multidisciplinary research team on neural tube defects which occur in a high incidence in Ethiopia.

Our research team meet with the World Health Organization

Going through this experience made me reflect on what has been important in my career. When I was a college student at Texas A&M, then a medical student at Harvard, and finally a resident at the University of Miami I was mostly focused on personal achievement and perhaps also personal recognition. Through out that experience and subsequent practice I saw my career as having two phases. Learning to be a neurosurgeon and then becoming a great neurosurgeon. However it was my experience at Mekelle University and Ayder Comprehensive Hospital that taught me there was still a greater accomplishment which was to train great neurosurgeons and neuroscientists.

Senior neurosurgery resident is supervised to remove a brain tumor

At first it was struggle. The hospital had little experience with neurosurgery. As a 60+ year old guy I was in the hospital every night doing surgery with young general surgeons and then residents with whom we had to start from scratch. Still they were eager to learn. With help from Indian and the few Ethiopian neurosurgeons we got up to date textbooks for them to read. Even though English was their second language they became proficient. At the end of the first year they knew more than I did at their level some 40 years ago.

During surgery they have to learn about anesthesia, positioning, hand control, to make movements less than millimeter which could mean life or death, how to control bleeding, how to do a 12 hour operation, and much more. We began to have weekly seminars on very complicated ideas where they absorbed the concepts so well I was learning as much they were. We were organized as most neurosurgical services in a sort of military style hierarchy to which the residents responded to well. Very quickly good and close relationships developed not only with those that were Tigray but also with others from other Ethiopian regions and other countries in the program.

I formed strong relationships with the research bodies of Mekelle University and we created a strong multi-disciplinary research team on neural tube defects which lead to meeting with government and World Health Organization officials, international NGOs, and a finally the beginning of a nationwide plan for prevention and treatment.

Before the Ethiopian occupation and blockade shut the neurosurgery training program down we had operated on more than 5,000 patients from not only Tigray but also Amhara, Eritrea, and occasionally Addis Ababa to Gambella. This week far away from Mekelle I had been doing the “paper work” for my first graduates. I wish we could have had a formal ceremony but I had good voice communication provided. Now I have learned that the best phase of a neurosurgeon’s career is seeing his trainees carry on and expand what I started.

Holiday dinner with my neurosurgery residents and fellow

I pray God will see fit to facilitate Ayder Comprehensive Hospital and myself to return to its service, teaching, and research missions once again.

The immune response to SARS-CoV-2 can be life-saving or deadly

A Toll Like Receptor Type 3 may hold the key to treating COVID 19

A fundamental difference in the immunity of men and women is leading to research in how a difference in response of the immune system to SARS-CoV-2 can be life saving or deadly.

Even though women contract COVID 19 more often then men in part because women outnumber men in jobs like nursing, teaching, cleaning, etc. where there is frequent interaction with large groups or areas of people they do not seem to get as seriously sick or die as often. The same phenomena was seen with previous epidemics involving different coronaviruses then the current SARS-CoV-2.

Although at first differences in smoking or hygienic practices between the sexes were considered, the evidence did not confirm this hypothesis.

The male and female sex have significant differences in their immune systems relating to the X chromosome. Females have two X chromosomes while males have one X and one Y normally. On the X chromosome are a group of genes for Toll-Like Receptors (TLR). The TLR are located in organs which are very active in immune responses to fight infection including the spleen and white blood cells as well as those with exposure to contaminants outside the body including the lungs and gastrointestinal tract. Humans have ten different TLRs labeled TLR 1 to 10. Some of the TLR (TLR 2 and 5) are specifically sensitive to bacteria while TLR 3 and 4 may be sensitive to viral antigens.

Stimulation of TLRs can cause two reactions. For most except TLR3 one reaction results in the production of cytokines which are powerful inducers of inflammatory responses affecting multiple organs. Previous coronavirus epidemics and the the current COVID 19 have been seen in some patients to cause a cytokine storm syndrome (CSS). A cascade of reactions occurs leading to severe destructive inflammation affecting the lungs, heart, kidneys and even sometimes the brain to varying degrees. Organ failure, hemodynamic instability, and ultimately death can occur. The other reaction is to stimulate interferon beta which causes macrophages to engulf antigens (invaders or under some circumstance human ) and activates a form of T-Cells called Natural Killers.

SARS-CoV-2 can trigger a fatal cytokine storm

These reactions can be exaggerated causing damage to normal organs or early on may be protective. Research in mice in 2015 showed that stimulating TLR3 could create a protective response to a coronavirus.

Now getting back to the differences between the sexes. Women generally have two sets of TLRs in the body with two different gene types while men have one. Although most of the cells in the woman will randomly choose one set to be active which could be either gene this means in whole body some cells of each type will be present. Sometimes both chromosomes are working creating an approximately 15% higher level of TLR function than normal. It is suggested by some that having this situation at the time of infection may give women more protection then men as a group statistically.

The problem is that it is well known that women suffer more severely than men from chronic inflammatory conditions such as systemic lupus erythematosus. The interaction of TLRs with normal human tissues to which they become sensitized is being researched. Why do women not have a worse reaction leading to cytokine storm and more frequent death than men? Why do women do better? Could it be that having higher levels at the beginning and of two different types is important?

The controversial drug, hydroxychloroquine inhibits TLR4 response to lipopolysaccharide which in vitro studies suggest can inhibit the virus entering the membrane of the intended cell target. However when given to very sick patients resulted in worsening of lung function. Thus now it is being considered more for prophylaxis than treatment by some.

Some researchers have said that TLRS are “double edged swords” that can cure or kill. How TLRs responses are regulated and when in the course of disease these reactions are therapeutically manipulated may determine if these interventions are helpful or harmful. Research is needed how to better control them to treat COVID 19, autoimmune diseases, and even cancer.

The Need for Physician-Scientists in Ethiopia

Discussing multidisciplinary research at Mekelle University

Ethiopia is now at a point where non-communicable disease is overtaking the classic major infectious and malnutrition disorders which dominated the major morbidity and mortality for the country. Now more than ever with scant resources and unique cultural situations there is a need for effective clinically related medical research at the top universities in Ethiopia. Effective clinically related medical research in Ethiopia requires that academic medical centers begin to train physician-scientists.

Unfortunately the model of how to do medical research and by whom it should be directed and/or overseen is outdated. Because medical schools lagged behind the development of fields like Public Health and Nursing these entities dominated the university structure. At the beginning there were no specialists and very physicians who were so overworked they really had no time for training in methods of research let alone doing it.

Today over 50% of the needs of Ethiopian doctors require specialist training. Additionally the experiments such as occurred in British National Health Service of relying on mostly non-physician scientists to direct and oversee medical research backfired. In the current system almost no funds are directed to physician directed medical research yet Ethiopia desperately needs physician-scientists to lead the way into dealing the health care needs of a growing population of over 100 million people.

We are currently advocating changing this system at Mekelle University. Similar changes are already occurring at St. Pauls Millenium and Addis Ababa University in Addis Ababa, Ethiopia.

The Alliance for Academic Internal Medicine has published these recommendations for training physician-scientists which I think should be strongly considered for adoption wholly or least substantially in Ethiopian university training centers.

Summary of Best Practice Recommendations for Physician-Scientist
(The American Journal of Medicine, Vol 131, No 5, May 2018)
Physician-Scientist Training Programs (PSTPs)
Curriculum and Infrastructure
A. Providing combined residency and subspecialty fellowship training is an attractive feature.
B. PSTPs should include training in study design, biostatistics, team science, ethics, scientific regulatory requirements,
institutional review board application, grant writing, time management, leadership, work/life balance, and mentor/mentee
relations.
C. Directors of PSTPs would benefit from organizing a formal alliance and meeting regularly.
Recruitment and Selection of Trainees
A. Candidates for PSTPs most likely to translate their training into successful careers as well-established physician-scientists
are those who have significant research experience and can demonstrate a balanced commitment to both science and
medicine.
B. PSTPs should make increasing diversity among its trainees a stated goal, with active efforts to recruit qualified women and
members of underrepresented minority populations.
C. Initiatives to recruit qualified international medical graduates as trainees should be increased and additional sources of
funding for international medical graduates trainees should be pursued.
Mentorship Practices
A. Mentoring teams are essential for PSTP trainees and should be carefully crafted.
B. Mentors need to be formally trained in mentoring, and they need to be recognized for their contributions.
4. Funding of PSTPs and Their Trainees
A. The success of PSTPs and their trainees is highly dependent on strong institutional support.
B. The success of PSTPs and their trainees is also highly dependent on adequate levels of external funding including the
successful receipt of individual career development awards.
Tracking Success of PSTPs and Their Graduates
A. Success factors of PSTPs and their graduates should be tracked.
B. Tracked data should be coordinated with other PSTPs and shared in a national data base.
6. Sustaining PSTPs and Employing Continuous Improvement Practices
A. Sustainability is contingent on institutional support and an adequate census of qualified applicants.
B. Sustainability is also impacted by the percentage of trainees who successfully complete their training.

Research:Neural Tube Defects in Tigray Ethiopia

Recent research we have done at Mekelle University soon to be published has confirmed that there is a high rate of neural tube defects affecting the brain and spinal cord in Tigray. Experience suggests this is also the case in other parts of Ethiopia as well. At least 131 out of every 10,000 births is affected with some areas having almost twice that number. Defects result in death at birth for about 77% of the pregnancies affected, usually with anencephaly, while the 23% born alive usually have severe paralysis of the lower extremities and often need a operations to close the open spine, closure of myelomeningocoel, and to control pressure in the brain, ventricular peritoneal shunt, for lumbar and thoracic myelomeningocoel associated with an Arnold Chiari II malformation causing hydrocephalus. Lesser numbers of encephalocoel often requiring closure were encountered as well.

Ethiopian mother hold her child with lumbar myelomeningocoel

The most likely significant cause is lack of diversity in the diet and especially failing to consume foods with the vitamin folic acid. This is usually found in green and leafy vegetables as well as fresh fruits. Cooking foods such as chick peas which may contain folic acid will destroy much of it.

Around the world these birth defects have been reduced about 75% by encouraging women to plan their pregnancy and take 4 milligrams of folic acid daily starting before conception. We are working with our research group at Mekelle University to help the Tigray Regional Health Bureau and the Ethiopian Ministry of Health come up with programs to reduce these defects but this will take time.

In the meantime we encourage all women in Ethiopia to plan their pregnancy, starting folic acid supplementation before they conceive, and practice dietary diversity. They should try to wait one year between pregnancies, and understand that breast feeding increases their need for folic acid. Very young and older women are more susceptible to having children with these defects. Other factors may be involved besides folic acid deficiency but the good news is that folic acid supplementation will likely still reduce these defects.