WINTER 2021

A 30-Year-Old
Female with
Postpartum
Hypertension

p. 29

The Effect of
Empagliflozin and
Spironolactone
Treatment on
COVID-19 Fibrosis Immediately
Re-infection: After Induction of
a Case-Series Myocardial Infarction
Review in Rats

p. 41 p. 16

Never interrupt someone doing Amelia Earhart (1897–1937),

American aviation pioneer and
something you said couldn't be done. author, the first female aviator to
fly solo across the Atlantic Ocean
w w w. j i m s .c o. i l
 The Israeli National Academy of

By the Israeli Medical Association

Vol 01, Number 1, Winter 2021 ISSN 1565-1088

38 Non-Invasive Thermal Imaging to Detect and Monitor

7 LETTERS TO THE EDITOR Various Diseases
N. Dunn and S. Bhat R.Y. Brzezinski, N. Rabin, E. Grossman, Z. Ovadia-Blechman,
J. Leor, and O. Hoffer

ORIGINAL ARTICLES 41 COVID-19 Re-infection: a Case-Series Review

A. Papish, D. Fridman, D. Venkert, N.S .Zuckerman, O. Mor,
8 The Effects of the Covid-19 Pandemic and E. Schwartz
on the Mental Health and Learning
Abilities of Medical Students:
A Cross-Sectional Study RESEARCH SPOTLIGHT
M. Peer, M. Rudolf, J. Essa-Hadad and L. Malatskey
53 Assessment of the Diagnostic Criteria of
16 The Effect of Empagliflozin and Spironolactone
Osteonecrosis of the Jaw in Cancer Patients with a
Treatment on Fibrosis Immediately After Induction
History of Radiation Therapy and Exposure to Bone-
of Myocardial Infarction in Rats
N. Bandel, E. Daud, O.Ertracht and S. Atar Modifying Agents
Y. Ganor
23 Attention Mediates the Similarity Effect in Decision
Making
O. Maor, M. Glickman and M. Usher 56 LETTERS TO THE EDITOR

CASE ARTICLES
DOCTOR'S RECOMMENDATIONS
29 A 30-Year-Old Female with Postpartum Hypertension
O. Hadad and E. Grossman
62 Science of Yoga by Ann Swanson
S. Barami

REVIEW
FROM THE PATIENT'S PERSPECTIVE
32 Preparing and coping strategies for
medical students' experience with 65 Discovering Destiny: A Researcher with Ichthyosis
a patient's death: systematic Dedicates her Career to Investigate her Own
narrative literature review Disorder
Y. Lisai and A. Shaulov J. Mohamad
 VOL 01 • WINTER 2021

EDITORIAL BOARD
Editor in Chief:
Guy Melamed Copyright © 2021
Journal of Israeli Medical Students
Executive Editor:
Daniella Vaskovich-Koubi, BMSc
Eden Engal, MSc Journal of Israeli Medical Students (JIMS),
email: info@jims.org.il
Gal Binshtok
Miki Goldenfeld, BMSc
Sari Assaf, BMSc All advertisements in this issue are put forward at
Shahar Barami the sole responsibility of the advertisers. Similarly,
all articles are the responsibility of the authors
Yael Erez
alone. The Israel Medical Association and the editors
SENIOR LEADERSHIP AND SCIENTIFIC BOARD of JIMS are not accountable for the contents of any
advertisement or article.
Angel Porgador, Phd
Dina Ben Yehuda, MD
To enter the JIMS website
Ehud Grossman, MD
scan this sign
Eithan Israeli, PhD
Elon Eisenberg, MD
Hannah Tamary, MD
Karl Skorecki , MD EDITOR’S WELCOME
Leah Wapner
Malke Borow
Michal Paul, MD
Rivka Carmi, MD
I t is a great honor to welcome you to the inaugural issue of
the Journal of Israeli Medical Students, - JIMS. JIMS is the
first Israeli student-led medical journal, dedicated to publish-
Ron Dagan, MD ing the research and ideas of Israeli medical and dental stu-
Shai Ashkenazi, MD dents worldwide.
Shlomi Israelit, MD JIMS was founded as a vision of a group of medical stu-
Yehuda Ullmann, MD dents during the first COVID -19 lockdown in October 2020,
Yehuda Zadik, MD during our first steps in the medical world. At the same time
Yuri Tsitrinbaum countries worldwide and health systems were, (and still are),
Zion Hagay, MD facing the biggest medical challenge of the past 100 years:
the COVID -19 pandemic. In addition to sickness and death,
A SPECIAL RECOGNITION as citizens of the world cautiously move forward, they are
Yafit Shenhav bombarded by misinformation alongside boundaries between
Ella Kave extraneous, politics and evidence-based science blurring. Pre-
Baruch Donenfeld cisely at a time like this, our mission to provide a platform
that will foster future physicians acquiring and practicing
Romi Azoulay
of medical research methods, and promote students contrib-
Alex Bensi Dagi
uteions to issues facing health and medicine, is essential.
Amelia Hallworth On account of the vast and swift changes we are witnessing,
Kate Woodford JIMS aims to cultivate a community of researchers, innovators,
Nicky Dunn thought-leaders, and policy-makers, while using the highest
Nikki Nabavi standards of scientific publications.
Nishu Uppal The Israeli medical system is unique, and so are the process-
Sameer Bhat es for medical school education, professional training, and com-
Wei Ng pleting an Israeli MD/ DMD/Ph.D. The average
Israeli student is older and more independent
MANUSCRIPT AND PRODUCTION EDITOR than its colleague in other countries, approxi-
Yoel Bogoch, PhD mately half of future Israeli practitioners study

4
 VOL 01 • WINTER 2021

abroad, and at the same time, despite the rela-
tively long years of studying and training, the
grade requirements for Israeli medicine facul-
ties is the highest of all fields of study. All these
factors and more demand attention and constant adaptation to
current global events to ensure a solid and sustainable Israeli
medical eco-system.
As after every global crisis, we learn a great deal, and take
a significant leap in education, technology, and science. Med-
ical studies should reflect this and adapt to a global changing
medical landscape. The need for physicians trained to think as
researchers and that are able to publish scientific articles is es-
sential and we hope JIMS will help promote this.
We were pleased to have received so many high-quality
manuscripts from students from around the world. The Editorial
Board did their best to select articles that emphasize the impor-
tance of student contributions to the medical field, while dis-
cussing topics that are relevant to students and new physicians.
We offer you in this issue the fruits of our dreams and
hard work and we invite your feedback. We would like to
extend our sincere gratitude to the Editorial Board of JIMS
who came together from the various Israeli medical schools.
JIMS wouldn’t exist without the endorsement and support of
the Israeli Medical Association (IMA), The National Academy
of Science in Medicine and the Forum of Deans of Medical
Schools in Israel.
We would like to congratulate all of the authors who have
contributed towards it and encourage all readers to submit their
work to JIMS in the future. We hope you enjoy reading the
works published in the JIMS, as much as we’ve enjoyed putting
our inaugural issue together.
With best wishes, JIMS Editorial Board

I came to Ichilov’s OR to photograph Dr. Marian Khatib, later that day, while I was at home reviewing the photos,
I suddenly noticed the student standing next to Dr. Khatib. I thought to myself that although, in a very classical way,
the surgeon is in the center of the frame, this picture reflects the unique role of the medical student. The fine bal-
ance between being an apprentice and a student, finding the right combination between learning and assisting. It is
interesting to contemplate that every surgeon, even the most senior ones, started as learning observers. We all be-
gin at the same point, being the one standing on the side, holding the suction tube with an amazed gaze on our face.

by: Dean Ariel

5
 Forum of Deans of Medical Faculties in Israel ‫פורום דקאני הפקולטות לרפואה בישראל‬

sA Chair of forum of dean of medical faculties in Israel, I am

excited to congratulate on the first issue of JIMS, our own- Is
raeli scientific medical and dental student oj urnal. h
T is inaugu
-
ral issue and the JIMS initiative in general are outstanding- ex
amples of the talent, passion, and leadership amongst the next
generation of Israeli physicians.

h
T e platform provides Israeli medical students from around the
world an opportunity to connect and transfer data, and further
-
more acquire the tools and means in research and publication
they must aspire to master, to be highly prepared for their excit
-
ing future as clinicians and researchers.

I believe that launching a blue and whitestudent oj urnal, and

thereby oj ining the exclusive club of such medical oj urnals,
among the best institutions in the world, will serve a great deal
for Israeli medicine and science.

h
T e Forum of Deans is proud to strongly support and enhance
the oj urnal and its establishing editorial board, which we have
assisted and guided during the past year in carrying out the
project, from an idea and iv sion to an excellent inaugural result.
If the following pages represent what is possible in an inaugural
issue, the future of the oj urnal and the issues to come are bright.

We are convinced that over the years the oj urnal will be widely
read and gain a level of prestige that will rapidly promote the
medical faculties of Israel.

PROF. Ehud Grossman

Chair of forum of deans of medical faculties in Israel

6
 VOL 01 • WINTER 2021
Journal of Israeli Medical Students:
A New Era for Medical Student Publishing in Israel
Nicky Dunn MSc1 and Sameer Bhat BSc1
Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
1
A s the current Editor-in-Chief and
Deputy Editor of the New Zealand
Medical Student Journal (NZMSJ), and
strong advocates of student research and
publishing, we are very pleased to wel-
come the Journal of Israeli Medical Stu-
dents (JIMS) to the international commu-
nity of Medical Student Journals (MSJs).
Similar to JIMS, the NZMSJ is an
entirely student-run, national, peer-re-
viewed academic journal which primar-
ily aims to promote research and provide
opportunities for national and interna-
tional medical students to publish in our
biannual issues. Our journal was first
initiated in 2003 by a group of passion-
ate and dedicated medical students, and
we would like to congratulate the JIMS
Editorial Board for their impressive es-
tablishment of the journal, which is by no
means an easy feat. We are very proud
to be able to contribute to this inaugural
issue of the JIMS.
Medical students to-date have made
significant contributions to medical and
surgical practice through basic scien-
tific or clinical research, with notable
examples such as the discovery of insu-
lin, heparin, and the sinoatrial node [1].
Participation in research fosters greater
scientific productivity and thought, and
builds a strong foundation for the under-
standing of evidence-based medicine [2].
This has short- and long-term implica-
tions for medical student authors, result-
ing in improved knowledge and attitudes
towards research, and more informed
career choices as a result. Moreover,
demonstrated research experience is in-
creasingly required for gaining entry into
postgraduate speciality training and resi-
dency programmes [3]. Therefore, it is of
particular interest for medical students to
begin involvement in research processes
early on in their medical training, such as
through publication of their course-relat-
ed and other work conducted during their
medical degree in a MSJ.
MSJs such as JIMS and the NZMSJ,
are essential to promote research in-
volvement among students enrolled in
medicine and other health profession-
al-related degrees, and rebuild the declin-
ing academic-clinician workforce [4].
A recent study showed students who
published in MSJs during their under-
graduate degree were more likely to
publish their research internationally
and attain higher academic degrees or
academic positions within institutions,
compared to matched controls [5].
Founded exclusively by a group
of medical students from Israel, JIMS
will be invaluable for providing local
and international medical students with
the necessary skills and experience for
to the editor
publishing their academic work, whilst
simultaneously inspiring the next gener-
ation of academic-clinicians in the Israel.
Congratulations once again to the es-
tablishment of JIMS. We look forward to
reading the interesting and educational
issues in the years to come.
Corresponding author
Nicky Dunn
Editorial Office, New Zealand Medical Student Journal
Medical Education Group, Dunedin School of Medicine,
PO Box 56, Dunedin 9054, New Zealand
Email: chief_editor@nzmsj.com
References
1. Stringer MD, Ahmadi O. Famous discoveries by
medical students. ANZ J Surg. 2009 Dec;79(12):901-
8. doi: 10.1111/j.1445-2197.2009.05142.x. PMID:
20002992.
2. Amgad M, Tsui MM, Liptrott SJ, Shash E. Medical
student research: an integrated mixedmethods
systematic review and meta-analysis. PLoS One.
2015;10:e0127470.
3. Katsufrakis PJ, Uhler TA, Jones LD. The Residency
Application Process: Pursuing Improved Outcomes
Through Better Understanding of the Issues. Acad
Med. 2016 Nov;91(11):1483-1487. doi: 10.1097/
ACM.0000000000001411. PMID: 27627632.
4. Sheridan DJ. Reversing the decline of academic
medicine in Europe. Lancet. 2006 May
20;367(9523):1698-701. doi: 10.1016/S0140-
6736(06)68739-4. PMID: 16714192.
5. Al-Busaidi IS, Wells CI, Wilkinson TJ. Publication
in a medical student journal predicts short- and
long-term academic success: a matched-cohort
study. BMC Med Educ. 2019;19(1):271.
7
 Articles VOL 01 • WINTER 2021

The Effects of the Covid-19 Pandemic on the Mental

Health and Learning Abilities of Medical Students:
A Cross-Sectional Study
Matan Peer M.P.H1, Mary Rudolf MD1, Jumanah Essa-Hadad PhD1 and Lilach Malatskey MD1
Azrieli Faculty of Medicine, Bar-Ilan University, Israel
1

ABSTRACT 
Introduction: Medical students suffer from high levels of (25.4%) for anxiety disorder, and 54 (27.4%) for stress
psychological distress. Prior to the COVID-19 pandemic, disorder. Remarkably, 31 students (15.7%) met the cri-
a meta-analysis found global rates of 28% for depression teria for at least one severe/extremely severe disor-
and 34% for anxiety. The pandemic has impacted medical der and 41 (20.8%) sought psychological/psychiatric
students. Of Australian medical students, 70% reported a therapy. The students were studying less efficiently (83
decline in well-being, and 75% of American students re- (42.1%)), 70 students (35.6%) were moderately/severely
ported their education had been significantly disrupted. concerned they would fail academically, and 49 (24.9%)
The objectives of this research were to examine how the reported lower academic achievement. Only 69 (35.0%)
COVID-19 pandemic affected the mental health and learn- had adequate resilience. A well-being score <35.5 was
ing abilities of Israeli medical students and report the key associated with higher rates of depression, anxiety,
coping strategies they employed. stress, and low resilience. The most common coping
Methods: An anonymous online survey was distributed strategies included movies/TV shows (61.9%), physical
to medical students from Bar-Ilan University, Israel, one activity (59.9%), and closeness to family (58.4%).
year into the pandemic. The survey included: sociodemo- Conclusions: To the best of our knowledge this is the first
graphic information, health, lifestyle, learning abilities, study which examined the effect of the COVID-19 pandem-
and coping strategies, as well as validated questionnaires ic on Israeli medical students’ mental health and learning
on well-being, depression, anxiety, stress, and resilience. abilities. There was an alarming impact on mental health
Results: 236 of 450 eligible students (52.4%) responded and detrimental effects on learning abilities. Urgent action
to the survey, among them 197 (43.8%) responded ful- is needed in terms of identifying, preventing, and treating
ly. 76 (38.6%) reported deterioration in mental health, students experiencing distress.
79 (40.0%) met the criteria for depression disorder, 50 JIMS 2021; 01: 8–15

KEY WORDS COVID-19, Medical students, Mental health, Learning abilities, Lifestyle behaviors.

The article was written as part of the requirements of the Azrieli Faculty of Medicine, Bar-Ilan University, Israel, for an M.D degree.

8
 VOL 01 • WINTER 2021
INTRODUCTION
On March 11th 2020, the World Health Organization (WHO)
declared a global pandemic due to the spread of the COVID-19
virus [1]. A year since the first COVID-19 case was discovered
in Israel, there have been over 700,000 authenticated cases,
more than 5,000 deaths, and a fifth of the country’s population
under quarantine. The Ministry of Health (MoH) declared three
general lockdowns and led a successful nationwide campaign
vaccinating over 4 million citizens in 4 months [2,3].
The spread of this life-threatening pandemic has had many
dire consequences on all walks of life. In Australia a study found
alarming rates of psychological distress in the general popula-
tion: 38.3% having depression, 21.2% anxiety, and 27.8% stress
disorder. Higher rates occur in younger individuals (18-45),
singles, and those with chronic medical conditions. They found
changes in lifestyle behaviors: 48.9% participants reported re-
duced physical activity, 40.7% reported poorer sleep quality,
and 26.6% reported increased alcohol consumption. An associa-
tion was shown between higher rates of depression, anxiety and
stress, and negative changes in physical activity, sleep, smoking
and alcohol intake [4].
Prior to COVID-19, a Canadian survey found higher rates
of depression, anxiety and psychological distress in 11,000
medical students than in age-matched controls [5]. In 2016,
a meta-analysis of 77 articles on depression involving 63,000
medical students found rates of 28% overall, with higher lev-
els in the Middle East (31.8%) and North America (30.3%) [6].
A meta-analysis in 2019 of 69 articles involving 30,000 med-
ical students found that 33.8% experienced anxiety disorder
[7]. This data shows that medical students suffered from con-
siderable psychological distress prior to the pandemic.
The COVID-19 pandemic changed the way medical stud-
ies are being taught. The pre-clinical years transitioned most-
ly to online education and clinical rotations in hospital wards
were severely affected [8]. When surveyed, 74.7% of Amer-
ican students stated that their medical education was signifi-
cantly interrupted and 61.0% felt that the pandemic affected
their ability to develop important skills needed for medical
residency [9].
Numerous studies have examined the effects of the COVID-19
pandemic on medical students’ mental health.In Australia,70% of
medical students reported a decline in their sense of well-being.
Over 80% were worried that the situation was affecting their stud-
ies, and 7% sought psychotherapy [10]. 25% of Saudi-Arabian
medical students felt depressed, and 50% reported a decline in
their study abilities [11]. In China 35% of medical students suf-
fered from depression, and 22% from anxiety [12]. Of American
medical students 66% suffered from anxiety, and of those 12%
experienced severe anxiety. Previous mental health was a strong
predictor for stress and anxiety. A strong correlation was also
Articles
found between self-reports of stress and anxiety levels and scores
on psychological scales [13]. Many Irish medical students report-
ed moderate to severe stress (54%), 36% were moderately or se-
verely financially concerned, 38% were moderately or severely
concerned for their own health, and 83% were concerned about
their families’ health [14].
In summary, medical students are known to encounter high
levels of psychological distress during their studies and ap-
pear to be at additional risk during the COVID-19 pandemic.
As of yet, no studies have examined the effects of the pan-
demic on Israeli medical students’ mental health. This study
examined the effects on students’ mental health, learning
abilities, and the coping strategies they employed to reduce
psychological distress.
METHODS
SETTING AND RESEARCH POPULATION
The research was conducted at the Azrieli Medical Faculty, Bar-
Ilan University (BIU), located in Safed, Israel. The research tar-
geted all 450 medical students studying in the Faculty’s two MD
programs: a 4-year program for students with a prior degree, and
a 3-year program for students who studied the first 3 years of
medical school abroad.
STUDY DESIGN
Students were invited to participate by e-mails sent from the
Faculty’s administrator and the student body with a link to an
anonymous and secured online survey via the “SurveyMonkey”
platform. The survey was open between 11/3/21 and 30/4/21.
SURVEY DEVELOPMENT
The research survey comprised 3 sections:
1. Background information:
a) Socio-demographic questions regarding age, gender,
country of birth, ethnic group, religiosity, marital status,
number of children, living conditions, program of study,
and year of study.
b) Life during the pandemic
• Quarantine either MoH ordered or self with a scale of
1(‘no’) to 3 (‘>14 days‘).
• High-risk group for COVID-19 complications: yes/no
• Being infected with COVID-19: yes/no.
• Close family member at high-risk group for COVID-19
complications: yes/no
• Close family member infected with COVID-19: yes/no
• Concerns during the pandemic: financial, failing medi-
cal school, becoming infected with COVID-19, infect-
ing close family member with COVID-19: scale of 1
(‘not concerned at all‘) to 3 (‘severely concerned‘).
9
 Articles
c) Health status: mental and physical health prior to the pan-
demic and current: scale of 1 (‘usually not good‘) to 4
(‘excellent‘).
d) Lifestyle behaviors: physical activity, adherence to a
healthy diet, sleep, smoking, alcohol consumption: scale
of 1 (‘significantly less‘) to 4 (‘significantly more‘).
2. Mental health:
Three validated questionnaires were used to assess mental
health:
a) Well-being [15]: A Hebrew questionnaire comprising 9
questions scored on a scale of 1-6, with no cut-offs for
adequate or poor well-being. The questionnaire has high
internal validity (Cronbach’s α 0.82).
b) Psychological distress - DAAS (Depression, Anxiety and
Stress) [16]: The questionnaire comprises 3 scales of 7
items each, scored on a scale of 0-3. Scoring is individual
for each scale and divided into 5 categories – Depression:
normal (0-4), mild (5-6), moderate (7-10), severe (11-13),
extremely severe (14+). Anxiety: normal (0-3), mild (4-
5), moderate (6-7), severe (8-9), extremely severe (10+).
Stress: normal (0-7), mild (8-9), moderate (10-12), severe
(13-16), extremely severe (17+). The questionnaire has
high internal validity (Cronbach’s α 0.93) for the overall
questionnaire, 0.88 for depression, 0.82 for anxiety and
0.9 for stress. A validated Hebrew version from the Israeli
MoH website was used.
c) Resilience - CD-RISC (Connor-Davidson Resilience
Scale) [17]: the short 10-items version, CD-RISC-10.
Rating is on a scale of 0-4. A score <32 indicates inad-
equate resilience. We gained a license to use a Hebrew
version from Connor & Davidson. The Hebrew scale has
a high internal validity (Cronbach’s α 0.91).
d) Coping strategies: Students were provided with 14 op-
tions of coping strategies that were adopted after a focus
group consultation involving ten students, and “other” for
open answers.
3. Learning abilities:
a) Learning efficacy and learning success: scale of 1 (‘sig-
nificantly less‘) to 4 (‘significantly more‘).
b) Concerns about failing medical school: scale of 1 (‘not
concerned at all‘) to 3 (‘severely concerned‘).
STATISTICAL ANALYSIS
Statistical analysis were performed using the Statistical Package for
the Social Sciences software version 26 (SPSS Inc., Chicago, IL,
USA). A P value of < 0.05 was considered significant. For questions
on lifestyle behaviors and learning abilities, we coalesced to three
categories: “more” (‘a bit more‘/‘significantly more‘), “same”, and
“less” (‘a bit less‘/‘significantly less‘). Change in mental health was
calculated as change from status prior to COVID-19 and current sta-
10
VOL 01 • WINTER 2021
tus; <2 levels was considered mild-moderate change, >2 levels se-
vere change. We combined the categories severe distress/extremely
severe distress in the DAAS questionnaire to identify students with
severe depressive, anxiety and stress disorders.
Pearson Chi-square, Pearson’s correlation, Spearman’s rho
correlation, and area under curve (AUC) were used for single
variant analysis.
ETHICS APPROVAL
The study received approval from the BIU Faculty of Medi-
cine (March 2021) Ethics committee, approval number 03-2021.
RESULTS
236 of 450 medical students (52.4%) responded to the sur-
vey. Thirty-nine submitted incomplete responses and were
excluded from the analysis leaving 197 (43.8%) for inclusion
in the analysis. 127 participants (64.5%) were in the 4-year
program, and 101 (51.8%) in the pre-clinical years (from both
programs). Of the respondents 120 were women (61.0%),
average age was 30 ± 3.39 years, 166 (84.3%) were born in
Israel, 166 (84.3%) were Jewish, 134 (68.0%) identified them-
selves as secular, 98 (49.8%) were living with a partner, and 31
(14.7%) had at least one child.
PANDEMIC RELATED STRESSORS
Regarding the quarantine, 84 (42.6%) of the students had been
in MoH-required quarantine; 46 (23.4%) remained quarantined
for 8-14 days; 71 students (36.0%) self-quarantined, and 54 of
them (27.4%) remained for up to 7 days.
Health-related issues showed that 165 students (83.7%) were
moderately/severely concerned about infecting close family
members, 114 students (57.8%) were moderately/severely con-
cerned about being infected. 111 (56.3%) had a close family
member in a high-risk group, and 48 (24.4%) had a close family
member infected at some point. Sixteen students (8.1%) were
in a high-risk group for complications, and only 13 students
(6.6%) had been infected with COVID-19. Among the students,
121 (61.4%) were moderately/severely financially concerned as
a result of the pandemic.
A summary of the impact of the pandemic is in Table 1.
Analysis of the mental health questionnaires (Fig. 1 and Fig.
2) showed that 79 students (40.0%) met the criteria for depres-
sion disorder, of whom 24 (12.2%) had severe/extremely severe
depression. Fifty (25.4%) students met the criteria for anxiety
disorder, of whom 20 (10.2%) had severe/extremely severe
anxiety. Stress disorder was found in 54 students (27.4%) of
whom 21 (10.7%) had severe/extremely severe stress. Overall
31 students (15.7%) had at least 1 severe/extremely severe dis-
order, of whom 29 (93.5%) had a well-being score <35. Elev-
en students (5.6%) had 3 severe/extremely severe disorders,
of whom all had a well-being score <35. The mean well-being
 VOL 01 • WINTER 2021 Articles

Table 1. Impact of COVID-19 on lifestyle, learning and mental health

Negative impact Positive impact

n (%) n (%)
Lifestyle
Less physically active 82 (41.6%) More physically active 63 (32.0%)
Eating less healthy 63 (32.0%) Eating healthier 56 (28.4%)
Sleeping worse 55 (27.9%) Sleeping better 37 (18.8%)
Increased smoking 27 (12.2%) Reduced / stopped smoking 2 (1.0%) / 3 (1.5%)
Increased alcohol consumption 27 (13.7%) Reduced / stopped alcohol consumption 27 (13.7%) / 0 (0%)
Learning
Studying less efficiently 83 (42.1%) Studying more efficiently 47 (23.9%)
Succeeding less in their education 49 (24.9%) Succeeding more in their education 37 (18.8%)
Students with moderate-severe concern they will fail Medical school 70 (35.6%) - -
Mental health
Low resilience 128 (65.0%) High resilience 69 (35.0%)
Deteriorated mental health status 76 (38.6%) - -
Increase in students reporting “good”
Decrease in students reporting “excellent” mental health 21 (10.7%) 25 (12.7%)
mental health
Decrease in students reporting “very good” mental health 28 (14.2%) - -
19 (9.6%)
Increase in students reporting “not good” mental health - -

Increase in students reporting “usually not good” mental health 3 (1.5%) - -

High rates of students with depression disorder 79 (40.0%) - -
Severe – extremely severe depression 24 (12.2%) - -
High rates of students with anxiety disorder 50 (25.4%) - -
Severe – extremely severe anxiety 20 (10.2%) - -
High rates of students with stress disorder 54 (27.4%) - -
Severe – extremely severe stress 21 (10.7%) - -
High rates of students in psychotherapy   41 (20.8%) - -

score was 36.17 ± 7.89, and only 69 (35.0%) met the cut-off for
adequate resiliency. 41 (20.8%) reported attending psychologi-
cal or psychiatric therapy. One student reported using psychiat-
ric medications. Overall, the self-reported mental health of 76
students (38.6%) worsened during the pandemic, 72 reporting
mild-moderate deterioration (36.6%) and 4 with severe deteri-
oration (2.0%).
No statistically significant differences were found between
mental health deterioration and program of study, year of medical
education, gender, place of birth, ethnic group, religiosity, living
conditions and parenthood. Statistically significant differenc-
es were also not found between mental health deterioration and
well-being levels, depression, anxiety, stress, and resilience levels.
The coping strategies that were most used by students were:
watching movies/TV shows (61.9%), physical activity (59.9%),
being close to family members (58.4%). 70.6% of students re-
ported using between 3 to 6 coping strategies [Fig. 3].
Students (83 (42.1%)) reported they were studying less ef-
ficiently during the pandemic, 70 students (35.6%) were mod-
erately/severely concerned that they would fail medical school,
and 49 (24.9%) reported lower academic achievement.
Regarding student lifestyle changes, 82 (41.6%) reported they
were less physically active, while 63 students (32.0%) reported
being more active. Sixty three students (32.0%) reported less ad-
herence to a healthy diet, while 56 (28.4%) were eating a health-
ier diet. Sleep quality deterioration was reported by 55 students
(27.9%). Among the 29 smokers, 24 (82.8%) smoked more, 2 less,
and 3 students stopped smoking. Of the students who consumed
alcohol 27 (21.3%) reported drinking more, and 27 (21.3%) less.
There was a significant linear correlation between current
physical health and current mental health (0.439, p<0.0001)
and between prior mental health and current mental health
(0.658, p<0.0001). Students whose mental health deteri-
orated were more likely to have close family in a high-risk

11
 Articles VOL 01 • WINTER 2021

Figure 1. The percentage of students self-reporting their mental health in different categories show that in general there is a deterioration in mental
health status post the coronavirus pandemic outbreak.

Self-reported mental health status in medical students prior to the Covid-19 pandemic and currently

Figure 2. The rates of depression, anxiety and stress among medical students. More than 10% of the students experienced severe/extremely severe
rates in all three scales.

Depression, anxiety and stress rates in medical students during the Covid-19 pandemic

12
 VOL 01 • WINTER 2021 Articles

Figure 3. Coping strategies that medical students employed to alleviate psychological distress. The most common were screen-time, physical
activity, and closeness to family. High rates of students needed psychological or psychiatric therapy.
Coping strategies for depression, anxiety and stress mitigation among medical students during the Covid-19 pandemic

Table 2. Correlation between well-being, depression, anxiety,

There was an inverse correlation between the well-being
stress, and resilience scores (n=197). All correlations significant score and depression, anxiety and stress [Table 2], as well as
at p<0.0001*** between resilience and depression, anxiety and stress. There
was a direct correlation between depression and anxiety, de-
Well-being Depression Anxiety Stress pression and stress, and anxiety and stress. A well-being score
score score score score
of <35.5 was associated with higher rates of depression (sensi-
Well-being score 1 -.516 -.391 -.501 tivity 69.5%, specificity 68.4%, p<0.0001), anxiety (sensitivi-
Depression score -.516 1 .743 .813 ty 63.3%, specificity 72.0%, p<0.0001), and stress (sensitivity
Anxiety score -.391 .743 1 .755 65.7%%, specificity 75.9%, p<0.0001), and inversely associ-
Stress score -.501 .813 .755 1
ated with low resilience level (sensitivity 68.1%, specificity
53.1%, p=0.001).
Resilience score .319 -.541 -.421 -.480
***
Significant at DISCUSSION
the 0.001 level
(2-tailed). This study examined how the COVID-19 pandemic affected the
mental health and learning abilities of Israeli medical students
group for COVID-19 complications (51 (70%) vs. 60 (51%), and the key strategies they employed to help them cope. As ex-
p<0.01) and to have inadequate resilience (59 (78%) vs. 69 pected, the pandemic majorly impacted students’ lives.
(57%), p=0.003). The students with mental health issues were The most significant findings concerned the effect of the
more likely to have slept poorly (32 (42%) vs. 23 (19%), pandemic on students’ mental health. Students reported a clear
p<0.0004), increased their smoking (16 (72%) of smokers vs decline, and validated questionnaires showed alarming numbers
8 (30%), p<0.002), reduced their physical activity (42 (55%) of students experiencing psychological distress. High numbers of
vs 40 (33%), p=0.002), and were eating less healthy (33 students met the criteria for depression, anxiety, and stress disor-
(43%) vs 30 (25%), p<0.006). Failing medical school, being der. One in six suffered from a severe or extremely severe mental
infected themselves, or having mental health problems before disorder and one in five students were in psychotherapy.  Only
COVID-19 did not affect the differences in mental health of one third were found to have ‘adequate’ resilience. In a me-
the students. ta-analysis performed before the COVID-19 pandemic, medical

13
 Articles
students had high rates of depression (28%) [6], and in Israel we
showed that the pandemic worsened the psychological distress of
medical students. The findings are similar to other research. In
China, medical students during COVID-19 experienced similar
rates of depression and anxiety [12], although in Saudi-Arabia,
there were lower rates of depression [11], in the US higher rates
of anxiety [13], and in Ireland higher stress rates [14]. A number
of factors were identified that were particularly prevalent in stu-
dents with significant deterioration in their mental health. These,
perhaps unsurprisingly, included poor sleep, increased smoking,
less physical activity, and worse eating habits which are in them-
selves concerning.
We found serious effects on students’ ability to learn effective-
ly resulting in fear of failure. Similar findings were found in Sau-
di-Arabia regarding studying efficiency [11], although concerns
about failing medical school were even higher in Australia [10].
Lifestyle behaviors were affected as well, although not uni-
versally for the worse. Some students reported improvement in
lifestyle, ability to study and success in academic achievements.
Students reported employing a number of coping strategies, the
commonest included watching movies/TV shows, engaging in
physical activity, and being close to family members. This dif-
fers from findings in other studies. In Australia, the main coping
strategies were video chats and social media and only 7% needed
psychotherapy [10].
There was a good correlation between students’ self-report-
ed mental health status and scores from validated psychological
questionnaires (including the well-being questionnaire), which
were similar to a study from the US [13].
Our study had strengths and limitations. We used validated
mental health questionnaires which gives a more precise under-
standing of the influence on mental health. Although Israelis are
accustomed to living in stressful circumstances, living a year
during a life-threatening pandemic with ever-changing regula-
tions, limitations, and constant fear of the unknown clearly had
detrimental effects. These effects were associated with mental fa-
tigue, increased rates of significant mental illness, and low levels
of resilience.
A number of limitations have to be considered. A response
rate of 40% might be considered low but given the ‘question-
naire fatigue’ so common among medical students we saw it as
something of an achievement. However, one cannot exclude the
possibility of response bias, although the direction of any bias
is unclear. Distressed students may be more or less inclined to
complete a survey of this nature. Even so in a ‘worst case’ sce-
nario where the non-responders were all in prime mental health,
a finding of 31 students with at least one severe mental illness
in a cohort of 450 students is extremely high. Another limita-
tion is the potential for recall bias. The survey was conducted a
year into the pandemic which was characterized by ever chang-
ing restrictions. Students’ recall and their perceptions of prior
health status might have been affected. By the time the survey
14
VOL 01 • WINTER 2021
was closed, the MoH gradually began to withdraw restrictions
(the 3rd lockdown had ended, requirement to wear masks in pub-
lic spaces was revoked, and the educational system returned to
frontal classes). There was a daily mortality rate of zero from
COVID-19, and approximately 5 million Israeli’s were already
vaccinated. This may well have affected mood and thus under-
or over-estimated the extent of early distress. Finally, the study
was limited to only one of Israel’s six medical schools. Although
there seems little reason to suspect that BIU medical school dif-
fers, caution must be applied before generalizing results.
Stressful situations will always come and go. Our research
sets the scene for further nationwide research exploring key
protective and aggravating factors for medical student's mental
health and the design of interventions to improve and strengthen
students’ learning efficacy and to mitigate psychological dis-
tress and build resilience in doctors of the future.
CONCLUSIONS
Our findings are a call for action. It is of utmost importance to
identify struggling students at high-risk for mental illness. A simple
and brief screening tool could be developed by using the well-be-
ing scale and 2 questions on prior and current mental health status.
Building a support system is evidently needed alongside other in-
novative efforts to strengthen student's mental health and lifestyle.
ACKNOWLEDGMENTS
The authors would like to thank the students who participated in
the focus group: Adi Dahan-nassy, Tidhar Donio, Yuval Perets,
Maor Hadad, Anna Sherman, Or Kadir, Yarden Rosenbaum, Or
Levkovitch Siany, and the medical faculty administrator Sha-
ron Mines and Head of the student’s body Lee Azulai. A special
thank you for all the help to Yael Sufrin, Shahaf Levin, Nadav
Bandel, and Oshry Amsalem.
DATA AVAILABILITY
The data presented in this study is available upon request from
the corresponding author. The data is not publicly available due
to its sensitive nature, and due to CD-RISC copyright.
Corresponding author
Matan Peer
Email: peermat@gmail.com
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Capsule
Cancer microbiome microbes hijack prostate cancer therapy
Androgens such as testosterone and dihydrotestosterone
are essential for male reproduction and sexual function.
Androgens can also influence the growth of prostate
tumor cells, and androgen deprivation therapy (ADT)
either by surgical means (castration) or pharmacological
approaches (hormone suppression), is the cornerstone
of current prostate cancer treatments. Pernigoni et al.
found that when the body was deprived of androgens
during ADT, the gut microbiome could produce
Capsule
Subcutaneous REGEN-COV antibody combination to prevent COVID-19
REGEN-COV (previously known as REGN-COV2), a
combination of the monoclonal antibodies casirivimab
and imdevimab, has been shown to markedly reduce the
risk of hospitalization or death among high-risk persons
with coronavirus disease-2019 (COVID-19). O’Brian et
al. randomly assigned, in a 1:1 ratio, participants (≥ 12
years of age) who were enrolled within 96 hours after a
household contact received a diagnosis of severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2)
infection to receive a total dose of 1200 mg of REGEN-
COV or matching placebo administered by means of
subcutaneous injection. Symptomatic SARS-CoV-2
infection developed in 11 of 753 participants in the
REGEN-COV group (1.5%) and in 59 of 752 participants in
the placebo group (7.8%) (relative risk reduction [1 minus
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Pandemic: Impact of quarantine on medical students’ mental wellbeing and
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Guo AA, Crum MA, Fowler LA. Assessing the psychological impacts of
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connordavidson-resiliencescale.com/user-guide.php
androgens from androgen precursors. Gut commensal
microbiota in ADT-treated patients or castrated mice
produced androgens that were absorbed into the
systemic circulation. These microbe-derived androgens
appeared to favor the growth of prostate cancer and
helped to facilitate development into a castration- or
endocrine therapy-resistant state.
Science 2021; 374: abf8403
Eitan Israeli
the relative risk], 81.4%; P < 0.001). In weeks 2 to 4, a
total of 2 of 753 participants in the REGEN-COV group
(0.3%) and 27 of 752 participants in the placebo group
(3.6%) had symptomatic SARS-CoV-2 infection (relative
risk reduction, 92.6%). REGEN-COV also prevented
symptomatic and asymptomatic infections overall (relative
risk reduction, 66.4%). Among symptomatic infected
participants, the median time to resolution of symptoms
was 2 weeks shorter with REGEN-COV than with placebo
(1.2 weeks and 3.2 weeks, respectively), and the duration
of a high viral load (>104 copies per milliliter) was shorter
(0.4 weeks and 1.3 weeks, respectively). No dose-limiting
toxic effects of REGEN-COV were noted.
N Engl J Med 2021; 385: 1184
Eitan Israeli
15
 Articles
The Effect of Empagliflozin and Spironolactone
Treatment on Fibrosis Immediately After Induction
of Myocardial Infarction in Rats
Nadav Bandel BEMS1,2, Elias Daud MD2,3, Offir Ertracht PhD2 and Shaul Atar MD1,2,3
1
Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
2
Cardiovascular Research Laboratory, Galilee Medical Center, Nahariya, Israel
3
Department of Cardiology, Galilee Medical Center, Nahariya, Israel
ABSTRACT Background: Coronary heart disease is a leading western world
cause of death. The adult mammalian heart has negligible re-
generative capacity. Damaged myocardium is replaced by ex-
tracellular matrix (ECM) in a deleterious process named fibro-
sis, which involves the renin-angiotensin-aldosterone system
(RAAS) activation. Aldosterone antagonists, such as spirono-
lactone (SPIR), are cardiac anti-fibrotic agents. Sodium/glucose
cotransporter 2 inhibitors (SGLT2i), with empagliflozin (EMPA)
being a key player within this group, prevent renal glucose reab-
sorption. SGLT2i also inhibit sodium-hydrogen exchange in the
heart, which may lead to cardiac fibrosis attenuation.
 Hypothesis and aims: We hypothesized that administering
SPIR combined with EMPA would have a synergistic effect on
the attenuation of collagen deposition post-MI in rats.
Methods: The 21 rats who underwent myocardial infarction
induction procedure were divided randomly into 3 groups.
The first group was treated with EMPA (30 mg/kg/day per
os (P.O.), the second with an EMPA and SPIR (20 mg/kg/day,
subcutaneous, S.C.) combination, and the third was used as
control. After 4 weeks the rats were sacrificed, and the heart
was excised and underwent histological analysis.
Results and Discussion: EMPA alone and EMPA+SPIR therapy
increased left ventricular cavity perimeter (23.8 ± 4.9 mm and
29.5 ± 2.8 mm for EMPA and EMPA+SPIR therapy, respectively).
These results were attributed to the mechanisms of eccentric
hypertrophy. At the remote area, EMPA+SPIR therapy decreased
CVF (4.6 ± 1.6% for the control group, 2.5 ± 1.3% for EMPA, and
2.1 ± 1.5% for EMPA+SPIR therapy). At the scar both treatments
decreased CVF, with EMPA+SPIR therapy showing intensified
effect (79.9 ± 6.2%, 53.5 ± 5.4% and 41.6 ± 2.6% for the control
group, EMPA and EMPA+SPIR therapy, respectively). To the best
of our knowledge, this is the first study to show the synergistic
effect of these two drugs on the level of cardiac fibrosis.
JIMS 2021; 23: 16–22
KEY WORDS 
Aldosterone inhibitors, Empagliflozin, extracellular matrix,
myocardial fibrosis, SGLT2 inhibitors,
16
VOL 01 • WINTER 2021
INTRODUCTION
Myocardial infarction (MI) is the leading cause of death in the
western world. MI is defined as ischemic loss of myocardial tis-
sue, usually due to occlusion of a coronary vessel [1]. Ischemia
induces profound metabolic and ionic disturbances in the affect-
ed cardiomyocytes, resulting in ventricle function decrease [1].
The adult mammalian heart has negligible regenerative capac-
ity, thus the infarcted myocardium is replaced by extra cellular
matrix (ECM) in a process named fibrosis [1].
Fibrosis is an excess deposition of ECM components, main-
ly collagen, which results in hardening and scarring of the tis-
sue [2]. Myocardial fibrosis promotes ventricular arrhythmias
and the development of heart failure (HF) [3]. Although many
factors, such as pressure overload, volume overload, metabol-
ic dysfunction (obesity and diabetes), and aging may promote
cardiac fibrosis, MI remains the single most important cause of
rapid-onset cardiac remodeling through fibrosis [4].
Deposition of extracellular proteins, the cornerstone of fi-
brosis, is a complex multistep process that involves, among
others, the activation of the renin-angiotensin-aldosterone sys-
tem (RAAS) [1]. As RAAS plays a key role in the regulation
of water, sodium and potassium metabolism, enhancing its ef-
fect causes intensified intravascular volume and blood pressure.
This, leads to increased left ventricular (LV) wall stress, LV hy-
pertrophy and consequent fibrosis [5-7]. Both aldosterone and
angiotensin-II induce fibroblast hyperplasia, collagen biosyn-
thesis and inhibit its degradation, thus promoting fibrosis [8].
Therapeutic agents that antagonize the effects of aldoste-
rone, such as spironolactone (SPIR), have been proposed as
treatments to reduce collagen deposition in the infarcted heart
[9,10]. Pre-clinical experiments showed that SPIR abolishes fi-
brosis in both ventricles and atria, diminishes hypertrophy, and
preserves myocardial functions [11- 13]. Accordingly, clinical
studies proved that SPIR treatment significantly reduces mor-
tality and morbidity in patients with HF [14].
Sodium/glucose cotransporter-2 inhibitors (SGLT2i), with
empagliflozin (EMPA) being a key player within this group, are
 VOL 01 • WINTER 2021
antidiabetic drugs that inhibit the glucose reabsorption in the
proximal tubule of the nephron [15]. As yet, SGLTi are the only
glucose-lowering agents that have been reported to decrease the
risk of cardiovascular events in HF patients with type 2 diabetes
mellitus [16]. It was shown that the administration of EMPA to
rats caused reduction of cardiac injury and blunted its functional
decline [17,18]. This effect was related to inhibition of the cardi-
ac sodium-hydrogen exchanger in the heart [16].
We hypothesized that administering SPIR combined with
EMPA would have a synergistic effect on the attenuation of col-
lagen deposition post-MI in a rat model.
METHODS
ANIMALS
All animal experiments were conducted according to the institution-
al animal ethical committee guidelines, which conform to the Guide
for the Care and Use of Laboratory Animals published by the US
National Institutes of Health (Eighth edition 2011) (Ethics 47-07-
2019). We used 250-300 g. male Sprague-Dawley rats (Envigo Ltd,
Jerusalem, Israel), which were maintained at a constant temperature
and relative humidity under a regular light-dark schedule (12h:12h),
fed with normal rodent diet and with tap water ad libitum.
STUDY DESIGN
Twenty-one rats underwent MI procedure. Then, the animals
were randomly divided into 3 experimental groups, 7 rats in
each group. The first group was treated with EMPA, the second
group was treated with SPIR and EMPA, and the third was not
treated and used as a control group. After euthanasia, the heart
was excised and preserved for histological analysis.
MI INDUCTION
Briefly, we intubated the rats under deep anesthesia with a mix-
ture of 87mg/kg ketamine and 13 mg/kg xylazine and ventilated
them at a rate of 80-90 breaths per minute, and 1 to 2 ml/100 g
tidal volume. Using intercostal space left thoracotomy, the chest
was opened, and the pericardial sac was dissected. A stich was
placed through the myocardium at a slightly greater depth than
the perceived level of the left anterior descending (LAD) artery.
Next, we tightened the suture to ensure complete LAD occlu-
sion, the chest was closed, the skin stitched, and the rat was
placed in its cage for recovery.
DRUG THERAPIES
EMPA (Generously, provided by Boehnringer-Ingelheim GmbH,
Germany) (30 mg/kg/day) was dissolved in the drinking water.
SPIR (Sigma chemicals, St Louis, MO, USA) treatment (20 mg/
kg/day) was administered by S.C. injection. Rats of both groups
were weighted weekly to adjust dosage. The control group was
treated with the same volume of water P.O. and S.C. saline.
Articles
ANIMAL SACRIFICE AND ORGAN HARVESTING‬
Four weeks post-MI the animals were euthanized by overdose
of anesthetic and the heart was stopped by direct KCl-1M injec-
tion. The heart was excised and fixed in 4% buffered formalde-
hyde and then embeded in paraffin for histology.
HISTOLOGY
The paraffin-embedded apex was sectioned into 5 μm using a mi-
crotome and was stained with Hematoxylin and Eosin (H&E) and
Picro-Sirius red staining. Picro-Sirius red stains collagen in red, and
higher content of collagen can be viewed as red areas, compared
to specimens with diminished amount of collagen and increased
amount of muscle tissue and fat tissues, appearing as yellow in color.
Sections were viewed under a microscope (Nikon Eclipse
Ci-L, Nikon Corporation, Tokyo, Japan). The H&E sections
were photographed and analyzed for structural measurements:
Cross-sectional area, left ventricle (LV) cross-sectional area, LV
cavity area, and septal and anterior wall widths using the ImageJ
freeware (NIH, Bethesda, Md, USA) [Figure 1A]. Collagen ar-
ea was measured in scar and remote regions of the Sirius-red
stained sections, using the ImageJ freeware, and the Java-based
image analyses plug-in program.
COLLAGEN VOLUME FRACTION (CVF) MEASUREMENT
We assessed the mean collagen area of 6 fields from each slide.
Briefly, for each photograph, the red colour (collagen) was mea-
sured and so was the total tissue area and total picture size, sub-
sequently, we calculated the percentage of the CVF according
to the formula:
STATISTICAL ANALYSIS
Data are presented as mean ± SD, comparisons between groups
were performed by 1 way ANOVA in which the treatment group
is the independent variable, and the parameter – the dependent,
using the SigmaPlot 12 software (Systat, San-Jose, CA,USA). A
P value of <0.05 was considered significant.
RESULTS
Of the 21 experimental animals, 18 survived four weeks post-op-
eration, (86% total survival rate). Survival rates for the differ-
ent pharmacological regimens were 7/7 animals in the EMPA
group, 6/7 in EMPA+SPIR group, and 5/7 in control group.
H&E STAINING
Figure 2 shows gross anatomy histological sections of hearts
treated by the different protocols. The sections are of a trans-
verse cut at the papillary muscle level, and show the LV, free
wall, septum, and occasionally part of the right ventricle.
17
 Articles VOL 01 • WINTER 2021

Though difficult, it is possible to locate the damaged scar re-
gion, mainly in Fig 2B, and to distinguish it from remote areas
of the ventricle. One may locate the scars principally, according
to the narrowing of the muscle [Fig 2]. As seen in the figure,
treatment with either protocol, i.e. EMPA or EMPA+SPIR, lead
to an increase in the perimeter of the LV cavity.
Figure 3 summarizes the gross anatomical measurments of the
cardiac histological sections. The average total muscle cross-sec-
tional areas were 95.0 ± 22.7 mm2, 89.2 ± 9.3 mm2, and 87.6 ± 8.9
mm2 for the control, EMPA and EMPA+SPIR groups respectively
(P > 0.05, Fig. 3A). The total muscles perimeters were 38.0 ± 5.2
mm, 36.6 ± 2.7 mm, and 36.1 ± 2.2 mm at the control, EMPA and
EMPA+SPIR, respectively (P > 0.05, Fig. 3B). Collectively, the
results indicate that the whole cardiac muscle did not change its
dimensions due to the EMPA or EMPA+SPIR treatments.
The effects on the LV size were studied by measuring the LV
area and its circumference. Those were 57.4 ± 13.6 mm2 and
34.0 ± 5.8 mm in the control group, 55.9 ± 11.3 mm2 and 32.5
± 4.0 mm in the EMPA group, and 50.3 ± 13.8 mm2 and 31.6
± 3.3 mm in the EMPA+SPIR treated group, respectively (P >
0.05 for all, Fig. 3C and 3D).
We showed that while the LV cross-sectional areas were
comparable among the groups, the LV cavity perimeter was
significantly higher in the experimental groups compared to
control: 18.3 ± 3.9 mm, 23.8 ± 4.9 mm and 29.5 ± 2.8 mm for
control, EMPA and EMPA+SPIR, respectively (P < 0.05, Fig.
3F). This indicates some enlargement of the LV cavity, which
was not significant in other measurements [Fig. 3D].
Septal and free wall widths are summarized in Fig. 3G and
3H, respectively. It is apparent that these variables are compara-
ble between the 3 experimental groups (P > 0.05).
COLLAGEN STAINING
Both pharmacological regimens resulted in less collagen con-
tent, seen as less red stain at both the scar areas and remote
regions in comparison to the control specimen [Figures 4A-4F].
Figures 5A and 5B illustrate the calculated CVF in two
studied areas of the heart: (A) the remote area and (B) the scar,
respectively. Measurements at the remote area showed a reduc-
tion in CVF only when treated with the EMPA+SPIR protocol
compared to control or EMPA as a single agent (P < 0.05 vs.
control, Figure 5A).

Figure 1. A Gross anatomy of a rat's heart at the apical level after H&E staining, showing: A. LV B. Free wall C. Septum D. Part of the right ventricle.
Gradation marks are 1 mm apart. B Picro-Sirius red staining of a rat's heart - Scar area (showing mostly collagen stained in red). Magnification X40.
C Remote area (showing very little collagen). Magnification X40

A B C

Figure 2. H&E staining in 3 experimental groups A. control group B. EMPA treatment C. EMPA+SPIR treatment. Gradation marks are 1 mm apart.

A B C

18
 VOL 01 • WINTER 2021
Figure 3. Gross anatomical measurment of cardiac histological sections A. Total heart cross sectional area B. Total heart perimeter C. LV cross
sectional area D. LV perimeter E. LV cavity cross sectional area F. LV cavity perimeter G. Septal width H. Free wall width, for the 3 experimental
groups: Control (white), EMPA (gray), EMPA+SPIR (black).
* P < 0.05 vs. Control, ** P < 0.01 vs. Control.
A B
D E
Likewise, treatments with EMPA or with EMPA+SPIR reduce
CVF in the scar area. Specifically, control scar CVF showed signifi-
cant reduction after treatment with EMPA (P < 0.001 vs. control, Fig
5B). Furthermore, EMPA+SPIR treatment resulted in even greater
reduction of CVF (P < 0.001 vs. control and EMPA alone, Fig 5B).
DISCUSSION
Our study compared the effect of EMPA alone and EMPA+SPIR
administration protocol on fibrosis (as seen by collagen deposi-
tion), as well as other morphological variables. After 4 weeks,
EMPA alone and EMPA+SPIR combined therapy increased LV
cavity perimeter. At the remote area, the combined treatment
decreased CVF, while at the scar area both treatments decreased
CVF, with combined therapy showing intensified effect.
STRUCTURAL CHANGES
EMPA and SPIR exert their effect on the heart directly and via
systemic routes. EMPA was shown to reduce sodium tissue con-
tent, vascular stiffness and cardiac glucotoxicity, as well as reduce
plasma volume, cardiac preload, cardiac wall stress, afterload and
intra-cardiac filling pressures [19]. A recent study by Daud et al.
showed that EMPA has direct attenuating effect on cardiac fibro-
sis and remodeling through the TGF-β1/Smad3 pathway [20].
Alternatively, aldosterone is known to promote fibrosis via stimu-
lation of mineralocorticoid receptors. Specifically at the molecu-
lar level, Nakamura et al. [21] showed that aldosterone promotes
apoptosis by activating signal-regulating kinase-1, causing an
Articles
C
F
effect known as aldosterone-induced cardiac injury, which leads
to replacement of normal tissue by fibrotic tissue. SPIR, as an
aldosterone-antagonist agent, blocks these effects and attenuates
the deposition of collagen and fibrotic tissue formation.
In our study, we applied EMPA and EMPA+SPIR imme-
diately after ligation of the LAD artery, and for 28 consecutive
days. Our data indicates that early administration of either EM-
PA as a single agent or in combination with SPIR caused an
increase of only LV cavity perimeter, without affecting other
structural variables. This finding may potentially be attributed
to eccentric hypertrophy mechanism.
Three mechanisms may explain post-MI hypertrophy de-
velopment: first, the physical effect of volume overload and
consequence over-use to exhaustion of the Frank-Starling law
of the heart. Sasayama [22] showed that although the initial re-
sponse to volume overload consists of near-maximum use of the
Frank-Starling mechanism. over-using this mechanism eventu-
ally leads to eccentric hypertrophy development by addition of
sarcomeres. In addition, Spingeling et al. [23] showed that in-
duction of acute MI leads to eccentric hypertrophy of the remote
myocardium, which is responsible for LV dilatation.
Alternatively, an over activation of the extracellular signal-reg-
ulated kinases 1/2 (ERK 1/2) pathway stimulate concentric hyper-
trophy, while inhibition of this pathway is associated with eccen-
tric hypertrophy [24]. In two distinct studies EMPA did not cause
any significant increase in the expression of ERK1/2 compared
to control [25,26]. Accordingly, ERK 1/2 was un-phosphorylated
and inactive with administration of EMPA, thus it could poten-
19
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Figure 4. Picro-Sirius red staining in scar and remote areas of 3 animals from different
experimental groups: A. control group, scar area B. EMPA group, scar area C. EMPA+SPIR
group, scar area, D. control group, remote area, E. EMPA group, remote area F. EMPA+SPIR
group, remote area. Magnification x40.
tially contribute, or for the least not inhibit, the development of
eccentric hypertrophy in the presence of volume overload.
The third mechanism that may explain the LV cavity increased
perimeter involve loss of tissue at the remote area and subsequent
induction of apoptosis. Palojoki et al. [26] showed cardiomyo-
cytes apoptosis in the non-infarcted myocardium (i.e. remote ar-
ea) caused an increase in diastolic LV diameter and was a major
factor in cardiac remodeling up to 4 weeks post infarction in rats.
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VOL 01 • WINTER 2021
Figure 5. CVF in A. the remote area and B. scar of the 3 experimental
groups, Control (white), EMPA (gray), EMPA+SPIR (black). * P<0.05 vs.
Control, *** P<0.001 vs. Control, ††† P<0.001 vs. EMPA.
DECREASE OF CVF
Fibrosis initiates at the cellular level, as necrotic cells activate
innate immune pathways, triggering an inflammatory response,
including the stimulation of toll-like receptors (TRL's) and
complement system. Suppression of the inflammation is initi-
ated as leukocytes clear the infarct zone from dead cells. Con-
sequentially, fibroblasts proliferate and deposit large amounts
of ECM proteins (collagen), which maintain the structural in-
tegrity of the infarcted ventricle, with the help of RAAS and
the transforming growth factor (TGF) β family [27].
Our CVF measurements indicated attenuation of collagen
deposition. Several studies have shown the cardiac effect of
EMPA in ameliorating cardiac fibrosis in several rat models of
cardiac damage with and without diabetes [28-30]. At the mo-
lecular level, several pathways were proposed as possible mech-
anisms for the attenuation of fibrosis, among them, decreased
expression of the pro-fibrotic signaling pathway protein SGK1,
 VOL 01 • WINTER 2021
and decreased expression of epithelial sodium channel (ENaC)
[31]. Genetically, it was found that EMPA decreases mRNA
expression of several genes, including ANP and beta-myosin
heavy chain, both associated with the pro-fibrotic mitogen-ac-
tivated protein kinase pathways [32]. It was also shown that
reactive oxygen species, induced by hyperglycemia, can pro-
mote myocardial fibrosis by activating pro-fibrotic factors, and
by differentiation of cardiac fibroblasts into ECM producing
myofibroblasts [33]. EMPA, by reducing blood glucose, may
attenuate these pro-fibrotic pathways as well.
Our results for EMPA as a single agent are consistent with re-
sults obtained in previous studies [16,30,33]. Briefly, these studies
used either rats or mice models with special characteristics, i.e. dia-
betes, pre-diabetes or hypertensive heart-failure. EMPA treatments
ranged from 2 to 12 weeks and lead to decrease in body weight and
adipocytes mass, decreased myocardial oxidative stress, improved
systolic function, and ameliorated cardiac injury and fibrosis in the
ventricles and atria. A recently published paper suggests that EM-
PA attenuated TGF-β1-induced fibroblast activation [20].
SPIR is an aldosterone-receptor antagonist that also proved
to be beneficial in reducing the risk of sudden cardiac death
and death from progressive HF [35]. Studies have tested SPIR's
efficacy showed comparable results regarding the attenuation
of fibrosis [3,5,12,13]. Specifically, 4-24 weeks of SPIR treat-
ment prevented collagen proliferation in the surviving myocar-
dium (i.e. remote area), decreased hypertrophy and fibrosis in
both atria and ventricles, and attenuated HF. Yet, no study, up
to date, has tested the synergistic effect of SGLT2i and aldo-
sterone-antagonists as a possible treatment to reduce cardiac
fibrosis. Thus, our results suggest novel insights about the pro-
found synergistic effects of EMPA+SPIR in the attenuation of
fibrosis in the immediate timeframe after acute MI.
REMOTE VS. SCAR AREAS
We quantified CVF in two distinct regions of the heart, i.e. the scar
itself and remote cardiac areas. In the scar area, the results show
significant reduction of CVF in both EMPA and in EMPA+SPIR
groups compared to the control group, and in the EMPA+SPIR
group vs. the EMPA group. In the remote area, CVF was lower
only in the EMPA+SPIR group compared to the control.
The natural development post-MI includes induction of
apoptosis, followed by an inflammatory reaction and progres-
sive fibrosis both at the scar and at remote areas. The latter is the
part of the heart that is still capable of remodeling in a process
known as "reactive fibrosis"[37], which is driven by the excess
work required in the remote area due to loss of contracting tis-
sue. This, in turn, may lead to apoptosis and deposition of col-
lagen. In later stages, when the scar is formed due to infarction,
morphological and physiological changes occur solely in the
remote area, potentially leading to HF. Thus, prevention of fi-
brosis in the remote area is a leading clinical application as it
might prevent deterioration to HF.
Articles
As of the time of this study, only one recently published study
compared the efficacy of EMPA to SPIR on variables related to
HF in rats, proving that administration of SPIR resulted in lower
physical tolerance, reduced cardiac output and increased body
weight compared to administration of EMPA [37]. To the best
of our knowledge, no study has ever shown their synergistic an-
ti-fibrotic effect, and specifically no study compared this effect
on both remote and scar areas.
STUDY LIMITATIONS
Our goal in this study was to describe and quantify the synergis-
tic effect of EMPA+SPIR on collagen deposition post-MI in a
rat model. We used several methods that are not without flaws,
as such studies require histological analysis which rely upon the
subjective evaluation of the investigators.
The fact that there was no significant change in the remote
area could be the result of a relatively small study group. The
use of a computer program, "ImageJ", to analyze the amount of
collagen based on color could have been biased, as the examiner
had to use his own sight to approximate the lines and colors in
each picture. Finally, the rat models were not as reproducible
as we might have wanted, meaning that the animals differed in
size, weight etc., although we overcame this problem by adjust-
ing the drugs doses according to the animal's weight.
CONCLUSIONS
The effect of EMPA or SPIR on fibrosis was widely investigated
in past studies, but their synergistic effect was not evaluated. Our
study shows that early combined administration of EMPA+SPIR
attenuates the collagen deposition in hearts of rats post-MI, both
at the scar itself and in remote areas. Thus, this treatment can po-
tentially delay the development of adverse cardiac remodeling
post-MI, and the consequent development of HF.
Corresponding author
Nadav Bandel
Email: nadavban@gmail.com
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Tumor immunology a niche in the node
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development is unclear. Using a mouse model of lung
adenocarcinoma programmed to express neoantigens,
Connolly and colleagues identified a stable reservoir
of tumor-specific TSL cells in the tumor-draining lymph
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node (dLN). TSL cells migrated from the dLN to the
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Sci Immunol 2021; 6: abg7836
Eitan Israeli
 VOL 01 • WINTER 2021
Attention Mediates the Similarity Effect
in Decision Making
Omri Maor 1,2, Moshe Glickman3 and Marius Usher 2,3
1
sackler school of medicine, Tel Aviv university
2
Sagol school of neuroscience, Tel Aviv university
3
The School of Psychological Sciences, Tel Aviv University
ABSTRACT  Background: Preference reversal effects are among the most
puzzling phenomena that challenge our understanding of hu-
man decision-making, and its relationship with the principles
of rationality.
 Methods: We used a Rapid Sequential Visual Presentation
(RSVP) with triples of numerical values, while monitoring the
participants' attentional selection using the dot-probe paradigm.
 Aims: Our aims were to examine the attentional bias underly-
ing the Preference reversal effects (similarity) as suggested
by the selective integration model.
 Results: We first managed to replicate a similarity effect as
seen in previous research. By measuring attentional selection
using the dot-probe paradigm we showed that subjects gave
more attention to higher values compared to lower values, a
difference that increased when the dot probed the target com-
pared to the competitors.
 Conclusions: These results fully support our hypotheses and
suggest that attention is drawn into information congruent with
observer's goals, whereas incongruent information is discarded.
JIMS 2021; 23: 23–27
KEY WORDS attention, cognitive psychology, decision making, irrationality,
selective integration
INTRODUCTION
Decision making is a ubiquitous cognitive process that is part
of almost every aspect of our lives, from deciding which shirt
to put on to purchasing a house. Since the early days of the
20th century, a body of mathematical work has developed the
modern axiomatic approach to rationality in choice behavior.
According to that approach, humans evaluate each alterna-
tive independently, and choose the option that has the highest
utility. This assumption relies on two axioms known as the
"independence of irrelevant alternatives" and "regularity". The
"independence of irrelevant alternatives" claims that adding
a third option to two existing options should not affect the
relative attractiveness of the existing options (i.e., if the two
options were equally attractive, adding another option will not
Articles
make one of the original options more attractive than the other
[1,2]. The "regularity" axiom claims that adding a novel op-
tion to a set of existing options can not raise the probability of
choosing one of the original options [1].
Though the modern axiomatic approach describes choices
as consistent with the idea of utility maximization, experimen-
tal research has shown a set of "non-rational" behaviors which
collides with the rationality theory, such as framing effects (pre-
ferring option A over B when looking for the best alternative,
but option B over A when looking for the worst one [3]), and
contextual preference reversals (evaluate the options in the con-
text in which they are given in, instead of evaluating each option
independently with the help of a stable criteria).
The similarity effect refers to a situation in which a person
is indifferent between two equally attractive choices, and then
given a third option, which is very similar to one of the origi-
nal options. Instead of perceiving all three options as equally
attractive, the novel option is perceived as equally attractive to
its similar original choice, and the other original choice (the
different one) is perceived as equal to the sum of attractive-
ness of the other two choices. When someone demonstrates
the similarity effect, there is a higher probability that they will
pick option A (the dissimilar option) over option B or C (the
similar options).
A large body of research has investigated the cognitive mech-
anism underlying the similarity effect [4]. In two studies, Tset-
sos et al. suggested a mechanism of Selective-Integration (SI)
– increased relative weighting of the largest payoffs (among of a
pair or triple) – as a source of the similarity effect (among other
choice-biases [5,6] [Fig. 1A]). In these studies, they used a rapid
sequential visual presentation (RSVP) with numerical rewards
(triples) presented at rates of 2/sec. This method mimics rapid
internal sampling of values in multi-attribute decisions, as pre-
vious studies suggested it to represent internal decision making
[7,8] [Fig. 1B]. The research showed that the cognitive integra-
tion of preferences is subject to several biases. For instance, in
a previous research, participants were biased towards the differ-
ent sequence compared to the other two similar sequences, thus
showing the similarity effect [5].
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Figure 1 [A]. The selective integration model. Schematic illustration of the model (Tsetsos et al., 2016). On each time step, two values corresponding to
a specific attribute of two alternatives are sampled. These input feed into a bottleneck, which discount the input with the lower momentary value (via
selective gating), the transformed inputs are then relayed to the accumulators. Noise may arise in the input stage as well as in the accumulation stage.
[B]. The selective integration model. The pro-variance effect: the participants prefer the broad (right numbers) over the narrow distribution (left numbers).

A B

The objectives of this project are to explicitly examine the at-
tentional mechanism suggested in the selective integration model.
To this end, we replicated the results of previous research show-
ing the similarity effect [5], while monitoring attentional selection
using the dot-probe paradigm. We predicted that attention would
be directed toward the higher numbers, which are congruent with
the observers’ goals of maximizing their profit, and that more at-
tention would be directed toward the target as compared to the
distractors, since targets, unlike distractors, have no attentional
competitors. Thus, the detection rate of the dot in the dot-probe
paradigm would be higher when it is presented in higher num-
bers of the target sequence compared to higher numbers of the
competitor sequences, and there would not be any significant dif-
ference in the dot detection rates between lower numbers of the
target sequence and the competitor sequences.
METHODS
PARTICIPANTS
Thirty-one Tel-Aviv University undergraduate students (26
females) participated in the experiment, with ages ranging be-
tween 19 and 29 (mean = 23). All of them gave their consent to
participate in the research, and received 1 course credit and a
monetary bonus of 15-20NIS based on their performance in the
experiment. Approval from the ethics committee was provided.
STIMULI
In both parts of the experiment, black digits were presented
against a grey background on a 19'' ViewSonic Graphics Series
G90fB CRT monitor with a 60 Hz refresh rate, using 1024×768
resolution graphics mode, viewed from a 60cm distance. Each
numerical value had a width of 16 mm, and a length of 16 mm,
and was surrounded by a (2X2) cm black frame. The numbers
were located at the center of the square. In the first part of the
experiment two squares aligned horizontally, were presented
from both sides of the fixation cross – distant 2cm away from
it. In the second part of the experiment, a triplet of squares was
aligned in a virtual triangle – the triples were placed at the ver-
tices of an imaginary triangle. The left and right options were
each 1 cm away from the center of the screen, and the top option
was placed at the center and was raised by 2cm. The size of the
fixation cross was 0.5X0.5cm.
The stimulus in each part of the experiment was altered. The
first part of the experiment contained a stimulus consisting of 80
pairs of numerical values. Each pair of numerical values was pre-
sented for 500ms simultaneously, the numerical value was drawn
randomly from a Gaussian distribution (mean = 50, Standard De-
viation (SD) = 15). The second part of the experiment consisted
of 180 trials; each had 8 triples of numerical values. Each triple
of numerical values was presented for 1200ms. To reproduce an
analogue to the similarity effect, we used a method similar to
Tsetsos et al. [5]. Of the 180 trials, 120 trials were "critical trials"
- the numerical values (2 digits) were generated randomly from
one of two Gaussian distributions (first distribution had mean=70,
SD=7, the second distribution mean=40, SD=7).Every time the
"target" sequence of numbers sampled a number from one of the
distributions, the other two sequences of numbers sampled a num-
ber from the second distribution (thus called "competitor 1", and
"competitor 2" sequence). In each triple, the "target" sequence
picked randomly one of the two distributions [Fig 2A, 2B].
The rest of the 60 trials were "fillers" – which contained
numerical values (2 digits) that were sampled from 3 different
Gaussian distribution – one for each sequence (means of the

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 VOL 01 • WINTER 2021 Articles

distributions were [40, 50, 60], all had SD=10), thus creating Figure 2. [A] representation of the Similarity effect through Sequential triples of squares.
top sequence represents the Target sequence (i.e. the dissimilar option), while the
3 sequences with different means, but with the same variances.
bottom sequences represent the competitor sequences (i.e. the similar options).
In addition, a dot probe paradigm was used in both parts of [B] The staircase procedure in which the contrast of the dots color is being adapted to
the experiment. The first part of the experiment contained a the subject. [C] Triples with the red dot in all four situations – on high numbers in target
staircase procedure to adjust the contrast between the dot and sequence, low numbers in target sequence, high numbers in competitor sequence, and
the screen per subject. A red dot appeared in the center of one of low numbers in competitor sequence.
the squares (the square which had the red dot was picked ran-
domly). The dot appeared for the last 50ms of the trial. In every
successive pair of squares, the contrast between the dot and the A
background was altered based on previous detection of the red
dot by the participant, according to the 3-up-1-down staircase
method [Fig.2B]. In the second part of the experiment, the red
dot appeared in 80 of the critical trials, once in each of the trials
[Fig. 2C]. It appeared in the center of the square for the last
50ms of the trial. In each of the trials containing the red dot –
the dot randomly appeared in one of the 8 triples between the
3rd and the7th. The color of the dot was determined by the final
color of the dot in the previous part of the experiment (there was
a staircase procedure for the color of the red dot in the first part
of the experiment).

EXPERIMENTAL DESIGN
The participants were divided into 2 groups – the "dot high"
group, for which the red dot appeared on the higher numbers of
B
the triples (the second part of the experiment), and the "dot low"
group, for which the red dot appeared on the lower numbers.
The experiment took place in a dark room in front of a com-
puter screen. At the first part of the experiment, 2 numbers
were simultaneously presented to the subjects for 500ms, and
a red dot appeared in the center of one of them for the last
50ms of the trial. The participants were asked to determine
which number was higher, and then to report whether the red
dot appeared in the right or left square. A feedback was given
after each trial – a visual feedback for the higher numerical
value (the square was painted in green for a correct answer,
and red for an incorrect answer), and an auditory feedback for
the red dot detection (a "beep" sound was heard for an incor-
rect answer). The participants carried out six practice trials to
make sure that the task was understood. For the second part of C
the experiment, the participants were asked to notice the 3 se-
quences of numbers which were presented simultaneously, and
choose the sequence that would yield the highest extra sam-
ple in their opinion (the 3 sequences represented 3 slot-ma-
chines and the participants had to choose the one they thought
was most attractive). After the participants chose a sequence,
they were asked if they detected a red dot during the trial. In
that part of the experiment the participants received a differ-
ent feedback for their choices – an extra sample was given to
them out of the sequence they chose, and added up to a total
sum during the experiment for motivation purposes. The task
of choosing the sequence in this part of the experiment was
presented to the participants as the main task which is being

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Figure 3. [A] Choice as a function of sequence type (target, competitor1, competitor2) in the experiment. [B] Choice as a function of sequence type and
groups. [C] the similarity effect per subject. [D] Dot detection rate as a function of the group of the subject and the type of sequence which presented the dot.
tested, and the participants were told that the monetary reward
they would receive at the end of the experiment was depended
on their success in that task. The participants carried out six
practice trials to make sure they understood the second part of
the experiment. Throughout the experiments the participants
were given short breaks.
Statistical analysis was conducted with STATISTICATM
(TIBCO, 3307 Hillview Avenue, Palo Alto, CA 94304, USA).
RESULTS
SIMILARITY
Our first goal was to replicate the similarity effect found by
Tsetsos et al. [5]. To this end, we conducted a repeated mea-
sure analysis of variances (ANOVA), on the choice rate of
each alternative, with the type of the sequences (target, com-
petitor1, competitor2) as a within-subject factor [Fig. 3A].
The ANOVA yielded a significant effect for the type of the
sequence, <0.000001. The target sequence was chosen in
48.71% of the trials (SD=11.176). The competitor sequences
were chosen in 26.478% (SD=6.34), and 24.811% (SD=6.16)
of the trials. Post-hoc contrasts revealed that the participants
preferred the target over the competitors, P<0.0000001, how-
26
VOL 01 • WINTER 2021
ever, the competitors did not significantly differ from each
other, P=0.107.
Next, we examined whether the appearance of the red dot
affected choice [Fig. 3B]. To this end, we added the variable
"group type"(high numbers vs. low numbers) as a between-sub-
ject factor to the previous analysis. The ANOVA revealed a
significant effect for the type of sequence factor, p<0.0000001.
however, none of the other effects reached a statistical signifi-
cance (all s>.64), indicating that the participants' choices were
not affected by the location of the dot.
The similarity effect was also tested per subject [Fig. 3C].
The graph shows the difference between the amount of times
a subject chose the target sequence, and the average amount of
times the subject chose the distractors choices( i.e., a positive
score indicates a preference for the target over the competitors).
The results show that 30 out of the 31 participants preferred the
target in higher rates than the competitors.
DOT-PROBE
The data from three participants were excluded from the anal-
ysis, because their rates of false-alarms exceeded the group's
mean by more than 3 standard deviations.
We conducted an ANOVA on the detection rate of the dot,
with the "group type" as a between-subject factor, and the "type
 VOL 01 • WINTER 2021
of sequence" as a within-group factor [Fig. 3D]. The ANOVA
revealed a significant main effect for the "group type" factor,
P=0.008. In addition, the ANOVA yielded a significant inter-
action between the "group type" and the "type of sequence"
factors, P=0.005. Simple effect analysis revealed that for the
higher numbers, the detection rate of the dot was higher when
it was placed within the target rather than the competitors,
P=0.00014, however, for the lower numbers, no effect was
observed P=0.9.
These results cannot be accounted by differences in the lev-
els of false alarm, which were quite low – as seen in figure D
(the false-alarms rate for the "dot high" condition were M=0.01,
SD=.01, and M=.003, SD=.8 for the "dot low" condition).
FILLERS
The accuracy of the participation in the filler trials was very
high 0.97, thus the participants did not choose the sequence
randomly.
We managed to replicate the similarity effect as shown in
[Fig. 3A]. In addition, we ruled out the effect of "group type"
factor (the location of the red dot) on the participants' choic-
es [Fig. 3B]. The attentional selection was tested with the dot
probe – which was located either on the target sequence (the
anti-correlated sequence) or on one of the competitors (the cor-
related sequences). In addition, the probe in every sequence
was placed on either high values or low. Our hypotheses about
the dot detection are described in [Fig. 2C]. We hypothesized a
main effect for the "type of sequence" factor in the dot detection,
and an interaction between the "type of sequence" factor and the
"group type" factor.
DISCUSSION
The goal of this study was to examine the effect of attentional
selection on decision making. First, we replicated the results of
a previous research [5], showing the Similarity effect. Further-
more, using the dot-probe paradigm, we measured attentional
selection during task performance. We showed that: i) the de-
tection rate of the dot was higher when it was placed within
high compared with low values, and ii) this difference increased
when the dot probed a target compared to the probing a dis-
tractor. These results support our hypotheses and suggest that
attention is drawn into information congruent with observer’s
goals, whereas incongruent information is discarded.
An alternative explanation for our results is that instead of
addressing each frame in the trial independently and integrating
between them at the end, the participants' would start to pay
more attention towards the 'to be chosen' option, which held
more attractive values at the beginning of the trial. However,
if this was indeed the case then they would detect the dot only
if it appeared on the preferred sequence, disregarding the value
of the number, even if the dot appeared on a low value. This
Articles
explanation does not fit with the results since attention was ab-
sent from the lower values compared to high values - meaning
attentional shifts occurred within each frame, rather than across
the trial. It is worth mentioning that the similarity effect was not
affected by the location of the dot.
In this study, we reproduced an analogue to the similari-
ty effect by using triples of numbers, and temporally manip-
ulated their pay-offs. Contextual effects consist of at least 2
traits (e.g. quality and economy). In this experiment we tried
to make an analogue to 2 traits by making the sequences ex-
ample numbers randomly from 2 distributions. Future studies
can employ the dot probe paradigm using stimuli that consists
of triples of histograms – each has 2 bars and represents 2 dif-
ferent traits of the option.
An eye-tracking paradigm can be used in future studies of
the experiment in order to examine more carefully the amount
of time a participant focuses on each sequence and analyzing
their preference in each frame. Additionally, follow-up re-
search could examine the attentional mechanism underlying
other contextual effects, such as the Attraction effect, or the
Compromise effect.
To conclude, the selective integration model is a deci-
sion-making model that has successfully explained several ra-
tionality violations. In this project we examined the attention-
al bias underlying the similarity effect according to SI model.
Our results provided behavioral support for this mechanism by
showing that observers attend more to high values and more so
when they appear on targets than on competitors.
Corresponding Author
Phone: +972 502343047
Email: omrimaor2@gmail.com
References
1. Luce, R. D. (1959). On the possible psychophysical laws. Psychological review,
66(2), 81.
2. Von Neumann, J., & Morgenstern, O. (1947). Theory of games and economic
behavior, 2nd rev.
3. Tversky, A., & Shafir, E. (1992). Choice under conflict: The dynamics of deferred
decision. Psychological science, 3(6), 358-361.‫‏‬
4. 
Trueblood, J. S., Brown, S. D., & Heathcote, A. (2014). The multiattribute
linear ballistic accumulator model of context effects in multialternative choice.
Psychological review, 121(2), 179.‫‏‬
5. Tsetsos, K., Chater, N., & Usher, M. (2012). Salience driven value integration
explains decision biases and preference reversal. Proceedings of the National
Academy of Sciences, 109(24), 9659-9664.
6. Tsetsos, K., Moran, R., Moreland, J., Chater, N., Usher, M., & Summerfield,
C. (2016). Economic irrationality is optimal during noisy decision making.
Proceedings of the National Academy of Sciences, 201519157.‫‏‬
7. Tversky, A. (1972). Elimination by aspects: A theory of choice. Psychological
review, 79(4), 281.‫‏‬
8. Roe, R. M., Busemeyer, J. R., & Townsend, J. T. (2001). Multialternative decision
field theory: A dynamic connectionst model of decision making. Psychological
review, 108(2), 370.‫‏‬
27
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Publishing your research in JIMS doesn’t block further publishing in in international index.
 VOL 01 • WINTER 2021
A 30-Year-Old Female with Postpartum Hypertension
Ori Hadad BSc1 and Ehud Grossman MD PhD1,2
1
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
2
Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel,
ABSTRACT 
Postpartum hypertension is usually due to persistent gesta-
tional hypertension, preeclampsia, or pre-existing chronic
hypertension. In about 10% of the cases there is a secondary
underlying cause. We describe a case of a 30- year old healthy
women woman with a normal pregnancy that developed se-
vere postpartum hypertension due to Page kidney.
JIMS 2021; 23: 29–31
INTRODUCTION
Hypertensive disorders of pregnancy are responsible for signif-
icant maternal and perinatal morbidity and mortality. In some
cases, hypertension may develop postpartum. Postpartum hy-
pertension may be related to persistent gestational hypertension,
preeclampsia, or pre-existing chronic hypertension, and it could
be developed de novo in the postpartum period secondary to
other causes [1]. The exact incidence of de novo postpartum
hypertension is difficult to ascertain, since in clinical practice
most women will not have their blood pressure (BP) measured
until they visit their physician about 6 weeks after delivery. Ad-
ditionally, women with symptomatic postpartum hypertension
are often managed in the emergency department and will not be
coded as hypertensive unless hospitalized [2]. Gestational hy-
pertension and preeclampsia are thought to account for 86% of
postpartum hypertension cases, while worsening chronic hyper-
tension, superimposed preeclampsia, and other rare secondary
causes account for the remainder of the cases [3].
Hypertension complicating pregnancy, including postpar-
tum, is defined as systolic BP of 140 mmHg or higher, and/
or diastolic BP of 90 mmHg or higher, on at least two mea-
surements four hours apart. Severe hypertension is defined as
systolic BP greater than 160 mmHg and/or diastolic BP greater
than 110 mmHg on at least two measurements, repeated at a
short interval of several minutes [1].
The initial diagnostic evaluation of postpartum hypertension
should include a detailed history and physical examination to de-
termine the disorder causing the hypertensive situation. In addi-
tion, medications associated with causing hypertension, including
nonsteroidal anti-inflammatory drugs (NSAIDs) and Methylergo-
Articles
metrine should be considered as part of the detailed history. If the
patient does not clearly meet criteria for the usual hypertensive
disorders of pregnancy (gestational hypertension, preeclampsia,
chronic hypertension, or superimposed preeclampsia), an evalu-
ation for secondary causes of maternal hypertension should be
considered. This evaluation should include measurement of thy-
roid stimulating hormone and free thyroxine (FT4), electrolytes
(sodium, potassium), creatinine, 24-h urine for catecholamines/
metanephrines, 24-h urinary free cortisol (only if clinical symp-
toms of Cushing’s syndrome present), polysomnography and
urine drug screen and renal ultrasound with Doppler flow [4].
IT IS IMPORTANT TO MEASURE BLOOD PRESSURE
POSTPARTUM TO DIAGNOSE POSTPARTUM HYPERTENSION
The differential diagnosis for secondary causes of postpar-
tum hypertension includes renovascular hypertension, primary
kidney disease, primary hyperaldosteronism, hyperthyroidism,
sleep apnea, pheochromocytoma and Cushing’s disease [4].
Since severe hypertension is known to cause maternal stroke,
when present it should be treated regardless of the etiology. Accord-
ing to the American College of Obstetricians and Gynecologists
(ACOG) recommendations, the treatment should include intrave-
nous administration of labetalol (β-channels blocker), hydralazine
(direct vasodilator), and oral labetalol [5]. Despite these recom-
mendations, several studies showed indirect evidence that nifed-
ipine (dihydropyridines Ca-channels blocker) may be superior to
labetalol, showing significantly faster time to achieve normal BP
with nifedipine than with labetalol [4]. In addition, magnesium sul-
phate should be considered for seizures prophylaxis with new-onset
postpartum preeclampsia with severe features, or severe gestational
hypertension, especially in the first postpartum week [6].
POSTPARTUM HYPERTENSION IS USUALLY DUE TO
PERSISTENT GESTATIONAL HYPERTENSION, PREECLAMPSIA,
OR PRE-EXISTING CHRONIC HYPERTENSION.
The ACOG also suggests that women with continued post-
partum hypertension (defined as 2 or more measurements of
BP higher than 150 mmHg systolic and/or 100 mmHg diastolic)
should be administered a long-acting oral hypertensive agent [6].
29
 Articles
Figure 1. [A] Computed tomography (CT) scan without contrast, showing a mass in the region of the left kidney. [B] CT scan with contrast, showing
the mass is not enhanced other than its medial part. [C] CT scan with contrast, in the level of the adrenal glands, showing normal bilateral adrenal
glands, separated from the mass.
We present the case of a woman with unusual cause of post-
partum hypertension.
CASE DESCRIPTION
SY is a 30 years old woman married +2, with no significant
medical history, with 2 previous normal-course pregnancies.
SY gave birth for the third time on 13 September 2011 in
week 41, following a normal pregnancy course. Delivery went
well with normal BP levels.
Nine days postpartum, she presented to the emergency room
with left-sided flank pain. Physical examination showed regular
heart rate of 84 beats per minute and a BP of 130/86 mmHg.
The pain was related to a gynaecological infection, and she was
discharged with antibiotic treatment.
WHEN THE BLOOD PRESSURE IS NOT WELL CONTROLLED
WITHIN 2 WEEKS, A FULL EVALUATION SHOULD BE DONE TO
EXCLUDE A SECONDARY UNUSUAL CAUSE.
Several weeks later she complained of sudden palpitations
and confusion. Her BP was 240/140 mmHg and she was referred
to the emergency department (ED). In the ED her pulse rate was
120 beats per minute (regular) and the BP was 220/120 mmHg.
ECG showed sinus tachycardia without signs of left ventricular
hypertrophy (LVH). Lab results showed normal renal functions,
normal glucose levels with normal sodium levels (138 mmol/l)
and low potassium levels (3.5mmol/l). The rest of the laborato-
ry evaluation was normal. Echocardiography showed no signs
of LVH, and a slight decrease in systolic function (Ejection
Fraction = 50%). She was treated with sub-lingual Captopril
(Angiotensin Converting Enzyme inhibitor) and was released
with a recommendation to start treatment with Lercanidipine
(Ca-channel blocker) and continue an ambulatory follow-up.
Seven days later, she still felt unwell, with palpitations and
high BP values. A physical examination revealed a regular pulse
of 120 beats per minutes, BP of 170/120 mmHg when lying
down and 160/110 mmHg when standing up. A large, stiff, pal-
pable mass was detected in the left upper abdominal quadrant.
30
VOL 01 • WINTER 2021
The rest of the physical examination was normal. An abdom-
inal ultrasound showed a 15 cm mass in the left upper quad-
rant. 24-hours urine catecholamine excretion was normal. Nor-
epinephrine 98.9 µg/24 hours (normal range = 0-100 µg/24h),
Epinephrine were undetectable, and Dopamine 377 µg/24 hours
(normal range = 60-1,000 µg/24h).
IN ABOUT 10% OF THE CASES OF POSTPARTUM
HYPERTENSION THERE IS SECONDARY UNDERLINE CAUSE
Since she continued to be symptomatic with tachycardia and
elevated BP levels, she was started on a treatment of Doxaz-
osin (α-channels blocker) up to 16mg per day, and Bisoprolol
(β-channels blocker) 5mg per day. Under the treatment the pulse
was stable around 80 beats per minute, and BP stabilized around
160/100 mmHg, with a significant improvement in her symp-
toms. An MIBG scan was also performed.
The lack of response to a combination of adequate doses of α
and β blockers, normal levels of urine catecholamines and their
metabolites, and a negative MIBG scan excluded the diagnosis
of pheochromocytoma.
For further evaluation, a CT scan and MRI were performed.
The CT scan did not show a clear origin of the mass, but it was
clear that the mass was separated from the adrenal gland [Fig.
1]. The MRI demonstrated left peri-renal hematoma [Fig. 2].
Renal scintigraphy showed impaired function of the left kidney,
contributing only 10% to the general renal function. PRA (plas-
ma renin activity) was elevated [11.6 ng/ml/h (normal range =
0.2-2.8)], and plasma aldosterone levels was slightly elevated
[802 pmol/l (normal range = 110-800)].
The clinical picture confirmed the diagnosis of peri-renal
hematoma (Page Kidney). Ramipril (angiotensin-converting
enzyme inhibitor) was added to the treatment and the BP was
normalized within a few days.
DISCUSSION
Page kidney causes systemic hypertension as a result of extrinsic
compression of the renal parenchyma, leading to activation of the re-
 VOL 01 • WINTER 2021
Figure 2: [A] Magnetic resonance imaging (MRI) T1-weighted scan without contrast enhancement, showing a hyperintense mass in the region of the
left kidney. [B] MRI T1-weighted scan with contrast enhancement, showing the mass is not enhanced. [C] Deduction of (b) by (a) showing the mass
is not enhanced other than in its medial part
nin-angiotensin-aldosterone (RAAS) system [7]. Experimentally, it
was first described by Dr Page in 1939 in a dog by wrapping the kid-
ney with cellophane tape which induced hypertension in the dog [8].
The compression of the kidney is caused by a hematoma or
a mass, usually caused by blunt trauma (sports injuries, motor
vehicle accidents, violence, or a fall), but may also be iatrogenic
(following kidney biopsy, shockwave therapy, ureteral surgery,
sympathetic nerve block) or spontaneous (anticoagulation, AV
malformation, tumour, vasculitis, pancreatitis). Non-bleeding
causes of external compression include lymphoceles, particularly
in a transplanted kidney, urinoma, retroperitoneal paraganglioma,
or large simple cysts [7, 9]. We found only one case report of Page
kidney postpartum, secondary to HELLP (haemolysis, elevated
liver enzymes and low platelets) syndrome, attributable to the
thrombocytopenic state [10]. In our patient we did not find any
abnormality of the coagulation system and therefore we assume
that it was induced by external pressure during the delivery. In
fact, several days postpartum she complained of left flank pain
which was probably the first sign of the peri-renal hematoma.
The clinical presentation of Page kidney is, in some but not
all cases, flank pain, flank ecchymosis, proteinuria, haematuria,
hypertension, and in non-trauma causes, decreased Glomerular
Filtration Rate (GFR) (calculated by MDRD formula) [9].
Definitive treatment options of Page kidney have evolved, from
radical nephrectomy and hematoma evacuation open surgeries in
the past, to non-invasive procedures, such as percutaneous drain-
age of hematoma, endoscopic interventions, and mesh hood fascial
closure in the present. Medical treatment options nowadays are
medications that block the RAAS system, such as angiotensin-con-
verting enzyme (ACE) inhibitors, angiotensin receptor blockers
(ARBs), and mineralocorticoid receptor antagonists (MRAs) [7].
Percutaneous drainage of the hematoma may lead to further bleed-
ing from the kidney and therefore in our patients we decided to
postpone the procedure and performed the drainage only several
weeks after the diagnosis and after the BP was well controlled.
During a long term follow-up the patient was treated with valsar-
tan (angiotensin receptor blocker) and her BP was well controlled.
Recently she considered an additional pregnancy and therefore we
had to stop treatment with RAAS blockers and switch the treatment
Articles
to labetalol which is one of the drugs of choice for hypertension in
pregnancy. The BP was less well controlled, but she became preg-
nant and a question was raised whether to add aspirin. In her case
we decided that the risk from bleeding was higher than the benefit
of aspirin in high risk pregnancy and we decided not to add aspirin.
PERI-RENAL HEMATOMA SHOULD BE CONSIDERED AS A
SECONDARY CAUSE FOR POSTPARTUM HYPERTENSION.
SUMMARY
We described an unusual case of postpartum hypertension induced
by spontaneous peri-renal hematoma in an otherwise healthy young
woman. To our knowledge this is the first case of Page kidney de-
scribed postpartum in a healthy woman with normal pregnancy.
REFERENCES
1. Tan L-K, de Swiet M. The management of postpartum hypertension. BJOG : an
international journal of obstetrics and gynaecology. 2002;109(7):733-6.
2. 
Sibai BMMD. Etiology and management of postpartum hypertension-
preeclampsia. American journal of obstetrics and gynecology. 2012;206(6):470-5.
3. Al-Safi Z, Imudia AN, Filetti LC, Hobson DT, Bahado-Singh RO, Awonuga AO.
Delayed postpartum preeclampsia and eclampsia: demographics, clinical course, and
complications. Obstetrics and gynecology (New York 1953). 2011;118(5):1102-7.
4. Sharma KJ, Kilpatrick SJ. Postpartum hypertension: etiology, diagnosis, and
management. Obstetrical & gynecological survey. 2017;72(4):248-52.
5. 
Committee Opinion No. 623: Emergent therapy for acute-onset, severe
hypertension during pregnancy and the postpartum period. Obstetrics and
gynecology (New York 1953). 2015;125(2):521-5.
6. American College of Obstetricians and Gynecologists CoOaG, Task Force on
Hypertension in Pregnancy FoHiP. Hypertension in pregnancy. Report of the
American College of Obstetricians and Gynecologists' task force on hypertension
in pregnancy. Obstetrics and gynecology (New York 1953). 2013;122(5):1122-31.
7. Dopson SJDO, Jayakumar SMD, Velez JCQMD. Page Kidney as a rare cause of
hypertension: Case report and review of the literature. American journal of kidney
diseases. 2009;54(2):334-9.
8. Page, Irvine H, The production of persistent arterial hypertension by cellophane
perinephritis: J. A. M. A. 113: 2046, 1939. American Heart Journal. 1940;19(2):246.
9. Kamath SU, Patil B, Patwardhan SK. Postpartum Page Kidney secondary to HELLP
Syndrome. Journal of clinical and diagnostic research. 2018;12(10):PD05-PD6.
10. Smyth A, Collins CS, Thorsteinsdottir B, Madsen BE, Oliveira GHM, Kane G, et al.
Page Kidney: Etiology, renal function outcomes and risk for future hypertension.
The journal of clinical hypertension (Greenwich, Conn). 2012;14(4):216-21.
31

Preparing and coping strategies for medical students'
experience with a patient's death: systematic narrative
literature review
Yaara Lisai2 and Adir Shaulov MD1,2 The national Academy for Science in Medicine
The excellence award for young researchers
1
Department of Hematology, Hadassah medical Center, Jerusalem, Israel
2
Faculty of Medicine, Hebrew University, Jerusalem, Israel
ABSTRACT  The experience of a patient's death for medical students is
emotionally powerful and may cause feelings of distress and
anxiety. Over the last 15 years, a a growing number of stud-
ies have been published, dealing dealing with the students'
perspective, addressing preparation through End-of-life edu-
cation, the experience itself, coping strategies and the impor-
tance of processing emotions. The purpose of this paper is to
review this experience as perceived by medical students.
 Although time and resources are invested in preparation for
a patient's death, some of the students feel inadequately pre-
pared. On an emotional level, the experience of death mainly
brings about feelings of sadness and anger. The patient's iden-
tity and the student's past exposure to death were found to
influence the way students perceive the experience. Students
can cope with the experience in a variety of different meth-
ods such as conversations, reflections, and turning to religion.
Coping strategies that include emotional processing usually
result in better communication with the patient and family and
improve the treatment quality.
 Conclusion: The medical world is undergoing a change in per-
ception towards the experience of a patient's death. Students
may encounter several different approaches to deal with the
loss of a patient during their clinical years. It is important that
they know which approach is beneficial to their well-being and
can contribute to their personal and professional development.
JIMS 2021; 23: 32–37
KEY WORDS coping strategies, end-of-life, medical students, patient death
D eath is a natural occurrence that every person is exposed
to at some point in their life. In most medical specialties,
exposure to death and tragedy is inevitable. Physicians are ex-
pected to continue acting professionally amidst the emotional
difficulty of experiencing a patient death.
Over the years, studies have focused on the care team's re-
sponse to patients' death, mainly addressed doctors' experience.
However, over the last 15 years, the student's point of view has
been receiving more attention. It is agreed that students expe-
rience difficulty facing patients' death, which for many will be
their first-hand exposure to death and occasionally will be ac-
companied by a feeling of helplessness.
32
VOL 01 • WINTER 2021
Previous publications in the field of end-of-life (EOL) that
focus on the students' experience commonly review the follow-
ing subjects: preparation during pre-clinical years by EOL edu-
cation, the students' experience and emotional response, coping
strategies, and the effect of unprocessed feelings. Most of these
publications are limited in depth or in scope, focusing on one
or two aspects. Therefore, this review of the entire process as
experienced by medical students is necessary.
We conducted a narrative review of the literature address-
ing EOL education and students' experience of losing a patient.
To that end, we searched PubMed for peer-reviewed, English
language articles published between 1990-2021 using the key
terms 'medical students', 'patient death', 'end-of-life', or 'coping
strategies', in several variations. We first read the abstracts and
excluded articles which mainly discussed the clinical aspects
of EOL. Key articles which shed a new light on the research
field in the different periods were selected. Subsequently, we
reviewed the references lists of these articles and identified ad-
ditional papers. A total of 57 articles were selected for review.
PREPARATION FOR THE FIRST EXPERIENCE OF PATIENT DEATH
Until the early 1990's, formal end-of-life teaching was relatively
scarce [1]. The Institute of Medicine published a notable report
in 1997 that determined that physicians are not trained properly
to provide satisfactory EOL care, and therefore recommended
that "Educators and other health professionals should initiate
changes in undergraduate, graduate, and continuing education
to ensure the practitioners have relevant attitudes, knowledge,
and skills to care well for dying patients." [2].
Over the years, more Palliative issues had been assimilated
into the curriculum of medical schools [3], and yet in some pro-
grams EOL education is not sufficiently thorough [4]. Although
the number of EOL courses has increased in the last decade [5,6]
and pre-clinical education has improved students' confidence
while treating dying patients [7], students still feel inadequately
prepared to deal with patients' death [8-11]. Some students have
difficulty coping with patients' fears and thoughts about dying
and death, and struggle to support the grieving family [12,13]. A
possible explanation for the students' feeling of unpreparedness
 VOL 01 • WINTER 2021

is that EOL issues are often learned through lectures and rational sic senses; sounds, smells, and sights, for instance many stu-
philosophical discussions [14], while the experience of a patient dents report that a strong memory that accompanies them from a
death is primarily emotional [13]. This gap may cause tension patient's death is the skin color [24] and the voices of the family
between pre-clinical EOL education and the students' emotional heard from the hallway [10].
response [10]. This tension causes some students to believe that Many students experience distress and anxiety in response to
medical school cannot properly prepare them for patients' death a patient's death [27], sometimes even in cases where they had
[8], and that it is impossible to teach about EOL care, which to no personal connection to the deceased [10]. The emotions most
their mind, can only be learned by experience [15]. According- widely described are sadness, anger, guilt [13,28] and shock
ly, young doctors report a lack of exposure to terminal patients [24,29]. Additionally, after a patient death, some students report
with palliative needs during their medical school training [16]. feeling fear that their knowledge is inadequate, they exercised a
Notably, some institutions have attempted to incorporate stu- wrong judgment call [15], or acted incorrectly [24].
dent meeting with palliative patients during EOL training in the Another issue which can contribute to the experience's diffi-
pre-clinical years [17-19]. culty, stems from the fact that many students did not feel emo-
tionally supported by the attending physicians [29]. Doctors'
MEDICAL STUDENTS EXPERIENCE OF PATIENT'S DEATH responses influence the way students experience EOL situations
One student described his experience of a patient's death: [30]. In some cases, students who cried after a difficult emotional
"I saw this patient twice before he died. He had a great sense situation were met by ridicule or contempt [31]. In contrast, when
of humor and was always polite. One afternoon, as I was just senior physicians showed empathy toward the dying patients and
about to leave home, I heard the nurse calling for help from patience for the students' emotional responses, the students expe-
his room. The staff tried to resuscitate, I kind of helped them, rienced significant relief and feelings of appreciation [13]. This
but mostly stared. I remember wrappers of syringes all over the illustrates the fact that a great amount of the medical education is
place. His skin color was so pale, and he just looked so dead, based on role modeling, and not only the formal curriculum [30].
it was awful. I did not expect it to happen, we are supposed to Heightened emotional experience Patients' characteristics
save lives. How is it possible that this man walked in alive and have a crucial impact on the emotional reaction of healthcare
is left covered in a hospi- providers. Universally,
tal sheet? His family was THE MEDICAL WORLD IS UNDERGOING A CHANGE IN PERCEPTION students perceive the death
suddenly there, and the TOWARDS THE EXPERIENCE OF A PATIENT'S DEATH. of a young child as unjus-
crying was heartbreaking. tified [15], and when it
I just could not stop thinking about how the word ALIVE sud- occurs, they experience significant emotional distress. The dif-
denly became so fragile. The doctors and nurses kept doing their ference in the emotional impact can be explained by the fact that
routine duties and I did not know what to do. He had just died in children are naturally perceived as innocent and weak, which elic-
front of my face, and everything was going on as usual." its the need to protect them [13]. Conversely, the death of elder-
The subject of patients' death is of great interest to many ly patients, particularly when they suffer from severe or chronic
medical students [20] and is a major concern to many of them in diseases, tends to be perceived as a natural event [15].
the transition to clinical years [21]. Students experience patient Another factor thought to influence the emotional experience
death in the following forms. of the students is the personal connection with the patient [9]
Death as a failure In the past, the overarching goal of the phy- and his family, a phenomenon also common among senior staff
sician was death prevention, and therefore any death that occurred [15]. Additional situations that may cause increased distress are
was considered a failure [22-23]. This approach is still present, cases of unexpected death [9] as well as cases where errors of
especially among some of the veteran doctors [24]. However, the judgment may have been contributed to the patient's death [13].
medical world emphasizes other goals besides preventing death, Students Identity It has been suggested that healthcare pro-
and physicians are also expected to reduce pain and prevent pa- viders identity, personal characteristics, and life circumstances
tient suffering [25]. This perceptual change has permeated into may influence the way they face EOL issues [32-33]. Many
the curriculum [13] and consequently, the majority of students medical students have previously experienced the death of a
today do not comprehend death as a professional failure [12-13]. relative or a friend [1,34] even prior to medical school, with
Notable exceptions are cases in which human error has occurred reports ranging from 29% to 99% [35]. A personal loss may in-
and may have contributed to the patient's death [13]. deed be a source of motivation to becoming a physician [36].
Memories and emotions The effect of a patient death on When treating dying patients, this motivation may lead to com-
practitioners has a few common characteristics, the most nota- plex emotions, which can manifest in several ways. Following
ble being the memories and emotions that surfaced at the event. the death of a relative, there is an increased chance the students
The most memorable death among students is that of their first will actively avoid situations involving death [37]. Additionally,
patient [26]. The most powerful memories are linked to the ba- exposure to dying patients may evoke the previous experience of

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bereavement and cause stress and anxiety [34,37]. When taking an emotional aspect are rare, when they occur, students find it
care of patients with similarities to their relatives, students report helpful and feel a great appreciation [8,24].
difficulty interacting with the patients and their families [1,24,26].
Communication avoidance with the patient and their relatives, Reflection is a central component of physicians' profession-
may bring about a distant relationship [34], and consequently may alism and an essential skill for both personal and professional
harm students' satisfaction in their own professional role [38]. development [44]. General Medical Council outcomes for grad-
Alternatively, some studies suggest that in cases when stu- uates 2018, determine that reflections are a necessary coping
dents had properly processed their emotions following a per- strategy for caregivers to recover from complex emotional situ-
sonal loss, they benefited both professionally and personally ations during clinical practice [45].
[34] and were more likely to regard EOL care positively [39]. In Students who use reflective practice as a coping strategy
addition, students who have personal experience with death felt when treating a palliative patient find it beneficial because their
more comfortable dealing with dying patients, conversing with awareness of their knowledge, confidence, and sense of com-
the family, and supporting them [27], and were more realistic fort with the situation has increased, helping them learn about
towards the patients' needs and emotions [40]. their responses to emotionally complex situations. In addition,
reflection strengthened what the students had learned from the
COPING STRATEGIES experience, and therefore was useful in their learning process
Patient loss is not the first time a student encounters death in his [17] as well as developing their professional identity [18]
studies. Most commonly it will be during the pre-clinical years Hobbies are related to a lower risk of burnout among students
while dissecting cadavers. [46] and palliative care physicians [47]. In the clinical years, ex-
The dissection experience might provoke a powerful emo- haustion and high pressure might decrease the time that can be
tional response, however, students can feel peer-pressure to invested in hobbies [27]. Nonetheless, many students still make
avoid acknowledging or expressing their emotional distress and a point of adapting a hobby as a coping strategy to relieve stress
anxiety, which can lead to a casu- [30], such as exercise, watching
al outlook on death [41]. STUDENTS MAY ENCOUNTER SEVERAL DIFFERENT movies and reading, which can
This kind of response can be APPROACHES TO DEAL WITH THE LOSS OF A PATIENT also provide a helpful distraction
regarded as an example of a cop- DURING THEIR CLINICAL YEARS. them from thoughts about death
ing strategy. Avoidance-based [24].
coping strategies have been commonly reported as well. Engaging in different tasks allows to focus on rational as-
According to Neimeyer et al. widespread coping strategies pects and reduce emotional preoccupation. Although a patient
among physicians included detachment, avoidance, and emo- death is a powerful experience, doctors and students' profession-
tional withdrawal [42]. A study conducted in 1991 which ex- al duties are essential [24,43]. However, acceptance and inter-
amined strategies of coping with patient death among medical nalizing events are vital as well [13], and a balance between
students, found that "the most frequently used strategy was them is necessary. Some students choose to stay busy and focus
that of passive acceptance, which entailed accepting, rational- on their ward tasks [24] and on the perception that there are
izing and assimilating the event into one’s everyday work per- other patients who need to be helped, which is a crucial profes-
formance". Only 21% of the participants talked to other peo- sional attribute [13]. In other cases, there are students who carry
ple for support [43]. Current literature suggests a few common on with their clinical responsibilities to avoid having to face an
strategies with different methods students use to cope with a emotional response, while not acknowledging the professional
patient's death. gain [9].
Conversations with others were found as a commonly used Following a patient's death, some students cope with their
coping strategy among medical students [8,24]. Beside the emotional reaction by avoiding negative emotions [9] and let-
fact that conversations provides a source of emotional comfort ting them wane with time without any external support [43].
[9,10,27], they also contributes to the development of profes- Others prefer to discuss the experience only at the clinical level
sional qualities [27]. Students prefer to talk with friends or fam- [18]. In other cases, students avoid or deny the loss, because as
ily rather than with doctors [8,9], since they feel free to express they see it, discussion or thinking about death is not necessary
their thoughts and emotions without concern of academic and or helpful, as it is irreversible [43].
professional evaluation [27] or judgement [18]. Moreover, when Religion is a frequent coping strategy among medical stu-
the conversation takes place outside the hospital environment, dents [13,24,27]. Spirituality and belief in the afterlife have
students' perspective expands beyond the academic aspect [18]. been found to have an inverse association with death anxiety,
In most cases, physicians do not initiate discussions with stu- and emotional distress [48]. Religious beliefs may help with the
dents about the patients' death, and when they do, it particularly acceptance of death, following the view of the limited control
addresses the clinical aspects. While discussions which include over life and the impossibility of changing "god's will". Interest-

34
 VOL 01 • WINTER 2021

ingly, students who do not define themselves as religious some- whether this event was appropriately processed prior to the med-
times embraced religious attitudes to deal with a patient's death. ical school years. Further research is needed.
In addition, some students find prayer as helpful for the dying Studies from the last decade have found that students do not
patient [13]. According to see a patient's death as a pro-
Firth-Cozens and Field [43], IT IS IMPORTANT THAT THEY KNOW WHICH APPROACH fessional or personal failure.
religious students experi- IS BENEFICIAL TO THEIR WELL-BEING AND CAN CONTRIBUTE Additionally, they perceive
enced the loss of a patient TO THEIR PERSONAL AND PROFESSIONAL DEVELOPMENT. their emotions as a natural re-
as a less stressful event and action. Students use different
have a lower risk of becoming afraid of death. strategies to cope with a patient's death. Efforts should be made to
promote helpful methods of processing these experiences.
THE IMPORTANCE OF EXPERIENCE PROCESSING The attention given by doctors to student's experiencing
The importance of processing the feelings that emerge follow- death is crucial as role modeling has a central role in the stu-
ing an emotionally powerful experience is recognized in the lit- dents' perception of the clinical practice. In some cases, post
erature [49-50] and among educators [51], and accordingly is patient death discussions do not occur, or are only focused on
practiced in different medical education programs. the clinical aspect. Those doctors' attitude towards the event
Students who do not come to terms with their feelings after probably stems from the fact that they were educated in an en-
the experience of a patient's death, may see their emotional re- vironment which avoided discussion about death and the emo-
sponse as unprofessional [10]. They may therefore be exposed tions that followed it.
to a higher risk of distress and burnout [52], and more frequently The medical world is currently undergoing a process of
become cynical physicians [53]. modifying its perception of experiencing a patient's death. Con-
Caregiver burnout is "a work-related syndrome involving sequently, during their clinical years students will most likely
emotional exhaustion, depersonalization and a sense of reduced encounter a variety of responses from doctors, who are also ex-
personal accomplishment" [54], which may lead to reduced ef- periencing the process themselves. It is essential to be aware of
fectiveness at work [55]. Burnout was found to be a prevalent this in order to avoid adopting non-optimal behavioral mecha-
phenomenon among medical students as well [56]. nisms which may harm the student's well-being and therefore
A physically and emotionally exhausted student, with unrec- patient's treatment.
ognized and unresolved emotional issues, will likely find com-
munication with patients and families more difficult [57]. Addi-
tionally, they will commonly have difficulty with helping and Corresponding author
supporting the dying patient and his relatives [1]. On the other Yaara Lisai
Email: yaara.lisai@mail.huji.ac.il
hand, when emotional processing is conducted appropriately,
the students can improve the quality of care they provide [2].
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Capsule
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Capsule
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infection who could be evaluated. There was a gradual
decline in vaccine efficacy. Vaccine efficacy of 86–100%
was seen across countries and in populations with diverse
ages, sexes, races or ethnic groups, and risk factors
for COVID-19 among participants without evidence of
previous infection with SARS-CoV-2. Vaccine efficacy
against severe disease was 96.7% (95%CI 80.3–99.9). In
South Africa, where the SARS-CoV-2 variant of concern
B.1.351 (or beta) was predominant, a vaccine efficacy of
100% (95%CI 53.5–100) was observed.
N Engl J Med 2021; PMID: 34525277
Eitan Israeli
37

Non-Invasive Thermal Imaging to Detect and Monitor
Various Diseases
Rafael Y. Brzezinski MSc1,2, Neta Rabin3 PhD, Ehud Grossman MD4,6, Zehava Ovadia-Blechman PhD5, Jonathan Leor MD1,2,
and Oshrit Hoffer PhD7
1
Neufeld Cardiac Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
2
Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel.
3
Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel.
4
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
5
School of Medical Engineering, Afeka Tel Aviv Academic College of Engineering, Tel Aviv, Israel.
6
Internal Medicine Wing and Hypertension Unit, Sheba Medical Center, Tel Hashomer, Israel.
7
School of Electrical Engineering, Afeka Tel Aviv Academic College of Engineering, Tel Aviv, Israel.
N on-invasive thermal imaging is a potential tool to screen
physiological processes and diseases. Most reports on ther-
mal imaging in medicine have focused on diseases that project
intense thermal manifestations in the skin, including inflamma-
tory diseases [1], superficial wounds [2], diabetic neuropathy,
peripheral vascular diseases, dermatological diseases, and ocular
pathologies [3-5]. However, whether skin thermography can be
used to investigate pathology and inflammation in internal organs
such as the heart, liver, and lungs is not clear. Furthermore, the
effect of chronic diseases with elevated systemic inflammation
such as hypertension, obesity, and fatty liver disease on body sur-
face temperature distribution has not been determined.
Heat is a fundamental sign of inflammation. Both local and
systemic inflammation include complex molecular and cellular
processes that lead to increased body temperature and changes in
heat expression of diseased organs. Therefore, we aimed to exam-
ine the ability of non-invasive thermal imaging to detect and mon-
itor pathology in internal organs. We sought to test the hypothe-
sis that changes in heat expression can be used to diagnose and
monitor various organ-specific diseases. The long-term goal was
to diagnose and monitor inflammation and structural changes in
internal organs with a quick and easy-to-operate imaging device.
Our working hypothesis was that internal organs with vast
vascular beds such as the heart, liver, and lungs produce strong
thermal energy which ultimately manifests in the skin. Our re-
search aimed to study the association of changes in skin sur-
face temperature distribution with pathological changes in these
organs in chronic diseases such as hypertensive heart disease
and fatty liver disease, along with acute infections such as
COVID-19 pneumonia.
Toward this end, we developed novel image processing algo-
rithms based on images captured on a portable thermal camera.
Multiple texture and shape features were extracted from the ob-
tained thermal images, which were then used for downstream
machine learning analysis. We applied this new imaging mo-
38
VOL 01 • WINTER 2021
dality on a variety of cardiac and liver animal models of disease
that display a spectrum of pathological changes including in-
flammation, fat infiltration, fibrosis, and changes in blood flow.
The extensive physiological and molecular characterization we
performed on these models revealed some of the biological fac-
tors responsible for the observed changes in heat expression of
diseased organs. Finally, we studied the potential use of auto-
mated non-invasive thermal imaging in humans.
In our first study [6], we determined the ability of non-inva-
sive thermal imaging to detect cardiac inflammation and remod-
eling in mice. We used a mouse model for cardiac hypertrophy
and fibrosis (the subcutaneous angiotensin II infusion model)
and showed that a clear thermal representation of the heart could
be isolated by using non-invasive thermal imaging. Furthermore,
the increase in cardiac blood volume in diseased hearts strongly
affected the heat expression captured by the thermal imaging de-
vice. Overall, for the first time, we suggest that a thermal camera
using a new image-processing algorithm could potentially be
used to study cardiovascular diseases in mice.
Our conclusions regarding the robust effect of blood flow
and volume on heat expression supported the rationale for im-
aging additional organs with vast vascular beds that lay close to
the skin surface, such as the liver and lungs.
Thus, we then studied the changes in skin temperature dis-
tribution caused by liver steatosis, inflammation, and fibrosis
in mice [7]. First, we recapitulated key features of non-alco-
holic fatty liver disease (NAFLD) in vivo by feeding mice a
6-week course of a methionine-choline deficient (MCD) diet.
MCD diet-fed mice had severe liver steatosis and impaired
liver function, and demonstrated increased levels of pro-in-
flammatory monocyte infiltration. Non-invasive thermal im-
aging of the abdomen was able to detect diseased livers and
demonstrated a sensitivity rate of 100% already from week 3
of the experiment. Most importantly, we validated the findings
seen on non-invasive skin thermography by capturing direct
 VOL 01 • WINTER 2021
Figure 1. A schematic illustration summarizing the central hypothesis of our research
thermal images of the liver in live (sedated) mice. We also
show that findings on thermal imaging can potentially monitor
the different stages of NAFLD, that range from simple liver
steatosis to steatohepatitis (elevated inflammation) and ulti-
mately liver cirrhosis.
Finally, in our most recent report [8], we studied an addi-
tional organ with a vast vascular bed located in close proximity
to the skin surface, namely the lungs. We imaged patients with
pneumonia due to all etiologies, especially COVID-19. In con-
trast to patients with fatty liver disease or hypertensive heart
disease, which are chronic conditions, the rationale here was to
determine the effects of acute inflammation on changes in heat
expression. Our original hypothesis was that patients infected
with severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) will have a unique pattern of heat distribution in the
skin covering their lungs, which is the primary organ affected
by the disease [9]. We aimed to develop a new portable imag-
ing tool based on thermal imaging for lung injury in suspected
COVID-19 individuals. However, to our surprise, our findings
showed a unique systemic pattern of heat distribution across the
entire torso associated with COVID-19 that was not limited to
the upper back region covering the lungs. For the first time, our
findings suggest that a hand-held thermal imaging device that
connects directly to smartphones can detect individuals with
COVID-19. Automated thermal image processing of the back
yielded two risk scores that demonstrated up to 92% sensitivity
in detecting COVID-19. We suggest that the differences in skin
temperature distribution across the back, as measured by our
advanced texture features, reflect microvascular and endothelial
dysfunction caused by COVID-19.
The main findings of the three reports highlighted above are
that disease-associated processes such as inflammation, fibro-
sis, and changes in blood flow alter the heat expression of dis-
eased tissue and that these changes lead to distinct temperature
variation patterns across the skin. We show that these changes
in skin thermography can be monitored by portable and non-in-
vasive thermal cameras, and can potentially detect and monitor
diseases of the heart, liver, and lungs. The advanced image pro-
cessing tools applied in this study did not focus only on absolute
temperature measurement, but rather on more advanced texture
and shape parameters of heat distribution in various regions of
interest across the skin. This approach holds potential for the
future study of thermal imaging in other diseases.
Notably, the thermal camera used throughout this study is
portable and connects directly to smartphones. Potential future
use in humans could enable rapid and close monitoring of dis-
ease progression, various treatments, and associated biomark-
ers with relatively reduced effort and time. This new imaging
tool could be especially relevant for out-of-hospital settings and
low-resource regions and could possibly also improve follow-up
of home-care patients. Future research is needed to optimize the
sensitivity and specificity of non-invasive thermal imaging for
identifying different degrees of inflammation and tissue damage
over time in specific clinical applications.
Corresponding Author
Rafael Y. Brzezinski
Email: brzezinski@mail.tau.ac.il
References
1. Capo A, Di Paolo J, Celletti E, Ismail E, Merla A, Amerio P. Thermal alterations in
patients with inflammatory diseases: a comparison between psoriatic and rheumatoid
arthritis. Reumatismo. 2018;70(4):225-231. doi:10.4081/reumatismo.2018.1050
2. Xue EY, Chandler LK, Viviano SL, Keith JD. Use of FLIR ONE Smartphone
Thermography in Burn Wound Assessment. Ann Plast Surg. 2018;80(4):S236-S238.
doi:10.1097/SAP.0000000000001363
3. Lahiri BB, Bagavathiappan S, Jayakumar T, Philip J. Medical applications of
infrared thermography: A review. Infrared Phys Technol. 2012;55(4):221-235.
doi:10.1016/j.infrared.2012.03.007
4. Ring EFJ, Ammer K. Infrared thermal imaging in medicine. Physiol Meas.
2012;33(3):R33-R46. doi:10.1088/0967-3334/33/3/R33
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5. Diakides M, Bronzino J, Peterson D. Medical Infrared Imaging. (Diakides M,
Bronzino JD, Peterson DR, eds.). CRC Press; 2012. doi:10.1201/b12938
6. Brzezinski RY, Ovadia-Blechman Z, Lewis N, et al. Non-invasive thermal imaging
of cardiac remodeling in mice. Biomed Opt Express. 2019;10(12). doi:10.1364/
BOE.10.006189
7. Brzezinski RY, Levin-Kotler L, Rabin N, et al. Automated thermal imaging for
the detection of fatty liver disease. Sci Rep. 2020;10(1):15532. doi:10.1038/s41598-
Capsule
Antibodies to treat muscular dystrophy
Latent transforming growth factor β-binding protein 4
(LTBP4) has previously been shown to be a modifier of
muscular dystrophy in mice. Demonbreun and colleagues
developed a monoclonal antibody to human LTBP4
that binds to the protein’s hinge region, thus preventing
proteolytic cleavage. In dystrophic mice expressing the
human LTBP4 protein, anti-LTBP4 treatment protected
muscle function, with enhanced force production and
Capsule
Long COVID in a prospective cohort of home-isolated patients
Blomberg and colleagues conducted a long-term follow-up in
a prospective cohort study of 312 patients, 247 home-isolated
and 65 hospitalized, who comprising 82% of total cases in
Bergen during the first pandemic wave in Norway. At 6 months,
61% (189/312) of all patients had persistent symptoms, which
were independently associated with severity of initial illness,
increased convalescent antibody titers, and pre-existing
chronic lung disease. The authors found that 52% (32/61)
of home-isolated young adults, aged 16–30 years, had
Capsule
Lung inflammation LRRK2 to restrict pulmonary fibrosis
In pulmonary fibrosis, the lungs become scarred over
time. This is a serious and irreversible disease and new
treatments are greatly needed. Tian et al. uncovered
a critical role for leucine-rich repeat kinase 2 (LRRK2)
in mediating innate immune responses to lung injury
and safeguarding against pulmonary fibrosis. The
researchers found that the expression of the LRRK2
gene was decreased in human and mouse fibrotic
lungs compared with healthy controls. Mice deficient for
40
VOL 01 • WINTER 2021
020-72433-5
8. Brzezinski RY, Rabin N, Lewis N, et al. Automated processing of thermal imaging
to detect COVID-19. Sci Reports 2021 111. 2021;11(1):1-10. doi:10.1038/s41598-
021-96900-9
9. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology,
Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A
Review. JAMA - J Am Med Assoc. 2020;324(8):782-793. doi:10.1001/jama.2020.12839
reduced fibrosis. Twenty-four weeks of treatment also
improved diaphragm muscle function. The combination
of anti-LTBP4 treatment with prednisone substantially
enhanced muscle function and protected against injury
in dystrophic mice, suggesting that anti-LTBP4 antibodies
may be useful in treating muscular dystrophies in humans.
Sci Transl Med 2021;13: abf0376
Eitan Israeli
symptoms at 6 months, including loss of taste and/or smell
(28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61),
impaired concentration (13%, 8/61), and memory problems
(11%, 7/61). The findings that young, home-isolated adults
with mild COVID-19 are at risk of long-lasting dyspnea and
cognitive symptoms highlight the importance of infection
control measures, such as vaccination.
Nature Med 2021; 27: 1607
Eitan Israeli
LRRK2 showed more rapid progression of experimentally
induced pulmonary fibrosis, and this was accompanied
by exacerbated immune responses. The alveolar type II
epithelial cells of these mice had an increased capacity
to recruit macrophages to the lung and to mediate
profibrotic inflammatory responses by CCL2/CCR2
chemokine signaling.
Proc Natl Acad Sci USA 2021; 118: e2106685118
Eitan Israeli
 VOL 01 • WINTER 2021
COVID-19 Re-infection: a Case-Series Review
Anna Papish1*, Dvir Fridman1*, Dana Venkert2, Neta S.Zuckerman MD4, Orna Mor MD3,4 and Eli Schwartz MD3,5
1
Faculty of Medicine, University of Campania, Luigi Vanvitelli, Italy
2
Faculty of Life Sciences Tel Aviv University, Tel Aviv, Israel
3
Faculty of Medicine Tel Aviv University, Tel Aviv, Israel
4
Central Virology Laboratory-Ministry of Health, Chaim Sheba Medical Center, Tel-Hashomer, Israel
5
Center for Geographic Medicine, Chaim Sheba Medical Center, Tel-Hashomer, Israel
ABSTRACT  eports concerning cases of re-infection with SARS-CoV-2 are
R prolonged and intermittent positive PCR testing is well docu-
increasing. In this review, we analyzed all the confirmed re-in-
fection cases published in the scientific literature by the end of
April 2021. According to our findings, the symptoms in both in-
fections were mostly "mild" and no common profile between the
cases was found. Of the patients, 9 had background diseases,
and 2 patients died following the second infection. IgG antibod-
ies developed in 70% of the patients following the first infec-
tion (16/23), of them 44% developed neutralizing antibodies. No
clear correlation between the presence of antibodies and symp-
tom severity was found. Our findings suggest that new emerg-
ing variants and new mutations in the spike protein could cause
re-infection, despite the development of IgG and neutralizing
antibodies. In the era of new emerging variants and vaccination,
the re-infection phenomenon should not be underestimated, and
should be further investigated.
JIMS 2021; 23: 41–52
*These first authors contributed equally to this work.
B y the end of April 2021, coronavirus disease 2019
(COVID-19) infected approximately 147 million people
worldwide and caused more than three million deaths. The data
collected so far by the scientific community suggest that most
of the patients infected with SARS-CoV-2 will develop an IgG
antibody response [1]. Questions regarding the persistence, ro-
bustness, and functionality of these specific antibodies are still
under investigation.
So far, durability of up to 6-8-month of these antibodies has
been documented [2]. Their ability to neutralize SARS-CoV-2
was tested, demonstrating that more than 90% of sero-converters
make a detectable neutralizing antibody response that persists for
at least several months [3]. However, a recent large-scale study
performed in Israel has shown that about 5% of patients do not
develop anti SARS-CoV-2 IgG antibodies [4]. Nevertheless, de-
spite the waning titers of these antibodies, or in cases where the
IgG results are negative, showed that B and T-cell responses are
detected, lasting for at least several months [5,6].
Re-infection with COVID-19 in patients who had recovered
from a documented first infection is thought to be a very rare
event. Technically, confirmation of re-infection mainly during
the first year of this pandemic is challenging, particularly since
mented [7]. Therefore, to confirm a true re-infection event,
comparison of the viral sequence between the initial infection
and the re-infection is required. According to the center for dis-
ease control and prevention (CDC)’s definition, re-infection is
considered confirmed when the viruses from the first and sec-
ond infections are different enough to belong to different clades
or lineages or when they differ by more than 2 substitutions per
month, which is the general population-level viral substitution
rate as assessed by multiple studies [8]. A genuine re-infection
event may suggest either lack of immunity or waning of effec-
tive immune response. In more recent months of this pandemic,
re-infection may result from new viral variants that are emerg-
ing and are resistant to the immune response against the first
infecting variant [9]. After vaccination, re-infection with a strain
not actively repressed by the immune response in a person with
detectable titers of anti IgG antibodies acquired following vac-
cine administration, should also be carefully examined.
We review all cases of SARS-CoV-2 re-infection that were re-
ported by the end of April 2021 and assess the possible implications
of the phenomenon arising from confirmed documented cases.
METHODS
DATA SOURCES AND KEYWORDS
This study includes a systematic literature review of SARS-
CoV-2 re-infection cases confirmed by genomic sequencing and
published in the scientific literature by the end of April 2021.
Search terms and keywords used were (in the following or-
der) “COVID-19”, “SARS-CoV-2”, “re-infection”, “genomic
variation” and “antibodies”. All publications including scientif-
ic pre-print and peer-reviewed studies were reviewed.
CONFIRMED RE-INFECTION DEFINITION
Cases were defined as” confirmed” based on detection of distin-
guishable genomic differences between the first and second in-
fection. Cases were considered confirmed if a positive real-time
PCR (rt-PCR) result was detected in both infections. In addition,
cases in which the original and the re-infection reports included
information on the genomic sequences of both samples, with a
41

change of >2 nucleotides per month during the interval between
the two infections or identification of different clade or lineage [8].
All other reports regarding re-infection cases in the stated time-
frame that did not meet those criteria- were excluded, with only
one exception (for more details see Table 2)
RETRIEVED DATA
The following data was retrieved from all sources: date of pub-
lication, date of second infection, demography, age and sex of
patient, background diseases, time interval between the 2 in-
fections, symptom severity in both infections, presence of anti-
bodies in both infections, rt-PCR Cycle threshold (Ct) value of
SARS-Cov-2 results in both infections (only the lowest value
reported), existence of negative rt-PCR test between the 2 infec-
tions, and recovery of patients. Available information about the
exact genetic variation in both infections was recorded.
RESULTS
Our search revealed 39 confirmed cases of SARS-CoV-2 re-in-
fection, reported from four continents [Figure 1]. All were con-
firmed by genomic sequencing.
Included in this review are 20 males and 16 females (no avail-
able information, NA= 3). The average age was 42.8 years (range
2 - 89, NA = 6).16 patients were healthy before contracting the
disease and 9 patients had background diseases (NA= 14)
Most of the results are summarized in Table 1.
Figure 1. Distribution of re-infection cases worldwide
42
VOL 01 • WINTER 2021
CT VALUES IN BOTH INFECTIONS
Ct values in the first infection ranged between 13 - 36.8 and
those of the re-infection ranged between 12 - 39.36. In 29 cases,
at least one negative rt-PCR between the infections was docu-
mented (Transcription mediated amplification, TMA in 1 case)
[Appendix table 1].
THE TIME INTERVAL BETWEEN THE INFECTIONS
Most of the papers reviewed in our study reported about re-in-
fection cases that occurred no later than December 2020. The
average time interval between the two infections was ~93 days.
In the majority of the cases the time interval between the infec-
tions was less than 3 months (16 cases > 3 months, 23 cases < 3
months, among them 9 cases < 40 days).
THE DIFFERENCE IN THE SEVERITY OF DISEASE BETWEEN
THE INFECTIONS AND RE-INFECTIONS
Patients were either asymptomatic, or had symptoms referred to
“Mild”, “Moderate” or “Severe”. The description of symptoms’
severity described in this review is based on the information
provided by the authors of the reviewed publications.
In the first infection a total of 28 symptomatic patients and 6
asymptomatic patients (NA=5). In the second infection a total of
26 symptomatic patients and 5 asymptomatic patients (NA=8). In
both infections the symptoms were mostly "mild". In the majority
of the cases, the symptoms severity between the first and second
infections remained unchanged (17, NA= 8), among them 12 pa-
 VOL 01 • WINTER 2021

Table 1. Summary of confirmed cases reported in scientific publications

Full details regarding the patients are available in ]able 1 – supplements. The symptoms were referred to as “Mild”, “Moderate” or
“Severe” according to the authors of each publication.

  Male (20) Female (16) Total (including 3 NR)

Average age* (years) 42.6 41.9 42.8
(NR† =6)
Average interval between infections (days) 76 101.9 93.4

Background diseases Positive 4 4 9

(NR =14) Negative 9 7 16
Symptoms -
first infection 11 14 28
(NR = 5)
Symptoms
Symptoms -
second infection 11 12 26
(NR =8)
Asymptomatic 5 1 6
Severity - Mild 6 11 19
first infection
(NR =5) Moderate 4 2 6
Severe 1 1 3
Asymptomatic 5 3 5
Severity - Mild 7 11 21
second infection
(NR =8) Moderate 1 0 1
Severe 3 1 4

Severity - Less severe 2 0 3

second infection relative More severe 7 1 8
to first infection
(NR =11) Unchanged 3 12 17
IgM: 8 IgM: 3 IgM: 12
First infection IgG: 8 Neutralizing IgG: 6 IgG: 16
(NR =16) antibodies: 4 Neutralizing antibodies: 3 Neutralizing antibodies: 7
(IgG negative: 4) (IgG negative: 3) (IgG negative: 7)
Antibodies
IgM: 7 IgM: 5 IgM: 13
Second infection IgG: 10 IgG: 12 IgG: 22
(NR =15) Neutralizing antibodies: 6 Neutralizing antibodies: 7 Neutralizing antibodies: 13
(IgG negative: 1) (IgG negative: 2) (IgG negative: 3)

*In cases in which age was given as a range, the average number was used in the calculation.
†NR, information was not reported.

tients were females. In the rest of the cases, symptom escalation
was predominant (8, of them 7 were males) compared to symp-
tom de-escalation (3, of them 2 were males). The symptom es-
calation included 4 cases from "asymptomatic" to "mild", 1 case
from "mild" to ”moderate", 2 cases from "mild" to severe, and
in 1 case from "moderate" to "severe". On the other hand, those
with declining symptom severity included 1 case that de-esca-
lated from "mild" to "asymptomatic", 1 case from "moderate" to
"mild", and 1 case from "severe" to "mild" [Figure. 2A].
In 17 cases the symptoms severity remained unchanged and
in 5 and 8 cases the symptoms severity was unknown in the first
and second infection, respectively [ Figure. 2B].
Two confirmed re-infection cases resulted in death. In the
first case, the patient was an 89-year-old female, with a pre-ex-
isting condition of Waldenström macroglobulinemia (treated
with B-cell–depleting therapy). The patient suffered from mod-
erate symptoms during the first infection, and severe symptoms
during the second infection. The patient died 2 weeks after the
second infection. No documentation of antibodies test after the
first infection was available, but the patient was found negative
to IgG and IgM 10 days post the second infection [26]. In the
second case, the patient was a 39-year-old male with chronic
cardiovascular disease and diabetes mellitus. During the first
infection the symptoms and clinical signs of the patient had not

43

Figure 2.
[A] Symptom severity in the first and second infections
[B] Symptom severity in the second infection compared to the first infection
A ing the first infection, mostly exhibited mild symptoms in the
B
been reported, and the second infection involved complications.
The patient was hospitalized in an Intensive Care Unit (ICU)
and intubated due to severe loss of pulmonary capacity and
eventually died.
DETECTION OF ANTIBODIES FOLLOWING INFECTIONS
Information regarding the presence of detectable antibodies af-
ter the first infection was available for 23/39 patients. 16 patients
had a second infection despite the presence of IgG antibodies
after the first infection, among them seven had a neutralizing an-
tibodies response. 7 additional patients tested negative for IgG
antibodies following the first infection.
Among the 16 patients that tested positive for IgG antibod-
ies, information regarding symptoms was available for 10 pa-
tients. The majority experienced mild symptoms during the sec-
44
VOL 01 • WINTER 2021
ond infection (7), 2 patients were asymptomatic, and one patient
experienced severe symptoms. Among the 7 patients that had
neutralizing antibodies, 3 experienced mild symptoms (NA= 4).
The 7 patients that tested negative for IgG antibodies follow-
first infection and the symptoms severity remained unchanged
in the second infection (4). However, in 2 patients escalation of
symptoms between the two infections was observed, and in 1
patient the symptoms severity decreased.
Interestingly, in 5/7 (71%) of the patients that exhibited the
presence of neutralizing antibodies following the first infection,
the Ct value decreased in the second infection.
Among the 7 patients that tested negative for IgG antibodies
following the first infection, 5 tested positive after the second
infection, and 2 remained negative.
Information regarding presence of detectable antibodies after
the second infection was available for 24 cases. 22 of the cases
were positive for IgG antibodies, among them a neutralizing anti-
bodies response was reported in 13 cases. Three additional cases
tested negative for IgG antibodies following the second infection.
Detailed information regarding each patient is presented in
Appendix table 1 and summary is present in table 1.
GENOMIC VARIATION BETWEEN TWO INFECTIONS
Specific information regarding the genomic variations between
the first and second infections was available for all the patients
in our cohort [Table 2]. In 29/39 of the patients, D614G muta-
tion in the spike protein (S) was present in one or both infections.
In 13 patients, the D614G mutation in S was present in both the
first and second infections and in 16 patients the D614G mutation
was present only in one infection. Additionally, in 4 patients, the
E484K mutation was present only in the second infection and in
one patient this mutation was present in both infections. More-
over, the S477N mutation in the receptor binding domain (RBD),
the N440K mutation, and the N501Y mutation were present in 3
different patients. In 10 patients, the second infection was char-
acterized by a different clade, in 14 patients by a different lineage
and in 15 patients a difference of >2 nucleotides per month be-
tween the sequences was recorded.
Of the patients that tested positive for IgG antibodies fol-
lowing the first infection 75% (16, among them 7 that exhib-
ited presence of neutralizing antibodies), had a new mutation
in the spike protein in the second infection. In 12/16 of the
patients, the D614G mutation in the spike protein (S) was
present in one or both infections. In 4/12 of these patients, the
D614G mutation in S was present in both the first and sec-
ond infections, and in 8/12 patients, the D614G mutation was
present only in one infection. In addition, in 2/16 patients the
E484K mutation in S was present only in the second infection.
Furthermore, one patient did not have mutations in S despite
the presence of neutralizing antibodies following the first in-
fection [Appendix Table 2]
 VOL 01 • WINTER 2021

fections also contributes to the small number of proven patients.

DISCUSSION
At the time of writing, re-infection in patients diagnosed with
COVID-19 appears to be an extremely rare phenomenon. In our
review we found only 39 confirmed re-infection patients out of
147 million Covid19 patients worldwide. The patients report-
ed with confirmed re-infection did not have a common profile
(e.g., age, gender, co-morbidity), and it seems that clinically
there were no significant differences between the first and the
second infections.
Underestimation and underreporting of the actual number of
re-infection certainly exists. Reasons for this underestimation may
be technical, such as lack of genomic sequencing abilities which
requires a higher level of laboratory facilities and lack availabil-
ity of all past samples of the first infection. In addition, missing
the asymptomatic patients either in the first or at the second in-
Furthermore, under-reporting in peer-reviewed journals or in pre-
prints may be an additional factor. Despite this underestimation
and the existence of numerous suspected patients that were not
confirmed by genomic sequencing, these still seem negligible by
orders of magnitude compared to the total number of COVID-19
patients reported globally. If we consider the under-reporting of
SARS-Cov-2 infections worldwide and assume a high rate of
asymptomatic infections, the denominator could be much higher
and therefore the occurrence of re-infection might be even lower.
Several recent epidemiological reports from Qatar, UK and
Denmark suggest an 80% or higher protective effect for re-in-
fection after previous infection. The study from Qatar screened
43000 people by PCR and concluded that protection against
repeated infections occurred in 95% of individuals who tested
positive, lasting for at least 7 months [21]. Another study, exam-

Table 2. Genetic variation of confirmed cases

Viruses from the primary infection and reinfection belong to 2 different lineages.
Viruses from the primary infection and reinfection belong to 2 different clades.
>2 nucleotide changes per month.

The phylogenetic nomenclature in this table is used according to the authors of each paper.

Re- Patient's Genetic information New spike

Date infection Country age and Interval regarding the first Genomic variations in the second infection Reference
mutations
date sex infection
P.1 lineage*, carrying
Apr. 20 P.2 lineage, carrying the E484K and D614G
1 May-20 Brazil 39/M 101 d the E484K† and 9 [10]
(2021) mutations.
D614G mutations†.
clade 19A*, a strain
Apr. 9
2 May -20 Brazil 57/F 61 d carrying the D614G clade 20 B, carrying the D614G mutation. 0 [11]
(2021) mutation.
clade 20B, a strain carrying the D614G
Apr. 9 clade 20B, carrying
3 May -20 Brazil 34/M 64 d mutation, and they do not cluster together in 0 [11]
(2021) the D614G mutation. the same branch.
lineageB.1.36, carrying the D614G and the
lineage B.1.36, N440K mutation. The analysis revealed a
Apr. 5 carrying the D614G
4 Aug-20 India 47/M 39 d total of 15 and 17 genetic variants in the 0 [12]
(2021) and the N440K† genomes of which 14 variants were common
mutation. between the two episodes.
lineage B, clade B.1, lineage B, clade B.1.280 carrying the D614G
Mar. 26 United carrying the D614G
5 Nov-20 60-70/M 207 d mutation and polymorphism at spike A1078S 1 [13]
(2021) States mutation in the spike (not located within the RBD).
protein.
B.1.1.269 lineage, with six substitutions in
Mar. 19 total (two located in the ORF1ab gene, one
6 Aug-20 Colombia 54/F 30 d B.1 lineage 1 [14]
(2021) in the spike gene and the remaining three
located in the N gene).
lineage B.1.195.
Mar. 15 lineage P.1, carrying the D614G and E484K
7 Dec-20 Brazil 29‡ 281 d carrying the D614G 11 [15]
(2021) mutations.
mutation.
lineage B.1.1.33.
Mar. 15 lineage P.1, carrying the D614G and E484K
8 Oct-20 Brazil 50‡ 92 d carrying the D614G 11 [15]
(2021) mutations.
mutation.

45
 VOL 01 • WINTER 2021

Re- Patient's Genetic information New spike

Date infection Country age and Interval regarding the first Genomic variations in the second infection Reference
mutations
date sex infection
lineage B.1.195,
Mar. 15 lineage P.1, carrying the D614G and E484K
9 Jan-21 Brazil 40/F 282 d carrying the D614G 12 [15]
(2021) mutations.
mutation.
Mar. 09 clade 19A, carrying
10 NR ¶ India 51/F 139 d clade 20B, carrying the D614G mutation. 0 [16]
(2021) the D614G mutation.
Mar. 09
11 NR India 24/F 54 d clade 19A clade 20B, carrying the D614G mutation. 1 [16]
(2021)
clade 20B, there was 7 nucleotide changes
Mar. 09 clade 20B, carrying
12 NR India 31/M 64 d between the two infections (including 2 [16]
(2021) the D614G mutation. mutations in the spike region).
Mar. 09
13 (2021) NR India 27/M 65 d clade 20A clade 19A 0 [16]

20A clade, sequencing revealed that the two

viruses different in with only one nonsynonymous
Feb. 25 mutation in the spike protein (S477N) † and
14 Oct-20 Switzerland F/36 203 d 20A clade 1 [17]
(2021) clustered with viruses circulating locally
in the hospital clusters during each of the
corresponding episodes.
clade 20B, carrying the D614G mutation.
(Additionally, presence of 3 unique variations
Feb. 16 clade 20B, carrying between both episodes and a large number of
15 Nov-20 India 38/M 18 d 1 [18]
(2021) the D614G mutation. shared variants. One of the unique variations
was in the Spike protein; however, it was a
synonymous change).
20B clade, and carry the D614G mutation.
Sequencing revealed the presence of 10
Feb. 16 20B clade, carrying
16 Nov-20 India 61/M 75 d unique variations between the viral genomes 0 [18]
(2021) the D614G mutation. of both episodes. (No variation was observed
in the spike protein).
lineage B.1, the two genomes differed in
nucleotide sequence at 17 different positions.
Feb. 10
17 Aug-20 USA F§ 142 d lineage B.1 The first and second samples from this NR [19]
(2021) patient fall in different local phylogenetic
clades in the Bronx phylogenetic tree.
Jan. 27 lineage B.1.1.248 (a lineage derived from
18 Oct-20 Brazil 45/F 147 d lineage B.1.1.33 3 [20]
(2020) B.1.1.28). carrying the E484K mutations.
Jan. 16
19 NR Qatar 35-39/ F 59 d NR 13 nucleotides changes. NR [21]
(2021)
Jan. 16 Presence of the D614G mutation at the
20 NR Qatar 35-39 /M 84 d NR ≥1 [21]
(2021) reinfection swab— 13 nucleotides changes.
lineage B.1, carrying D614G. (This variant
was almost completely absent in China
Jan.11 prior to March, and was identified as the
21 Mar-20 China 84/F 33 d lineage B.2 1 [22]
(2021) predominant variant in Europe, gradually
becoming frequent worldwide toward the end
of March).
Jan.11 lineage B.1.1, carrying the D614G mutation
22 Mar-20 China 33/M 19 d lineage B 1 [22]
(2021) in the spike protein.
Jan.11
23 Apr-20 China 59/M 57 d lineage B.2 lineage B.1, carrying D614G mutation. 1 [22]
(2021)
Jan.11
24 Apr-20 China 33/M 35 d lineage B lineage B.1, carrying the D614G mutation. 1 [22]
(2021)
Jan.11
25 Mar-20 China 2/F 22 d lineage B lineage B.1, carrying the D614G mutation. 2 [22]
(2021)
Jan.11
26 Mar-20 China 74/M 24 d lineage A lineage B 0 [22]
(2021)

46
 VOL 01 • WINTER 2021

Re- Patient's Genetic information New spike

Date infection Country age and Interval regarding the first Genomic variations in the second infection Reference
mutations
date sex infection
lineage B.1.1.7 and carrying the D614G
mutation. Sequencing revealed accumulation
Jan. 9 United of 18 amino-acid replacements across the
27 20-Dec 78/M 250 d lineage B.2 9 [23]
(2021) Kingdom genome. reinfection was
with the “new variant” VOC-202012/01.
Carrying the N501Y† mutation.
Nov. 21 Clade G, carrying the D614G mutation in the
28 Apr-20 South Korea 21/F 26 d Clade V 1 [24]
(2020) spike protein.
Nov. 9 Clade V, differing by 18 nucleotides and
29 Sept-20 Belgium 35-40/F 185 d Clade G 2 [25]
(2020) carrying the D614G mutation.
Oct. 12 United
30 Jun-20 25/M 48 d Clade 20C Clade 20 C, differing by seven nucleotides. 0 [26]
(2020) States
Oct. 09
31 NR Netherlands 89/F 54 d NR The 2 strains differed at 10 nucleotides. 2 [27]
(2020)
Sept. 29 multiple changes of allele frequency and
32 Apr-20 Qatar 25-29/M 45 d NR NR [28]
(2020) carrying the D614G mutation.
Sept. 29 multiple changes of allele frequency and
33 Apr-20 Qatar 40-44/M 70 d NR NR [28]
(2020) carrying the D614G mutation.
Sept. 19 United
34 Jul-20 60s‡ 118 d Clade 19B Clade 20 A, carrying the D614G mutation. NR [29]
(2020) States
10 unique variant differences between first
Sept. 15 presence of the and second infections. Genetic variation within
35 Sept-20 India 28/F 111 d 3 [30]
(2020) D614G mutation. the RBD was found in the second infection. in
addition, carrying the D614G mutation.
9 unique variant differences between first
Sept. 15 presence of the
36 Aug-20 India 25/M 108 d and second infections. presence of the D614G 2 [30]
(2020) D614G mutation. mutation.
Clade 20A, lineage
Sept. 08
37 Jul-20 Ecuador 46/M 63 d B1.p9, presence of the Clade 19B, lineage A.1.1 1 [31]
(2020) D614G mutation.
Sept. 05
38 Jun-20 Belgium 51/F 93 d lineage B.1.1 lineage A, differing by 11 nucleotides. 3 [32]
(2020)
Clade 19A, lineage Clade 20A, lineage B.1.79 (Clusters
Aug. 25 B.2 (Clusters with
39 Aug-20 Hong Kong 33/M 142 d with viruses from Spain), differing by 24 4 [33]
(2020) viruses from Hong nucleotides. Carrying the D614G mutation.
Kong).

* In bold: phylogenic clade/lineage.

† In bold: specific mutation in the spike protein (D614G/ E484K/N440K/S477N/N501Y).
‡ Information regarding the gender of the patient was unavailable.
§ Information regarding the age of the patient was unavailable.
¶ NR, information was not reported.

ining 12541 UK health-care workers, showed 89% protection
lasting at least 6 months [34]. An additional study from the UK
examining more than 20,000 health-care workers, found that the
risk of reinfection with SARS-CoV-2 was reduced by 83% for at
least 5 months after primary infection [35]. In a study conducted
in Denmark among 4 million PCR- tested individuals in 2020
[36], the protection in the population was found to be 80% or
higher in those younger than 65 years, but only approximate-
ly 47% in those aged 65 years and older. However, a different
study reported a high degree of protection against reinfection
among older people [37].
Data from recent reports suggests that 5% of confirmed
COVID-19 patients are negative for IgG antibodies. This finding
was also supported by 95% efficacy demonstrated by the avail-
able mRNA vaccines [38]. It will be interesting to learn whether
the 5% non-responders, either post-infection or post-vaccination,
are those who will be more susceptible to re-infection or will be
those who will contract the disease post vaccination. In our co-
hort, 30% of the patients that were tested for antibodies follow-
ing the first infection were seronegative (7/23; and 2 of them re-
mained seronegative also after the second infection). This finding
may further reinforce this assumption. With the onset of world-

47

wide vaccination, reliable data on the serological status should be
obtained in the near future. Furthermore, 5 out of the 7 patients
that were seronegative in the first infection, developed IgG anti-
bodies following the second infection. This may suggest that the
second infection acted as a "booster dose", and in these patients,
this finding further emphasizes the importance of such booster
doses for effective immunity.
In our cohort we observed cases of re-infection occurring
despite the presence of neutralizing antibodies. These find-
ings may support the possibility that despite sustained humoral
response to the original infecting virus and the production of
neutralizing antibodies, it is still possible that re-infection might
occur. This phenomenon also has been observed in seasonal
coronavirus patients, where re-infections even in the presence
of antibodies were shown [39], mainly due to different variants.
The occurrence of breakthrough infections in patients that are
fully vaccinated against COVID-19 can also support this state-
ment. These breakthrough infections can also be attributed to
the emergence of new variants that are able to evade the immune
response [40].
Indeed, the recent emerging COVID-19 new variants can
provide another explanation and a new concern for future re-in-
fection patients. A recent study from Brazil reported the first
patient of re-infection from a genetically distinct SARS-CoV-2
lineage harboring the E484K spike mutation [20]. Since this
patient, 4 other re-infections with the same variant were docu-
mented [10,15], two of these patients had IgG antibodies after
the first infection. This variant has also been demonstrated to
cause post vaccination breakthrough infections [41]. Develop-
ment of such and other new variants, that are capable of evad-
ing the host neutralizing antibodies, such as variants carrying
the N440K, S477N or N501Y mutations that were observed in
our cohort [12,17,23], might increase the rate of re-infections.
In our cohort 75% of the patients (12/16) that demonstrated
the presence of IgG antibodies following the first infection, \
had new mutations in S in the in the second infection, while
in the patients that developed neutralizing antibodies the pro-
portion was even higher (85% , 6/7). The mutations observed
it this group included the E484K, N501Y, S477N and D614G
mutation. These findings may support the hypothesis above and
further underline the importance of continuous monitoring of
re-infection events, especially with the global rise in the number
and variety of different variants of this virus [42].
Another finding in our cohort demonstrates that the D614G
mutation in S was present in the majority of the re-infection
patients. This finding may be explained by the greater repli-
cative fitness of such variants [43] that causes increased in-
fectivity. However, it should be noted that this variant is very
common worldwide [44].
Since the majority of the papers we reviewed (90%), pub-
lished data about re-infection patients that occurred before De-
cember 2020, when emerging mutations were less common, the
48
VOL 01 • WINTER 2021
possibility of more re-infection patients published in the scien-
tific literature in the near future, in correlation with the emerg-
ing of new variants worldwide, is highly plausible.
In order to enable identification of re-infection patients,
despite the technical restriction and difficulties of conducting
large-scale sequencing, the effect of the different variants on the
variety of rt-PCR kits should also be taken into consideration.
A single-gene “drop-out” rt-PCR assay which detects several
different viral genes, may be useful to identify some variants
in high probability. Indeed, it was previously demonstrated re-
garding the HV69-70 deletions in S in variant B.1.1.7 and other
variants carrying this mutation, such as B.1.525 and Denmark’s
mink-related variants [45-47].
Immunological responses following the infection can the-
oretically influence the clinical severity of the re-infection. If
neutralizing antibodies develop during the first infection, the
re-infection may be milder, as reported with other respiratory
viruses [48]. On the other hand, the possibility of antibody de-
pendent enhancement (ADE) [49] should be taken into consid-
eration and may suggest that a severe clinical status during the
re-infection, in some patients, may be due to the presence of
existing antibodies. We did not see a correlation between the
presence or absence of antibodies in the first infection and the
severity of the second infection was not found [Table S1]. The
lack of information about humoral immune responses results
from the fact that a large amount of the first infections occurred
during the first wave of the pandemic, when serological testing
was not available. With the availability of wide-spread serolog-
ical tests, there is a better chance to obtain better and more ac-
curate information.
The current proposed definition of re-infection requires that
the two infections be phylogenetically different with more than
two nucleotide differences per month. However, since this re-
quirement is difficult to meet in practice, a reasonable alterna-
tive definition suggested by Yahav et al. [50] requires:
a. Confirmation of a first infection by RT-PCR with a Ct value
< 35.
b. Proof of a re-infection occurring more than 90 days follow-
ing the onset of the first infection, with two positive RT-PCR
Ct values < 35.
c. At least one, and ideally two, negative RT-PCR tests, on two
different specimens collected in the time between the first
and re-infections.
Notably, the majority (23/39) of confirmed patients reviewed
herein, reported a re-infection (confirmed by genomic sequenc-
ing) within less than 90 days. Moreover, in few patients, the Ct
values were >35 either in the first, the second infection or in
both infections.
This review demonstrates that currently, re-infections are
still a rare event. The main limitations of our study stem from
the fact that sequencing data in many patients is lacking. Fur-
thermore, suspected (but not confirmed) patients which could
 Date of Age Interval Symptoms Symptoms Antibodies Antibodies Ct† in 1st ≥1 negative Background
Reported 2nd infection Location (years) Sex (days) (1st infection) (2nd infection) (1st infection) (2nd infection) infection
Ct in 2nd PCR
infection the in between Recovery diseases Details Source
infections
1 Apr. 20 (2021) Mar-21 Brazil 39 M 101 d NR* Sever NR NR 30.07 18.83 NR No Yes Details ResearchSquare (pre-print)
2 Apr. 9 (2021) May -20 Brazil 57 F 61 d Mild Mild (more intense) IgG, IgM and IgA positive IgM, IgG, and IgA positive 36.31 21.84 Yes Yes Yes Details CDC
3 Apr. 9 (2021) May-20 Brazil 34 M 64 d Asymptomatic Mild IgG, IgM and IgA positive IgM, IgG, and IgA positive 35.71 16.87 Yes Yes NR Details CDC
4 Apr. 5 (2021) Aug-20 India 47 M 39 d Asymptomatic Mild NR NR 19.1 19.2 Yes Yes NR Details Journal of Medical Virology
IgM, IgG and neutralizing IgM, IgG and neutralizing Yes
5 Mar. 26 (2021) Nov-20 United States 60-70 M 207 d Moderate Mild antibodies positive antibodies positive 16.3 25.3 (TMA test- Yes Yes Details medrxiv (pre-print)
negative)
6 Mar. 19 (2021) Aug-20 Colombia 54 F 30 d Mild Mild NR NR 21.2 30.6 Yes Yes NR Details vaccines
7 Mar. 15 (2021) Dec-20 Brazil 29 NR 281 d Mild Mild IgG positive NR 27.5 20.5 NR Yes NR Details ResearchSquare (pre-print)
8 Mar. 15 (2021) Oct-20 Brazil 50 NR 92 d Mild Mild IgG and IgM positive NR 34 19.17 Yes Yes NR Details ResearchSquare (pre-print)
9 Mar. 15 (2021) Jan-21 Brazil 40 F 282 d Mild Mild NR NR 19.9 21 Yes Yes Yes Details ResearchSquare (pre-print)
10 Mar. 09 (2021) NR India 51 F 139 d Mild Mild (more intense) IgG negative IgG and neutralizing 31 22 Yes Yes No Details frontiers in medicine
antibodies positive
VOL 01 • WINTER 2021

11 Mar. 09 (2021) NR India 24 F 54 d Mild Mild (more intense) IgG negative IgG and neutralizing 32 17 Yes Yes No Details frontiers in medicine
antibodies positive
12 Mar. 09 (2021) NR India 31 M 64 d Asymptomatic Mild IgG negative IgG negative 32 36 Yes Yes No Details frontiers in medicine
13 Mar. 09 (2021) NR India 27 M 65 d Mild Mild (more intense) IgG negative IgG and neutralizing 32 23 Yes Yes No Details frontiers in medicine
antibodies positive
14 Feb. 25 (2021) Oct-20 Switzerland 36 F 203 d Mild Mild IgG and neutralizing IgG and Neutralizing 29.1 21 Yes Yes NR Details CMI
antibodies positive antibodies positive
15 Feb. 16 (2021) Nov-20 India 61 M 75 d Asymptomatic Mild NR NR NR NR Yes Yes No Details Clinical Infectious Diseases
16 Feb. 16 (2021) Nov-20 India 38 M 18 d Mild Mild NR NR NR NR NR Yes yes Details Clinical Infectious Diseases
17 Feb. 10 (2021) Aug-20 USA 10-15 F 142 d Mild Mild NR IgM positive IgG negative NR NR Yes Yes NR Details medRxiv (preprint)
18 Jan. 27 (2021) NR Brazil 45 F 147 d Mild Mild (more intense) NR IgG positive 25 12 NR Yes No Details Preprints (pre-print)
19 Jan. 16 (2021) NR Qatar 35-39 F 59 d NR Asymptomatic IgG positive NR NR NR NR Yes NR Details medRxiv (preprint)
Appendix table 1. Detailed data regarding the confirmed cases

20 Jan. 16 (2021) NR Qatar 35-39 M 84 d NR Asymptomatic IgG positive NR NR NR NR Yes NR Details medRxiv (preprint)
21 Jan.11 (2021) Mar-20 China 84 F 33 d Sever NR IgM, IgG and neutralizing IgM, IgG and neutralizing 33 28 Yes Yes Yes Details NSR
antibodies positive antibodies positive
22 Jan.11 (2021) Mar-20 China 33 M 19 d Moderate NR IgM, IgG and neutralizing IgM, IgG and neutralizing 32 28 Yes Yes No Details NSR
antibodies positive antibodies positive
23 Jan.11 (2021) Apr-20 China 59 M 57 d Moderate NR IgM, IgG and neutralizing IgM, IgG and neutralizing 29 25 Yes Yes No Details NSR
antibodies positive antibodies positive
24 Jan.11 (2021) Apr-20 China 33 M 35 d Moderate NR IgG and IgM positive IgM, IgG and neutralizing 29 32 Yes Yes No Details NSR
antibodies positive
25 Jan.11 (2021) Mar-20 China 2 F 22 d Moderate NR IgG and IgM positive IgM, IgG and neutralizing 33 37 Yes Yes No Details NSR
antibodies positive
26 Jan.11 (2021) Mar-20 China 74 M 24 d Sever NR IgM, IgG and neutralizing IgM, IgG and neutralizing 33 24 Yes Yes No Details NSR
antibodies positive antibodies positive
27 Jan. 9 (2021) 20-Dec United Kingdom 78 M 250 d Mild Severe IgG and IgM positive NR 26.4 27.5 Yes NR Yes Details IDSA
28 Nov. 21 (2020) Apr-20 South Korea 21 F 26 d Mild Mild IgG and neutralizing IgG and neutralizing approximately 23 32.36 Yes No Details Pubmed (pre-print)
antibodies negative antibodies positive Yes
29 Nov. 9 (2020) Sept-20 Belgium 35-40 F 185 d Mild Mild (Milder) IgG and neutralizing IgM, IgG and neutralizing 13 19 Yes Yes No Details MedRxiv (pre-print)
antibodies positive antibodies positive
30 Oct. 12 (2020) Jun-20 United States 25 M 31 d Mild severe NR IgM and IgG positive 35.24 35.31 Yes Yes No Details The Lancet
31 Oct. 09 (2020) NR Netherlands 89 F 54 d Moderate severe NR IgM and IgG negative 26.2 25.2 No No Yes Details IDSA
32 Sept. 29 (2020) Jun-20 Qatar 25-29 M 46 d NR NR NR NR 36 28 NR Yes NR Details MedRxiv (pre-print)
33 Sept. 29 (2020) Jul- 20 Qatar 40-44 M 71 d NR NR NR NR 17 29 NR Yes NR Details MedRxiv (pre-print)
34 Sept. 25 (2020) Jul-20 United States 60-69 NR 118 d Sever Mild NR IgM and IgG positive 22 39.6 Yes Yes Yes Details MedRxiv (pre-print)
35 Sept. 15 (2020) Sept-20 India 28 F 101 d Asymptomatic Asymptomatic NR NR 28.16 16.92 Yes Yes NR Details OSF (pre-print)
36 Sept. 15 (2020) Aug-20 India 25 M 100 d Asymptomatic Asymptomatic NR NR 36 16.6 Yes Yes NR Details OSF (pre-print)
37 Sept. 08 (2020) Jul-20 Ecuador 46 M 47 d Mild Moderate IgM positive and IgG negative IgM and IgG positive 36.85 NR Yes Yes NR Details SSRN (pre-print)
38 Sept. 05 (2020) Jun-20 Belgium 51 F 93 d Mild Mild (milder) NR IgG positive 25.6 32.6 NR Yes No Details IDSA
39 Aug. 25 (2020) Aug-20 Hong Kong 33 M 123 d Mild Asymptomatic IgG negative IgG positive NR 26.69 Yes Yes No Details IDSA

*NR, information was not reported.

† Ct, cycle threshold.

49
 VOL 01 • WINTER 2021

Appendix table 2. Detailed data regarding the genomic variations in relation to antibodies presence or absence
IgG antibodies positive
IgG antibodies negative

Ab* in genetic sequence genetic sequence New mutations Ab in the second Ct‡ first Ct second Ct
first Case in the first infection in the second infection in S† infection infection infection trend
infection
clade 19A§ carrying the
Brazil, 09.04.21, 57/F clade 20 B carrying the D614G mutation 0 IgG+ 36.3 21.8 ↓#
D614G mutation
clade 20B carrying the D614G
Brazil, 09.04.21,34/M clade 20B carrying the D614G mutation 0 IgG+ 35.7 16.9 ↓
mutation
Brazil, 15.03.21, 29‡‡ lineage§ B.1.195 lineage P.1 carrying E484K¶ mutation 11 NR†† 27.5 20.5 ↓
Brazil, 15.03.21, 50‡‡ lineage B.1.1.33 lineage P.1 carrying E484K mutation 11 NR 34 19.2 ↓
Qatar, 16.01.21, 35-39/F NR NR NR NR NR NR  
IgG+**

Qatar, 16.01.21, 35-39/M NR Presence of the D614G mutation ≥1 NR NR NR  

IgG + &
China, 11.01.21, 33/M lineage B lineage B.1 carrying the D614G mutation 1 29 32 ↑#
Neutralizing Ab +
IgG + &
China, 11.01.21, 2/F lineage B lineage B.2 carrying the D614G mutation. 2 33 37 ↑
Neutralizing Ab +
lineage B.1.1.7 carrying the D614G and
UK, 09.01.21, 78/M lineage B.2 N501Y mutations Re-infection was with the 9 NR 26.4 27.9 ↑
“new variant” VOC-202012/01.
lineage B, clade B.1 carrying IgG + &
United States, 28.03.21, 60-70/M B.1.280 carrying the D614G mutation 1 16.3 25.3 ↑
the D614G mutation Neutralizing Ab +
20A clade carrying the D614G 20A clade carrying the D614G and S477N IgG + &
Switzerland 25.02.21, 36/F 1 29.1 21 ↓
mutation mutations Neutralizing Ab +
IgG + & Neutralizing Ab +

IgG + &
China, 11.01.21, 84/F lineage B.2 lineage B.1. carrying D614G mutation 1 33 28 ↓
Neutralizing Ab +
IgG + &
China, 11.01.21, 33/M lineage B lineage B.1.1 carrying the D614G mutation 1 32 28 ↓
Neutralizing Ab +
IgG + &
China, 11.01.21, 59/M lineage B.2 lineage B.1. carrying D614G mutation 1 29 25 ↓
Neutralizing Ab +
IgG + &
China, 11.01.21, 74/M lineage A lineage B 0 33 24 ↓
Neutralizing Ab +
IgG + &
Belgium 09.11.20, 35-40/F clade G clade V carrying the D614G mutation 2 13 19 ↑
Neutralizing Ab +
clade 19A carrying the D614G
India 09.03.21, 51/F clade 20B carrying the D614G mutation 0 IgG+ 31 22 ↓
mutation
India 09.03.21, 24/F clade 19A clade 20B carrying the D614G mutation 1 IgG+ 32 17 ↓
clade 20B carrying the D614G
India 09.03.21, 31/M clade 20B 2 IgG- 33 36 ↑
mutation
IgG -**

India 09.03.21, 27/M clade 20A clade 19A 0 IgG- 32 23 ↓

IgG + &
South Korea 21.11.20, 21/F clade V clade G carrying the D614G mutation 1 23 32.4 ↑
Neutralizing Ab +
clade 20A lineage B1.p9.
Ecuador 08.09.20, 46/M clade 19B, A.1.1 lineage 1 IgG+ 36.85 NR  
carrying the D614G mutation
clade 20A, lineage B.1.79, carrying the
Hong Kong 25.08.20, 33/M clade 19A, lineage B.2 4 IgG+ NR 26.7  
D614G mutation

* Ab, antibodies; Prescence of detectable titer antibodies.

† S, spike protein.
‡ Ct, cycle threshold.
§ In bold: phylogenic clade/lineage.
¶ In bold: specific mutation within the spike region.
#↑, Ct value was higher in the second infection compare to the first; ↓, Ct value was lower in the second infection compare to the first.
**+, IgG positive result; -, IgG negative result.
††NR, information was not reported.
‡‡ Gender of the patient was not reported.

50
 VOL 01 • WINTER 2021
not meet the criteria that define re-infection as stated above
were excluded from this review. However, our study demon-
strates that re-infection should not be underestimated, particu-
larly due to the rising of new emerging mutations and circulat-
ing variants, and new patients should be closely monitored and
analyzed, even in those with detectable titers of anti-IgG anti-
bodies following the first infection. Similarly, careful attention
should be paid to infections post-vaccination.
Corresponding author
Dvir Fridman;
Email: dviranna181818@gmail.com;
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16. Shastri J, Parikh S, Agrawal S, et al. Clinical, Serological, Whole Genome Sequence
Analyses to Confirm SARS-CoV-2 Reinfection in Patients from Mumbai, India.
Front Med 2021;8:631769.
17. Vetter P, Cordey S, Schibler M, et al. Clinical, virological, and immunological
features of a mild case of SARS-CoV-2 re-infection. Clin Microbiol Infect. 2021;5:
791.e1-791.e4.
18. Onkar D, Narreddy S, Zaveri L, Kalal IG, Tallapaka KB, Sowpati DT. Evidence of
SARS-CoV-2 reinfection without mutations in Spike protein, Infectious Diseases
Society of America 2020.
19. Fels JM, Khan S, Forster R, et al. Genomic surveillance of SARS-CoV-2 in the
Bronx enables clinical and epidemiological inference. medRxiv : the preprint
server for health sciences, 2020.
20. Nonaka CKV, Franco MM, Gräf T, et al. Genomic Evidence of a SARS-CoV-2
Reinfection Case with E484K Spike Mutation in Brazil. Preprints 2021, 2021010132.
21. Abu-Raddad LJ, Chemaitelly H, Coyle P, et al. SARS-CoV-2 reinfection in a cohort
of 43,000 antibody positive individuals followed for up to 35 weeks. medRxiv. 2021.
22. Zhang J, Ding N, Ren L, et al. COVID-19 reinfection in the presence of neutralizing
antibodies. National Science Review, 2021;4:8.
23. Harrington D, Kele B, Pereira S, et al. Confirmed Reinfection with Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variant VOC-
202012/01. Clin Infect Dis 2021.
24. Lee JS, Kim SY, Kim TS, et al. Evidence of severe acute respiratory syndrome
coronavirus 2 reinfection after recovery from mild coronavirus disease 2019.
Clinical Infectious Diseases. 2020.
25. Selhorst P, Van Ierssel S, Michiels J, et al. Symptomatic SARS-CoV-2 re-infection
of a health care worker in a Belgian nosocomial outbreak despite primary
neutralizing antibody response. medRxiv. 2020.
26. Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with
SARS-CoV-2: a case study, The Lancet Infectious Diseases, 2021;21:52-58.
27. Mulder M, van der Vegt D, Oude Munnink B, et al. Reinfection of SARS-CoV-2 in
an immunocompromised patient: a case report [published online ahead of print,
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29. Goldman J, Wang K, Röltgen K, et al. Reinfection with SARS-CoV-2 and Failure of
Humoral Immunity: a case report. Medrxiv. 2020.
30. Shastri J, Parikh S, Agarwal S, et al. Whole Genome Sequencing Confirmed SARS-
CoV-2 Reinfections Among Healthcare Workers in India with Increased Severity
in the Second Episode. SSRN Electronic Journal, 2020.
31. Prado-Vivar B, Becerra-Wong M, Guadalupe JJ, et al. COVID-19 re-infection by
a phylogenetically distinct SARS-CoV-2 variant, first confirmed event in South
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reinfection by a phylogenetically distinct strain. Clin Infect Dis. 2020; ciaa1330.
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by a phylogenetically distinct severe acute respiratory syndrome coronavirus 2 strain
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Testing Group. Antibody status and incidence of SARS-CoV-2 infection in health
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lower SARS-CoV-2 infection rates than antibody negative healthcare workers?
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November 2020. medRxiv. 2020:2021-01.
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protection against reinfection with SARS-CoV-2 among 4 million PCR-tested
individuals in Denmark in 2020: a population-level observational study. The
Lancet. 2021;397:1204-1212.
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against re-infection during outbreaks in care homes, September, and October
2020. Euro Surveill. 2021;26(5):pii=2100092.
38. Olliaro P. What does 95% COVID-19 vaccine efficacy really mean?. The Lancet
Infectious Diseases. 2021;17:S1473-3099(21)00075.
39. Edridge AWD, Kaczorowska J, Hoste ACR, et al. Seasonal coronavirus protective
immunity is short-lasting. Nat Med 2020;26:1691–1693.
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Vaccination (April 2021): https://www.cdc.gov/coronavirus/2019-ncov/vaccines/
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CoV-2 Variants. New England Journal of Medicine. Epub ahead of print (2021).
51

42. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications
and Definitions, (2021). https://www.cdc.gov/coronavirus/2019-ncov/cases-
updates/variant-surveillance/variant-info.html.
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Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell,
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Capsule
Clinical features of vaccine-induced immune thrombocytopenia and thrombosis
Vaccine-induced immune thrombocytopenia and
thrombosis (VITT) is a new syndrome associated with
the ChAdOx1 nCoV-19 adenoviral vector vaccine against
severe acute respiratory syndrome coronavirus-2. Data
are lacking on the clinical features of and the prognostic
criteria for this disorder. Pavord and colleagues conducted
a prospective cohort study involving patients with
suspected VITT who presented to hospitals in the United
Kingdom between 22 March and 6 June 2021. Among 294
patients who were evaluated, the authors identified 170
definite and 50 probable cases of VITT. All the patients had
received the first dose of ChAdOx1 nCoV-19 vaccine and
presented 5 to 48 days (median 14) after vaccination. The
age range was 18 to 79 years (median 48), with no sex
preponderance and no identifiable medical risk factors.
Overall mortality was 22%. The odds of death increased by
Capsule
In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains
Rapidly emerging SARS-CoV-2 variants jeopardize antibody-
based countermeasures. Although cell culture experiments
have demonstrated a loss of potency of several anti-spike
neutralizing antibodies against variant strains of SARS-CoV-2,
the in vivo importance of these results remains uncertain.
Chen et al. reported the in vitro and in vivo activity of a panel
of monoclonal antibodies (mAbs), which correspond to many
in advanced clinical development by Vir Biotechnology,
AbbVie, AstraZeneca, Regeneron, and Eli Lilly, against
SARS-CoV-2 variant viruses. Although some individual mAbs
showed reduced or abrogated neutralizing activity in cell
culture against B.1.351, B.1.1.28, B.1.617.1, and B.1.526
viruses with mutations at residue E484 of the spike protein,
low prophylactic doses of mAb combinations protected
52
VOL 01 • WINTER 2021
46. Stanford University, CORONAVIRUS ANTIVIRAL & RESISTANCE DATABASE
A Stanford HIVDB team website. Spike Variants. 2021. https://covdb.stanford.
edu/page/mutation-viewer/#sec_b-1-525
47. World Health Organization. Rapid Risk Assessment: Detection of new SARS-
CoV-2 variants related to mink World Health Organization. Regional Office for
Europe; 2020.
48. Siggins MK, Thwaites RS, Openshaw PJ. Durability of immunity to SARS-CoV-2
and other respiratory viruses. Trends in Microbiology. 2021. Online ahead of print.
49. Lee WS, Wheatley AK, Kent SJ, DeKosky BJ. Antibody-dependent enhancement
and SARS-CoV-2 vaccines and therapies. Nature microbiology. 2020;5(10):1185-91.
50. 
Yahav D, Yelin D, Eckerle I, et al. Definitions for coronavirus disease 2019
reinfection, relapse, and PCR re-positivity. Clin Microbiol Infect. 2021;27:315-318.
a factor of 2.7 (95% confidence interval [95%CI] 1.4–5.2)
among patients with cerebral venous sinus thrombosis, by
a factor of 1.7 (95%CI 1.3–2.3) for every 50% decrease in
the baseline platelet count, by a factor of 1.2 (95%CI 1.0–
1.3) for every increase of 10,000 fibrinogen-equivalent
units in the baseline d-dimer level, and by a factor of 1.7
(95%CI 1.1–2.5) for every 50% decrease in the baseline
fibrinogen level. Multivariate analysis identified the
baseline platelet count and the presence of intracranial
hemorrhage as being independently associated with
death; the observed mortality was 73% among patients
with platelet counts below 30,000 per cubic millimeter and
intracranial hemorrhage.
N Engl J Med 2021; August 11, DOI: 10.1056/NEJMoa2109908
Eitan Israeli
against infection by many variants in K18-hACE2 transgenic
mice, 129S2 immunocompetent mice and hamsters, without
the emergence of resistance. Exceptions were LY-CoV555
monotherapy and LY-CoV555 and LY-CoV016 combination
therapy, both of which lost all protective activity, and the
combination of AbbVie 2B04 and 47D11, which showed
a partial loss of activity. When administered after infection,
higher doses of several mAb cocktails protected in vivo
against viruses with a B.1.351 spike gene. Therefore, many,
but not all, of the antibody products with emergency use
authorization should retain substantial efficacy against the
prevailing variant strains of SARS-CoV-2.
Nature 2021; 596: 103
Eitan Israeli
 VOL 01 • WINTER 2021 Spotlight

Assessment of the Diagnostic Criteria of Osteonecrosis

of the Jaw in Cancer Patients with a History of Radiation
Therapy and Exposure to Bone-Modifying Agents
Yotam Ganor DMD1
1
Dental Branch, Medical Corps, Israel Defense Forces

Figure 1. Clinical appearance of osteonecrosis in the maxilla of a

INTRODUCTION metastatic prostate carcinoma patient. The patient had history of
zoledronic acid treatment and radiation therapy. Note the exposed
In cancer patients, necrosis of the jawbone [Fig. 1] may be necrotic bone and suppuration. Courtesy of Prof. Yehuda Zadik, Hebrew
University-Hadassah, Jerusalem, Israel.
caused by radiation therapy or bone-modifying agents (BMAs),
resulting in osteoradionecrosis (ORN) or medication-related
osteonecrosis of the jaw (MRONJ), respectively. Each of these
diseases is viewed as a distinct clinical manifestation, encom-
passing different treatment approaches [1,2]. For the develop-
ment of jaw necrosis after radiation therapy (i.e., ORN), the spe-
cific site in the jaw must be exposed to a radiation dose greater
than 40 Gy [3].
MRONJ diagnosis and treatment may be challenging. There-
fore, for the purpose of helping the healthcare providers in ev-
eryday practice, during the past decade several guidelines were
published by different associations and societies regarding the
diagnostic criteria of MRONJ [Table 1] [4]. In all cases a crite-
rion of no history of radiation therapy to the jaws, craniofacial
region, or head and neck was included. If the clinician rules out
MRONJ according to this criterion because of previous radia-
tion therapy, the necrotic lesion should be classified and treated
as ORN. However, "previous radiation therapy" may be of low
dose (e.g. <40 Gy to the necrotic bone) and thus not be the real The 2014 American Association of Oral and Maxillofacial
cause of the necrosis. Surgeons (AAOMS) diagnostic criteria were used as a base for
the proposed modified criteria of our study [5]. For MRONJ di-
agnosis in cancer patients, we proposed that the following three
HYPOTHESIS criteria are mandatory:
The hypothesis of this study was that in a significant number 1. Current or past treatment with intravenous/subcutaneous
of jaw osteonecrosis cases, the maximum radiation exposure to BMAs.
the jaw is low enough (<40 Gy) to be considered negligible in 2. Exposed necrotic bone or bone that can be probed through
osteonecrosis pathophysiology and diagnosis. an intraoral or extraoral fistula or sinus in the maxillofa-
cial region, that has been present longer than 8 weeks fol-
lowing identification by a healthcare provider.
METHODS 3. No history of radiation exposure greater than 40 Gy to the
In the study [4] we analyzed data of oncologic patients who necrotic site or apparent metastatic disease.
were exposed to BMAs, radiation therapy to the head and neck, The maximal diagnostic radiation exposure parameter was
or both. Radiation exposures to the jaw necrotic site were deter- based on previous studies exploring radiation dosimetry effects,
mined and a set of modified diagnostic criteria were compared to where ORN cases were found in radiation exposures exceeding
the above-mentioned accepted guidelines for patient diagnosis. 40 Gy [3].

53
 Spotlight VOL 01 • WINTER 2021

Table 1. Comparison of the diagnostic criteria of osteonecrosis of the jaw

The Italian Society Korean Society for Multinational Association of

American
for Maxillofacial International Bone and Mineral Japanese Allied Supportive Care of Cancer
Association
Society / Surgery and the Task Force on Research/Korean Committee on (MASCC), International Society
of Oral and Our proposal
Association Italian Society of Osteonecrosis Association of Oral Osteonecrosis of Oral Oncology (ISOO); and
Maxillofacial
Oral Pathology and of the jaw [7] and Maxillofacial of the Jaw [9] American Society of Clinical
Surgeons [5]
Medicine [6] Surgeons [8] Oncology (ASCO) [10]
Current or Current or past
Patients have
Exposed to the previous Exposure Current or past use Current or previous treatment with
a history of
treatment with treatment with to an of antiresorptive treatment with a bone- an intravenous
1 treatment with
nitrogen-containing antiresorptive or antiresorptive or antiangiogenic modifying agent or / subcutaneous
bisphosphonate
bisphosphonates antiangiogenic agent agents angiogenic inhibitor bone-modifying
or denosumab
agents agent
Exposure of
alveolar bone in Exposed bone or
the oral cavity, bone that can be
Exposed bone or Exposed jaw, and/or face probed through
bone that can be bone in the is continuously an intraoral
probed through maxillofacial observed for Exposed bone or bone that or extraoral
Progressive an intraoral Exposure of the jaw
region that longer than 8 can be probed through an fistula in the
destruction and or extraoral bone or intraoral
does not weeks after first intraoral or extraoral fistula maxillofacial
2 death of bone fistula in the or extraoral fistula
heal within 8 detection by a in the maxillofacial region region that has
that affects the maxillofacial persisting for more
Criteria*

weeks after medical or dental and that has persisted for persisted for
mandible or maxilla region that has than 8 weeks
identification expert, or the longer than 8 weeks longer than 8
persisted for by a health bone is palpable weeks after
longer than 8 care provider in the intra- or identification
weeks extraoral fistula by a healthcare
for longer than 8 provider
weeks
Patients have No history
no history of of radiation
No history radiation therapy therapy of
of radiation No history to the jaw. Bone No history of radiation maximal
Absence of a therapy to the of radiation No history of head lesions must be therapy to the jaws or radiation dose
3 previous radiation jaws or obvious therapy to the and neck radiation differentiated metastatic disease to the of >40 Gy to
treatment metastatic craniofacial therapy from cancer jaws the necrotic
disease to the region metastasis to site or obvious
jaws the jawbone metastasis to
by histological necrotic site
examination

*For an established diagnosis of MRONJ, all 3 criteria must be met

Modified from Zadik et al. Radiotherapy and Oncology 2021;156:275-28 [4]

results highlight the inaccuracythat in all cases of radiation ex-

RESULTS
The results of the study showed that only in primary head and
neck cancer patients, the necrotic jaw sites were exposed to an
average radiation dose greater than 40 Gy, and therefore should
be diagnosed as ORN. The radiation exposure at the necrotic
site in patients with multiple myeloma, and metastatic breast,
lung or prostate cancer, amongst others, was significantly lower
than 40 Gy, ranging from 0 to 1.4 Gy [4]. Based on the present
results, almost two-thirds of ORN diagnoses are incorrect and
should be diagnosed as MRONJ [4].
DISCUSSION
The relatively large sample size of this study sufficiently
demonstrates that current diagnostic criteria for osteonecrosis of
the jaw are limiting and lack specificity, which may lead to mis-
diagnosis and ultimately suboptimal patient treatment. These
posure to the head and neck/craniofacial/jawbone region should
be considered as ORN. It is advisable that accepted MRONJ di-
agnostic criteria be modified with respect to radiation dosimetry
consideration. MRONJ diagnosis criteria should be adjusted to
include cases of previous radiation therapy in the head and neck
regions where the necrotic site was exposed to 40 Gy or less.
Moreover, the substantially lower exposures seen in this study,
emphasize the importance of case specific radiation dosimetry
for accurate diagnosis.
Some cancer patients with osteonecrosis were exposed to ra-
diotherapy doses greater than 40 Gy at the necrotic site in the jaw
and who were also treated with intravenous (IV) bisphosphonate
and/or subcutaneous (SC) denosumab. In such cases, both mo-
dalities can be contributing factors to the development of jaw ne-
crosis. Given the comparable prevalence of ORN and MRONJ,
from an epidemiological standpoint, one diagnosis cannot take
preference over the other. The treatment approaches of ORN are

54
 VOL 01 • WINTER 2021
generally more invasive than those of MRONJ, and may involve
surgical debridement or resection of the affected area followed
by vascular reconstruction. Surgery is not a favorable option in
the treatment of MRONJ as the influence of BMAs on the jaw
may interfere with the healing of surgical margins, creating a risk
for additional necrosis development. Therefore, in cases of ne-
crotic lesions in patients with a history of both radiation exposure
greater than 40 Gy to the jaw and IV/SC BMAs, the therapeutic
approach should favor that of the more conservative MRONJ
rather than ORN. In such cases where the cause of jaw osteone-
crosis is disputable, we recommend an additional modification
to the diagnostic criteria of ORN and MRONJ, addressing a new
category of diagnosis, namely medication- and radiation-related
osteonecrosis of the jaw. The addition of a new osteonecrosis di-
agnostic type will allow for more focused research and treatment
protocols to be initiated.
CONCLUSIONS
More specific diagnostic criteria of MRONJ are required not
only to improve diagnostic accuracy and subsequent treatment
plans, but to enhance overall ability to investigate and under-
stand this distressing side effect of anticancer treatment.
Corresponding Author
Yotam Ganor
Email: yotam.ganor@mail.huji.ac.il
Capsule
Physical rehabilitation for older patients hospitalized for heart failure
Kitzman and colleagues conducted a multicenter,
randomized, controlled trial to evaluate a transitional,
tailored, progressive rehabilitation intervention that
included four physical-function domains (strength,
balance, mobility, and endurance). The intervention
was initiated during, or soon after, hospitalization for
heart failure and was continued after discharge for 36
outpatient sessions. The primary outcome was the score
on the Short Physical Performance Battery (total scores
range from 0–12, with lower scores indicating more
severe physical dysfunction) at 3 months. The secondary
outcome was the 6-month rate of re-hospitalization for any
cause. A total of 349 patients underwent randomization;
175 were assigned to the rehabilitation intervention and
174 to usual care (control). At baseline, patients in each
group had markedly impaired physical function, and 97%
were frail or pre-frail. The mean number of coexisting
conditions was 5 in each group. Patient retention in
Spotlight
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2. Grisar K, Schol M, Schoenaers J, et al. Osteoradionecrosis and medication-related
osteonecrosis of the jaw: similarities and differences. Int J Oral Maxillofac Surg
2016: 1592–9.
3. Owosho AA, Tsai CJ, Lee RS, et al. The prevalence and risk factors associated
with steoradionecrosis of the jaw in oral and oropharyngeal cancer patients
treated with intensity-modulated radiation therapy (IMRT): The Memorial Sloan
Kettering Cancer Center experience. Oral Oncol 2017: 44–51.
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Zadik Y, Ganor Y, Rimon O, Bersudski E, Meirovitz M. Assessment of jaw
osteonecrosis diagnostic criteria in cancer patients with a history of radiation therapy
and exposure to bone-modifying agents. Radiotherapy and Oncology 2021: 275-80.
5. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and
Maxillofacial Surgeons position paper on medication-related osteonecrosis of the
jaw: 2014 update. J Oral Maxillofac Surg 2014: 1938–56.
6. Bedogni A, Fusco V, Agrillo A, Campisi G. Learning from experience: Proposal of
a refined definition and staging system for bisphosphonate-related osteonecrosis
of the jaw (BRONJ). Oral Dis 2012: 621–3.
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Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of
osteonecrosis of the jaw: a systematic review and international consensus. J Bone
Miner Res 2015: 3–23.
8. Kim KM, Rhee Y, Kwon Y-D, Kwon T-G, Lee JK, Kim D-Y. Medication related
osteonecrosis of the jaw: 2015 position statement of the Korean Society for Bone
and Mineral Research and the Korean Association of Oral and Maxillofacial
Surgeons. J Bone Metab 2015: 151.
9. Yoneda T, Hagino H, Sugimoto T, et al. Antiresorptive agent-related osteonecrosis
of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis
of the Jaw. J Bone Miner Metab 2017: 6–19.
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jaw: ASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol 2019: 2270–90.
the intervention group was 82%, and adherence to the
intervention sessions was 67%. After adjustment for
baseline Short Physical Performance Battery score and
other baseline characteristics, the least-squares mean ±
SE score on the Short Physical Performance Battery at 3
months was 8.3 ± 0.2 in the intervention group and 6.9 ±
0.2 in the control group (mean between-group difference,
1.5; 95% confidence interval [95%CI] 0.9–2.0; P < 0.001).
At 6 months, the rates of re-hospitalization for any cause
were 1.18 in the intervention group and 1.28 in the control
group (rate ratio, 0.93; 95%CI 0.66–1.19). There were 21
deaths (15 from cardiovascular causes) in the intervention
group and 16 deaths (8 from cardiovascular causes) in
the control group. The rates of death from any cause
were 0.13 and 0.10, respectively (rate ratio, 1.17; 95%CI
0.61–2.27).
N Engl J Med 2021; 385: 203
Eitan Israeli
55
 to the editor
What Do Patients Want?
Roi Shternin, BEd/MA1 and Emine Nur Avci, MD2
1
Health & Social Managment Department, Management Center Innsbruck
I have been asking myself what patients
want for a while now. I am a chronic
illness patient who suffered for almost a
decade of my life due to miscommunica-
tion with my doctors.
I spoke with dozens of patients like
me, who are confused by bureaucracy,
left to their own devices, and who have
lost faith in the system and the doctors
in it. As one of the next generation of
doctors, I feel it necessary to convey my
thoughts to you.
I have been privileged to lead a pa-
tient community myself and the ideas
and feelings of patients are known to
me. However, when the patients tell
me what they want, the answers are
conflicting. I have been a clinician, a
policymaker, and a patient, and the ex-
perience of patients are very different.
Some patients want to be treated as a
VIP, some want healthcare to be more
personal, and some want it to be com-
pletely client centric. However, all agree
that they want to be understood.
To treat patients who suffer, a phy-
sician must possess not only scientific
knowledge and technical abilities but
also an understanding of human nature.
The patient is not just a group of symp-
toms, damaged organs, and altered emo-
tions. The patient is a human being, wor-
ried and hopeful, who is searching for
relief, help, and trust. The importance of
an intimate relationship between patient
and physician can never be overstated
because, in most cases, an accurate diag-
nosis, as well as an effective treatment,
relies directly on the quality of this re-
lationship [1]. This relationship is sim-
ple: a patient wants to be listened to, be
included in the decisions made on their
health and future, and never want to fall
56
2
Marmara University School of Medicine
between the cracks again. We simply
don’t want to feel lonely on this journey.
Taking control and responsibility
for our health is a big step that may be
life-changing once decided and acted up-
on. Receiving comprehensible knowledge
through our journey may empower us.
Patients want to feel in control over
the decisions made over their body and
future and want to have a voice. The phy-
sicians should treat them as they would
treat a family member. Patients are not a
byproduct of the healthcare system, we
are the system, and it is supposed to he-
al, cure our aches, and treat our wounds.
You, as future physicians, are the ones
that will alleviate our pain.
I have often been invited to speak at
medical schools around the world, and I
feel the wind of change blowing within
the halls of medical schools worldwide.
A humane, humbled, participatory ap-
proach to patient care is already seeping
through the study programs, such as the
wonderful one I’m honored to take part
of as a mentor at the Tel- Aviv University.
The Sheba Medical Center in Israel just
recently appointed Human Experience
Officers in its departments and plan on
listening to opinions of Patients in Res-
idence.
We are not here to be served, charged,
or gotten rid of. We are mostly here due
to a sickness or pain, and we might be
experiencing the worst moments of our
lives. We are here to be healed, empow-
ered, educated, and become better, not
only to get better. You, our physicians,
are also here because you are on a mis-
sion to save and improve lives.
You are here because you chose the
difficult path of healing others. Please
remember before you put on your
VOL 01 • WINTER 2021
white coats or scrubs that we can be
stronger if we work together despite
the burden, Covid, and the daily burn-
out. We can work together despite the
overwhelming stress, responsibility,
and sacrifices. Even if you are often
underpaid, without sufficient rest and
that you must deal with grief and death
in your daily lives.
Doctors need specialized knowledge
and the power to be their patients’-ad-
vocates. Patients are unlikely to choose
a doctor whom they perceive or know to
be powerless. Therefore, doctors need
the ability to share information with pa-
tients, respond to the patients’ cues, and
obtain a complete understanding of pa-
tient’ wants (accountability). They need
to help patients tell their stories, formu-
late, and express preferences, and make
informed decisions on treatments (auton-
omy). They need to act in a trustworthy
manner in health care matters on behalf
of, and for, patients (fidelity). They need
to interact with patients with sensitivi-
ty and compassion, bearing in mind the
increased emotional vulnerability that
illness and fear of death can produce (hu-
manity) [1].
To summarize, doctors need pow-
er in all these domains to facilitate the
healing of patients as persons and to
maintain their professional integrity.
The relationship between the doctor and
patient promotes healing, as evidenced
by the so-called placebo effect of the
“doctor as a drug.” How power is used
and exchanged is influenced by the per-
sonal qualities of the doctor and patient.
This includes aspects such as trust, eth-
ics, communication skills, assertiveness,
and the sense of confidence within the
interaction [2].
 VOL 01 • WINTER 2021 to the editor

We know what you have been through.
We admire you. The anger and frustration
we might feel are natural. We are tired,
in pain, and mainly in an uncertain, un-
controllable situation and we need you
to help us regain control over our bodies
and lives. Include us in your decisions. In
the journey you plan for us, make every-
thing you can transparent, clear, and in a
language that we can understand without
an advanced science degree. Every single
day you put on your stethoscope on your
neck. Stop for a second. Breathe in and
understand that it represents the trust, the
responsibility, the sheer belief in you as
our helpers, as our healers, guiding our
way back to health.
Remember, we are all patients, and
one day it could be you who will be on
the other side of the bed.
ACKNOWLEDGMENTS
We want to thank the following who
helped us form the opinion and practice,
required for this article.
Michal Menashe, CXO, Sheba Medi-
cal Center Department of Human Ex 
Michal Brush, Shahar Barami (MD
candidate), Tel-Aviv University Sackler
medical school Department of medical
communications.
Barrie Dowdeswell, Managment cen-
ter Innsbruck, Department of Health &
social Managment
Dr. Emine Öztürk, CMO, The Patient
School, UK
Corresponding author
Roi Shternin
Email: roi@shternin.com
References
1. Goodyear-Smith F, Buetow S. Power issues in the
doctor-patient relationship. Health Care Analysis.
2001;9(4):449–62.
2. 
Kaba R, Sooriakumaran P. The evolution of
the doctor-patient relationship. International
Journal of Surgery [Internet]. 2007 Feb [cited
2019 Jun 18];5(1):57–65. Available from: https://
www.sciencedirect.com/science/article/pii/
S1743919106000094

Capsule

Gene therapy to replace or edit?

Mitochondrial diseases are a complex set of maladies caused
by mutations in mitochondrial DNA (mtDNA). Mitochondrial
replacement techniques, in which maternal nuclear DNA is
transferred into enucleated donor egg cells or zygotes, are
showing promise for preventing the transmission of these
diseases from at-risk mothers to offspring. Indeed, at least
one child has been born using this technique. However,
questions have arisen about the efficacy and safety of
mitochondrial replacement. In a Perspective, Adashi and
co-authors discussed the potential issues with mitochondrial
replacement and the alternative approach of editing mtDNA
using targeted and specific nucleases. Although much more
development of the mtDNA-editing approach is needed, the
authors suggest that this may be a powerful approach that
might even be combined with mitochondrial replacement to
optimize mitigation of mitochondrial diseases.
Science 2021; 373: 1200
Eitan Israeli

Capsule

Distinct transcription factor networks control neutrophil-driven inflammation

Neutrophils display distinct gene expression patters
depending on their developmental stage, activation
state and tissue microenvironment. To determine the
transcription factor networks that shape these responses
in a mouse model, Khoyratty and co-authors integrated
transcriptional and chromatin analyses of neutrophils
during acute inflammation. The authors showed active
chromatin remodeling at two transition stages: bone
marrow-to-blood and blood-to-tissue. Analysis of
differentially accessible regions revealed distinct sets of
putative transcription factors associated with control of
neutrophil inflammatory responses. Using ex vivo and in
vivo approaches, we confirmed that RUNX1 and KLF6
modulate neutrophil maturation, whereas RELB, IRF5,
and JUNB drove neutrophil effector responses and RFX2
and RELB Wpromoted survival. Interfering with neutrophil
activation by targeting one of these factors, JUNB,
reduced pathological inflammation in a mouse model of
myocardial infarction. This study represents a blueprint
for transcriptional control of neutrophil responses in acute
inflammation and opens possibilities for stage-specific
therapeutic modulation of neutrophil function in disease.
Nature Immunol 2021; 22: 1093
Eitan Israeli

57
 to the editor
A Discussion About LGBTQ + health
1
Faculty of Medicine, Masaryk University, Brno, Czech Republic
2
Icahn School of Medicine at Mount Sinai, New York, NY, USA
T he term LGBTQ+ is an umbrella term
for Lesbian, Gay, Bisexual, Transgen-
der, and Queer. Over the years, additional
terms have fallen under this umbrella term
which is why the plus sign has been added.
The term LGBTQ+ medicine means med-
ical care that specifically revolves around
that community, their specific needs, and
raising awareness within that community.
However, there are many who raise the
question whether there is a need for such
specific medical care.
The LGBTQ+ community is less like-
ly to seek medical care. They will often
seek medical attention only when the
symptoms are so severe they require ur-
gent care. One bad experience with a less
accepting medical professional will cause
LGBQT+ people to be more hesitant to
seek out medical care the next time.
Furthermore, medicine is becoming
more and more precise and specific. As
such, LGBTQ+ medicine should also
address the specific needs of the com-
munity. In the past we had only general
specializations such as Orthopedics and
Cardiologists. Nowadays, the Orthopedic
might continue to specialize in spinal sur-
gery and the cardiologist may specialize
in Interventional cardiology. The same
approach should and is being applied
to LGBTQ+ health. Medical providers
administrating hormonal treatment to
a transgender patient should be able to
adjust the patient’s HIV prevention and
treatment plan accordingly to minimize
any drug-drug interactions and adverse
effects. The medical provider should also
be able to take into consideration possi-
ble substance issues, vaccinations and
more. Until recently there never was a
structured syllabus and specialization for
this kind of medical care.
58
Omer Rott1 and Roy Zucker MD2
In this letter, we will focus on a few
main topics of LGBTQ+ medicine to
help us cultivate a more understanding
mindset when treating a patient from the
LGBTQ+ community.
PRE-EXPOSURE PROPHYLAXIS (PREP):
An antiretroviral medication (containing
tenofovir and emtricitabine) that if tak-
en as prescribed will reduce the chances
of contracting HIV via sexual contact by
99% [1]. Any health care provider licensed
to write prescriptions can prescribe PrEP.
Unfortunately, not everyone who
might benefit from this drug receives it.
For instance, in the United States it is
estimated that out of the 1.1 million po-
tential candidates, only 8% receive PrEP
[2]. This disparity could be due to lack of
knowledge or because the patient might
need to “out” themselves to their medical
provider to receive the prescription.
SEXUALLY TRANSMITTED INFECTION (STIS)
Refers to Syphilis, Chlamydia trachoma-
tis (LGV & Non-LGV), Neisseria gonor-
rhoeae, and Mycoplasma genitalium. As
a medical provider, if a heterosexual male
asks for an STI test he will be sent for a
urine and blood test. However, men who
have sex with men (MSM) should be sent
for additional tests. Both Chlamydia and
Gonorrhea are “site-specific” infections,
meaning if the patient had oral sex, we
will do a pharyngeal swab and if they
had anal sex we will do a rectal swab. In
many countries, the guidelines for STI
screening don’t acknowledge the specif-
ic needs of patients from the LGBTQ+
community. An easy solution to avoid
missing an infection is to ask the patient
about their sexual encounters, in order to
determine the screening tools that will
VOL 01 • WINTER 2021
provide the most accurate results.
The increased use of PrEP led to a
decrease in the use of condoms which
might increase the risk of contracting an
STIs [3]. The lack of LGBQT+ specific
guidelines for accurate screening tests
could lead to a misdiagnosis.
THE LESBIAN COMMUNITY
Suffers higher rates of breast and cervi-
cal cancer, the main reason for this is the
low rates of lesbian patients who undergo
prevention and screening tests, compared
to heterosexual females [4]. In addition,
the lesbian community suffers more from
obesity, substance abuse, and smoking [5].
THE BISEXUAL COMMUNITY
Bisexual people, when compared to the
other members of the LGBTQ+ commu-
nity, have higher rates of mental health
problems and suicide [6]. Additionally,
they experience body image issues, eat-
ing disorders, and substance abuse.
THE TRANSGENDER COMMUNITY AND
HORMONE THERAPY
When first seeing a patient the physician
should not hesitate to ask what pronouns
to use when addressing them. Physicians
should avoid the term “biological gen-
der”, instead ask about their assigned
gender at birth and about their current
gender identity. This data should be in
the patient’s file.
Less than 1% of Americans identify
as transgender. Despite the general mis-
conception, most transgender people do
not undergo gender reassignment surgery
[7]. Some of them choose to only take
hormones. There are many discussions
regarding the age a person can begin hor-
monal therapy. Beginning the treatment
 VOL 01 • WINTER 2021 to the editor

March 4-7, 2018. Boston, MA. Abstract 1022LB.

during puberty, the medical provider will
administer reversible therapy with a go-
nadotropin-releasing hormone agonist.
This therapy will be testosterone based
This letter is a summary of a previous-
3. Nguyen V, Greenwald Z, Trottier H, et al. Incidence
ly published article by Omer Rott and Dr. of sexually transmitted infections before and
Zucker at Osmosis.org. after preexposure prophylaxis for HIV. AIDS.
2018;32(4):523-530.

regimen for transgender men, and an 4. Brandenburg D, Matthews A, Johnson T, Hughes

estrogen based regimen for transgender
women. For transgender women who are
taking estrogen, there is an associated
risk of venous thromboembolism; to re-
duce this risk, androgen lowering agents
(e.g. spironolactone) may be added al-
lowing reducing the estrogen dose.
In conclusion, you can see that the
medical attention given to the LGBTQ+
community needs to be specific and tar-
geted to provide the best medical care.
Corresponding author
Omer Rott
Email: omerrott1@gmail.com
References
1. Cottrell ML, Yang KH, Prince HMA, Sykes C, White
N, Malone S, et al. A translational pharmacology
approach to predicting outcomes of preexposure
prophylaxis against HIV in men and women using
tenofovir disoproxil fumarate with or without
emtricitabine. J Infect Dis. 2016;214(1):55–64.
2. 
Siegler AJ, Mouhanna F, Giler-Mera R, et al.
Distribution of active PrEP prescriptions and the
Prep-to-Need ration, US Q2 2017. CROI 2018.
T. Breast cancer risk and screening: A comparison
of lesbian and heterosexual women. Women &
Health. 2007;45(4):109-130.
5. Weisz VK. Social justice considerations for lesbian
and bisexual women’s health care. J Obstet Gynecol
Neonatal Nurs. 2009;38(1):81–7.
6. Chan, R., Operario, D. and Mak, W. 2020. Bisexual
individuals are at greater risk of poor mental health
than lesbians and gay men: The mediating role of
sexual identity stress at multiple levels. Journal of
Affective Disorders, 260, pp.292-301.
7. Table 1, Nolan I, Kuhner C, Dy G. Demographic and
temporal trends in transgender identities and gender
confirming surgery. Translational Andrology and
Urology. 2019;8(3):184-190.

Capsule

Efficacy and safety of upadacitinib vs. dupilumab in adults with moderate-to-severe

atopic dermatitisl
Blauvelt et al. discussed whether the efficacy and safety of
oral upadacitinib was superior to subcutaneous dupilumab
in adults with moderate-to-severe atopic dermatitis (AD).
This randomized, blinded, head-to-head comparator
clinical trial of 692 patients with moderate-to-severe
AD demonstrated clinically meaningful skin clearance
and itch relief, with statistically significant superiority for
upadacitinib compared with dupilumab. There were no
new safety signals reported for either upadacitinib or
dupilumab. Upadacitinib provided superior and more
rapid skin clearance and itch relief with tolerable safety
compared with dupilumab in patients with moderate-to-
severe AD.
JAMA Dermatol Published online 4 August 2021. doi:10.1001/
jamadermatol.2021.3023
Eitan Israeli

Capsule

mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351

variants and severe COVID-19 disease in Qatar
Chemaitetly and co-authors assessed the real-world
effectiveness of mRNA 1273 vaccine (Moderna) against
SARS-CoV-2 variants of concern, specifically B.1.1.7
(Alpha) and B.1.351 (Beta) in Qatar, a population that
comprises mainly working-age adults, using a matched test-
negative, case-control study design. The authors showed
that vaccine effectiveness was negligible for 2 weeks after
the first dose, but increased rapidly in the third and fourth
weeks immediately before administration of a second
dose. Effectiveness against B.1.1.7 infection was 88.1%
(95%confidence interval [95%CI] 83.7–91.5) ≥ 14 days
after the first dose but before the second dose, and was
100% (95%CI 91.8–100.0) ≥ 14 days after the second dose.
Analogous effectiveness against B.1.351 infection was
61.3% after the first dose (95%CI 56.5–65.5) and 96.4%
after the second dose (95%CI 91.9–98.7). Effectiveness
against any severe, critical, or fatal COVID-19 disease due
to any SARS-CoV-2 infection (predominantly B.1.1.7 and
B.1.351) was 81.6% (95%CI 71.0–88.8) and 95.7% (95%CI
73.4–99.9) after the first and second dose, respectively.
Nature Med 2021; 27: 1614
Eitan Israeli

59
 to the editor
The Importance of Studying Artificial Intelligence
and Data Science to Medical Students
1
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
A dvanced technologies are dramat-
ically changing the face of medi-
cine. Technologies in the fields of data
science and AI (artificial intelligence)
affect almost every diagnostic field, in-
cluding radiology, pathology, dermatol-
ogy, oncology, genetics, and even emer-
gency medicine. As medical students,
we hear about smart algorithms being
used on a daily basis in clinics, in some
cases even providing more accurate di-
agnoses compared to human physicians.
However, how much do we, the next
generation of physicians, actually know
about these algorithms and should we
know more?
Physicians will be asked to adopt new
medical technologies, evaluate them and
their added value, make decisions regard-
ing their usage in clinics [1]. These re-
quirements demand a sufficient level of
technological literacy which many medi-
cal students do not have.
Currently, there are physicians who
provide diagnoses based in part, if not pri-
marily, on data driven algorithms and this
is likely to become more common in the
coming years. Therefore it is reasonable
to expect the physician to sufficiently un-
derstand the algorithm in order to be able
to identify potential biases, inaccuracies,
and special cases in which the algorithm
may fail. Furthermore, an essential part
of the physicians work is to communicate
the finding to patients. Can you imag-
ine a situation where the doctor says,
"I don't quite know why, but that's what
the computer says"?
Poor understanding of the relative ad-
vantages and possible failures of AI algo-
rithms could lead to a lack of implementa-
tion of AI based tools or even to improper
use and a wrong diagnosis. This is demon-
60
Yoad Cohen1
strated by a study conducted regarding an
AI model for diagnosing mammography
results [2]. Radiologists who were shown
a false negative diagnosis by the mod-
el were more likely to agree with it and
did not correctly identify the findings in
the scan, compared to radiologists who
received the results without the pre-diag-
nosis of the algorithm.
Another field, tightly related to AI,
that is changing medicine as we know it,
is data science and advanced data min-
ing tools. In recent years the ability to
identify meaningful information and in-
sights from large amounts of data by us-
ing statistical and programming tools has
become an essential skill in almost every
field. In medicine, where vast amounts
of data need analysis in order to provide
clinical knowledge, data mining skills are
essential. In fact, even the research we
carry out as students in medical school
could benefit from the use of extraction,
mining, and digital processing of various
datasets. Moreover, analyzing big data
could help not only with diagnosis, but
also with choosing a precise treatment by
querying relevant databases..
These days, medical school training
does not provide the studies in the fields
of computer science, technological inno-
vation, or algorithmic thinking. Math-
ematical and statistical training, which
forms a large part of the basis required
for understanding complex computation-
al concepts, exist in a very limited scale
in medical school syllabuses.
Claims that anachronism dominates
certain parts of medical school are not
new. Is it not time for physicians to learn,
alongside traditional lab methods, about
innovative information technologies that
have changed, are changing, and will
VOL 01 • WINTER 2021
change medicine as we know it? Is it not
important that physicians possess basic
skills of querying databases as much, and
perhaps even more, than pipette operat-
ing skills in the laboratory?
The importance of learning the ba-
sics of data science and AI has already
been identified by the Royal College of
Physicians and Surgeons of Canada as
part of a dedicated report published by a
task force exploring the subject [3]. The
authors of the report acknowledged that
the impact of AI and innovative digital
technologies on the world of medicine is
so profound that it requires rethinking the
guidelines of medical training in Canada,
the CanMEDS physician training frame-
work. They even recommended that digi-
tal literacy be defined as a required com-
petency for all training residents, with an
emphasis on understanding how artificial
intelligence algorithms work and a strong
statistical-mathematical base.
The same report presents results of sur-
veys conducted among physicians in Can-
ada, which show that almost half of the
respondents indicate no or little familiar-
ity with AI and its related concepts, while
85% of respondents who are residents be-
lieve that they have not received adequate
information or training to prepare them
for using those technologies in their future
practice. Similar surveys [4] among med-
ical students present similar results and a
strong need to integrate these topics into
the curriculum.
The purpose of basic AI and data sci-
ence training for medical students is not
aimed to provide them with real profi-
ciency in those subjects or the ability to
program complex algorithms. The main
purpose is to increase the student's literacy
in the subject, lower concerns and enhance
 VOL 01 • WINTER 2021 to the editor

the student's sense of ability to understand
the technology, ask the right questions,
challenge appropriate issues, and accu-
rately place it in the diagnostic-therapeutic
sequence.
One recently published article on
the subject argues that medical students
should understand data science and AI
solutions the same way that they un-
derstand any technology that influences
medical decision making, such as MRI
[5]. In doing so, they need to understand
how to:
•  Make use of the technology
in what medical situations and con-
texts would this technology bring
added value, and what inputs are re-
quired to get meaningful results.
•  Interpret the results
understand and interpret results ac-
curately, including identifying faults,
errors, and biases. For example, AI
models trained on samples that do
not represent minority populations
or sample that have been incorrectly
annotated or do not reflect up to date
medical knowledge.
Communicate
• 
be able to explain the results and the
process on which they are based to col-
leagues and patients. This point may
be challenging due to the fact that AI
models often act as a "black box" and
the difficulty of identifying the consid-
erations that led the model to make a
decision, but it is still important to be
able to communicate the result and the
process as much as possible.
The problem will not be solved solely
by fostering technological literacy and
appropriate knowledge among medical
students. Medical schools should identi-
fy students with a natural affinity for the
field and high curiosity, and offer them
extracurricular training that will enable
those who choose to do so to deep dive
into innovative technologies in medicine.
This move will help nurture a new gener-
ation of physicians who can lead medical
innovation, act as early adopters in hospi-
tals and clinics, and be the first to identify
the current challenges that will drive the
technologies of tomorrow.
Corresponding Author
Yoad Cohen
Email: yoadc@mail.tau.ac.il
References
1. 
Pucchio, A., Eisenhauer, E.A. & Moraes, F.Y.
Medical students need artificial intelligence and
machine learning training. Nat Biotechnol 39.
2021. 388–389.
2. Yu KH, Beam AL, Kohane I. Artificial intelligence
in healthcare. Nat Biomed Eng 2. 2018 October.
719-731.
3. Reznick RK, Harris K, Horsley T. Task Force Report
on Artificial Intelligence and Emerging Digital
Technologies. Royal college of physician and
surgeons of Canada; February 2020.
4. 
Pinto dos Santos, D., Giese, D., Brodehl, S. et
al. Medical students' attitude towards artificial
intelligence: a multicenter survey. European
Radiology 29. 2019. 1640–1646.
5. McCoy, L.G., Nagaraj, S., Morgado, F. et al. What
do medical students actually need to know about
artificial intelligence?. npj Digit. Med. 3. 2020. 86 p.

Capsule

Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity

The global decline in malaria has stalled, emphasizing
the need for vaccines that induce durable sterilizing
immunity. Mwakingwe-Omari et al. optimized
regimens for chemoprophylaxis vaccination (CVac),
for which aseptic, purified, cryopreserved, infectious
Plasmodium falciparum sporozoites (PfSPZ) were
inoculated under prophylactic cover with pyrimethamine
(PYR) (SanariaPfSPZ-CVac(PYR) or chloroquine (CQ)
(PfSPZ-CVac(CQ), which kill liver-stage and blood-
stage parasites, respectively, and assessed vaccine
efficacy against homologous (that is, the same strain
as the vaccine) and heterologous (a different strain)
controlled human malaria infection CHMI 3 months after
immunization. They reported that a fourfold increase in
the dose of PfSPZ-CVac (PYR) from 5.12 × 104 to 2
× 105 PfSPZs transformed a minimal vaccine efficacy
(low dose, two out of nine (22.2%) participants protected
against homologous CHMI, to a high-level vaccine efficacy
with seven of eight (87.5%) individuals protected against
homologous and seven out of nine (77.8%) protected
against heterologous CHMI. Increased protection was
associated with Vδ2 γδ T cell and antibody responses.
At the higher dose, PfSPZ-CVac (CQ) protected six
of six (100%) participants against heterologous CHMI
3 months after immunization. All homologous (four
of four) and heterologous (eight of eight) infectivity
control participants showed parasitaemia. PfSPZ-
CVac (CQ) and PfSPZ-CVac (PYR) induced a durable,
sterile vaccine efficacy against a heterologous South
American strain of P. falciparum, which has a genome
and predicted CD8 T cell immunome that differs more
strongly from the African vaccine strain than other
analysed African P. falciparum strains.
Nature 2021; 595: 289
Eitan Israeli

61
Doctor's
Science of Yoga by Ann Swanson
Y oga has become a way for many
people to expend energy, release
tension and find some peace within their
busy and stressful western lifestyle.
Many Israelis traveling in the Far East
and other parts of the world encountered
the practice of Yoga and today Yoga ac-
companies many of us in our daily rou-
tine. It is clear to all that training Yoga
stretching, bending, and strength exer-
cises, while adhering to slow and mea-
sured series of breaths, has many phys-
ical benefits, especially preserving our
joints, ligaments, muscles, and flexibil-
ity for many years. Moreover, yoga can
help lower our blood pressure, decrease
inflammation, and prevent age-related
brain changes.
Many studies have been conducted
to evaluate the effect of yoga on various
CEREBRAL CORTEX
Compared to other mammals, our brains are massive for
our bodies, with a particularly developed cerebral cortex.
Most of the cortex is on the outside of the brain, except
the insula. It is composed of grey matter, which is filled
with synapses or connection points between neurons.
Your cortex has five lobes and many functional areas.
LOBES OF THE BRAIN
The brain is separated into five main divisions,
called lobes, including the insula which is
inside the brain (not seen here).
Temporal lobe
Involved in Parietal lobe
Frontal lobe smell, hearing, Processes body
Responsible for and memory sensation
decision-making and
motor functions
LATERAL VIEW
24
62
Shahar Barami1
1
Sackler School of Medicine, Tel-Aviv University
disease states, both physically and men-
tally. The scientific research now backs
up what were once anecdotal claims
about the benefits of yoga to almost ev-
ery system in our body. The conclusion
that emerges from the vast majority of
the studies is that Yoga is a practice that
may have significantly beneficial effects
on our body and mind. In an attempt to
develop a multidisciplinary and holistic
view of our future patients and possible
treatments for them, Yoga may be a sig-
nificant treatment for relieving and im-
proving various disease states.
In 2013 Lakkireddy and Dawn [1]
presented the YOGA My Heart Study
which demonstrated the physical and
mental impact of daily yoga practice
on patients with atrial fibrillation (AF).
The study involved a 3-month control
INSIDE THE BRAIN
The brain contains many different structures
and scientists are still working out what their
functions are. Some of these structures
monitor conditions inside your body and
relay information. The limbic system is the
emotional centre of your brain.
INTERNAL STRUCTURES
This image shows the brain as if it were cut
in half down the middle (a mid-sagittal section)
to reveal structures inside the cerebrum.
Occipital lobe
Back area Corpus callosum Thalamus
of the cortex Connects two sides Relay centre for
processes vision of brain information
Hypothalamus
Controls much of
neuroendocrine
function
MID–SAGGITAL
SECTION
VOL 01 • WINTER 2021
period followed by a 3-month period,
in which 49 patients participated in an
Iyengar yoga class at least twice weekly
and were encouraged to practice pos-
tures at home on a daily basis. Yoga was
associated with reductions in the mean
number of symptomatic AF episodes
(2.1 vs. 3.8 in the control period), symp-
tomatic non-AF episodes (1.4 vs. 2.9),
and non-symptomatic AF episodes (0.04
vs. 0.12) over 3 months (P <0.001 for
all). Almost one-quarter (11) of the pa-
tients with AF during the control period
experienced no AF episodes during the
yoga training.
A new book named "Science of Yoga"
reveals the facts, with annotated artwork
that shows the mechanics, the angles, how
blood flow and respiration are affected, the
key muscles and joints actions working
HUMAN ANATOMY Nervous system
How yoga affects your brain Brain alpha wave activity increased Dopamine regulated Dopamine
This chart looks at the neuroscience that may Alpha waves are associated with relaxation acts as your body’s reward system and
explain the vast mental and physical benefits GABA increased Gamma-aminobutyric dysfunction is associated with addiction.
of yoga. Modern science shows us that the acid counteracts anxiety and stress Research suggests that meditation results
brain maintains its ability to adapt across a symptoms, leading to more relaxation. in improved self-regulation.
lifetime, making it possible to break bad habits Serotonin increased Serotonin helps
and negative patterns. It can also create the regulate your mood. Low levels of usable Cortisol reduced Cortisol is a stress
key chemicals that pharmaceutical companies serotonin are associated with depression. hormone. When your baseline increases
synthesize in a lab. Research is uncovering the BDNF increased Brain-derived and levels are too high for too long, it can
huge potential of yoga therapy to help people neurotrophic factor is a protein responsible lead to inflammation and weight gain.
on a global scale. These effects stem from for neuron health and neuroplasticity. Yoga Norepinephrine reduced A decrease
yoga’s multidimensional approach, reflected in can boost levels of BDNF, which may help in norepinephrine, or adrenaline, means
its 8-limb structure (see p.198), which includes people with chronic pain or depression. fewer stress hormones in your system.
guidelines on self-control and self-regulation.
Caudate nucleus Putamen
Pineal gland Involved in learning Involved in Fornix
Regulates and processing movement and Plays a role in
sleep–wake cycle memories learning memory processing
Cingulate gyrus
Regulates emotions
and behaviour
Olfactory bulb
Detects scents
and triggers
memories
Amygdala
Fear centre
Cerebellum Hippocampus
Involved in bodily Memory centre
movement, that allows
muscle control, neurogenesis
and balance (see pp.26–27)
Brainstem Pons
Regulates Communication
autonomic centre on brainstem
functions like
breathing and
heart rate LIMBIC SYSTEM
25
 VOL 01 • WINTER 2021 Doctor's

THE ASANAS Inversions

DOWNWARD- Torso ALIGNMENT

Your transversus abdominis stabilizes your KEY Although your arms appear to be 180 degrees
spine and core. Your spinal extensors engage Joints Engaging overhead, they are in a safe range of slightly less

FACING DOG
while your spine remains neutral or in slight flexion. Your spine is neutral or in a slight backbend.
extension. Your middle and lower trapezius Muscles Engaging while
engage to stabilize and slightly depress your stretching Angle of Pelvis and Angle at hips
scapulae. Your latissimus dorsi stretches. shoulder flexion spine approximately
Adho Mukha Svanasana Stretching approximately
120–150 degrees
neutral 90 degrees

Also known as “Down Dog”, this is a common pose in Shoulders Heels reach
Tra rotated towards
modern yoga classes, particularly as an integral part of n
Sp sversu outwards ground
R ine s ab
dom
Sun salutations or flow sequences. This arm balance is Se ectus inis
rra a Fingers spread
a forward fold and partial inversion, stretching the back tu bdom

La ctora s
sa i and hands

Pe peziu
n

tis
nt is Relax head

Tra aspinatu
of your legs and strengthening your shoulders. flat down

sim s ma
eri
Infr and neck
Teres m
or

us
li

do
rsi
Forearms rotated
inor

jor
inwards
THE BIG PICTURE
s

In this pose, the back of your body – including your buttocks, Takes pressure
thighs, and calf muscles – is stretching. Your shoulders are off shoulders
strengthening as you press into the floor.

Arms Chair
Your shoulder flexors engage Should provides
er

imus
– including your pectoralis stability
major, which has some Del

oris
s max
toid

s
s

osu
lengthening muscle fibres due Tr

s fem
ic

din
to shoulder external rotation and

s
eps

Gluteu
VARIATION

ori
Hip
slight abduction. Your deltoids bra

Rectu

iten

lis
fem
For those who have an injury or
Bi

ch

era
dynamically engage to stabilize ii
cep

Sem
health condition or don’t want

eps

at
Elb

an
sb

your shoulder in position, and

sl
b
Pron

Bic
to get on the floor, the chair
al
ow

ra
Wrist

Brachiora

stu
Pronator quadratus

externally rotate your shoulders ibi

c

version is a great option.

hi

Va
iot
ator

with the help of your Il s Also try with your hands

ee miu
infraspinatus and teres minor. Kn cne on a wall or desk.
teres

Your rotator cuff muscles stro

dialis

are active to stabilize your Ga

Sp us
shoulders. Your triceps len Sole terior
iu lis an
extend your elbows. sm Tibia gus
us llucis lon
cle Flexor ha
s
s
Extensor hallucis longu
Ankle
Extensor
digitorum
longus

Neck Thighs and lower legs

Your splenius capitis, splenius
cervicis, and upper trapezius are
either fully relaxed and stretching, or
slightly engaging while lengthening
to keep your ears approximately in
line with your arms.
Your hip flexors engage, quadriceps
extend your knees, and adductors
stabilize your thighs and hips. Your hip
extensors and plantar flexors stretch.
Your ankle dorsiflexors engage as you
press your heels towards the ground.

124 125

Images. Science of Yoga by Ann Swanson, reprinted by permission of DK, a division of Penguin Random House LLC. Copyright ©️2019 Ann Swanson
& Dorling Kindersley Limited.

below the surface of each pose, safe alignment, and much more. is a whole section on various physical conditions and injuries
This book gave me a new, more comprehensive understanding of explaining which asanas to avoid, and which could help with
our body, a greater awareness of how we use and treat it, and a healing and relieving pain. This is not information often found
much better relationship to it through the practice of Yoga. in yoga books, and yet it is very important so that people curious
The book includes a collection of illustrations of the various about the practice do not exacerbate aches and pains they may
asanas (Asana; means "seat" in the Sanskrit language, referring to already be experiencing.
the many positions in which a person sits or stands to do Yoga). I believe that deepening our knowledge in holistic medicine
Most of the asanas are the basic and classic poses – often illustrat- which considers the whole human being – body, mind, spir-
ed from many different angles. Each illustration shows the mus- it and emotions - is important and necessary for us as future
cles that are engaged, which are stretching, the alignment instruc- physicians. The faculties of medicine in Israel are also placing
tions, and what happens in our organs while we are holding the more and more emphasis over the years on these subjects and
pose. The book looks at all the systems that are included in human increasing the number of study hours talking about various top-
anatomy: the musculoskeletal system obviously is an important ics related to the world of holistic medicine, such as nutrition,
anatomical aspect of yoga practice, but yoga also influence the meditation, mindfulness and more.
cardiovascular, digestive, lymphatic, nervous systems, and more. In an article published last year in the New England Journal
There is a chapter devoted to each, providing detailed image and of Medicine, Dossett et al [2] emphasized our mission as present
explanations, as well as useful notes discussing how those various and future physicians to develop and elaborate the knowledge
aspects are manifested in different asanas. about Mind-Body practices, as Yoga, and its application as a
These illustrations are what make the book absolutely gor- significant complementary therapeutic tool for ourselves and for
geous to leaf through. An amazing team of illustrators and our patients in the new era of mind–body medicine.
graphic artists collaborated together to create these precise and "As we continue to develop models for integrating these
comprehensible anatomical illustrations. I praise this aspect not tools into our health care and education systems, we have
just because it is beautiful, but because it is very important for an important opportunity and obligation to study these ex-
a book like this to be both detailed and visual. In addition, there periments so that we can learn how best to personalize these

63
Doctor's VOL 01 • WINTER 2021

approaches and maximize their public
health potential. We need to understand
whether particular approaches are more
likely to help certain people, tempera-
ments, or conditions; whether psycho-
logical or genetic factors predict who
will respond best to certain practices;
what constitutes optimal “dosing”; and
to what extent these practices can shift
the course of disease and reduce the
need for pharmaceuticals and expensive
tests and procedures".
In conclusion, in striving to be the best
doctors we can in the future, I believe we
can at least learn the basic terms of some
of the practices. These practices may im-
prove our patients' condition and help us
to be better physicians for them. More-
over, practicing Yoga by ourselves can
help us live a more balanced and healthy
life and give inspiration to our patients to
practice Yoga as well.
This book will give you a deep and
friendly glimpse into the intricacies of the
practice of yoga, one of the most common
physical exercises in Israel and around the
world. I now understand what it means to
have well-lubricated joints, why twisting
poses are good for your belly, why healthy
quadriceps are linked to longevity and
how Drishti (or focal point in Sanskrit)
helps you with balancing poses.
Now all I have left is to wish you an
enjoyable and instructive reading.
Corresponding Author
Shahar Barami
Email: barami.afik@gmail.com
References
1. Effect of Yoga on Arrhythmia Burden, Anxiety,
Depression, and Quality of Life in Paroxysmal
Atrial Fibrillation: The YOGA My Heart Study,
Lakkireddy D, Buddhadeb D. J Am Coll Cardiol
2013 Mar Vol. 61 Issue No. 11 pp 1177-1182
2. Dossett ML, Fricchione GL, Herbert H. A new
era for mind–body medicine, N Engl J Med 2020;
382:1390-1391 DOI: 10.1056/NEJMp1917461).

Capsule

Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity

The linkage between neutrophil death and the development
of autoimmunity has not been thoroughly explored. Li et
al. showed that neutrophils from either lupus-prone mice
or patients with systemic lupus erythematosus (SLE)
undergo ferroptosis. Mechanistically, autoantibodies
and interferon-α present in the serum induce neutrophil
ferroptosis through enhanced binding of the transcriptional
repressor CREMα to the glutathione peroxidase 4 (Gpx4,
the key ferroptosis regulator) promoter, which leads to
suppressed expression of Gpx4 and subsequent elevation
of lipid-reactive oxygen species. Moreover, the findings
that mice with neutrophil-specific Gpx4 haploinsufficiency
recapitulate key clinical features of human SLE, including
autoantibodies, neutropenia, skin lesions, and proteinuria,
and that the treatment with a specific ferroptosis inhibitor
significantly ameliorates disease severity in lupus-prone
mice reveal the role of neutrophil ferroptosis in lupus
pathogenesis. Together, their data demonstrated that
neutrophil ferroptosis is an important driver of neutropenia
in SLE and heavily contributes to disease manifestations.
Nature Immunol 2021; 22: 1107
Eitan Israeli

Your ideas ARE WORTH

SHARING

w w w. ji ms .co. i l

64
 VOL 01 • WINTER 2021 From the

Discovering Destiny: A Researcher with Ichthyosis

Dedicates her Career to Investigate her Own Disorder
Janan Mohamad BMSc1,2
1
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2
The Laboratory of Molecular Dermatology, Tel Aviv Sourasky Medical Center

J anan Mohamad, 29, originally from Kawkab Abu Il-heja in

the Lower Galilee, Northern District of Israel, is part of the
MD/PhD program at the Tel Aviv University and a research as-
sistant at the Tel Aviv Sourasky Medical Center. Surrounded by
her family, friends, and colleagues it is hard to guess that her
personal story and life choices, which brought her so far, are
quite exceptional.
Janan was born with a rare congenital disorder, known as
autosomal recessive congenital ichthyosiform erythroderma,
which mainly affects the skin in the form of scales and erythe-
ma, and which compels her to constantly apply moisturizer or
lubrication creams as well as to avoid being outdoors in hot
weather, due to lack of sweating. But this perhaps “easy to han-
dle” disorder has changed every aspect of her life and remains
a daily struggle.
Janan was born to a warm, loving family, which she believes
has played a major role in her ability to cope with her disease:
"My parents always knew that I was different, that my skin was
different, but they never treated me differently. Thanks to their defeat me; I will defeat it!”, and from that moment, I accepted
support and to the acceptance of my close family, I lived a nor- myself for who I am and decided to discover the positive aspects
mal life, unaware of my disorder. To this day, I feel truly blessed of ichthyosis”.
for having grown up surrounded by such wonderful people". Unfortunately, social problems were not the only challenges
During her first years in elementary school, when she was she faced as an ichthyosis patient, and she had much more to deal
about six old, she started noticing that other children were star- with, most importantly, her health issues. “The fact that there is
ing at her, some of them keeping a distance and many of them no definitive treatment for my disease was difficult to accept. This
not wanting to become friends with her. In those moments, she was yet another obstacle to overcome”. And so, after three years
began to understand that she was somehow different. as a dental student in the dental medical school in Tel Aviv Uni-
When she became a teenager, she began to realize the full versity, she decided to join a PhD program in order to investigate
extent of her disease and its social impact. Janan describes: “At her disorder and broaden the knowledge regarding ichthyosis
that age, I wanted to be popular, to be “cool,” but I couldn’t with hopes of paving the way for novel therapeutic approaches.
hide my condition. My face was constantly red from erythema, In her PhD work, she has been fortunate to learn and draw
and I had to deal with stares, teasing, and repetitive questions inspiration from the mentorship of two extraordinary research-
regarding my look or my disease. These years were difficult for ers at the Tel Aviv Sourasky Medical Center: Prof. Eli Sprecher,
me, and I had to be very strong to get through and deal with my Chairman of the Department of Dermatology and Deputy Direc-
condition. I owe it to my family, especially my parents, that I tor for Research & Development, and Dr. Ofer Sarig, manager
found the strength to keep going”. of the Laboratory of Molecular Dermatology. Her study focuses
Janan continues: “When I was 16 years old, after a long and on the genetic basis of ichthyosis and aims to delineate the cause
difficult journey living with my disorder, I felt that I was strong of ichthyosis and the biological and genetic pathways, which are
enough to alter the reality of my life. I decided to ignore the involved in the disease.
people who don’t accept me because I am different and change Janan says: “In the first months of my PhD, I wanted to know
the way I perceive myself. I told myself, “This disease won’t what is the cause of my disorder and to reveal the mutation that

65
From the VOL 01 • WINTER 2021

has affected me since birth and changed my dreams and my

path in life. With the help of my dear mentors we succeeded in
identifying the causative point mutation that altered my entire
life”. She recalls the moment of her scientific discovery: “When
I identified the mutation reading the results of the Sanger se-
quencing, I began to cry and wondered how it is possible that
this single point mutation had such an impact on my life. It was a
moment of closure for me and I decided to continue to help other
patients with Ichthyosis".
While Janans' scientific journey has just began, she has al-
ready made some major contributions in her field. With the help Prof. Eli Sprecher Dr. Ofer Sarig
of her colleagues and under the supervision of her mentors, she
successfully uncovered the genetic causes of dozens of ichthy-
osis cases in Israel and in the Middle East, giving families the
option for better genetic consulting for any future pregnancies
they might consider; "For some people having children is an
easy decision to make, but for parents with children affected
by genetic diseases or for the patients themselves, it may be a
very complicated dilemma with an unknown end. Every time
we discover the genetic cause of a familial ichthyosis case, I
remind myself what I had to endure as a child and as a teen-
ager and how my work will hopefully make someone else's
childhood easier". Her work has recently culminated in what
might be called Janans` magnum opus, when she has published
publishing a major paper describing the molecular epidemiol-
ogy of autosomal recessive congenital ichthyosis (ARCI) in
the Middle East. "This paper will helpfully assist physicians to
provide better and quicker diagnosis of causes of ARCI in the
Middle East, thus making the life of patients and their parents
slightly easier. In addition, I hope that my work might serve
as a basis for identification of additional molecular pathways
leading to ichthyoses which might hopefully lead, one day, to
a cure", she remarks. This research is just part of the proj-
ects Janan has been working on during her PhD and she hopes
to continue investigating not only the mutations underlying
these diseases but also potential therapeutic options. "Today,
we know more about the genetic and molecular pathways of
various cornification disorders than ever before – and I hope
that eventually, my work, and that of others, will pave the way
for novel therapies and for a better, and happier life to those
affected by the disorders".
Nowadays, Janan is in her third year in medical school in
the four-year medical program at Tel- Aviv university while
also working as a research assistant in the laboratory of mo- your life. To understand that society can't choose your destiny –
lecular dermatology at the Tel Aviv Sourasky medical center. it is up to you”. She summarises: “I believe that the change must
After finishing her MD degree, she hopes to combine clinical come from within ourselves, and only when we accept ourselves
work, most probably as a dermatologist, with medical research for who we truly are, then will we be able to live a full and
on ichthyosis. productive life”.
Finally, Janans’ advice to anyone who suffers from ichthyo-
sis or other chronic and difficult disease is as follows: “The key Corresponding author
is to believe in yourself and to find the strength to cope with Janan Mohamad
your disease or any other situation and to change the course of Email: janan@mail.tau.ac.il

66
It’s your time to make an

Impact
on the future of medicine

w w w. j i m s .c o. i l
 ‫ד"ר ק‪.‬‬ ‫שיר של יום חולין‬
‫נֹוׁש ֶמת ִּב ְכבֵדּות‬‫ֶ‬ ‫ֶחזֶה‬‫ַּכ ֵא ִבים ּב ָ‬ ‫יבי ֶאת ה ְ‬ ‫ַּת ְׁש ִּכ ִ‬
‫ַציָה‬ ‫ִּת ְּקחוּ ָלּה ָסטּור ְ‬ ‫ַּכ ָליֹות‪,‬‬‫ָנים ּב ְ‬ ‫ְליַד ָה ֲאב ִ‬
‫ָה ַא ְס ְט ָמה ְמ ַצ ְפ ֵצף ְּכמֹו ַק ָּטר‬ ‫ָא ְמ ַצע ‪-‬‬ ‫ֲפי ָּכאן ּב ֶ‬ ‫'שבָץ ִּת ְדח ִ‬ ‫ַּת  ָ‬
‫ינ ָה ַל ְציָה‪.‬‬ ‫ִּת ְּתנּו לֹו ִא ְ‬ ‫ֲחיֹות‪,‬‬‫מּול ַּת ֲחנַתא ָ‬
‫ַּמ ָּטה ‪-‬‬
‫ֶצת ּב ִ‬ ‫יל ְּפ ְסיָה ִמ ְת ַּכּו ֶ‬
‫ָה ֶא ִּפ ֶ‬ ‫יטי‪,‬‬‫ַּמ ָּצב ֶׁשל ַה ֶס ְּפ ִסיס ְק ִר ִ‬ ‫הַ‬
‫ִּת ְק ְראּו ַלּנֹויְרֹולֹוג‬ ‫ְתן לֹו נֹוז ְִלים‪,‬‬ ‫ַקח ֶׁש ֶתן ו ֵ‬
‫יטה‬‫ְּג ֶברֶת‪ְּ ,‬ג ֶברֶת! ַהּכֹל ִּב ְׁש ִל ָ‬ ‫ֶטן ל‪,C.T‬‬ ‫קֹור ִאים ַל ְּכ ֵאבּב ֶ‬ ‫ְ‬
‫ֵאין ָל ְך ָמה ִל ְדאֹג‪.‬‬ ‫ַּלים?‬ ‫ַלּג ִ‬‫ֵאיפֹה יֵׁש ּפֹה ִּכ ֵּסא ּג ְ‬
‫תּוקה‪,‬‬
‫ּדֹוקטֹור ֵלוִי לֹא ָּכאן ְמ ָ‬ ‫ְ‬ ‫ְּג ֶברֶת‪ְּ ,‬ג ֶברֶת‪ִ ,‬ט ָּפה ַס ְב ָלנּות‪,‬‬
‫ָק ְראּו לֹו ִמ ִּטּפּול ִנ ְמרָץ‬ ‫חֹולים‪.‬‬‫יֵׁש ּפֹה עֹוד ִ‬
‫עֹולה ַל ַּמ ְח ָל ָקה‪,‬‬‫ֶּת ֶכף ַא ְּת ָ‬ ‫יסי ֵערּוי‪,‬‬‫ֶמיָה‪ַּ ,‬ת ְכ ִנ ִ‬ ‫ימ ִנים ְל ָאנ ְ‬ ‫ִּת ַּקח ִס ָ‬
‫ֲאבָל קֹדֶם ‪-‬‬ ‫יׁשֹונים ֻמ ְר ָח ִבים‪,‬‬ ‫ַל ָּׁשבָץ ִא ִ‬
‫ַּׁשבָץ‪.‬‬‫הָ‬ ‫לֹא ֵמ ִגיב ְלגֵרּוי‬
‫קֹוד ַחת ֵמחֹם‬ ‫ֵיאּומֹוניָה ַ‬
‫ְ‬ ‫ַה ְּפנ‬
‫ְלה‪,‬‬
‫ָאה ִמ ְׁש ֶמרֶת ַה ַּלי ָ‬
‫רּוכה ַהּב ָ‬
‫ְּב ָ‬ ‫יכה ָא ָקמֹול‪,‬‬ ‫ִהיא ְצ ִר ָ‬
‫הֹול ִכים‬
‫ָׁשלֹום ַל ְ‬ ‫רֹוצה ִסיר‪,‬‬ ‫ַּצ ָלעֹות ֶ‬ ‫ָרים ּב ְ‬ ‫ַה ְּׁשב ִ‬
‫ְּת ַפּנּו ָמקֹום ‪-‬‬ ‫הּוא עֹוד ָּכאן ֵמ ֶא ְתמֹול??‬
‫יעה‬
‫ַמ ִּג ָ‬ ‫ִיקי ֶאת ַאּבָא‪,‬‬ ‫ְּג ֶברֶת‪ְּ ,‬ג ֶברֶת‪ַּ ,‬ת ְחז ִ‬
‫ָכים‪.‬‬
‫ְּתאּונַת ְּדר ִ‬ ‫ֶׁשּלֹא ִיּפֹל‪.‬‬
‫ָטּיּות‪ְ ,‬ל ַמ ַען ה'‪ִּ ,‬ת ְס ְּגרּו וִילֹון‪,‬‬ ‫ִט ָּפה ְּפר ִ‬
‫ַּק ֶׁשת‬ ‫יא ֶט ִרית ְמב ֶ‬ ‫יכ ָ‬
‫ַה ְּפ ִס ִ‬
‫הכותבת היא רופאה בכירה בבית חולים בישראל‬ ‫ַה ְת ַא ְּבדּות‬ ‫ְל ַה ְר ִחיק ֶאת ִנ ְסיֹון ה ִ‬
‫הליקון ‪” 128‬אני החולים“ אביב תשע“ט ‪2019‬‬ ‫ֵיאּומֹוניָה ֵמ ַה ַחּלֹון‪.‬‬
‫ְ‬ ‫ַה ְּפנ‬

‫‪A visionary moment when a character has a sudden insight or realization that changes their understanding of themselves‬‬