Print ISSN: 2436-293X Online ISSN: 2436-2956

Open
Global Health & Medicine Open
Volume 1, Number 1
August, 2021

www.ghmopen.com

Print ISSN: 2436-293X
Online ISSN: 2436-2956
Language: English

GHM Open
GHM Open (Print ISSN 2436-293X, Online ISSN 2436-2956) is an international, open-access, peer-reviewed journal, publishedby the National Center for Global Health and Medicine (NCGM), which is a national research and development agency in Japanthat covers advanced general medicine, basic science, clinical science, and international medical collaboration. It is publishedby NCGM and supported by the International Research and Cooperation Association for Bio & Socio-Sciences Advancement(IRCA-BSSA).
1. Mission and Scope
GHM Open is dedicated to publishing high-quality original research that contributes to advancing global health and medicine,with the goal of creating a global information network for global health, basic science as well as clinical science oriented forclinical application.
The articles cover the fields of global health, public health, and health care delivery as well as the seminal and latest researchon the intersection of biomedical science and clinical practice in order to encourage cooperation and exchange among scientists
and healthcare professionals in the world.
2. Manuscript Types
GHM Open publishes Original Articles, Brief Reports, Reviews, Policy Forum articles, Study Protocols, Case Reports,
Communication, Editorials, Letters, and News.
3. Editorial Policies
GHM Open will perform an especially prompt review to encourage submissions of innovative work. All original researchmanuscripts are to be subjected to an expeditious but rigorous standard of peer review, and are to be edited by experienced copy
editors to the highest standards.
We aspire to identify, attract, and publish original research that supports advances of knowledge in critical areas of global
health and medicine.

Editor-in-Chief
Norihiro Kokudo, M.D., Ph.D.
President,
National Center for Global Health and Medicine;
Professor Emeritus,
The University of Tokyo.

Editorial and Head Office
GHM Open
National Center for Global Health and Medicine,
1-21-1 Toyama Shinjuku-ku, Tokyo 162-8655, Japan
URL: www.ghmopen.com
E-mail: office@ghmopen.comiPrint ISSN: 2436-293X
Online ISSN: 2436-2956
Language: English

Associate Editors
Masayuki Hojo
Tokyo

Tatsuya Kanto
Tokyo

Hong-Zhou Lu
Shenzhen

Wataru Sugiura
Tokyo

Yukihito Ishizaka
Tokyo

Takashi Karako
Tokyo

Tetsuro Matano
Tokyo

Guido Torzilli
Milan

Office Director & Executive Editor
Peipei SongTokyo

Editorial Board
Daniele Del Fabbro
Milan

Yukio Hiroi
Tokyo

Norio Ohmagari
Tokyo

Yasuhide YamadaTokyo

Nermin Halkic
Lausanne

Takeshi Inagaki
Tokyo

Shinichi Oka
Tokyo

Hidekatsu Yanai
Chiba

Kiyoshi Hasegawa
Tokyo

Akio Kimura
Tokyo

Fabio Procopio
Milan

Kojiro Ueki
Tokyo

Hiromi Obara
Tokyo

Nobuyuki Takemura
Tokyo

Advisory Board
Nobuyoshi Aoyanagi
Tokyo

Hiroaki Mitsuya
TokyoHaruhito SugiyamaTokyo(As of August 2021)

ii

CONTENTS		

Volume 1, Number 1, 2021

Editorial
1-2

GHM Open – A new journal dedicated to advancing global health and medicine.
Norihiro Kokudo

Study Protocol
3-11

Prevention of Worsening Diabetes through Behavioral Changes by an IoT-based Self-Monitoring
System in Japan (PRISM-J): Study design and rationale for a multicenter, open-label,randomized parallelgroup trial.
Ryotaro Bouchi, Kazuo Izumi, Hiroshi Ohtsu, Kengo Miyo, Shigeho Tanaka, Noriko Satoh-Asahara,Kazuo Hara, Masato Odawara, Yoshiki Kusunoki, Hidenori Koyama, Takeshi Onoue, Hiroshi Arima,
Kazuyo Tsushita, Hirotaka Watada, Takashi Kadowaki, Kohjiro Ueki

Review
12-19

Effects of COVID-19 on vital organs in patients infected with SARS-CoV-2.
M. Ibrahim Hossain, Esha Binte Shahriar, Anamika Sarker, Nafisa Lubna, Mehjabeen Haque,
Md. Ibrahim Khalil

Brief Report
20-27

Survey of motor function and activities of daily living in hemophilia patients with HIV.
Kazuko Kikuchi, Toshiharu Komachi, Yoshinori Honma, Tomoyuki Endo, Keiko Watabe,
Yoshiyuki Yokomaku, Chieko Hashiba, Masahiro Yamamoto, Yukiko Nagayo, Toshihiro Ito,
Junji Imamura, Tomoko Suzuki, Junko Fujitani

Communication
28-30

Trends in prostate cancer diagnosis during the COVID-19 crisis: A report from one highvolume Japanese center.
Daisuke Yamada, Taketo Kawai, Yusuke Sato, Yuta Yamada, Yoshiyuki Akiyama, Jimpei Miyakawa,
Sayuri Takahashi, Haruki Kume

31-35

Development of active learning materials and use of those materials to educate nursing students
primarily in respiratory nursing and to train new nurses.
Fumino Sugiyama, Tomoko Inoue, Kimikazu Kashiwagi, Mitsumi Masuda, Namiko Nagaoka,
Ayako Narita

Letter
36-37

Japan's first online media seminar on antimicrobial resistance.
Yoshiaki Gu, Yumiko Fujitomo, Rie Takahashi, Norio Ohmagari

38-39

Home-visit services for the families with newborns during the COVID-19 pandemic.
Yukari Isaka, Ai Hori, Takahiro Tabuchi, Sumiyo Okawa, Masao Ichikawa

iii

CONTENTS		
40-42

iv

(Continued )Seroprevalence of antibodies against SARS-CoV-2 among workers in a national research instituteand hospital in Central Japan.
Akihiko Nishikimi, Masayo Kojima, Ken Watanabe, Atsushi Watanabe, Mikako Yasuoka,
Hironori Oshima, Haruhiko Tokuda, Shumpei Niida

Editorial

GHM Open. 2021; 1(1):1-2.
DOI: 10.35772/ghmo.2021.01027

GHM Open — A new journal dedicated to advancing global healthand medicine
Norihiro Kokudo*
National Center for Global Health and Medicine, Tokyo, Japan.

Abstract: To generate high-quality evidence and serve as a platform for interdisciplinary communication regarding
challenging issues in global health and medicine, we are launching a new open-access multispecialty journal —GHM Open (www.ghmopen.com) – with the goal of creating a network to share global health information andfindings from basic science and clinical science for use in practice. GHM Open will be an inclusive and global
journal; the diversity of our editorial board, authors, and reviewers will allow us to showcase rich and wideranging content, making it ever more relevant to researchers and clinicians around the world. The journal prioritizes
specialized research with wider general relevance that will influence clinical care, global health, public health,
medical education, and the direction of future research. We aim to be relevant, accessible, and enjoyable, not only toresearchers but also to global health and medical care providers. We sincerely look forward to having you join us asa reader, author, reviewer, or editorial board member to address challenging issues in global health and medicine.
Keywords: global health, medicine, health care, basic science, clinical science

Academic journals are responsible for facilitating the
rapid dissemination of reliable information. This has
become even more true amidst the challenges andunprecedented situations created by the COVID-19
pandemic. The sharing of data and global collaborationis leading to various solutions, including predictionof outbreaks, virus tracking, diagnosis and treatment,
vaccine development, and drug research. Moreover, therapid sharing of scientific information is an effective
way to reduce public panic given the need for timely
and reliable medical information during the COVID-19
pandemic (1,2).
The COVID-19 pandemic has been accompanied
by an explosion in scientific discourse in peer-reviewed
journals as research data and relevant findings are
rapidly shared and highlighted to support the global
response to this threat (3,4). Our first journal – Global
Health & Medicine (www.globalhealthmedicine.com)– is an academic journal that actively disseminates
reliable information and that has published a large
number of articles since the outbreak, including two
special issues on COVID-19 (5,6), in the hopes ofcontributing to the global fight against COVID-19 inany way possible.
The COVID-19 pandemic has reinforced theimportance of robust journal processes in advancing
knowledge and managing information. What is more,
the dissemination of scientific information on othercommunicable diseases (CDs) and non-communicablediseases (NCDs) is also important to advancing global
health and medicine (7).
To generate high-quality evidence and serve as aplatform for interdisciplinary communication regardingthese challenging issues in global health and medicine,
we are launching a new open-access multispecialty
journal – GHM Open (www.ghmopen.com) – withthe goal of creating a network to share global healthinformation and findings from basic science and clinicalscience for use in practice.
GHM Open (Print ISSN 2436-293X, Online ISSN
2436-2956) is an international, open-access, peerreviewed journal published by the National Center
for Global Health and Medicine (NCGM), which is anational research and development institute in Japanthat covers advanced general medicine, basic science,clinical science, and international medical collaboration.
Closely aligned with Global Health & Medicine, GHM
Open will provide an important forum for high-quality
multidisciplinary communication targeting a broadinternational readership, and it will adopt the evaluation
criteria, editorial standards, and author service being
applied by Global Health & Medicine.
GHM Open is dedicated to publishing high-quality
original research that helps to advance global healthand medicine. Articles will cover the fields of global
health, public health, and health care delivery as well
as seminal research and the latest research on theintersection of biomedical science and clinical practice(1)

GHM Open. 2021; 1(1):1-2.

www.ghmopen.com

in order to encourage interaction and collaboration
among scientists and healthcare professionals aroundthe world.
GHM Open will be an inclusive and global journal;
the diversity of our editorial board, authors, andreviewers will allow us to showcase rich and wideranging content, making it ever more relevant toresearchers and clinicians around the world. The journal
prioritizes specialized research with wider general
relevance that will influence clinical care, global health,public health, medical education, and the direction of
future research. We aim to be relevant, accessible, andenjoyable, not only to researchers but also to global
health and medical care providers. The first issue of
GHM Open contains a delightfully diverse selection ofresearch articles. The topics include global health, type2 diabetes, hemophilia, antimicrobial resistance, and
COVID-19.
GHM Open seeks to work closely with theinternational academic community to ensure that the
research we publish is novel, high-quality, diversein content, and timely. We sincerely look forward to
having you join us as a reader, author, reviewer, or
editorial board member to address challenging issues in
global health and medicine. And we are always happy
to receive suggestions regarding new ways and meansof communicating important research findings.

3.
4.
5.

6.

7.

---Received August 10, 2021; Accepted August 17, 2021.

Funding: None.

Norihiro Kokudo

Conflict of Interest: The author has no conflict ofinterest to disclose.

MD, PhD, FACS, FRCS

Editor-in-Chief, GHM Open

References1.
2.

psychosocial considerations during the COVID-19
outbreak. https://www.who.int/docs/default-source/coronaviruse/mental-health-considerations.pdf (accessed
August 10, 2021).
Mitsuya H, Kokudo N. Sustaining containment of
COVID-19: Global sharing for pandemic response. Glob
Health Med. 2020; 2:53-55.
Kokudo N, Sugiyama H. Hospital capacity during the
COVID-19 pandemic. Glob Health Med. 2021; 3:56-59.
Global Health & Medicine. Volume 2, Number 2, 2020.
Special Topic: COVID-19. https://globalhealthmedicine.
com/files/GHM_2020Vol2No2_pp53_150.pdf (accessed
August 10, 2021).
Global Health & Medicine. Volume 3, Number 2, 2021.
Special Topic: COVID-19. http://globalhealthmedicine.
com/files/GHM_2021Vol3No2_pp56_124.pdf (accessed
August 10, 2021).
Mitsuya H. Fight against COVID-19 but avoid disruptionof services for other communicable diseases (CDs) andnoncommunicable diseases (NCDs). Glob Health Med.
2020; 2:343-345.

President, National Center for Global Health and Medicine
Professor Emeritus, The University of Tokyo
President (2012 - 2016), Japan Surgical Society
President (2015 - 2017), Asian-Pacific Hepato-Pancreato-Biliary Association
President (2020 ~), International Hepato-Pancreato-Biliary Association
President-elect (2021 ~), Asia-Pacific Primary Liver Cancer Expert Association

The Lancet. COVID-19: Fighting panic with information.
Lancet. 2020; 395:537.
The Word Health Organization. Mental health and(2)Study Protocol

GHM Open. 2021;1(1):3-11.
DOI: 10.35772/ghmo.2021.01004

Prevention of Worsening Diabetes through Behavioral Changes by an
IoT-based Self-Monitoring System in Japan (PRISM-J): Study design
and rationale for a multicenter, open-label, randomized parallelgroup trial
Ryotaro Bouchi1,2, Kazuo Izumi3, Hiroshi Ohtsu4, Kengo Miyo5, Shigeho Tanaka6,7, Noriko Satoh-Asahara8, Kazuo Hara9,
Masato Odawara10, Yoshiki Kusunoki11, Hidenori Koyama11, Takeshi Onoue12, Hiroshi Arima12, Kazuyo Tsushita6,13,
Hirotaka Watada14, Takashi Kadowaki15, Kohjiro Ueki2,16,*
1

Diabetes and Metabolism Information Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan;
Department of Diabetes and Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan;
3
Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan;
4
Department of Clinical Study and Informatics, Clinical Epidemiology Section/JCRAC Data Center, Center for Clinical Sciences, National Center
for Global Health and Medicine, Tokyo, Japan;
5Center for Medical Informatics Intelligence, National Center for Global Health and Medicine, Tokyo, Japan;
6
Faculty of Nutrition, Kagawa Nutrition University, Saitama, Japan;
7
Department of Nutrition and Metabolism, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health andNutrition, Tokyo, Japan;
8Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute, National Hospital Organization Kyoto Medical
Center, Kyoto, Japan;
9Department of Endocrinology and Metabolism, Saitama Medical Center, Jichi Medical University, Saitama, Japan;
10
Department of Diabetology, Metabolism, and Endocrinology, Tokyo Medical University Hospital, Tokyo, Japan;
11
Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Hyogo, Japan;
12Departments of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan;
13
Comprehensive Health Science Center, Aichi Health Promotion Foundation, Higashiura-cho, Aichi, Japan;
14
Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan;
15
Toranomon Hospital, Tokyo, Japan;
16
Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
2

Abstract: The use of the Internet-of-Things has improved glycemic control in individuals with diabetes in several
small-scale studies with a short follow-up period. This large-scale randomized controlled trial investigates whether asmartphone-based self-management support system prevents the worsening of glycemic control in individuals with
type 2 diabetes. Individuals with type 2 diabetes (age range 20-74 years; n = 2,000) will be recruited, enrolled, andrandomly assigned to two groups: the intensive therapy group and the conventional therapy group. Participants in
the intensive therapy group will be supervised to use an automated Internet-of-Things system that demonstrates asummary of lifelogging data (e.g., weight, blood pressure, and daily activities) obtained from each measurement device
and will receive feedback messages via smartphone applications to encourage them to increase their physical activity
and to monitor weight and blood pressure. Participants in the conventional therapy group are allowed to use the samemeasurement devices as part of the routine diabetes care but without the Internet-of-Things system. The primary
endpoint is the between-group difference in HbA1c levels from baseline to 52 weeks. This randomized controlled study
will test the hypothesis that an Internet-of-Things-based self-monitoring system could effectively prevent the worseningof diabetes in individuals with type 2 diabetes. The expected results of the study should facilitate the development ofnovel strategies for both diabetes treatment and social health.
Keywords: behaviour modification, application, glycemic control, type 2 diabetes

Introduction

complications, including retinopathy and nephropathy,
and have a 2- to 3-fold increased risk of incident
cardiovascular disease (CVD) (1,2). Early detection ofdiabetes and its complications and ensuring adequate

Individuals with diabetes who have inadequate
glycemic control develop diabetes-related microvascular(3)

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GHM Open. 2021;1(1):3-11.
glycemic, blood pressure, and lipid control by using
pharmacotherapy is necessary to reduce the risk of both
micro- and macrovascular diabetes-related complications(3-6). Moreover, regular medical check-ups are effective
for diabetes prevention and to prevent or delay theworsening of diabetes-related complications. In Japan,
healthcare activities for "specific medical check-up" and"specific health guidance" have been carried out sinceApril 2008 (7). Specific health check-ups are available
to people aged 40-74 years, and specific healthcare
guidance is provided to those with increased abdominal
circumference, blood glucose, blood pressure, andlipid levels. However, approximately 50% have neveravailed specific medical check-ups because individuals
with early-stage non-communicable diseases, such astype 2 diabetes, are mostly asymptomatic. People who
were newly diagnosed with diabetes during a medical
check-up had a low persistence rate for regular visits fordiabetes management (8). Accordingly, hurdles persist
for the early detection of and initiation of interventions
for diabetes; thus, novel strategies are necessary to
overcome these challenges.
Behavioral change plays an important rolein the efficacy of diabetes treatment and patient
education. Meta-analyses of type 2 diabetes foundthat psychological interventions significantly improve
glycemic control (9). Telephonic or web-based
counselling and education by medical staff are effective
for diabetes management (10,11). Multifacetedbehavioral interventions, including lifestyle advice bytelephone, can significantly reduce the dropout rate forregular visits and improve the quality of diabetes carein people with type 2 diabetes in primary-care settings(12). However, evidence-based lifestyle interventions
are expensive and require extensive use of humanresources (13). Therefore, an effective and low-cost
self-management tool needs to be developed. Withthe technological advent of the Internet-of-Things(IoT), several studies have shown that IoT-based
activation of self-monitoring can accelerate behavioral
changes and improve glycemic control in people withdiabetes (14-19). Given the limitations of small study
samples or short follow-up period in these studies,
their preliminary results need to be validated in larger
randomized controlled trials (RCTs) with long followup durations. Therefore, this large-scale randomized
controlled trial will investigate whether a smartphonebased self-management support system prevents theworsening of glycemic control in individuals with type2 diabetes.

System in Japan (PRISM-J) is a multicenter, openlabel, parallel-group, RCT to investigate whether
both behavioral changes and glycemic control could
be improved by interventions via messages that areautomatically generated from health-related information
obtained from wearable devices in people with type 2
diabetes.
Organization and funding
This study is supported by the Japan Agency for Medical
Research and Development (AMED), Research Programfor Health Behavior Modification by using IoT during
fiscal years 2017-2019.
Eligibility
The PRISM-J inclusion and exclusion criteria arepresented in Table S1 (https://www.ghmopen.com/site/
supplementaldata.html?ID=22). We initially planned
to include patients who were receiving up to two oral
antidiabetic agents; however, in April 2018, we modified
the protocol to promote the recruitment of patients who
were being treated with up to three oral antidiabetic
agents. Patients who were treated with insulin or
glucagon-like peptide-1 agonist were excluded in thisstudy.
Screening and enrolment
Screening was performed through: i) regular medical
check-ups provided by health insurance societies (Table
S2, https://www.ghmopen.com/site/supplementaldata.
html?ID=22) and ii) chart review of medical recordsof outpatients who regularly visited the participating
hospitals/clinics of PRISM-J (Table S3, https://www.
ghmopen.com/site/supplementaldata.html?ID=22).
Eligible participants were recruited from January 1, 2018
to December 31, 2018.
Participation model for collaborators
This study comprises two participation models (Figure 1).
One is a "Hospital registration group" wherein physiciansin each hospital/clinic recruit candidates; obtain informed
consent for study participation; register, allocate andeducate the participants on diabetes management and
IoT devices; and follow-up with them during the entire
study period. The other model is an "On-site registrationgroup" that research staff at National Center for Global
Health and Medicine (NCGM) host for the orientation
for participants who are introduced through collaborators,
including health insurance societies (Table S2, https://www.ghmopen.com/site/supplementaldata.html?ID=22)
and hospitals/clinics (Table S3, https://www.ghmopen.
com/site/supplementaldata.html?ID=22); the staff also
obtain informed consent and register, allocate, andMethods
Study design
The Prevention of Worsening Diabetes throughBehavioral Changes by an IoT-based Self-Monitoring(4)

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GHM Open. 2021;1(1):3-11.

Figure 1. Flowchart of study processes and participant disposition.

educate participants on diabetes management and IoT
devices. Thereafter, the participating medical institutions
will follow up on the participants. For participants
who were newly diagnosed with type 2 diabetes anddid not have a primary care physician, PRISM-J
indicated medical institutions where they could be
introduced (Table S3, https://www.ghmopen.com/site/
supplementaldata.html?ID=22).

Japan) and activity monitor (HJA-405T, Omron
Healthcare, Kyoto, Japan). This activity monitor has
been proven to provide valid estimation of total andphysical activity-related energy expenditure (20).
All devices could transmit measurement data over awireless network to a cloud server via a Bluetoothconnection (Figure S1, https://www.ghmopen.com/
site/supplementaldata.html?ID=22). Participants
were instructed to measure weight once a day at
approximately the same time. Home blood pressure
was measured according to the Japanese Societyof Hypertension guidelines for the management ofhypertension 2014 (21). Participants were instructed
to wear the activity monitor from the time they woke
up until they went to bed every day for the assessmentof daily physical activity. In both groups, participants
are treated in accordance with the "Treatment Guidefor Diabetes 2016-2017" edited by the Japan Diabetes
Society (JDS) (22), and physicians were, at theirdiscretion, allowed to select and adjust the medications
for diabetes, hypertension, and dyslipidemia forthe optimal control of these diseases. Investigators
recommended practical ways to reduce or maintainweight with careful consideration of the participants'
lifestyles and physical activity.
After randomization, participants in the ITG
download the "Omron connect App", which allows
them to transfer measurements to their smartphone.
Data are displayed in clear and insightful graphs that
can help participants see their health trends. In addition
to the "Omron connect App", participants in the ITG
download the "Shichifukujin" application (SFJA),

Informed consent, registration, and random allocation
All participants provided written informed consent before
participation. Participants were randomized to either theconventional therapy group (CTG) or the IoT group (ITG)
with an allocation ratio of 1:1 using a stratified blocked
randomization (block size set to 10) based on age (≥50 or < 50 years), sex (male/female), body mass index(BMI; ≥ 25 or < 25 kg/m2) and glycated hemoglobin(HbA1c; ≥ 8.0 [64 mmol/mol], < 8.0%). Based on theeligibility information, registration forms were senton website or faxed to the Data Center (JCRAC Data
Center of NCGM, Tokyo, Japan) for registration andrandomization. The registration codes and the assigned
treatment groups were emailed or faxed to the attending
medical staff on the same day.
Interventions
All participants were lent free IoT devices, including
a weight and body composition monitor (HBF-255T,
Omron Healthcare, Kyoto, Japan), blood pressure
monitor (HEM-7271T, Omron Healthcare, Kyoto,(5)www.ghmopen.com

GHM Open. 2021;1(1):3-11.
which has been described elsewhere (23). Shichifukujin
means "The Seven Deities of Good Luck" (Figure
S1, https://www.ghmopen.com/site/supplementaldata.
html?ID=22); each god has a specific role for thepatient's self-monitoring and gives feedback messages
for lifestyle modification to the patient twice a week
based on data obtained from the "Omron connect App".
All the ITG participants are provided printed support
materials that describe the use of both applications.
Every four weeks, participants in the ITG received
summary messages, including the number of days thatthe participants used the devices and the changes andmeans of weight, blood pressure, and physical activity.
The SFJA automatically sends reminder messages
when the participants do not access the SFJA or they do
not use the devices for 3 and 7 consecutive days (Table
S4, https://www.ghmopen.com/site/supplementaldata.
html?ID=22) . T h e s e m e s s a g e s a r e g e n e r a t e dautomatically, according to the 'Treatment Guide for
Diabetes 2016-2017' edited by the JDS (22), "JSH
Guideline for the Management of Hypertension 2014"(21), 'Treatment Guideline for Obesity Disease 2016'edited by the Japan Society for the Study of Obesity(24), the Exercise and Physical Activity Reference for
Health Promotion 2013 (25), and the Japanese official
physical activity guidelines for health promotion (26).
Primary care physicians can access patient data via
the Shichifukujin cloud that regularly connects to thedevice database (Omron Cloud); check/confirm thesummary of the measurement data, graphs and lifestyle
habits; and use them appropriately as supportive data/
documents for medical treatment and guidance based on
the participant's lifelogging records (Figure S1, https://www.ghmopen.com/site/supplementaldata.html?ID=22).

Observation and evaluation schedule
The data collection schedule is summarized in Table
1 and Figure S2 (https://www.ghmopen.com/site/
supplementaldata.html?ID=22). Participants regularly
visited their outpatient clinic at least once every 12
weeks. At 52 weeks or later, participants in the ITG
continue to use the IoT system until the end of the study
whereas participants in the CTG receive education andinstructions related to IoT, similar to that in the ITG, andthe period during which IoT can be used will be specified
as a maximum of 52 weeks before study termination (until
December 31, 2019). Therefore, the maximum study
participation period of the study participants is presumed
to be 104 weeks (~2 years).
The lifestyle questionnaire included medical history,
family history, and behavioral modification stages related
to diet and exercise (Table S5, https://www.ghmopen.
com/site/supplementaldata.html?ID=22). Treatment
satisfaction and quality of life (QOL) were assessedusing the Diabetes Therapy-Related QOL (DTR-QOL)(27). Food intake was estimated using a Brief-type Selfadministered Diet History Questionnaire (BDHQ) thatwas developed for the assessment of Japanese diets (28).
Information obtained via connected devices are listed inTable 2.
The method used for providing data in this study is
unique in that participants take pictures of laboratory
data and of the forms of their weight and blood pressure
measurements, which are measured at clinics/hospitals
and of prescription information, and upload them to a
portal site. After anonymization, data are sent to the Data
Center. To promote participant retention and complete
follow-up, the Research Support Center will contact

Table 1. Schedule of data collection

Physical examination
HeightWeightBlood pressure
Laboratory examination
HbA1c
GlucoseTotal cholesterol
HDLC
ALT
Creatinine
Urinary protein
Health assessment questionnaire
Lifestyle questionnaire
DTR-QOL
BDHQ
Information on medication

Baseline

12 weeks

24 weeks

36 weeks

52 weeks

Study end

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ALT, alanine transaminase; BDHQ, Brief-type Self-administered Diet History Questionnaire; DTR-QOL, diabetes therapy-related quality of life;
HDLC, high-density lipoprotein cholesterol.

(6)

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GHM Open. 2021;1(1):3-11.

study and whose HbA1c values were available in2017. The HbA1c was 7.05 ± 0.67% in 8,416 people
with type 2 diabetes (unpublished data). Most patientsin the registry are enrolled from facilities designatedby the JDS as educational facilities; thus, the data areconsidered representative of patients in clinics/hospitals
specializing in diabetes care in Japan. Therefore, we
initially estimated SD of HbA1c as 0.6, but it was finallyconfirmed as 1.2 because of the multicenter study designand evidence that HbA1c levels were 7.4 ± 1.2% in 2,199
Japanese patients with type 2 diabetes in primary care(30). Based on these facts, when the power was set to 0.8
or 0.9, the required number of cases was calculated to
be 567 or 758, respectively (SAS Ver 9.4 [SAS InstituteInc., Cary, NC, USA]) in this study to prevent loss.
As the dropout rate is assumed to be 20%, 680 to 910
people are required in each group. Therefore, the total
number of patients in each group was 1,000. To recruita sufficient number of participants, we extended theregistration period from 6 to 9 months in February 2018
and, subsequently, to 12 months in September 2018.

Table 2. Information obtained via connected devices
Weight and body composition monitor (HBF-255T)
WeightBody fat percent level
Percent body fat
Basal metabolic rate
Body mass index
Physical age
Visceral fat level
ImpedanceFat-free mass
Blood pressure monitor (HEM-7271T)
Systolic blood pressure
Diastolic blood pressure
Pulse
PostureRoom temperature
Flag related to irregular pulse wave
Flag related to the detection of body motion
Frequency of artefact detection
Frequency of irregular pulse wave detection
Activity monitor (HJA-405T)
Steps
Exercise steps
Brisk steps
Stair steps
Calories related to activity
Calories related to moderate- to high-strength activity
Total calorie consumption
Calories related to walking
Distance
Fitting flag
Unrecorded flag
Fat combustion amount
Exercise amount
Exercise (walking) amount
Basal metabolic rate
Sedentary time
Activity time related to low-intensity exercise
Activity time related to moderate-intensity exercise
Activity time related to high-intensity exercise

SafetySerious adverse events (SAEs) include those that:i) result in death, ii) are life-threatening, iii) require
inpatient hospitalization or prolongation of existing
hospitalization, iv) result in persistent or significant
disability or incapacity, or v) cause a congenital anomaly
or birth defect in the offspring. Serious hypoglycemia,
defined as hypoglycemia necessitating someone else's
assistance and/or hospitalization, was included as an SAE
in this study. The safety assessment committee oversees
the evolving safety profile by reviewing cumulative
SAEs.

participants by email or phone if they do not send thedata.

Discontinuance and dropout

Outcomes

The criteria for discontinuance in this study were: i)refusal to participate in the study, ii) participants were
judged as unsuitable for the study participation byphysicians, iii) treatment continuation would be difficult
due to the worsening of diabetes and its complications
or other adverse events, iv) pregnancy confirmation, v)
aborting of the study, and vi) investigators determine thatthe discontinuance of the study is appropriate for reasons
other than those mentioned above. Even in the case of
discontinuance, a patient who consented to participate
can be followed up until the end of the study. Dropout
in this study was defined as participants with whom thestudy team had lost contact or those who had revokedconsent during the follow-up after discontinuing thestudy.

The study endpoints are shown in Table 3.
Sample size
In this study, the difference between the effects of HbA1c
was set at 0.2, assuming a 1-year intervention throughout
Japan. Furthermore, it is assumed that the variations ofother data would be widened. Due to the study design,
participants are expected to be recruited from bothprimary-care settings and clinics/hospitals specializing indiabetes care. To estimate the SD of HbA1c in patientswith type 2 diabetes in clinics/hospitals specializing indiabetes care in Japan, we calculated the SD of people
with type 2 diabetes who were enrolled in the Japan
Diabetes CompREhensive database project basedon an Advanced Electronic Medical record System(J-DREAMS) (29), met the inclusion criteria of thisEthical principles
This study is to be conducted in accordance with the(7)www.ghmopen.com

GHM Open. 2021;1(1):3-11.
Table 3. Study endpoints

Primary endpoint• Intergroup differences in HbA1c levels from baseline to 52 weeks
Secondary endpoints• Intergroup differences in HbA1c levels from baseline to 12, 24, and 36 weeks and the end of the study• Intergroup differences in plasma glucose, total cholesterol, HDLC, ALT, creatinine, weight, systolic and diastolic blood pressures, and total
number of antidiabetic agents for the following 12, 24, 36, and 52 weeks from the baseline.
• Intragroup changes in scores obtained from the BDHQ from baseline to 52 weeks and the DTR-QOL from baseline to 24 and 52 weeks andthe end of the study
Explanatory endpoints• Self-measurement (sphygmomanometer, scale and activity monitor)
The transition from the start date is illustrated for each group.
Information from the day closest to 12, 24, 36, and 52 weeks from the start of the study is extracted, and repeated-measures analysis ofvariance is performed.
• Stages in dietary and exercise-related behavioral change
Create a contingency table for each time point and repeat the entire test for intergroup comparison. Comparison between time points is
performed for reference.
• Prescription information
Total number of prescriptions at each time (except for oral antidiabetic agents)
ALT, alanine transaminase; BDHQ, Brief-type Self-administered Diet History Questionnaire; DTR-QOL, diabetes therapy-related quality of life;
HDLC, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin.

principles of Declaration of Helsinki, as well as the"Ethical Guidelines for the Conduct of Clinical Studies"and the "Ethical Guidelines for Medical and HealthResearch Involving Human Subjects" both of which
are established by the Ministry of Health, Labour andWelfare in Japan. This study was approved by the EthicalCommittee of NCGM (NCGM-G-002373) and by theInstitutional Review Board/Ethics Committee at eachstudy site in a hospital registration group and in thefacilities of the executive committee members (Table
S6, https://www.ghmopen.com/site/supplementaldata.
html?ID=22). Primary care physicians who intend toaccess the administrator section in the SFJA would
need to be ethically reviewed. Following approval by
the ethical committee, the protocol of this study and its
revisions are to be reviewed and approved by the ethics
committee of each institution for their feasibility as wellas their ethical and scientific validity. For collaborators
who do not have a local Institutional Review Board/
Ethics Committee, the ethical committee of the NCGM
assumes ethical review. This study was registered at
the University Hospital Medical Information Network
Clinical Trials Registry (UMIN-CTR) before the firstparticipant was enrolled (UMIN 000030823).

which are considered significant when they are below
0.05. For the missing values, there are no plans at thistime to supplement them with the last observation carriedforward method or with other methods. Furthermore,
given the difficulty in defining non-compliance withthis study's protocol, a per-protocol analysis will be
performed to check the agreement of the analysis. For adetailed analysis, the statistician will make a statisticalanalysis plan before the data lock, as indicated below:i) Primary endpoint:• Difference in HbA1c levels from baseline to 52
weeks
Calculate the difference 1 year after the baseline andcompare the two groups.
ii) Secondary endpoint:• HbA1c, plasma casual glucose, total cholesterol,
high-density lipoprotein cholesterol, alaninetransaminase, and creatinine levels; weight; systolicand diastolic blood pressures; and total number ofantidiabetic agents
Repeated data for the 12, 24, 36, and 52 weeks fromthe baseline for between-group comparisons (except for
HbA1c levels at 52 weeks).
• BDHQ
Analyse the change for each subgroup based on thevalues surveyed at baseline and at 52 weeks.
• DTR-QOL
We analysed the change for each subgroup based on
the values surveyed at baseline, at 24 and 52 weeks andat the end of the study.
iii) Planned other analyses• Self-measurement (sphygmomanometer, scale,activity monitor)
The transition from the start date is illustrated foreach group.
• Blood pressure and weight

Data management
Data obtained from the weight and body composition,
blood pressure, and activity monitors were captured
electronically and stored on a server. Laboratory and
QOL data were reported through the patient portal or
through the healthcare institutions. The JCRAC Data
Center oversees data management.
Statistical analyses
All analyses will be based on an intention-to-treat
principal and will be performed with two-sided P-values(8)www.ghmopen.com

GHM Open. 2021;1(1):3-11.
Information from the day closest to 12, 24, 36, and52 weeks from the study initiation was extracted, and a
repeated-measures analysis of variance was performed.
• The dietary and exercise-related behavioral change
stagesCreate a contingency table for each time point andrepeat the entire test to ascertain the between-groupdifferences. Moreover, a comparison between time points
is performed for reference.
• Prescription information
The total number of prescriptions at each time (except
for antidiabetic agents).
iv) Safety
Based on the adverse event surveys conductedindividually, the reported cases are added using thereported cases as the denominator. The chi-squared test is
performed because it depends on the report, but it is used
as a reference value.
For SAEs (e.g., death, hospitalization), events
reported individually to the secretariat are to be tabulated.
The PRISM-J clinical investigators are not allowed
to access data on outcome measurements until the endof this study, when the primary endpoint data analysis iscompleted.

Aichi Health Promotion Foundation) in providing
training and guidance to staff on the IoT systems; Yumi
Maeda, Yuko Takano, Yuka Ikeda, and Yoko Hirata(Mitsubishi Research Institute, Inc., Tokyo) for providing
support in project management; Kohei Higuchi, Masato
Yamashin, Kazuhiko Ikebe, and Takaaki Matsuda (Omron
Healthcare Co., Ltd. Kyoto) for the construction of the
IoT system and technical operational assistance; Yasuhiro
Igarashi (ABeam Consulting Ltd., Tokyo) and Kengo
Ozeki (2nd Factory, Tokyo) for the construction of theintervention system and operation service; ToyotakaMori (IROM CS Co., Ltd., Tokyo) for the support service
at the participation facility; and Shibuki Iimori, Kazumi
Kimura, Azusa Mizuma, and Naohide Nomi (IBERICA
Co., Ltd., Fukuoka) for support at the research office. We
would like to thank the members of the Project Office of
PRISM-J (Mikiko Uwano, Tomoko Ogawa, and Minori
Matsuda) and of the JCRAC Data Center (Chiyoko
Toyama, Keiko Momose, Misuzu Yoshida, and Mariko
Tateo).
Funding: This study was supported by the Japan Agency
for Medical Research and Development (AMED) and the
Research Program for Health Behaviour Modificationby using IoT during fiscal years 2017-2019. The AMED
does not/will not have any role in the study design,
management, data analysis and interpretation, writing of
the report or the decision to submit the report.

History of modifications of the protocol
Modifications in the protocol, including those on the
inclusion criteria and registration period, have been
approved by the Ethical Committee of NCGM as statedearlier.

Conflict of Interest: The authors have no conflicts ofinterest to disclose.

Discussion

Additional Statement

We have presented the study design of and rationale for
the PRISM-J study. This is the first large-scale RCT toinvestigate the efficacy of an IoT-based self-monitoring
system on behavioral changes and glycemic control in
individuals with type 2 diabetes. This study aimed toobtain daily physical activity and behavioral changes,
both in exercise and diet, over 1 year in more than 1,000
people with type 2 diabetes. We recognize that this study
may face challenge in terms of participant adaption
to the IoT system and retention for long term follow
up, however, due to strengths in the large sample size,
we will be able to descriptively determine the types offood and exercise behaviors that could be associatedwith the improvement of glycemic control, which could
presumably lead to the development of customized
exercise and diet therapies. We believe that the expected
results of the PRISM-J trial will provide novel strategies
for both diabetes treatment and social health.

Authors' contributions
RB designed the protocol, guided the study, enrolled
participants, managed onsite registration, researched
the data, and wrote the manuscript. KI designed theprotocol, guided the study, and researched the data. HO
designed the protocol, generated the allocation sequence,
assigned participants to interventions, and guided thestudy as a biostatistician. KM guided the study as anexpert of medical information. ST designed the protocol
and guided the study as an expert in exercise physiology.
NSA, KH, MO, YK, HK, TO, and HA guided the study,
enrolled participants, and researched the data. KT
designed the protocol, guided the study, and researched
the data. HW and TK supervised the study. UK designed
the protocol, guided the study, researched the data, andreviewed and edited the manuscript and, as the guarantorof this work, takes responsibility for the integrity of thedata and the accuracy of the data analysis.

Acknowledgements

Steering Committee
Ryotaro Bouchi (National Center for Global Health andMedicine, Tokyo), Kazuo Izumi (National Center for
Global Health and Medicine, Tokyo), Hiroshi Ohtsu

We acknowledge the contributions of Eri Nomura andMaki Iwatake (Comprehensive Health Science Center,(9)www.ghmopen.com

GHM Open. 2021;1(1):3-11.
(National Center for Global Health and Medicine,Tokyo), Kengo Miyo (National Center for Global Healthand Medicine, Tokyo) and Kohjiro Ueki * (National
Center for Global Health and Medicine, Tokyo).
*Principal investigator

Trial registration number: University Hospital Medical
Information Network Clinical Trials Registry (ref:UMIN000030823).
Protocol Version: Ver 13.0 (Approval date: July 10,2020).

Safety Assessment Committee
Hiroshi Sakura* (Tokyo Women's Medical University
Medical Center East, Tokyo) *Chief

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Data Center
Hiroshi Ohtsu* (JCRAC Data Center, Tokyo) *Chief
Koji Kitajima (JCRAC Data Center, Tokyo)
Statistical Team and Allocation
Hiroshi Ohtsu* (National Center for Global Health andMedicine, Tokyo) *Chief
Data Monitoring
Shinji Inagaki* (ACCERISE, Inc., Tokyo, Japan) *Chief
Audit
Natsue Matsumoto (ACCERISE, Inc., Tokyo, Japan),and Otoji Mori* (ACCERISE, Inc., Tokyo, Japan) *Chief
Auditing will be conducted at four sites, including
Nagoya University, Hyogo Medical University,
ACCERISE, and IBERICA, which are independent of
the investigators and the sponsor.
Collaborators
The PRISM-J Study Group.
Ethics and Dissemination
Patient consent: Obtained prior to study participation.
Ethics approval: NCGM-G-002373-13.
Dissemination policy: The researchers plan to present
their findings to the participants, healthcare professionals,
the public, and other relevant groups via publications andconference presentations.
Provenance and peer review: Not commissioned;
externally peer reviewed.
Data sharing statement: No additional data are available.
Compliance with Ethical Standards: This study is to be
conducted in accordance with the ethical standards ofthe responsible committee on human experimentation(Ethical Committee of NCGM/September 29, 2017/
NCGM-G-002373-13) and with the Helsinki Declarationof 1964 and later versions. No potential conflicts ofinterest relevant to this article were reported. Informed
consent is to be obtained from all patients for being
included in the study.

(10)www.ghmopen.com

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Li H, Senior P, Greiner R. Improved A1C levels in type 1
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17. Waki K, Fujita H, Uchimura Y, Omae K, Aramaki E, Kato
S, Lee H, Kobayashi H, Kadowaki T, Ohe K. Dialbetics: anovel smartphone-based self-management support system
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18. Cho JH, Kim HS, Yoo SH, Jung CH, Lee WJ, Park CY,
Yang HK, Park JY, Park SW, Yoon KH. An Internet-based
health gateway device for interactive communication
and automatic data uploading: clinical efficacy for type 2
diabetes in a multi-centre trial. J Telemed Telecare. 2017;23:595-604.
19. Onoue T, Goto M, Kobayashi T, Tominaga T, Ando
M, Honda H, Yoshida Y, Tosaki T, Yokoi H, Kato S,
Maruyama S, Arima H. Randomized controlled trial
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20. Murakami H, Kawakami R, Nakae S, Nakata Y,
Ishikawa-Takata K, Tanaka S, Miyachi M. Accuracy ofwearable devices for estimating total energy expenditure:comparison with metabolic chamber and doubly labeledwater method. JAMA Intern Med. 2016; 176:702-703.
21. Shimamoto K, Ando K, Fujita T, et al. The JapaneseSociety of Hypertension Guidelines for the Managementof Hypertension (JSH 2014). Hypertens Res. 2014;37:253-392.
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2016-2017. http://www.jds.or.jp/modules/en/index.

php?content_id=1 (accessed January 22, 2021).
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A, Eguchi Y, Onoue T, Goto M, Muto S, Yatsuya H,
Arima H. Automated feedback messages with shififukujin
characteristics using IoT system-improved glycemic
control in people with diabetes: a prospective multicenter
randomized controlled trial. J Diabetes Sci Technol. 2019;13:796-798.
24. Japan Society for the Study of Obesity. Guidelines forthe management of obesity disease 2016, Life Science
Publishing Co., Ltd., Tokyo, Japan.
25. Miyachi M, Tripette J, Kawakami R, Murakami H. "+10min of physical activity per day": Japan is looking for
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26. Ministry of Health, Labor, and Welfare. ActiveGuide.
http://www.nibiohn.go.jp/eiken/info/pdf/active2013-e.pdf(accessed January 22, 2021).
27. Ishii H. Development and psychometric validation of thediabetes therapy-related QOL questionnaire. J Med Econ
2012; 15:556-563.
28. Kobayashi S, Murakami K, Sasaki S, Okubo H, Hirota N,
Notsu A, Fukui M, Date C. Comparison of relative validityof food group intakes estimated by comprehensive andbrief-type self-administered diet history questionnaires
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Health Nutr. 2011; 14:1200-1211.
29. Sugiyama T, Miyo K, Tsujimoto T, Kominami R, Ohtsu
H, Ohsugi M, Waki K, Noguchi T, Ohe K, Kadowaki
T, Kasuga M, Ueki K, Kajio H. Design of and rationale
for the Japan diabetes CompREhensive database projectbased on an advanced electronic medical record system(J-DREAMS). Diabetol Int. 2017; 8: 375-382.
30. Hayashino Y, Suzuki H, Yamazaki K, Goto A, Izumi K,
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Med. 2016; 33: 599-608.
---Received April 14, 2021; Revised May 17, 2021; Accepted
May 19, 2021.
*Address correspondence to:Kohjiro Ueki, National Center for Global Health and Medicine,
1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
E-mail: uekik@ri.ncgm.go.jp(11)Review

GHM Open. 2021; 1(1):12-19.
DOI: 10.35772/ghmo.2021.01010

Effects of COVID-19 on vital organs in patients infected with SARSCoV-2
M. Ibrahim Hossain*, Esha Binte Shahriar, Anamika Sarker, Nafisa Lubna, Mehjabeen Haque, Md. Ibrahim Khalil
Laboratory of Preventive and Integrative Biomedicine, Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences,
Jahangirnagar University, Savar, Bangladesh.

Abstract: The world is now facing one of the most devastating public health concern where the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection is spreading all over the world initiating from Wuhan, China, started
from December, 2019. The World Health Organization (WHO) already announced the situation as pandemic all over
the world. According to the webpage of WHO, this SARS-CoV-2 has been spreading all over the world (223 countries,
areas or territories) with 126,890,643 confirmed cases of coronavirus disease 2019 (COVID-19) and 2,778,619
confirmed deaths (as of March 30, 2021). Accumulated published documents indicate that the SARS-CoV-2 virus
primarily affects the lungs causing hypoxia, which is the leading cause of death. There are many reports describing thatwith the progress of this disease, many other organs (such as heart, kidney, liver, brain) of the affected person start tomalfunction. Though SARS-CoV-2 uses the cell surface receptor angiotensin-converting enzyme 2 (ACE-2) expressedby lungs, cardiovascular system, and kidneys but it is still not clear except for lungs that all these other organs are
directly affected by this virus or not. Therefore, the aim of this review is to gather informations about affected/damaged
organs or tissues and consequences of this damage in COVID-19 patients.
Keywords: SARS-CoV-2, COVID-19, ACE-2, multi-organ failure, ARDS

Introduction

is declared as the most serious crisis situation sinceWorld War 2 by World Health Organization (WHO).
Though currently some vaccines are approved by WHO
and these vaccines are used in different countries allover the world, in many countries where vaccines are
inadequate, treatment of COVID-19 largely depends on
the usual treatment of pneumonia and the experience ofthe clinicians (10).
Therefore, the aim of this current review is to gather
information about the complications of patients infectedwith this novel virus, SARS-CoV-2.

Coronaviruses are a family of related viruses that cause
diseases, ranging from mild to lethal, in mammals
and birds. In humans such types of coronavirus cause
deadly pneumonia with other life threating diseases.
The first coronavirus was reported in 1931 but the firsthuman coronavirus (HCoV-229E) was isolated fromhumans in 1965 (1). However, five coronaviruses havebeen reported at different times during this century:
severe acute respiratory syndrome coronavirus (SARSCoV) in 2002 (2,3), human coronavirus (HCoV-NL63)
in 2003 (4), coronavirus HKU1 (CoV-HKU1) in 2004(5), Middle-East respiratory syndrome coronavirus(MERS-CoV) in 2012 (6) and severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) in 2019 (7,8).
Among them SARS-CoV-2 (also called the 2019 novel
coronavirus, 2019-nCoV) is the coronavirus strain thatcauses the deadly respiratory illness, severe pneumonia,
along with other severe health problems and is known
as coronavirus disease 2019 (COVID-19).
Since December 2019 starting from Wuhan, China,
this SARS-CoV-2 has been spreading all over the world(223 countries, areas or territories) with 126,890,643
confirmed cases and 2,778,619 confirmed deaths (as ofMarch 30, 2021) (9). This situation in the current World

Clinical features
Persons infected with SARS-CoV-2 showed similar
symptoms of normal flu. But the most important
clinical feature is the occurrence of severe pneumonia.
Within February 2020, three major case studies
reported pneumonia as a major clinical feature ofpatients infected with SARS-CoV-2 in Wuhan, China(7,11,12). One study about the clinical manifestationsof COVID-19 patients infected with SARS-CoV-2
had been reported. The study reported about 278
COVID-19 patients where all of them were sufferingfrom severe pneumonia. All the patients were older
than 18 years and about 61.9% (n = 172) were males.

(12)GHM Open. 2021; 1(1):12-19.

www.ghmopen.com

Fever was the most common symptom (92.8%; n =258), followed by cough (69.8%; n = 194), dyspnoea(34.5%; n = 96), myalgia (27.7%; n = 77), headache(7.2%; n = 20) and diarrhoea (6.1%; n = 17) (13).
However, symptoms of COVID-19 can vary from mildfeatures to a critical state. In addition to those thatwere mentioned earlier, the patients may show muscle
aches, confusion, headache, sore throat, rhinorrhoea,
chest pain, sputum production, nausea and vomiting
and many others (7,11,12). Following such types ofsymptoms acute respiratory distress syndrome (ARDS)
and multiple-organ failure occurred rapidly, resulting indeath within a short period of time (14). Patients with
underlying conditions like hypertension, cancer, kidneydisease, diabetes and many other comorbidities are
more prone to severe respiratory conditions and deaththan normal patients (11,12,14). However, as the virus
is spreading all over the world, newer symptoms mightoccur depending on the changed nature of this virus,
physiological status of patients as well as the region of
the world.

The reason behind the occurrence of severe
pneumonia (inflammation of the air sacs of lungs) in
the SARS-CoV-2 infected persons is that the virus
uses the surface protein called angiotensin-converting
enzyme 2 (ACE-2) (15) and cells of the lungs express
ACE-2 surface receptors (16). This ACE-2 cell surface
receptor is also expressed by some other cell types
such as cells of the gastrointestinal system (17), arterial
and venous endothelial cells, smooth muscle cells(16), cells of heart, kidney and testes (18). Structural
studies showed that the SARS-CoV-2 binds 10 to
20 times more strongly with the human ACE-2 thanthe SARS-CoV predecessor (19). This might be thereason why this new SARS-CoV-2 is more infectious
or contagious than its 2002 predecessor, SARS-CoV.
Since a variety of tissues express ACE-2 in their cells,
these tissues or organs might be affected first and dueto the malfunctions of one organ others are affected andas a result the person dies (Figure 1). In the following
section, we will try to summarize information foundin different articles affecting various vital organs of
COVID-19 patients (Table 1).
Lungs
As the name suggests, SARS-CoV-2, this virus
primarily/mainly affects the respiratory system withsevere infection in the lungs. There are a large numberof reports of severe pneumonia in COVID-19 patients(7,8,20,21). Although much is known about the rateof mortality in COVID-19 patients, less is known
about the pathophysiology of this virus. However,accumulating evidences suggest a general mechanism
causing pneumonia (22) (Figure 2). According to thisarticle the mechanism starts with binding of virus toepithelial cells in the nasal cavity and starts replicating.
This virus uses the cell surface receptor ACE-2 tobind to the cell (23). In the next few days, the virus
starts to migrate down the respiratory tract. During
this time the body responds by activating the innate
immune response by producing interferons. One of
the interferons that is produced during early phase of
infection of SARS is interferon-inducible protein-10,
CXCL-10. For this reason CXCL-10 has been reported

Figure 1. Distribution of SARS-CoV-2 in the COVID-19
patients. In COVID-19 patients, the SARS-CoV-2 is mainly
found in the lungs. Beside lungs, so far reported, this virus isfound in the cardiovascular system (a), in the brain (b), in theliver but at low levels (c) and in the gastrointestinal system (d).

Table 1. Summary of the effects of organs/tissues with their corresponding symptoms in the COVID-19 patients all overthe Globe
Name of the organ/tissue
Lungs (alveolus)
Gastrointestinal system (intestine)
Blood vessels (endothelial cells)
Heart (myocardium)
Kidney (nephron)
Liver (hepatocytes)
Brain (neuron, glia)

Expression of ACE-2
yes, highyes, highyes, highyes, highyes, highno (yes* low)no (yes**)Footnote: * non-conclusive; ** highly non-conclusive.

(13)

Symptoms of COVID-19 patients

Ref.

ARDS, pneumonia
diarrhea
blood coagulation
arrhythmia, myocardial damage
chronic kidney disease
liver injury, abnormal functions
anosmia, ageusia(7,8,16,20,21)(17,20,34)(16,40,41,42)(7,18,44,45)(18,48,49)(51,52)(62-64)

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Figure 2. Probable mechanism of the formation of ARDS in COVID-19 patients. (a) The alveolus of a healthy person shows
frequent exchange of gases between O2 and CO2 (O2 goes into the blood for use by different types of cells and CO2 goes into
alveolus to be expelled out from the body). (b) The alveolus of COVID-19 patient shows due to infection by SARS-CoV-2, theinfected alveolus secreted various cytokines and chemokines (shown as blue dots) causing damage of pulmonary microvascularand alveolar epithelial cell barriers. As a result H2O enters into the alveolus from blood capillaries causing pulmonary edema or
ARDS. Therefore exchange of gases is hampered causing breathing difficulties.

as a disease marker for SARS patients (24). Within
the next few days, the virus reaches the basic structureof the lungs, the alveolus. With the help of this basic
structure, the lungs perform its main function, whichis the exchange of gases (O2 and CO2). Probably, like
SARS-CoV, SARS-CoV-2 infects type-II alveolar cells(25). Influenza virus also infects the same alveolar
cells of the lungs (26). Type-II alveolar cells constitute
60% of lung alveolar cells and produce phospholipid
rich materials known as surfactant, which reduces thesurface tension between the two wet surfaces of thealveolus (27). As a result the alveolus fails to reinflate
causing ARDS with the body's excessive defense
mechanism. One of the major causes of ARDS andmultiple-organ failure is the cytokine storm (28).
The cytokine storm contains a large numberof different types of soluble mediators like proinflammatory cytokines (IL-1β, IL-6, IL-8, granulocytemacrophage colony stimulating factor and ROS) andchemokines (CCL2, CCL3, CCL5, IFNγ-induced
protein 10) that all contribute to the occurrence of ARDS
(29,30). Viral replication into the cell causes these proinflammatory cytokines or chemokines to release and as
a response to this there is induction of apoptosis in lungepithelial and endothelial cells involving mechanisms like
Fas-Fas ligand (FasL) or TRAIL-death receptor 5 (DR5)(31,32). Death of lung epithelial cells and endothelial
cells causes damage to pulmonary microvascular andalveolar epithelial cell barriers leading to formation ofalveolar edema ultimately causing hypoxia in the body.
Therefore, probably, the cytokine storm is the causeof ARDS in COVID-19 patients infected with SARSCoV-2.

with pneumonia or problems with respiratory systems
but with the increasing number of infection cases theincidence of diarrhea is also increasing (33). Now,
diarrhea is one of the frequent symptoms in COVID-19
infection as it was detected in up to 30% of patientswith MERS-CoV and 10.6% of patients with SARSCoV-2 (20,34). In addition to use the receptor protein
ACE-2 expressed on the cell surface, SARS-CoV alsouses cellular serine proteases (TMPRSS2) to get entry
inside the cell. The entry process into the cell involves
priming by TMPRSS2, which allows spike protein
cleavage and regulation of the entire mechanism (23).
But the major role of entry is by the surface protein
ACE-2, which first mediates the attachment of thevirus with the host cell membrane and then TMPRSS2
favors the fusion of the two (one is the virus and otherone is the host cell) cell membranes (23). Therefore,
the virus entry into the host cell or infectivity mainly
depends on binding with the ACE-2 surface receptor(35) and the ACE-2 surface receptor is also greatly
expressed by gastrointestinal epithelial cells (17,36).
Analyses of COVID-19 patients also confirmed thepresence of SARS-CoV-2 RNA in anal or rectal swabs(37,38) as well as in stool specimens (39). Even after
clearance of the virus in the upper respiratory system,
SARS-CoV-2 RNA is still found in anal or rectal swabs(37,38). All of this evidence indicates that diarrhea or
gastrointestinal abnormalities should be considered as amajor symptom of SARS-CoV-2 infections and absenceof SARS-CoV-2 RNA in anal or rectal swabs or instool specimens should be taken into account before
declaring an infected person to be a healthy person.
Blood endothelial cells

Gastrointestinal system

ACE-2 surface receptors are expressed in theendothelial cells of blood vessels (16). Therefore, theconsequences of infected endothelial cells of blood

Initially diarrhea or gastrointestinal problems wasconsidered as a minor symptom of this virus compared(14)

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vessels have not yet been addressed. However, there isevidence that some COVID-19 patients have prominentchanges in blood coagulation (40). For example,
the values of D-dimer, fibrin/fibrinogen degradation
products (FDP), and fibrinogen (FIB) in all SARSCoV-2 cases are substantially higher than those inhealthy controls and values of D-dimer and FDP
are higher in severe COVID-19 patients than milder
patients. And the prothrombin time activity (PT-act) islower in SARS-CoV-2 patients (40). In another article,
it was also reported that in the late stages of pneumonia
caused by SARS-CoV-2, fibrin-related markers (e.g.
D-dimer) are markedly elevated suggesting coagulation
activation and start of secondary hyperfibrinolysis, which
may be induced following severe COVID-19 infection(41). When some (n = 99) severe COVID-19 patients,
who had markedly elevated D-dimer, received heparinas anticoagulant therapy for 7 days or longer they had
better prognosis of the disease with a decreased rate ofmortality of about 20% (42). Therefore, changes in blood
coagulation is a prominent feature of severe infection
with SARS-CoV-2 and it was suggested that monitoring
D-dimer and FDP values may be helpful for early
identification of severe cases (40).

to support routine discontinuation of ACEIs or ARBs in
COVID-19 patients since the role of renin-angiotensin
system (RAS) inhibition in COVID-19 is controversial(47). Therefore, they suggest an urgent investigationin multicenter trials to test this hypothesis in patientswith COVID-19 before the medical community makes
recommendations for patients to withhold potentiallylife-saving drugs (47).
All of these data indicate that myocardium of infected
persons is somehow involved in the mortality rate of
COVID-19 patients. Though the mechanisms of such
acute cardiac injury in COVID-19 patients are not wellunderstood, however, Akhmerov and Marban proposed
one mechanism which likely involves increased
cardiac stress due to respiratory failure and hypoxemia,
direct myocardial infection by SARS-CoV-2, indirect
injury from the systemic inflammatory response, or a
combination of all three factors (43).
KidneysThough kidneys express ACE-2, there are no reports yet
about the presence of SARS-CoV-2 into the kidney likeheart. Chronic kidney disease (CKD) is a frequently
encountered disease in the general population of acountry. During the first two months of the current
outbreak in China, CKD was re-ported in 4.3% of theChinese patients infected with COVID-19 who had
severe presentation (48,49). End-stage kidney disease
patients are a highly susceptible group with an infection
rate of 16%, which exceeds that observed in otherpopulations (49). Persons infected with SARS-CoV-2
with this co-morbidity are at high risk of mortality. Andvarious kidney diseases are a vital candidate of thiscomorbidity. One article concludes that the prevalenceof kidney disease on admission and the developmentof acute kidney disease (AKI) during hospitalization inpatients with COVID-19 is high and is associated within-hospital mortality (50). Hence, clinicians should
increase their awareness of kidney disease in patientswith severe COVID-19 (50).

Heart and cardiovascular system
Since myocardium or cardiac muscle cells express ACE2 surface receptor (18), SARS-CoV-2 might attack
the heart as well though there is no report about thepresence of virus in the heart (43). In a case study of
138 COVID-19 patients admitted into the hospital,
16.7% developed arrhythmia and 7.2% presented acutecardiac injury (12). In another report, acute cardiac
injury was reported in 5 among the first 41 humans
infected with SARS-CoV-2 in Wuhan, China, with anincreased level of high-sensitivity cardiac troponin I,
cTnI (7). Another acute cardiac injury marker braintype natriuretic peptide (BNP) was also found to beelevated among patients admitted into a hospital ICU in
Washington (44). There is a report of 150 COVID-19
patients from Wuhan, China, where 68 (45%) died.
Among the 68 patients, 29 (40%) patients diedexclusively due to myocardial damage or in combination
with myocardial damage and circulatory failure (45).
COVID-19 patients with these comorbidities are more
likely to die than regular patients. According to the
New York State Health Department, among thesecomorbidities hypertension is number one in terms ofpatient's severity. Because hypertensive patients have to
use ACE inhibitors (ACEIs) or angiotensin II receptor
blockers (ARBs) and usage of these drugs can increase
ACE-2 expression. Since ACE-2 surface receptors areused by SARS-CoV-2, usage of these anti-hypertensive
drugs can be life threatening for a person who hasboth hypertension and COVID-19 (46). However,Tignanelli et al. claimed that no evidence is available

Liver
There are few reports concerning liver dysfunction
in COVID-19 patients. Though there are no reports
yet that hepatocytes express ACE-2 surface receptors,
although one article reported that bile duct epithelial
cells may express ACE-2 receptors more thanhepatocytes (51). In a study of 417 COVID-19 patients,
318 (76.3%) had abnormal liver test results and 90(21.5%) had liver injury during hospitalization. Theseabnormal liver tests became more pronounced in thenext 2 weeks where all the essential liver enzymes (ALT,
AST, total bilirubin and γ-GT) were elevated to morethan 3 times of the upper limits indicating abnormalliver tests had higher risks of progressing to severe(15)

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disease in SARS-CoV-2 infection (52). In another studyof 99 COVID-19 patients in China, 43% of patients had
differing degrees of liver function abnormalities with
ALT and AST with an upper range of ALT 7,590 U/L
and AST 1,445 U/L (55). An opposing state of arguments
was also reported concerning liver damage in COVID-19
patients. According to the report the derangement of liverfunction is mild and when liver function tests for patientswith different durations of symptoms are examined, there
is no evidence that later presentation is associated withgreater liver function derangement (53).
Therefore, whether SARS-CoV-2 has direct adverse
effects on liver function is currently not known due
to unavailable data on the expression of viral receptor
ACE-2 in hepatocytes. But according to Guan et al.
hepatocytes do express ACE-2 receptors but at very
low concentrations. They also proposed a mechanismof how hepatocytes are infected by SARS-CoV-2.
They reported that upon SARS-CoV-2 infection, theupregulation of ACE-2 in liver tissue is caused bycompensatory proliferation of hepatocytes derived frombile duct epithelial cells, which express ACE-2 at higher
levels than hepatocytes and this might play a role inliver damage in COVID-19 patients (51).

with general symptoms like cough, myalgia and lossof appetite, about 85.6% and 88% of patients sufferedfrom olfactory and gustatory dysfunctions, respectively(63). In another study of 72 COVID-19 patients in Italy,
60 cases had a variable degree of hyposmia with 2 casesof anosmia and 33 cases of hypogeusia and 1 case ofageusia (66) suggesting anosmia and ageusia as initialor unique symptoms after SARS-COV-2 virus infection(64,65). Since neither the olfactory neurons nor the otherbrain cells express the surface receptor ACE-2 for viralentry, further research is urgently needed to solve thisissue of how the olfactory or gustatory related neurons
are affected due to SARS-COV-2 virus infection.
There is an alternative way of SARS-CoV-2 invasion
into the brain of COVID-19 patients described by
Kabbani and Olds (67). According to them, if brain
is susceptible to SARS-CoV-2 infection then persons
will be at high risk if they have a habit of smoking.
Functional interactions between nicotine exposure and
ACE2 expression in lungs and other organ systems
such as heart and kidneys, as well as nicotine and othercomponents of the renin-angiotensin system (RAS)
suggest that smoking can promote COVID-19 cellular
entry through nicotinic acetylcholine receptor (nAChR)
signaling. Kabbani and Olds suggest that regions,which are known to express various types of nAChRs,
are putative sites for primary infection with COVID-19
in the human brain. Interactions between nAChRs and
ACE2 have been studied in several of these regions
including the ventrolateral medulla and smoking maylead to enhanced viral infection through the ability of
nicotine to upregulate nAChRs in regions such as thelungs. In this case, upregulation of nAChRs in either/both neurons and astrocytes could promote greater
viral entry and replication through augmented ACE2
expression in the cell (67). Supporting the notion thatsmokers are at high risk for SARS-CoV infection,
there is another report which demonstrated that ACE2 expression are increased in the small airway epitheliaof smokers (68). Dealing with all of these, SARS-CoV
might infect brain tissue and smokers are at high risk.

BrainThough the invasions of molecules or particles arestrictly regulated into the brain by the blood-brain barrier(BBB), many viruses (from human immunodeficiency
virus type 1 to togaviruses) can escape the BBB
by different mechanisms and enter into the brain(54). The neuroinvasive nature of coronaviruseshas been documented for different members of the
betacoronaviruses such as SARS-CoV (55), MERS-CoV(56), HCoV-229E (57), HCoV-OC43 (58), and mouse
hepatitis virus (MHV) (59). Since coronaviruses use thecell surface receptor protein ACE-2, now the question
arises do cells of the brain express the ACE-2 receptor?
Well, the answer is not known clearly yet but micetransgenic (Tg) for the expression of human ACE-2(hACE-2), called K18-hACE2 mice, were shown to be
extremely susceptible to SARS-CoV with infection of
the lungs and brain in all the experimental mice whichwere infected with intranasal inoculation (60). Later it
was reported that SARS-CoV causes neural death in
the brain of K18-hACE2 mice even in the absence ofencephalitis (61). There is another report shown to have
SARS-CoV RNA polymerase gene in neurons of an
infected person (62) indicating neurons might have theviral receptor ACE-2 but more studies are required tomake sure of the existence of SARS-CoV in neurons.
Several other recent reports described COVID-19
patients experienced anosmia and ageusia, whichmight be due to an invasion of this virus into the brain
causing olfactory and gustatory dysfunction (63-65). In
one study of 417 mild to moderate COVID-19 patients

Conclusion
In conclusion, we may say COVID-19 patients might die
due to lack of oxygen as lungs are suffering from ARDS.
But as the infection progresses within the body, various
other organs are being affected. But it is not yet known,
whether other organs are affected due to the direct attackof this virus or as a consequence of lack of oxygen since
lungs are not working properly or any other unknown
underlying reasons. More extensive research is required
to further rule out these possibilities.
Acknowledgements
We thank department of Biochemistry and Molecular(16)

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Biology, Jahangirnagar University, for their effort tocomplete this study.
Funding: None.

15.

Conflict of Interest: The authors have no conflicts ofinterest to disclose.

16.

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61. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S.
Severe acute respiratory syndrome coronavirus infection
causes neuronal death in the absence of encephalitis inmice transgenic for human ACE2. J Virol. 2008; 82:72647275.
62. Zhang QL, Ding YQ, Hou JL, et al. Detection ofsevere acute respiratory syndrome (SARS)-associatedcoronavirus RNA in autopsy tissues with in situ
hybridization. Di Yi Jun Yi Da Xue Xue Bao. 2003;
23:1125-1127. (in Chinese)
63. Lechien JR, Chiesa-Estomba CM, De Siati DR, etal. Olfactory and gustatory dysfunctions as a clinical(18)

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64.

65.
66.

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presentation of mild-to-moderate forms of the coronavirus
disease (COVID-19): a multicenter European study. Eur
Arch Otorhinolaryngol. 2020; 277:2251-2261.
Moein ST, Hashemian SMR, Mansourafshar B, KhorramTousi A, Tabarsi P, Doty RL. Smell dysfunction: abiomarker for COVID‐19. Int Forum Allergy Rhinol.
2020; 10:944-950.
Lee Y, Min P, Lee S, Kim SW. Prevalence and Durationof Acute Loss of Smell or Taste in COVID-19 Patients. J
Korean Med Sci. 2020; 35:e174.
Vaira LA, Deiana G, Fois AG, Pirina P, Madeddu G,
De Vito A, Babudieri S, Petrocelli M, Serra A, Bussu
F, Ligas E, Salzano G, De Riu G. Objective evaluationof anosmia and ageusia in COVID-19 patients: a singlecenter experience on 72 cases. Head Neck. 2020; 42:12521258.
Kabbani N, Olds JL. Does COVID19 infect the brain?

If so, smokers might be at a higher risk. Mol Pharmacol.
2020; 97:351-353.
68. Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL,
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---Received May 13, 2021; Revised June 13, 2021; Accepted June22, 2021.
*Address correspondence to:
M. Ibrahim Hossain, Department of Biochemistry and Molecular
Biology, Faculty of Biological Sciences, Jahangirnagar
University, Savar, Dhaka-1342, Bangladesh.
E-mail: ibrahim_bmb@juniv.edu(19)

Brief Report

GHM Open. 2021; 1(1):20-27.
DOI: 10.35772/ghmo.2021.01007

Survey of motor function and activities of daily living in hemophilia
patients with HIV
Kazuko Kikuchi1,2, Toshiharu Komachi2, Yoshinori Honma2, Tomoyuki Endo3, Keiko Watabe4, Yoshiyuki Yokomaku5,
Chieko Hashiba6, Masahiro Yamamoto7, Yukiko Nagayo8, Toshihiro Ito9, Junji Imamura9, Tomoko Suzuki10,
Junko Fujitani2,*
1

Japan Foundation for AIDS Prevention, Tokyo, Japan;
Department of Rehabilitation Medicine, National Center for Global Health and Medicine, Tokyo, Japan;
3
Department of Hematology, Hokkaido University Hospital, Sapporo, Japan;
4
Department of HIV Infection Medical Support Center of Hokkaido University Hospital, Hokkaido, Japan;
5
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan;
6
Department of HIV Infection Medical Support Center of National Hospital Organization Nagoya Medical Center, Aichi, Japan;
7Internal Medicine, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan;
8Department of HIV Infection Medical Support Center of National Hospital Organization Kyushu Medical Center, Fukuoka, Japan;
9Department of Hematology, Sendai Medical Center, National Hospital Organization, Miyagi, Japan;
10
HIV/AIDS Comprehensive Medical Center of Sendai Medical Center, Miyagi, Japan.
2

Abstract: This study aimed to clarify the current status of motor function, activities of daily living (ADL), andinstrumental ADL (IADL) in hemophilia patients with HIV infection due to treatment with non-heat-treated blood
products as they now enter middle and old age. Participants were 70 such patients (mean age, 52.1 years), and theirrange of motion (ROM), muscle strength, extremity circumference, walking speed, ADL, and IADL were evaluatedat checkups of motor function, ADL, and IADL that were held during patients' association meetings. Results showedthat ROM was limited in all joints. Ankle dorsiflexion, hip abduction, and shoulder abduction were particularly
restricted. Decreased muscle strength was most frequent in ankle plantarflexion, followed by hip extension. The
proportion of patients with walking speed and grip strength below reference values increased with age. Walking
speed was 73.9-110.9% of reference values. Factors affecting walking speed were knee flexion, ankle dorsiflexion,
and hip extension muscle strength. Grip strength was 58.0-83.5% of reference values. Thigh girth most greatly
differed between the patients and healthy individuals. Among the ADL items, "standing up from the floor" wasreported as "difficult"/"cannot do" by 45.7% of the patients. The most common IADL problem was "putting away
futons", which 17.2% responded was "difficult"/"cannot do". Parents were the most common helpers with householdtasks (12.9%). "Decreased muscle strength/limited ROM" was the most frequently reported troublesome problem(35.7%). These results reveal the current status of motor function, ADL, and IADL limitations in hemophilia patientswith HIV.
Keywords: hemophilia patients with HIV, aging, ADL, IADL, motor function, multicenter study

Introduction

life expectancy, hemophilia patients are now entering
middle to old age for the first time. At the same time,advances in the treatment of HIV infection havedramatically improved its prognosis and life expectancy(5). On average, hemophilia patients with HIV infection
caused by non-heat-treated blood coagulation factor
products are entering their fifties (6).
Although some previous studies have investigatedmotor dysfunction and ADL in hemophilia patientsentering middle and old age, there have been no
multicenter studies. Moreover, no report has specificallyfocused on patients affected by adverse events due to

In Japan mostly between 1982 and 1985, about 2,000
hemophilia patients, or about 40% of these patients,
were infected with human immunodeficiency virus(HIV) due to treatment with non-heat-treated blood
products (1). Since the 1980s, advances in blood
coagulation factor products and home self-injection
therapy have dramatically improved the prognosis andquality of life (QOL) of hemophilia patients, and theaverage age of death has become almost the same asthat of the general male population (2-4). With longer(20)

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blood products. Therefore, for the first time in Japan,
in this study we investigated the current status ofmotor function, activities of daily living (ADL), andinstrumental ADL (IADL) in hemophilia patients with
HIV infection due to contaminated blood products asthey enter middle and old age, by performing checkups
of motor function, ADL, and IADL during patients'
association meetings that were held in Hokkaido,
Sendai, Tokyo, Nagoya and Beppu between August andDecember 2019.

the lower leg and the thigh at 10 cm proximal from theupper edge of the patella were measured.

Patients and Methods

IADL was evaluated in a one-on-one interview. Patientswere asked about self-injection therapy for hemophilia,
in addition to putting away futons, laundry, cooking,moving furniture, cleaning, shopping, and using aphone, with reference to the Frenchay Activities Index
developed by Holbrook et al. (8). The response options
for each question were "can do without problems","difficult", and "cannot do".

ADL
ADL was evaluated in a one-on-one semi-structured
interview using questions from an interview guide withthe scale developed by Goto et al. (7).
IADL

Participants in this multicenter study were 70
hemophilia patients with HIV infection due tocontaminated blood products who were members of apatients' association and who provided written informed
consent.
Basic attributes
Sex and age of the patients were examined.

Interview survey on the person who mainly performs
household tasks

Joint range of motion (ROM)We asked who mainly performs household tasks.

Bilateral passive shoulder flexion/abduction, elbow
flexion/extension, forearm pronation/supination, hip
flexion/abduction/extension, knee flexion/extension,and ankle dorsiflexion/plantarflexion were evaluated.

Interview survey on things that are troublesome

Muscle strength

Analysis

The manual muscle test (MMT) was evaluated forbilateral passive shoulder flexion/abduction, elbow
flexion/extension, forearm pronation/supination, hip
flexion/abduction/extension, knee flexion/extension,and ankle dorsiflexion/plantarflexion, while considering
the burden on the joints.

The mean and standard deviation were calculated forjoint range of motion. Muscle strength was measured
using the MMT, and the proportions of the patientswith each score from 1 to 5 were obtained. The
individual means of the right and left grip strengths
were calculated and the proportion of patients withgrip strength below age-group reference values (9) was
determined. The proportion of patients with walking
speed below age-group reference values (10) was also
determined. To investigate the factors affecting walking
speed, we performed multiple regression analysis
with walking speed as the objective variable and joint
ROM, muscle strength of the lower extremities, andgrip strength as explanatory variables. Patients weredivided into 10-year age groups, and the mean girthmeasurements were compared with those of healthy
individuals. Ratios relative to standard values were
determined for grip strength, walking speed, and girthmeasurements. The answers for the ADL and IADL
items were divided into three groups according to
response ("can do without problems", "difficult", and"cannot do") and the proportion of patients in eachgroup was determined for each question. A simple
tabulation was performed for the answers to "things thatare troublesome" and "the person who mainly performs

Patients were asked to list up to three things that they
currently find troublesome.

Grip strength
Grip strength was measured twice on each side while
the patient was seated with the elbow extended, with anapproximately 30-s rest between measurements.
Walking
Patients were instructed to walk quickly for 10 m,
which was timed and analyzed.
Girth measurements
The girth of the bilateral upper and lower extremities
was measured using a tape measure in a sitting positionat the end of an examination table and in the supine
position. The maximum girth of the upper arm andforearm in elbow extension and the maximum girth of(21)

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household tasks". SPSS version 26 (IBM Corp.,
Armonk, NY) was used for analysis. The significancelevel was set at 5%.

ROM values were below the reference values for all
joints evaluated. Ankle dorsiflexion, hip abduction, andshoulder abduction showed especially restricted ROM.

Ethical considerations

Muscle strength

This study was approved by central review at the
Ethics Review Committee of the National Center
for Global Health and Medicine (approval number,
NCGM-G-003242-00), and appropriate ethics
procedures were followed at each participating facility.

Table 2 shows the muscle strength results. Muscle
strength was most frequently decreased in ankle
plantarflexion, with MMT scores of 3 and 2 in 8.5%
and 27.1% of the patients, respectively. Hip extension
was the second most frequently decreased, with MMT
scores of 3 and 2 each in 5.3% of the patients, followedby hip abduction, with MMT scores of 3 and 2 in 3.0%
and 3.7% of the patients, respectively.

Results and Discussion
Basic attributes

Grip strength

Patients were all male, with a mean age of 52.1 (standard
deviation, 9.08) years.

Table 3 shows the results for grip strength. Comparedwith healthy individuals by age group, the proportionsof patients with grip strength below the reference
values were 75.0% for patients in their 30s and 96.4%
for those in their 40s. All patients in their 50s and 60s

Joint ROM
Table 1 shows the results for joint ROM. Patients' mean

Table 1. Range of motion in the study population of 70 hemophilia patients with HIV infection from contaminated blood
products
Motionn

Mean (deg)SD (deg)

Ratio relative to the reference value (%)

Shoulder flexion
Shoulder abduction
Elbow flexion
Elbow extension
Elbow pronation
Elbow supination
Hip flexion
Hip extension
Hip abduction
Knee flexion
Knee extension
Ankle dorsiflexion
Ankle plantarflexion

138
138
138
138
138
138
138
138
138
138
138
138
138

147.2
143.3
125.6
−22.4
73.2
79.4
105.8
14.4
32.6
116.1
−8.5
2.1
35.1

20.6
30.5
19.6
22.3
18.2
24.9
18.2
13.5
13.4
31.5
13.3
11.0
11.6

81.8
79.6
86.6
87.2
81.3
88.2
84.6
96.0
72.5
89.3
95.3
10.4
78.0

Values are the percentage of the target joints. Ratio relative to the reference value (%) = [(mean measurement value of the target joint)/(reference
ROM of the target joint)] × 100. SD, standard deviation.

Table 2. Muscle strength measurements
Muscle strength (MMT)

n

5

4

3

2

1

MotionShoulder flexion
Shoulder abduction
Elbow flexion
Elbow extension
Forearm pronation
Forearm supination
Hip flexion
Hip abduction
Hip extension
Knee extension
Ankle dorsiflexion
Ankle plantarflexion

140
138
138
126
138
140
137
134
133
133
135
118

90.7%
88.4%
91.3%
85.7%
84.1%
82.9%
76.6%
73.9%
66.2%
85.0%
85.9%
44.1%

7.9%
9.4%
8.0%
13.5%
15.9%
16.4%
21.2%
19.4%
23.3%
12.8%
11.9%
20.3%

1.4%
2.2%
0.7%
0.8%
0.0%
0.7%
2.2%
3.0%
5.3%
2.3%
2.2%
8.5%

0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
3.7%
5.3%
0.0%
0.0%
27.1%

0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
0.0%
0.0%

Values are the percentage of target joints. MMT, manual muscle test.

(22)

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Table 3. Grip strength and walking speed
Grip strength
Age

30s
40s
50s
60s

Fast walking speednMean (kg)

Ratio relative to thereference value (%)

Patients below thereference value (%)

n

Mean (m/min)

Ratio relative to thereference value (%)

Patients below thereference value (%)

4
28
23
14

39.6
30.7
28.3
24.2

83.5
65.6
62.3
58.0

75.0
96.4
100.0
100.0

4
27
21
13

133.1
102.6
89.9
85

110.9
85.5
78.2
73.9

25.0
77.8
90.5
100.0

Grip strength ratio relative to the reference value (%) = [(mean grip strength of all patients)/(reference value)] × 100. Fast walking speed ratio
relative to the reference value (%) = [(mean fast walking speed of all patients)/(reference value)] × 100.

Table 4. Girth measurements
Upper arm
Ratio
relative Upper arm
Right Leftto thereference(cm) (cm)reference value (cm)
value

Age

30s
n=2
40s
n = 13
50s
n=9
60s
n=5

Mean
SD
Mean
SD
Mean
SD
Mean
SD

29.5
0.50
25.9
3.59
25.8
3.82
24.8
4.32

28.8
0.25
26.5
4.19
26.7
4.19
24.8
5.27

—
90.3%
90.8%
79.4%

—
—
29.0
2.6
28.9
2.4
28.1
2.2

Forearm

ThighLower leg

Right Left(cm) (cm)Ratio
relative
Thigh
Right Leftto thereference(cm) (cm)reference value (cm)
value

Ratio
relative Lower leg
Right Leftto thereference(cm) (cm)reference value (cm)
value

27.0
0.50
25.1
2.10
23.9
2.96
23.6
1.98

25.8
0.75
24.7
2.16
24.4
2.26
23.5
1.84

47.8
2.25
42.4
8.46
38.0
5.27
38.2
3.23

47.3
0.25
41.3
7.25
39.0
4.52
36.3
4.46

—
84.5%
78.7%
88.3%

—
—
49.6
3.80
48.9
3.80
46.9
3.50

36.5
1.50
33.5
4.81
30.8
2.69
31.2
3.80

37.3
0.75
32.8
4.75
32.0
3.54
30.4
4.17

—
89.7%
84.8%
86.6%

—
—
36.9
2.70
37.0
2.70
35.6
2.60

Upper arm girth was measured in elbow extension. We were unable to obtain a reference value for patients in their 30s. Reference values forpatients in their 40s, 50s, and 60s were taken from reference 11. Ratio relative to the reference value (%) = [(mean value of the target site of all
patients)/(reference value of the target site)] × 100. Ratios relative to the reference values (%) were obtained for the mean of the left and rightsides. SD, standard deviation.

had grip strength below the reference values. Muscle
strength relative to the reference values was 83.5%,
65.6%, 62.3%, and 58.0% for patients in their 30s, 40s,
50s, and 60s, respectively.

measurements taken. Mean values were highest forpatients in their 30s at all measurement sites and tended
to decline with age. Compared with reference valuesof healthy individuals in their 40s and 60s (11), themeasured values were below the reference values at allsites in all age groups. In particular, the difference was
the largest for thigh girth, at 84.5% of the reference
value for patients in their 40s, 78.7% in their 50s, and77.4% in their 60s.

Walking speed
Table 3 shows the results for walking speed. Walking
speeds by age group were below reference values ofhealthy individuals for 25% of patients in their 30s,
77.8% of those in their 40s, 90.5% of those in their50s, and all patients in their 60s. Measured values ofthe patients in their 30s were above the reference value
with a ratio relative to the reference value of 110.9%,
while the ratios were 85.5%, 78.2%, and 73.9% forpatients in their 40s, 50s, and 60s, respectively.
Factors contributing to walking speed were knee
flexion ROM (standardized coefficient, 0.446), hip
extension ROM (0.418), and ankle dorsiflexion ROM(0.216).

ADL
Table 5 shows the ADL results. The most frequentdifficulty in ADL was "standing up from the floor",
which 64.3% of the patients reported as "difficult"or "cannot do". The second most common difficultyin ADL was "squatting", which 62.9% reported was"difficult" or "cannot do". This was followed by"climbing up and down stairs", which was either"difficult" or "cannot do" for 54.3% of the patients.

Girth measurements

IADL

Table 4 shows the results for the four girth

Table 5 shows the results for IADL. In terms of(23)

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Table 5. ADL and IADLADLStanding up from the floor
Squatting
Climbing up and down stairs
Sitting on the floor
Walking on a slope
Clipping toenails
Washing face with both hands
Buttoning and unbuttoning top button
Washing body
Putting on and taking off socks
Walking without a cane
Sitting on a chair
IADL
Putting away futons
Laundry
CookingMoving furniture
Self-injection
Cleaning
Shopping
Using a phonen

Can do without problem

DifficultCannot do

Difficult/cannot do

70
70
70
70
70
70
70
70
70
70
70
70

35.7%
28.6%
41.4%
38.6%
47.1%
64.3%
72.9%
74.3%
74.3%
74.3%
75.7%
88.6%

45.7%
22.9%
51.4%
24.3%
40.0%
28.6%
12.9%
22.9%
24.3%
18.6%
10.0%
10.0%

18.6%
40.0%
2.9%
21.4%
2.9%
5.7%
12.9%
2.9%
2.9%
1.4%
2.9%
0.0%

64.3%
62.9%
54.3%
45.7%
42.9%
34.3%
25.7%
25.7%
25.7%
25.7%
21.4%
10.0%

70
70
70
70
70
70
70
70

55.7%
74.3%
74.3%
78.6%
82.9%
88.6%
90.0%
97.1%

5.7%
12.9%
10.0%
5.7%
2.9%
5.7%
4.3%
1.4%

22.9%
8.6%
11.4%
8.6%
11.4%
4.3%
5.7%
0.0%

28.6%
21.4%
21.4%
14.3%
14.3%
10.0%
10.0%
1.4%

Values are the percentage of patients. ADL, activities of daily living; IADL, instrumental activities of daily living.

difficulties in IADL, 5.7% of the patients responded
that "putting away futons" was either "difficult" or"cannot do". Next was "laundry", with 12.9% and8.6% responding "difficult" or "cannot do", and then"cooking" at 10% and 11.4%, respectively.

there are 6,596 hemophilia patients in Japan, 706 ofwhom are living with HIV infection due to receiving
contaminated blood products (6). This study involved
70 patients, representing 10% of this population.
In a multicenter study, Siboni et al. investigatedthe elbow, knee, and ankle joint function of 39 middle
aged and older hemophilia patients (mean age, 68
years; range, 65-78 years) (12) and found hemophilicarthropathy in 37 of the patients. Goto et al. also
investigated joint function in 31 hemophilia patients(mean age, 38.3 years; range, 16-61 years) targetingthe elbow, knee, and ankle joints and found end-stage
arthropathy in 60.2% (13). Our study, which also
included the shoulder and hip joints, showed that thesejoints and the elbow, knee, and ankle joints all had
limited ROM. In particular, ankle dorsiflexion showed
severely limited ROM at 10.4% of the reference value.
The next most severely affected joint motions were
hip abduction at 72.5% of the reference value and thenshoulder abduction at 79.6%. Our study is the first to
reveal limited ROM in the hip and shoulder joints.
Some previous studies have investigated muscle
strength in patients with hemophilia (13-15) but werelimited to the knee joint. The present study investigatedmuscle strength around the shoulder, elbow, hip, knee,
and ankle joints, finding that decreased muscle strength
was most frequently seen in ankle plantarflexion,
followed by hip extension and hip abduction. The
decline in muscle strength around the ankle joints
was attributed to immobility of the joints caused byintra-articular bleeding (pain and swelling), given theseverely limited ROM relative to the reference values ofankle dorsiflexion (10.4%) and plantarflexion (78.0%).

Persons who mainly perform household tasks
The persons who mainly performed household tasks
were the patients themselves (38.6%), followed bytheir spouses (25.7%), parents (12.9%), both patientsand spouse (8.6%), both patients and parents (4.3%),
siblings (2.9%), and parents- or siblings-in-law (1.4%).
Things that are troublesome
The most frequent responses for things that are
troublesome were "physical changes (decline in muscle
strength and limited joint ROM" (35.7%), followed by"pain" (31.4%), "parents" (20%), and then "limitationsof ADL/IADL" and "difficulty moving" (both 18.6%).
Only 1 patient listed bleeding.
Discussion
Hemophilia patients in middle and old age, whohave experienced the time when there was no regularreplacement therapy to suppress bleeding as can bedone with current therapy, often have limited ROM,
joint instability, joint contracture, muscle atrophy,
and synovitis (3). This is the first multicenter study
to investigate motor function and ADL in hemophilia
patients with HIV infection. As of May 31, 2019,(24)

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The decrease in hip joint ROM was attributed to pain
and immobility caused by arthropathy, given that theflexion and extension ROM were 84.6% and 96.0% of
the reference values, respectively.
Because bleeding is less common in the wrist jointcompared with other joints in hemophilia (16), we
did not include it in the evaluation of ROM or muscle
strength in this study. However, grip strength is anindex of muscle strength and is also correlated withcardiopulmonary function (17); thus, we evaluated grip
strength as an index of general physical function inthis study. The result showed that grip strength of thepatients in their 30s was 83.5% of the reference value,
which decreased with age. The grip strength of those in
their 60s was 58.0% of the reference value, indicating
deterioration of physical function with age. In a study
by Goto et al. measuring grip strength, the mean value
was 31.9 kg in patients with mean age of 38.3 years(15), which is lower than the mean grip strength of
our patients in their 30s of 39.6 kg. The reason for thehigher value of grip strength in our study is thought tobe selection bias. The patients in the study by Goto etal. were outpatients, whereas our patients participatedin the motor function, ADL, and IADL checkups thatwere held at patients' association meetings and thus
could be presumed to have better motor function and to
more actively exercise.
No conventional cross-sectional study of hemophilia
patients has examined walking speed. Given thatstudies of healthy individuals and stroke patients havedemonstrated the importance of being able to walkquickly to being able to walk practically (18,19), we
evaluated fast walking. We found the proportionsof patients in their 40s, 50, and 60s who could walkquickly were 85.5%, 78.2%, and 73.9% of the reference
values, respectively. These data indicate practicalwalking ability may decrease with age in these patients.
Knee flexion ROM, ankle dorsiflexion ROM, and hip
extension muscle strength were identified as factors
affecting walking speed. The hip extensor muscles
play a role in supporting body weight from initial
ground contact to mid-stance (20). Hip extensor muscle
weakness was frequently seen in the patients in thisstudy, suggesting that it may have also affected thewalking speed.
Siboni et al. (13) and Stephensen et al. (21) havereported that muscular atrophy is present in hemophilia
patients. However, no study has reported the four girthmeasurements that we examined in these patients, andboth Canaro et al. (2) and Stephensen et al. (22) havepointed out that there has been no quantitative studyof muscle atrophy. Here, we measured the girth of
the upper arm, forearm, and lower leg and thigh, andcompared the values with those of healthy individuals
in 10-year age groups (11). The values were smallerin our patients than in healthy individuals at allmeasurement sites, and the difference was largest in thethigh. In addition, a notable finding was that the mean
girth of the thigh in patients in their 50s and 60s was
38.5 cm and 37.2 cm, respectively, which was about thesame as the standard values of healthy individuals.
Siboni et al. also evaluated ADL in a multicenter
study (13) but did not evaluate items related to Japanese
lifestyle. Therefore, we used a scale developedby Goto et al. (7). Many patients responded thatmovements requiring deep flexion or heavy loading of
the lower limbs, such as "standing up from the floor","squatting", "climbing up and down stairs", "sitting
on the floor", and "walking on a slope" were either"difficult" or "cannot do", consistent with the resultsof Goto et al. (14) and Iwata et al. (22). More than
60% of the patients in the present study responded thatthe movements of "standing up from the floor" and"squatting" were "difficult" or "cannot do". The mean
age of patients of this study was 52 years, which meansthat aspects of the Japanese lifestyle are difficult forthese patients although they are only in their 50s.
Siboni et al. (12) examined IADL in patients withhemophilia, but their study was conducted outside
Japan. In the present study, "putting away futons"
was found to be the most difficult activity, revealingdifficulty in Japanese lifestyle, as with ADL. Moreover,"laundry" and "cooking" were listed as difficult
activities, showing that patients have difficulties in
activities related to food, clothing, and housing, which
are necessities of life.
In this study, we also included "self-injection",
which is necessary for treatment, as an IADL item. The
result showed that 14.3% of the patients answered that
"self-injection" was "difficult" or "cannot do". As thispatient population ages, it can be expected that ROM
will worsen and presbyopia will develop, so the numberof patients who have difficulties in "self-injection" mayincrease further in the future.
The results revealed that a "decrease in muscle
strength and limitation of ROM" was the most frequent
response, at 35.7%, for the most troublesome problem,
followed by "pain" (31.4%). On the other hand, only 1
patient listed "bleeding". These results reflect that the
problem of bleeding itself is being solved with advancesin treatment methods, but that joint dysfunction andpain are issues that remain to be addressed.
The study showed that the person who mainly
performs household tasks is someone other than thepatient in more than half of the cases. Notably, for12.9% of these patients, the primary helper was theirparents. Given that "pain", "parents", and "limitation in
ADL/IADL" were some of the most common problems,
we can surmise that many patients have pain and relyon their parents for ADL/IADL.
Limitations
Some limitations of this study include that we are(25)

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unable to determine whether the decline in motor
function revealed in this study was due to hemophilia
or HIV infection. The reason for this is that theprevious studies referred to in this report also included
some hemophilia patients with HIV infection, ranging
from 3.0% (13) to 38.7% (14), and it is not possible
to compare our results with those of the previous
studies with respect to the presence or absence of
HIV infection. In addition, because the patients in thisstudy voluntarily participated in patients' meetings
where motor function, ADL, and IADL checkups were
offered, our study population may have been biased
toward patients with relatively good motor function andthose who are proactive in maintaining or improving
motor function. The patients in this study accounted forabout 10% of hemophilia patients with HIV infection
due to contaminated blood products in Japan. A study
including all of these patients might show even greater
impairment of motor function and ADL. Based on
the above, it is necessary in the future to survey morepatients with hemophilia and compare those with andthose without HIV infection to accurately understandthe condition of motor function and ADL/IADL inthese patients.

3.
4.
5.

6.

7.
8.
9.

10.

Conclusion
11.

Evaluation of hemophilia patients with HIV infection
due to contaminated blood products who participated incheckups of motor function, ADL, and IADL that were
held during patients' association meetings revealed thatthey had locomotor disorders, impairment in functions
required for ADL, and pain even though they werefairly young, at a mean age of 52 years, and that they
were in the worrying situation that maintenance of daily
life may become difficult in the future depending on
their parents' condition.

12.

13.

Acknowledgements
We thank all the staff members who participated andcontributed to the patients' meetings.

14.

Funding: This study was supported by a Ministry of
Health, Labour and Welfare Policy Research Grant
and the AIDS Policy Research Project (H30-AIDSDesignated-002).

15.
16.

Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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2.

17.

Kimura S. Analyses and resolution of challenges to which
HIV-infected hemophiliacs are facing, by a group study
with participaton of patients. Antibiot Chemother. 2014;
30:130-138. (in Japanese)
Canaro M, Goranova-Marinova V, Berntorp E. The

18.

(26)

ageing patient with haemophilia. Eur J Haematol. 2015;
94 Suppl 77:17-22.
Angelini D, Sood SL. Managing older patients withhemophilia. Hematology Am Soc Hematol Educ
Program. 2015; 2015:41-47.
Shapiro S, Makris M. Haemophilia and ageing. Br J
Haematol. 2019; 184:712-720.
Nasi M, De Biasi S, Gibellini L, Bianchini E, Pecorini S,
Bacca V, Guaraldi G, Mussini C, Pinti M, Cossarizza A.
Ageing and inflammation in patients with HIV infection.
Clin Exp Immunol. 2017; 187:44-52.
Ministry of Health, Labour and Welfare. Nationwide
Survey on Coagulation Disorders 2019. Japan Foundation
for AIDS Prevention, Tokyo, Japan, 2020; pp 3-4. (inJapanese)
Goto M, Takedani H, Kawama K, Nitta O. Developmentof an activity scale for patients with hemophilia. J Jpn
Academ Health Sci. 2014; 16:184-189. (in Japanese)
Holbrook M, Skilbeck CE. An activities index for use
with stroke patients. Age Ageing. 1983; 12:166-170.
e-Stat. Physical fitness and athletic ability survey FY
2017. https://www.e-stat.go.jp/stat-search/files?page=1&layout=datalist&toukei=00402102&tstat=0000010888
75&cycle=0&tclass1=000001119456 (accessed October27, 2020). (in Japanese)
Ministry of Health, Labour and Welfare. Exercise
guidelines for health promotion 2006. ~To prevent
lifestyle-related disease~ Exercise guide 2006 (Draft).
https://www.mhlw.go.jp/shingi/2006/07/dl/s0719-3c.pdf(accessed October 27, 2020). (in Japanese)
National Institute for Longevity Sciences. Longitudinal
study of aging. https://www.ncgg.go.jp/cgss/department/
ep/monograph7thj/index.html (accessed October 27,2020). (in Japanese)
Siboni SM, Mannucci PM, Gringeri A, Franchini M,
Tagliaferri A, Ferretti M, Tradati FC, Santagostino E, vonMackensen S; Italian Association of Haemophilia Centres(AICE). Health status and quality of life of elderly
persons with severe hemophilia born before the advent ofmodern replacement therapy. J Thromb Haemost. 2009;
7:780-786.
Goto M, Takedani H, Nitta O, Kawama K. Associations
between joint function, activities of daily living, andhealth-related quality of life in patients with hemophilia.
Rigakuryoho Kagaku Sci. 2015; 30:413-419. (inJapanese)
Fearn M, Hill K, Williams S, Mudge L, Walsh C,
McCarthy P, Walsh M, Street A. Balance dysfunction in
adults with haemophilia. Haemophilia. 2010; 16:606-614.
Goto M, Takedani H, Nitta O, Kawama K. Joint function
and arthropathy severity in patients with hemophilia. J
Jpn Physic Ther Assoc. 2015; 18:15-22.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key
NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN,
Mulder K, Poon MC, Street A; Treatment Guidelines
Working Group on Behalf of The World Federationof Hemophilia. Guidelines for the management ofhemophilia. Haemophilia. 2013; 19:e1-e47.
Wu ZY, Han YX, Niu ME, Chen Y, Zhang XQ, Qian
HY. Handgrip strength is associated with dyspnoea andfunctional exercise capacity in male patients with stable
COPD. Int J Tuberc Lung Dis. 2019; 23:428-432.
Schmid A, Duncan PW, Studenski S, Lai SM, Richards
L, Perera S, Wu SS. Improvements in speed-based gaitclassifications are meaningful. Stroke. 2007; 38:2096-

GHM Open. 2021; 1(1):20-27.

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2100.
19. Bohannon RW. Comfortable and maximum walking
speed of adults aged 20-79 years: Reference values anddeterminants. Age Ageing. 1997; 26:15-19.
20. Sano K, Iida T, Ebisu S, Takahashi Y, Ito M, Kado N.
Physical therapy using a weight-transfer exercise for apatient with femoral neck fracture: A case report. J Kansai
Phys Ther. 2017; 17:127-131. (in Japanese)
21. Stephensen D, Rodriguez-Merchan EC. Orthopaedic comorbidities in the elderly haemophilia population: A
review. Haemophilia. 2013; 19:166-173.
22. Iwata N, Hachisuka K, Tanaka S, Naka Y, Ogata H.

Measuring activities of daily living among haemophiliacs.
Disabil Rehabil. 1996; 18:217-223.
---Received April 28, 2021; Revised June 4, 2021; Accepted June
14, 2021.
*Address correspondence to:Junko Fujitani, Department of Rehabilitation Medicine,National Center for Global Health and Medicine, 1-21-1
Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
E-mail: jufujita@hosp.ncgm.go.jp(27)Communication

GHM Open. 2021; 1(1):28-30.
DOI: 10.35772/ghmo.2021.01024

Trends in prostate cancer diagnosis during the COVID-19 crisis: A
report from one high-volume Japanese center
Daisuke Yamada1,*, Taketo Kawai1, Yusuke Sato1, Yuta Yamada1, Yoshiyuki Akiyama1, Jimpei Miyakawa1,
Sayuri Takahashi2, Haruki Kume1
1
2

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;
Department of Urology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract: Self-isolation to prevent the spread of the novel coronavirus SARS-CoV-2 began in April 2020. As a result,the number of prostate needle biopsies taken at our hospital for suspicion of prostate cancer decreased by 30.5%, from
403 in 2019 to 280 in 2020. The number of diagnoses of prostate cancer decreased by 35.4% from 189 to 122. Highrisk and intermediate-risk prostate cancers were 36.5% and 49.7%, respectively, in 2019. Assuming that this situationin our hospital reflects events nationwide, approximately 32,575 (high-risk; 11,890, intermediate risk; 16,189) patientsannually would be suffering delays in diagnosis. Furthermore, > 90% of the decrease are curable cases in their 60s and
70s, with prostate specific antigen levels of 30 ng/mL or less, with stage T2, and N0M0. Widely aware that more than
30,000 prostate cancers might be overlooked nationwide in 2020, we recommend establishing a health checkup systemwith infection control and undergoing early testing.
Keywords: coronavirus, biopsy, SARS-CoV-2, stage, prostate-specific antigen (PSA), age

A state of emergency was declared in Japan on April
7, 2020, due to the rapid nationwide spread of thenovel coronavirus SARS-CoV-2. Leaving home for
unnecessary or non-urgent purposes was restricted.
Employees teleworked from home, and schools adopted
online lessons. Accordingly, the number of outpatientsat our hospital decreased by 14.4%, from 683,275 in2019 to 585,187 in 2020; the number of outpatients in
our Department also decreased by 13.4%, from 24,896
to 21,567. Except for symptomatic cases, those withextremely high prostate-specific antigen (PSA), andthose with multiple metastases, patients solely with high
PSA tended to avoid medical consultation due to thestay-at-home rules. Furthermore, non-urgent prostatebiopsy was not prioritized, because of the restrictionof hospital medical service capacity under pandemic
conditions. Here, we analyze the number and breakdownof prostate needle biopsy cases in 2019 and 2020, in
order to provide an estimate of the indirect influence ofthe novel coronavirus SARS-CoV-2 crisis nationwide on
the clinical management of prostate cancer.
Patients who underwent prostate needle biopsy
between January 1, 2019, and December 31, 2020
were reviewed. Biopsies for known prostate cancer
cases (i.e., protocol biopsy on active surveillance) were
excluded from this analysis. Written informed consent
was obtained for the use of patients' medical information(Ethics Committee, Faculty of Medicine, University ofTokyo; #3124). The pre-biopsy PSA value was set as
the highest value within the six months prior to biopsy.
T staging was performed based on magnetic resonanceimaging, digital examination, and needle prostate biopsy
results according to the Union for International Cancer
Control TNM classification of malignant tumors 8thedition (1). Computed tomography and bone scintigraphy
were used for detecting regional lymph node metastasis
and distant metastasis. Statistical analysis was performed
using JMP pro ver.15.2.1, and Fisher's exact test wasused for stratified analysis.
We identified a total of 683 prostate needle biopsies
taken on suspicion of prostate cancer, 403 cases in2019 and 280 cases in 2020, representing a decrease of
123 cases (30.5%). The number of patients in their 60s
and 70s decreased by 36.5%, from 312 cases to 198
cases, accounting for 92.6% of the total decrease andsignificantly less in 2020 compared to 2019 (p = 0.0296,
Figure 1). The median (interquartile range) pre-biopsy
PSA level (ng/mL) increased from 6.9 (5.1-11.1) in 2019
to 7.1 (5.3-11.1) in 2020. The number of cases with apre-biopsy PSA level (ng/mL) of 30.0 or less decreasedby 31.7% from 384 to 262, accounting for 99.1% of thetotal decrease (Figure S1, https://www.ghmopen.com/site/
supplementaldata.html?ID=24). In contrast the numberof cases with PSA higher than 30.0 ng/mL was similar,
19 in 2019 and 18 in 2020 (not significant, p = 0.210).
The number of diagnoses of prostate cancer(28)

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Figure 1. Numbers of prostate needle biopsies by age. The number of patients in their 60's and 70's decreased by 58 and 56,
accounting for 92.6% of the total decrease. *Significantly less in 2020 compared to 2019 (p = 0.0296).

Figure 2. Numbers of prostate cancer diagnoses by T stage. Cases at T2a, T2b, and T2c decreased by 12, 21, and 33 cases,
accounting for 98.5% of the total decrease. *Significantly less in 2020 compared to 2019 (p = 0.0172).

decreased by 35.4% from 189 to 122. Cases at T2 stage
decreased by 45.2%, from 146 to 80, whereas T3 andT4 cases slightly decreased from 17 to 13 (Figure 2).
The total number of patients at T2 stage decreased
by 66, accounting for 98.5% of the total decrease andsignificantly less in 2020 than 2019 (p = 0.0172).
Finally, the number of patients with N0 and M0 disease
decreased by 36.9% from 175 to 111, accounting for95.5% of the total decrease, but this was not significant(p = 0.379, Figure S2, https://www.ghmopen.com/site/
supplementaldata.html?ID=24).
In 2020, the number of biopsies taken decreased by
30.5% compared to 2019, with > 90% of the decreaseaccounted for by patients in their 60's and 70's and withpre-biopsy PSA levels of 30 ng/mL or less. The numberof prostate cancer diagnoses decreased by 35.4%, morethan 90% of which were T2 and N0M0. In contrast, there
were few changes in advanced cases including those with
PSA over 30 ng/mL, with stages T3 or more, or withnodal and/or distant metastasis. These cases might be
symptomatic, or might have had to have a biopsy, evenduring the coronavirus crisis. In our Department, thenumber of all outpatients in their 60's and 70's decreased
by 13.0%, similar to the decrease of 13.4% across allages, while the number of patients at this age undergoingprostate needle biopsy decreased greatly.
One Italian study on colorectal cancer screening
reported that the number of tests during lockdown
due to the pandemic was reduced by a quarter, but theprobability of finding cancer increased from 1% to 8%(2). In that study, many of the cases examined during
lockdown were high-risk, including those with subjective
symptoms such as bloody stools and those with a family
history. In contrast, the cancer detection rate in our report
was similar before and after lockdown at 46.8% in 2019and 43.5% in 2020. This might result from the lower
accuracy of prostate biopsy compared with colonoscopy.
According to the National Cancer Center Institute(29)

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in Japan, the annual number of cases of prostate cancer
is 92,021 in 2018 (3). Prostate cancer diagnoses at
our hospital decreased by 35.4% from 2019 to 2020.
Assuming that this rate is the same across the nation,
the number of patients with a delayed diagnosis of
prostate cancer will reach 32,575. The number of highrisk (Gleason Score 8 and above) and intermediaterisk cases (Gleason Score 7) was 69 (36.5%) and 94(49.7%), respectively, of prostate cancer diagnoses at
our hospital in 2019. Assuming that this rate is the sameacross the nation, 11,890 are likely to be in the high-risk
group and 16,189 in the intermediate-risk group. Several
studies have reported that the time patients can wait fortreatment of prostate cancer should be 2.5-6 months in
the high-risk group and 9-24 months in the intermediaterisk group (4-11).
Delays in diagnosis occurred worldwide. De
Vincentiis et al. (12) reported that prostate cancer andbladder cancer diagnoses fell in 2020 by 75% and66%, respectively, compared with the average number
recorded in 2018 and 2019. There is also a concern thatcases of more advanced prostate cancer will increase
because health examinations and medical institutional
consultations were postponed due to the coronavirus
crisis.
One limitation of this research is that it is notnecessarily applicable to Japan as a whole, and the worldin general, because it involved only a single facility, asmall number of cases, and was a retrospective study. No
prospective study reports have been found on treatment
delays, and bias is unavoidable.
In conclusion, the number of prostate diagnoses in2020 was 35.4% lower than in 2019. More than 90% of
the decrease was accounted for by patients in their 60's
and 70's that would have been curable, with PSA of 30
or less, and at stage T2, N0M0. There is a concern that
because of delayed diagnosis the relative proportionof more advanced prostate cancer cases will increase
and some of them will no longer be curable. Widely
aware that more than 30,000 prostate cancers might
be overlooked nationwide in 2020, we recommend
establishing a health checkup system with infection
control and undergoing early testing.

Bazuro ME. Impact of COVID-19 pandemic on colorectal
cancer screening program. Clin Colorectal Cancer. 2021;
20:e5-e11.
3. Cancer Information Service, National Cancer Center,
Japan (National Cancer Registry, Ministry of Health,Labour and Welfare). Cancer Statistics. https://ganjoho.
jp/reg_stat/statistics/data/dl/index.html (accessed July 15,2021). (in Japanese)
4. Abern MR, Aronson WJ, Terris MK, Kane CJ, Presti JC Jr,
Amling CL, Freedland SJ. Delayed radical prostatectomy
for intermediate-risk prostate cancer is associated withbiochemical recurrence: possible implications for active
surveillance from the SEARCH database. Prostate. 2013;
73:409-417.
5. Khan MA, Mangold LA, Epstein JI, Boitnott JK, Walsh
PC, Partin AW. Impact of surgical delay on long-term
cancer control for clinically localized prostate cancer. J
Urol. 2004; 172:1835-1839.
6. Nam RK, Jewett MA, Krahn MD, Robinette MA, Tsihlias
J, Toi A, Ho M, Evans A, Sweet J, Trachtenberg J. Delayin surgical therapy for clinically localized prostate cancer
and biochemical recurrence after radical prostatectomy.
Can J Urol. 2003; 10:1891-1898.
7. Nguyen PL, Whittington R, Koo S, Schultz D, Cote KB,
Loffredo M, McMahon E, Renshaw AA, Tomaszewski JE,
D'Amico AV. The impact of a delay in initiating radiation
therapy on prostate-specific antigen outcome for patientswith clinically localized prostate carcinoma. Cancer. 2005;
103:2053-2059.
8. O'Brien D, Loeb S, Carvalhal GF, McGuire BB, Kan D,
Hofer MD, Casey JT, Helfand BT, Catalona WJ. Delay ofsurgery in men with low risk prostate cancer. J Urol. 2011;185:2143-2147.
9. Loeb S, Folkvaljon Y, Robinson D, Makarov DV,
Bratt O, Garmo H, Stattin P. Immediate versus delayed
prostatectomy: Nationwide population-based study. Scand
J Urol. 2016; 50:246-254.
10. Westerman ME, Sharma V, Bailey GC, Boorjian SA,
Frank I, Gettman MT, Thompson RH, Tollefson MK,
Karnes RJ. Impact of time from biopsy to surgery on
complications, functional and oncologic outcomes
following radical prostatectomy. Int Braz J Urol. 2019;45:468-477.
11. Zanaty M, Alnazari M, Ajib K, Lawson K, Azizi M, Rajih
E, Alenizi A, Hueber PA, Tolmier C, Meskawi M, Saad F,
Pompe RS, Karakiewicz PI, El-Hakim A, Zorn KC. Does
surgical delay for radical prostatectomy affect biochemicalrecurrence? A retrospective analysis from a Canadiancohort. World J Urol. 2018; 36:1-6.
12. De Vincentiis L, Carr RA, Mariani MP, Ferrara G. Cancer
diagnostic rates during the 2020 'lockdown', due to
COVID-19 pandemic, compared with 2018-2019: an audit
study from cellular pathology. J Clin Pathol. 2021; 74:
187-189.

Funding: None.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.

---Received June 25, 2021; Revised July 17, 2021; Accepted July28, 2021.

References
1.

2.

Gospodarowicz MK, Mason M. Prostate cancer:
Urological Tumors. In: UICC TNM classificationof malignant tumours. Eighth ed (Brierley JD,
Gospodarowicz MK, Wittekind C, eds.). Wiley-Blackwell;
Hoboken, NJ, USA, 2017; pp. 187-190.
D'Ovidio V, Lucidi C, Bruno G, Lisi D, Miglioresi L,*Address correspondence to:Daisuke Yamada, Department of Urology, Graduate School of
Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-8655, Japan.
E-mail: dyamada-tky@umin.net(30)

Communication

GHM Open. 2021; 1(1):31-35.
DOI: 10.35772/ghmo.2021.01008

Development of active learning materials and use of those materials
to educate nursing students primarily in respiratory nursing and to
train new nurses
Fumino Sugiyama1,*, Tomoko Inoue1, Kimikazu Kashiwagi1, Mitsumi Masuda2, Namiko Nagaoka1, Ayako Narita3
1

National College of Nursing, Japan;
Nagoya City University, Nagoya, Japan;
3
National Cancer Center Hospital East, Tokyo, Japan.
2

Abstract: The current study examined the effectiveness of using e-learning to teach respiratory nursing to students
and provide continuing education to new nurses. An e-learning system was developed for pre-learning activities incombination with simulations. Ten new nurses were interviewed about nursing practices to identify learning tasks
that were appropriate for new nurses. Based on those interviews, the current authors developed teaching materials
for the core program. The e-learning system used was a web-based platform that conforms to global standards (TAO,
Infosign Inc., Tokyo). The e-learning system was tested with students in their third and fourth years of nursing
school at two universities in January and February of 2017. A follow-up indicated that third- and fourth-year nursing
students who participated in clinical learning found the e-learning system (which was developed based on theexperiences of new nurses) useful.
Keywords: active learning, e-learning, new nurse, nursing student, respiratory nursing

Clinical learning is essential to reach a stage whereknowledge gained in the classroom can be put into
practice (1). However, the skills acquired during
practical training depend on the condition of patientsand the nursing students themselves. The skills requiredof a new nurse depend on the role of the facility where
the nurse will be working (2). The role differentiationof medical facilities presumably contributes to adiscrepancy between the skills acquired in nursing
school and the practical skills required of new nurses.
E-learning and simulation-based learning havebeen used in place of clinical learning to educate
nursing students (3,4). Members of the nursing
profession require continuing education, and they must
think independently. This type of human resource
development necessitates a shift from traditionalclassroom-based knowledge transfer to active learning,in which students identify problems and find solutions
independently (5-7).
Goal-based scenarios are an instructional design
theory consisting of the following seven elements:
mission, cover story, role, learning goals, scenario
operations, feedback, and resources (8). Although prelearning usually takes place in lectures, combining goalbased scenarios with e-learning should improve theunderstanding of learners. In addition, the effectivenessof an e-learning course can be evaluated by surveying
learners regarding their level of interest, the relevanceof content, and their level of confidence and satisfaction
after completing the course (9).
From this perspective, the current study developed
an e-learning system for nursing students in order toestablish the clinical competencies required of newnurses. This study focused on the continuity of educationin respiratory nursing for nursing students as they
became new nurses and it evaluated the effectiveness ofthat education.
This study was conducted in two stages: i) anassessment of learning needs and development of
e-learning materials, and ii) an assessment of thee-learning system's effectiveness.
First stage: Assessment of learning needs
Subjects
Subjects were 10 new nurses who had worked in one offour wards: internal medicine, surgery, internal medicine
and surgery combined, or intensive care. The nurses
worked in three large general hospitals in metropolitan
areas, each with more than 500 beds. A new nurse wasdefined as a nurse with less than one year of experience.

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Assessment

Hospital (15-042) before conducting interviews.

Between October 2015 and February 2016, semistructured interviews were conducted with the ten
new nurses regarding their observations, judgments,
performance, and difficulties they experienced due todifferences between their nursing school training andactual practice.

Outcomes
Overview of nursing practiceNine of the 10 new nurses were women. Most of thepatients under the care of the new nurses had lungcancer. The remaining patients had pneumonia or
pneumothorax. The new nurses worked together withsenior nurses who were in charge of educating them.
The new nurses had difficulties with several of thetasks, e.g. collecting all of the necessary information
at one time, sputum suction, supporting patients withdyspnea, and clinically assessing patient results.
Although they used viscous fluids to practice sputum
suction in school, they still had difficulty performing
sputum suction with real patients, as they had tosynchronize their actions with the patients' coughreflex. New nurses were unable to interact properlywith patients exhibiting dyspnea due to distress in thoseemergency situations.

Development of the e-learning system
Qualitative data were obtained from transcripts of therecorded interviews. The disease-related specializationsof the new nurses and situations in which they had
experienced difficulties were noted. The seven elementsof the goal-based scenario were identified based on
their correspondence to the qualitative data.
Based on these elements, an e-learning system wasdeveloped in which a nursing student would play therole of a nurse. The Question and Test Interoperability/
Learning Tools Interoperability of TAO (Infosign Inc.,Tokyo), a web-based testing system that complies withinternational standards, was used for this study.

Components of the e-learning system
The e-learning system included two scenarios: i)ambulatory support for patients after surgery forlung cancer, and ii) support for patients with chronic
obstructive pulmonary disease (COPD) and dyspnea.
Each program consisted of three parts: collection of
information, provision of care, and reporting (Table 1).
In the lung cancer scenario, the mission of the
new nurse was to provide ambulatory support for a

Ethical considerations
This study was conducted in compliance with the
ethical guidelines of the Japanese Ministry of Health,
Labor, and Welfare for medical and health research
involving human subjects. Approval was obtained fromthe Ethical Review Board of St. Luke's International
Table 1. Elements of the goal-based scenarios

A case of a patient after right lower lobectomy for lung cancer
Scenario context
Learner's mission
Cover story
Learner's role

The learner is to provide proper care and report to the lead nurse to help treat the patient.
The cover story is that the learner observes the patient and then reports to the lead nurse. At the beginning, the learnerobserves and evaluates the patient and predicts possible changes in the patient's condition. Then, the learner provides
necessary care. Finally, the learner reports on the patient's condition and care to the lead nurse.
After receiving detailed information on the patient's surgery, the learner (A) observes and evaluates the patient, (B)provides care and evaluates the patient's condition, and (C) reports the care provided and the patient's condition to thelead nurse.

Learning goals(1) Procedural knowledge
Using what the learner has observed, judged, performed, and evaluated as information, the learner will be able todevelop the skills to prepare a report that will facilitate the patient's treatment.
(2) Declarative knowledge
Based on a case of lung cancer, the learner will be able to understand postoperative complications and impacts ofinvasive surgery on the patient's body and learn how to manage drains. Based on a case of COPD, the learner will beable to understand hypoxemia and hypercapnia and learn how to assist the patient in performing pursed-lip breathing.

Scenario operations

To promote nursing practice, questions are prepared on (A) observation and evaluation, (B) care and evaluation,and (C) reporting.
When the learner fails to give the correct answer, the correct answer is provided before the learner proceeds to thenext section.

Scenario framework
Feedback
Resources

The learner can receive feedback after answering each question. After completing all of the questions, the learner canwatch a video that explains the two cases.
Information that serves as the basis for the answer is available whenever the learner wants it.

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patient one day after surgery. The learning goals wereto acquire the ability to observe patients to prevent
postoperative complications and to provide necessary
support. Learners were allowed to comment freely
in their responses using the Situation, Background,
Assessment, and Recommendations (SBAR) method.
The mission of the new nurse in the COPD scenario
was to provide care to a patient complaining of dyspnea
after walking to the bathroom. The learning goals wereto acquire the ability to observe a patient with COPD
and to provide the requisite support. Learners wereallowed to comment freely using the SBAR method toanswer questions for their report.
When the learner clicked on the answer button,
the correct answer was displayed as feedback. A video
explaining the two scenarios was viewed at the end of
the program.

Responses from 43 nursing students who answered two
or more of the questions were analyzed. All but one of
the students were using the e-learning system for the
first time. Of the 33 respondents, 27 (82%) were female
students. Eighteen (56%) of thirty-two respondents
were fourth-year students.
Ambulatory support for patients after surgery for lungcancerWhen asked about the most common complications
observed one day after surgery, 21% (9/43) of thenursing students responded correctly. Fifty-three percent(20/38) provided the correct answer regarding methodsof identifying subcutaneous emphysema. Sixty-five
percent (24/37) correctly identified the location of the
fourth rib on the midclavicular line for auscultation.
The location of the spinous process on the back of theseventh cervical vertebra was correctly identified by
73% (21/35) of the nursing students. Eight-one percent(35/43) of the nursing students responded to questions
about the provision of care was 81% (35/43), and thecorrect answer rate was 60% (21/35). Forty percent(17/43) of the nursing students responded to questions
about reporting, and 82% (14/17) of the correct answers
were based on the SBAR method.

Second stage: Assessing the effectiveness of thee-learning system
Subjects
Subjects were third- and fourth-year nursing students
from two schools.
Assessment

Support for patients with COPD and dyspnea
Seventy-seven percent (33/43) of the nursing students
responded to questions in the section on informationcollection. The correct answer rate for causes ofdyspnea was 76% (25/33). Twenty-four percent (8/33)
of the nursing students correctly identified the causesof hypoxemia and hypercapnia. Nine percent (3/34)
answered correctly regarding methods of identification.
Seventy-nine percent (34/43) of the nursing students
responded to the section on providing, and 79% (27/34)
of the respondents answered correctly. Forty-four(19/43) of the nursing students responded to the section
on reporting, and 79% (15/19) of the answers werebased on the SBAR method.

Assessment was performed in January and February of
2017. Subjects were asked to use the e-learning systemand fill out a follow-up questionnaire, which was
generated using TAO. The questionnaire was used toevaluate interest, relevance, confidence, and satisfaction
on a four-point scale and also included an open-ended
question about the e-learning system.
Methods of analysis
Descriptive statistics were calculated based on theanswers to questions about the e-learning materials, andthe responses to the open-ended question were analyzed
qualitatively.

Motivation to learn using the e-learning system
Questions regarding interest, relevance, confidence,and satisfaction had a response rate of 76% (33/43).
Responses were rated on a four-point scale. The meanscore for interest, or avoiding boredom, was 3.3. The
mean score for relevance was 3.1. The mean score for
confidence was 2.1 and that for satisfaction was 1.5.
Comments in the open-ended answer portion
included the following: "The materials allowed learners
to more fully understand what they had previously
understood superficially" and "It would be nice if there
were scenarios for other diseases." Students learned that
information should be collected with a purpose.

Ethical considerations
The study was conducted in compliance with the
ethical guidelines of the Japanese Ministry of Health,
Labor, and Welfare for medical and health research
involving human subjects. Approval was obtained fromthe Ethical Review Boards of the National Center for
Global Health and Medicine (NCGM-G-002354-00)
and Nagoya City University (172026-2) before thisstage of the study.
Outcomes

The necessity of a learning program that encourages
continuous learning

Overview of the subjects(33)

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The students had not practiced the nursing techniques
required for new nurses in a clinical setting. Many of
the new nurses had not cared for patients with lungcancer or COPD as nursing students, and they had
never practiced suction. Even in Japan, where lungcancer and pneumonia are the leading causes of death(10), nursing students having difficulty acquiring therequisite skills to become professional nurses throughpractical training.
Suction is an essential technique for regulating
breathing, but the resulting damage to the airway
mucosa and coughing are painful for the patient.
Synchronizing the patient's coughing with the timing ofaspiration allows the patient to be aspirated painlessly.
However, new nurses are forced to learn techniquesthat may require patient cooperation in the field. This
indicates that new nurses lack certain skills, and thiscan lead to patient harm (11). While aspiration skills
are important for new nurses in respiratory facilities,
different skills are required for nurses who begin
employment in other types of facilities. Based on thesefacts, the specific clinical skills that will be required of
new nurses in different facilities need to be considered.
Creating tailored programs with the most appropriate
learning tasks for nursing students will help them
respond to changes in medicine and the workplace andfacilitate reemployment.

simulation-based learning for nursing students will need
to be investigated and changes in the practical skills of
new nurses will need to be assessed. The opportunity tolearn repeatedly and safely through e-learning must be
available to learners.
Acknowledgements
The authors would like to thank everyone who helpedwith this study. The process used to identify learning
tasks was described at the Asia-Pacific Meeting on
Simulation in Healthcare. A review of the literature on
clinical decision-making was also announced at theInternational Meeting on Simulation in Healthcare.
A study on the effectiveness of e-learning materials
was presented at the Annual Meeting of the JapaneseSociety of National Medical Services.
Funding: This work was supported by the KAKENHI
program of the JSPS (grant no. 15K15837).
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
References
1.

Providing learners with opportunities for safe andrepeated training through e-learning
The combination of pre-learning in nursing school, thefreedom of e-learning, and repeated on-site care training
will contribute to the development of knowledge, criticalthinking, and problem-solving skills in the nursing
profession. Nursing students who use Information andCommunication Technology (ICT) are reported tohave a stronger sense of self-efficacy than nurses (12).
Incorporating ICT into primary nursing education andits use after graduation will showcase the strengths ofnursing students. Self-managed e-learning is also more
effective than being taught by others (13,14).
The results of the current study highlight theneed for repeated learning opportunities in realistic
situations, which will enable new nurses to practice ina clinical setting without experiencing anxiety. Thisis evinced by higher rates of anxiety and restlessness
after nurses care for patients, so they benefit more bylearning in a simulator (15). Therefore, learners need to
be given the opportunity to learn repeatedly and safely
via e-learning, and care-based training needs to be
combined with improved reproducibility in the field.

2.
3.
4.

5.
6.

7.

8.

Limitations and challenges for the future
E-learning and evaluations were performed only inthe context of pre-learning in this study. In the future,

9.

(34)

World Health Organization. (2006). Global Standards
for the Initial Education of Professional Nurses andMidwives. Nursing and Midwifery-Human Resources for
Health. 1-36. https://www.who.int/hrh/nursing_midwifery/
hrh_global_standards_education.pdf (accessed on June 7,2021).
Sugiyama F, Inoue T. A survey of learning needs about
oral care for intubated patients among new nursing staff.
Open J Nurs. 2020; 10:462-472.
Hayden JK. Use of simulation in nursing education:
National survey results. J Nurs Regul. 2010; 1:52-57.
Hayden JK, Smiley RA, Alexander M, Kardong-Edgren
S, Jeffries PR. The NCSBN National Simulation Study:
A longitudinal, randomized, controlled study replacing
clinical hours with simulation in prelicensure nursing
education. J Nurs Regul. 2014; 5:C1-S64.
Felder RM, Brent R. Active learning: An introduction.
ASQ Higher Education Brief. 2009; 2: 1-5.
The Central Council for Education, Ministry of Education,
Culture, Sports, Science, and Technology, Japan. (2012).
A qualitative shift in university education to build a
new tomorrow: Universities that offer lifelong learningand that foster independent thinking. https://www.mext.
go.jp/component/b_menu/shingi/toushin/__icsFiles/
afieldfile/2012/10/04/1325048_1.pdf (accessed March 2,2019). (in Japanese)
Smart D, Ross K, Carollo S, Williams-Gilbert W.
Contextualizing instructional technology to the demandsof nursing education. Comput Inform Nurs. 2020; 38:1827.
Nemoto J, Suzuki K. Application of Goal-based Scenario(GBS) theory to develop a fitness checklist' would beappropriate. Educational Studies in Japan. 2005; 29, 309318. (in Japanese)
Suzuki K. Training Design Manual-Instructional Design

GHM Open. 2021; 1(1):31-35.

10.

11.
12.

13.

www.ghmopen.com

for Human Resource Development. Kitaoji Shobo, Kyoto,
Japan. (in Japanese)
Cancer Information Service, National Cancer Center,
Japan. Cancer Registry and Statistics. https://ganjoho.
jp/reg_stat/statistics/stat/summary.html (accessed July 4,2019). (in Japanese)
Hezaveh MS, Rafii F, Seyedfatemi N. Novice nurses'
experiences of unpreparedness at the beginning of thework. Glob J Health Sci. 2013; 6:215-22.
Warshawski S, Itzhaki M, Barnoy S. Nurse and nurse
student attitudes and perceived self-efficacy in useof information and communication technologies:
Professional and cultural differences. Comput Inform
Nurs. 2019; 37:20-28.
Chipman JG, Beilman GJ, Schmitz CC, Seatter SC.
Development and pilot testing of an OSCE for difficult
conversations in surgical intensive care. J Surg Educ.

2007; 64:79-87.
14. Alfaro-LeFevre R. Critical Thinking, Clinical Reasoning,
and Clinical Judgement: A Practical Approach (7thEdition). Elsevier Health Sciences. 2019; pp.55-74.
15. Günay İsmailoğlu E, Zaybak A. Comparison of theeffectiveness of a virtual simulator with a plastic arm
model in teaching intravenous catheter insertion skills.
Comput Inform Nurs. 2018; 36:98-105.
---Received May 9, 2021; Revised June 8, 2021; Accepted June
14, 2021.
*Address correspondence to:Fumino Sugiyama, National College of Nursing, Japan, 1-2-1
Umezono, Kiyose-shi, Tokyo 204-8575, Japan.
E-mail: sugiyamaf@adm.ncn.ac.jp(35)Letter

GHM Open. 2021; 1(1):36-37.
DOI: 10.35772/ghmo.2021.01005

Japan's first online media seminar on antimicrobial resistanceYoshiaki Gu1,2,*, Yumiko Fujitomo1, Rie Takahashi1, Norio Ohmagari1,3
1

AMR Clinical Reference Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan;
Department of Infectious Diseases, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
3
Department of Infectious Diseases, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.
2

Abstract: According to the National Action Plan on Antimicrobial Resistance, published in 2016, various measures
have been implemented to combat antimicrobial resistance (AMR) in Japan. Subsequently, promoting public
education is important, as the Japanese public does not have sufficient knowledge about antimicrobials and AMR.
The AMR Clinical Reference Center (AMRCRC) of the National Center for Global Health and Medicine conducts
seminars for the media once a year as part of information and education services. In 2020, the AMRCRC conducted
the first online seminar since it was unable to conduct face-to-face seminars due to the novel coronaviral disease2019 (COVID-19) pandemic. An online seminar was considered effective in promoting education and awarenessthrough the media. Twenty-four media representatives (from 19 companies) participated in the online seminar.
Media articles related to the activities of AMRCRC were similar to those of the previous years despite the impact of
COVID-19.
Keywords: antimicrobial resistance, online seminar, awareness, media coverage

Combating antimicrobial resistance (AMR) is a global
challenge that is being tackled with the help of the
Global Action Plan on AMR (2015) (1). In Japan,
various measures are being implemented in accordancewith the National Action Plan on Antimicrobial
Resistance (NAP-AMR) (2016) (2). In both the actionplans, the emphasis is on promoting public education.
The first agenda (Strategy 1.1) in NAP-AMR is topromote awareness and education of AMR among
the public, as the Japanese people have insufficientknowledge about antimicrobials, AMR, and infectious
diseases in general (3). Although antimicrobial agentsare prescription drugs in Japan, many physicians believethat misconceptions among the general public is oneof the barriers to the proper use of antimicrobials (4).
Patients may ask for prescriptions for antimicrobials
even when they are not needed or may interrupt the useof prescribed antimicrobials to take them later at theirown discretion.
The AMR Clinical Reference Center (AMRCRC)
of the National Center for Global Health and Medicine
was established in 2017 as a commissioned projectof Japan's Ministry of Health, Labour and Welfare.
The AMRCRC conducts information and education
services along with clinical epidemiology services. Sucheducational and awareness-raising campaigns are aimed
at both healthcare professionals and the general public.
For the public, we are working on circulating necessary

information through our website and by conducting
events. Seminars for the media, however, are held in
the fall along with press releases with the expectationthat it will be reported in November, the month for
campaigning on AMR.
In 2020, it was impossible to conduct face-toface seminars due to the novel coronaviral disease2019 (COVID-19) pandemic. However, since wewere concerned that media coverage would decrease,
we decided to proactively provide information to themedia. Therefore, we conducted the first online seminaron October 6. The program consisted of a 20-minutepresentation each by the director of the AMRCRC
and the chiefs of the three divisions: Information and
Education Division, Pharmacoepidemiology Division
and Clinical Epidemiology Division.
Twenty-four media representatives (from 19
companies) participated in the seminars. The participants
were mainly journalists from the medical media andmedical beats of mass media and news services. The
number of participants was the highest ever. Dr. Yoshiaki
Gu, the chief of the Information and Education Division
explained the results of an awareness survey conductedon the public in August 2020. Dr. Yoshiki Kusama, thechief of the Pharmacoepidemiology Division focusedon the results of the latest survey on antimicrobial
usage. Dr. Nobuaki Matsunaga, the chief of the Clinical
Epidemiology Division introduced websites that compile(36)

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Table 1. Summary of media seminars by AMRCRC
Items
Date of Media Seminar
Number of companies (persons) participated

2017

2018

2019

2020

8 November(face to face)
9 (11)

30 October(face to face)
15 (21)

24 September(face to face)
16 (22)

6 October(Online)19 (24)

Number of media reports related to AMRCRC in November
TV programs
Newspapers and Magazines
Web articles
Total

4
20
79
103

2
14
148
164

data from hospitals and all over Japan and the process ofutilizing them. Finally, Dr. Norio Ohmagari, the Directorof the AMRCRC explained the progress made since the
NAP-AMR was launched as well as future challenges.
This was followed by an enthusiastic interaction session
lasting over 30 minutes.
A total of 94 media reports related to the activities
of AMRCRC were published from November 1 to 30,
including 24 newspaper and magazine reports and 70
web articles (Table 1). Although no television coveragehas been reported, the media coverage was no less thanthe previous years.
The media plays an important role in disseminating
appropriate information to the public. Despite thewidespread use of social networking services (SNS),mass media still has a great impact. The AMRCRC iscontinuously working to provide accurate information
about AMR to the public through media. Since
the public receives abundant information from themedia, awareness campaigns through the media cansignificantly increase their knowledge (5). The media
also has a critical influence on SNS (6). However, themedia should ensure dispersion of scientifically accurate
information to avoid misinformation (7).
Media seminars by AMRCRC provide a good
opportunity to present data on AMR that can beused as media coverages and deepen understanding
through interaction session. It is also an excellent
opportunity for experts to understand the importance of
explaining things in a more lucid manner through media
interaction. While COVID-19 coverage dominated in
2020, media coverage of the activities of AMRCRC wasabout the same as in the previous years. It was thoughtthat conducting media seminars online would have thesame effect as face-to-face seminars. Online seminars
for media can be used in the future to educate and raiseawareness about AMR.

2
32
46
80

0
24
70
94

Conflict of Interest: The authors have no conflicts ofinterest to disclose.
References
1.

2.

3.

4.

5.

6.

7.

World Health Organization. Global action plan on
antimicrobial resistance. http://www.who.int/antimicrobialresistance/publications/global-action-plan/en (accessed
January 14, 2021)
The Government of Japan. National action plan on
antimicrobial resistance (AMR), 2016-2020. https://www.mhlw.go.jp/file/06-Seisakujouhou-10900000Kenkoukyoku/0000138942.pdf (accessed January 14,
2021)
Kamata K, Tokuda Y, Gu Y, Ohmagari N, Yanagihara K.
Public knowledge and perception about antimicrobials andantimicrobial resistance in Japan: A national questionnaire
survey in 2017. PloS One. 2018; 13:e0207017.
Gu Y, Fujitomo Y, Soeda H, Nakahama C, Hasegawa N,
Maesaki S, Maeda M, Matsumoto T, Miyairi I, Ohmagari
N. A nationwide questionnaire survey of clinic doctors on
antimicrobial stewardship in Japan. J Infect Chemother.
2020; 26:149-156.
Robert A, Nguyen Y, Bajolet O, Vuillemin B, Defoin B,
Vernet-Garnier V, Drame M, Bani-Sadr F. Knowledge ofantibiotics and antibiotic resistance in patients followed byfamily physicians. Med Mal Infect. 2017; 47:142-151.
Andersen B, Hair L, Groshek J, Krishna A, Walker D.
Understanding and diagnosing antimicrobial resistance onsocial media: a yearlong overview of data and analytics.
Health Commun. 2019; 34:248-258.
Davis M, Whittaker A, Lindgren M, Djerf-Pierre M,
Manderson L, Flowers P. Understanding media publics
and the antimicrobial resistance crisis. Glob Public Health.
2018; 13:1158-1168.

---Received April 15, 2021; Revised May 14, 2021; Accepted
May 18, 2021.
*Address correspondence to:
Yoshiaki Gu, Department of Infectious Diseases, Graduate
School of Medical and Dental Sciences, Tokyo Medical and
Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan.
E-mail: yogu.cid@tmd.ac.jp

Funding: This study was supported by a Ministry of
Health, Labour and Welfare (MHLW) research grant ofJapan (H29-shinkougyouseishitei-005).

(37)

Letter

GHM Open. 2021; 1(1):38-39.
DOI: 10.35772/ghmo.2021.01025

Home-visit services for the families with newborns during the
COVID-19 pandemic
Yukari Isaka1,*, Ai Hori2, Takahiro Tabuchi3, Sumiyo Okawa3,4, Masao Ichikawa2
1

Doctoral Program in Human Care Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;
Department of Global Public Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan;
3
Cancer Control Center, Osaka International Cancer Institute, Osaka, Japan;
4
Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine,Tokyo, Japan.
2

Abstract: Home-visit services are provided to families with newborns as means of parenting support. These
services potentially are playing major roles during the coronavirus disease 2019 (COVID-19) pandemic, where
people have been socially isolated. However, the pandemic has deterred the use of this service to some extent. From
the Japan "COVID-19 and Society" Internet Survey, we identified that 15% of the survey respondents who delivered
between January 2020 and October 2020 refused home visit services. The proportion of the services used during
the pandemic (85%) was lower than those used before the pandemic (95%). Home-visit services provide a unique
opportunity for public health nurses to assess the risk of postpartum depression and child maltreatment in the family;
thus, families with newborns should be instructed to receive home-visit services as well as child immunization andhealth checkups, despite the continuation of the pandemic.
Keywords: SARS-CoV-2, maternal-child health service, social welfare

During the coronavirus disease 2019 (COVID-19)
pandemic, care for children's mental health is of growing
importance because their well-being has been affected by
the continued restriction of daily activities and the lossof social connectivity due to a state of emergency andtemporary school closures as of July 2021 (1). The samecan be said for mothers with newborns. It is noted thatthey are at risk of postpartum depression, and the risk
may have enhanced during the pandemic.
In Japan, given the high incidence of postpartum
depression (10-15%) (2) affecting maternal well-being
and increasing the risk of child maltreatment, home-visit
services have been provided to families with newborns
by a legislated welfare program called "Konnichiwa
Akachan Jigyo". The program aims at providing
information on parenting support through home-visits by
public health nurses or midwives within four months ofbirth (3).
Home-visit services, which can play a greater role
when people are more socially isolated than usual, arecontinuing during the pandemic. However, the pandemic
might have deterred families from receiving services forfear of COVID-19 infection. Thus, we examined whether
home-visit services have decreased during the pandemic,
using the Japan "COVID-19 and Society" Internet
Survey (JACSIS) data targeting pregnant and postpartum

women (4).
The survey participants included 1,000 pregnant andparturient women. The participants were recruited froman online panel of approximately 2.2 million individuals
managed by Rakuten Insight from October 15, 2020
to October 25, 2020, and were asked to fill out online
questionnaires that included questions regarding whether
they received home-visit services. Home visit services
are usually availed within 4 months of delivery but theappointment for such services is made shortly after
delivery. Thus, we assumed that the decision to receive
home-visit services was affected by the pandemic
situation around the delivery time. The study protocol
was approved by the Research Ethics Committee of the
Osaka International Cancer Institute on June 19, 2020
(approval number 20084).
Of the 479 women who delivered between January
2020 and October 2020, 409 (85%) received the service(i.e., 15% of women refused home visit services). Table
1 shows the proportion of service recipients by monthof delivery. Although caution should be exercised withthe small denominator, the proportion was lower (i.e.,
77–78% from March to May), just before and during thefirst state of emergency compared to other months.
Before the pandemic, families with newborns weremore likely to receive home-visit services: 95% of(38)

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for the Promotion of Science (JSPS) KAKENHI Grants(grant numbers 18H03062 and 21H04856), Research
Support Program to Apply the Wisdom of the University
to tackle COVID-19 Related Emergency Problems,
University of Tsukuba. The findings and conclusionsof this article are the sole responsibility of the authorsand do not represent the official views of the research
funders.

Table 1. Number and proportion of 479 families withnewborns receiving home-visit services by month ofdelivery in 2020a
Month
January
February
March
April
May
June
July
AugustSeptember
October
Total

Home-visit services
Numberb

Percentage (%)

31/33
29/34
17/22
75/97
79/101
35/36
37/42
32/34
19/22
55/58
409/479

94
85
77
77
78
97
88
94
86
95
85

Conflict of interest: The authors have no conflicts ofinterest to disclose.
References
1.

aJapan's first state of emergency lasted from April 7 to May 25, 2020.
Number of families with newborns receiving home-visit services/total
number of families with newborns.
b2.

927,816 families availing home-visit services received
it between April 2017 and March 2018 (5). Therefore,
the pandemic might have interrupted service use. To
respond to fear of COVID-19 infection in service use,
the Ministry of Health, Labour and Welfare advised
local governments to provide telephone or online
consultation if home-visit is not accepted (6). The
survey did not investigate to what extent telephoneor online consultation has been used by families withnewborns, and it is uncertain that such consultation isuseful for public health nurses to identify families atrisk of postpartum depression and child maltreatment. It
should be worth examining the usefulness of telephone
and online consultation for emergency preparedness.
Moreover, since our study investigated service use in the
online panel up to October 2020, further investigation is
warranted with a representative sample over a prolonged
period as the pandemic continues.
Home-visit services provide a unique opportunity
for public health nurses or midwives to contact families
with newborns at home, helping them assess the riskof postpartum depression and child maltreatment in thefamily. Families with newborns should be instructed toreceive home-visit services as well as child immunizationand health checkups despite the prevailing pandemic.

3.

4.

5.

6.

Usami M, Sasaki S, Sunakawa H, et al. Care for children's
mental health during the COVID-19 pandemic in Japan.
Glob Health Med. 2021; 3:119-121.
Tokumitsu K, Sugawara N, Maruo K, Suzuki T, Shimoda
K, Yasui-Furukori N. Prevalence of perinatal depression
among Japanese women: a meta-analysis. Ann Gen
Psychiatry. 2020; 19:41.
Ministry of Health, Labour, and Welfare. Outline of homevisit services for the families with newborns. https://www.
mhlw.go.jp/bunya/kodomo/kosodate12/01.html (accessed
June 28, 2021). (in Japanese)
Miyawaki A, Tabuchi T, Tomata Y, Tsugawa Y.
Association between participation in the government
subsidy programme for domestic travel and symptoms
indicative of COVID-19 infection in Japan: cross-sectional
study. BMJ Open. 2021; 11:e049069.
Ministry of Health, Labour, and Welfare. Survey on
home-visit services for the families with newborns.
https://www.mhlw.go.jp/content/11900000/000680041.pdf(accessed June 28, 2021). (in Japanese)
Ministry of Health, Labour, and Welfare. Response to
the maternal and child health services on COVID-19.
https://www.mhlw.go.jp/content/11920000/000636735.pdf(accessed July 14, 2021). (in Japanese)---Received July 1, 2021; Revised July 19, 2021; Accepted July27, 2021.
*Address correspondence to:
Yukari Isaka, Doctoral Program in Human Care Science,
Graduate School of Comprehensive Human Sciences,
University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058577, Japan.
E-mail: s1530359@u.stukuba.ac.jp

Funding: This study was funded by the Japan Society(39)Letter

GHM Open. 2021; 1(1):40-42.
DOI: 10.35772/ghmo.2021.01026

Seroprevalence of antibodies against SARS-CoV-2 among workers ina national research institute and hospital in Central Japan
Akihiko Nishikimi1, Masayo Kojima2,*, Ken Watanabe3, Atsushi Watanabe4, Mikako Yasuoka2, Hironori Oshima5,
Haruhiko Tokuda3,5, Shumpei Niida6
1

Biosafety Division, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan;
Department of Frailty Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan;
3
Bioresource Division, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan;
4
Research Advancement Division, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan;
5
Department of Clinical Laboratory, Hospital, National Center for Geriatrics and Gerontology, Aichi, Japan;
6
Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
2

Abstract: To achieve effective prevention and control strategies for COVID-19, regular survey of seroprevalenceof antibodies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is essential. Using four
serological tests, we examined the residual sera collected in an annual medical checkup of the staff members of the
National Center for Geriatrics and Gerontology in Aichi Prefecture, Central Japan in June 2020. Of the 631 samples,
two were positive for anti-SARS-CoV-2 antibodies in at least two tests, showing a seroprevalence of 0.32%. Foursubjects showed positive results in only one test. All individuals were asymptomatic and had not been in close
contact with patients diagnosed with COVID-19. Multiple antibody tests could be used to assess the prevalence of
SARS-CoV-2 infection including individuals without COVID-19 symptoms.
Keywords: SARS-CoV-2, COVID-19, seroprevalence

The spread of SARS-CoV-2 had various impacts onsocial activities. Since the first case of coronavirus
disease 2019 (COVID-19) was identified in January
2019, more than 813000 cases and 15000 deaths haveoccurred in Japan so far. Just before the opening of the
Olympics, the number of new cases has been again
increasing in Tokyo. Although the vaccination rollout
started in mid-February, only 29.6% of the population
has completed at least once in Japan and the pandemic
has still not ended. As a considerable number ofindividuals have only mild or no symptoms, the extent
of infection has been evaluated by seroepidemiologicalstudies (1). The seroprevalence in the Japanese general
populations was 0.03-0.17 in June 2020 and 0.14–0.91
in December 2020 (2,3). To achieve effective prevention
and control strategies for COVID-19, regular survey ofseroprevalence is essential.
The National Center for Geriatrics and Gerontology(NCGG), which comprises a hospital and research
institute, is one of the national centers for advanced
and specialized medicine located in Aichi Prefecture, acentral region of Japan. To investigate the seroprevalenceof SARS-CoV-2 among NCGG workers over time, we
designed a repeated cross-sectional study and reported
the results of the first survey using the sera collected atannual health checkups in June 2020.
Of the 743 NCGG employees invited, 632 agreed
to participate in the survey (participation rate: 85.0%).
However, one was excluded because of insufficientserum volume. Thus, 631 samples were tested foranti-SARS-CoV-2 antibody levels. In January 2021,
the participants were asked to answer an electronicquestionnaire on sociographic and COVID-19-related
factors. All participants provided written informed
consent, and the Institutional Review Board of the ethics
and conflicts of interest committee approved this study(No: 1481).
At the inhouse laboratory, serum anti-SARS-CoV-2
antibodies were measured using clinical diagnostic
systems manufactured by Sysmex, Abbott, and Roche.
We performed Sysmex SARS-CoV-2 N-IgG and SARSCoV-2 S-IgG assays that detect immunoglobulin G
against viral nucleoprotein and spike protein antigens,respectively. In addition, we performed Abbott SARSCoV-2 assay that detects IgG against nucleocapsid
protein. Further, we performed the Roche Elecsys AntiSARS-CoV-2 RUO assay that detects total antibodies,including IgG against nucleocapsid protein. Samples
with positive results in two or more tests were consideredantibody positive. To compare the distribution of values,(40)

GHM Open. 2021; 1(1):40-42.

www.ghmopen.com

Table 1. Individual index values of each test in samples that were tested positive in at least one test
Participants
A
B
C
D
E
F

Age Range

Gender

≥ 50
30-39
40-49
30-39
40-49
≥ 50

femalemale
male
femalefemalefemaleTests (positive threshold value)
Abbott (1.4)

Sysmex-S (10)Sysmex-N (10)Roche (1.0)

2.58
1.61
1.52
0.01
0.01
1.56

13.9
0.0
0.0
0.0
0.0
0.0

43.8
22.8
0.2
0.6
0.8
0.0

2.220
0.071
0.204
1.340
1.500
0.070

Positive values are indicated in bold letters.

logarithmic transformation of the index value +1 wasused.
Ta b l e S 1 ( h t t p s : / / w w w. g h m o p e n . c o m / s i t e /supplementaldata.html?ID=25) summarizes theparticipant characteristics. The proportions of participantsin their 20s, 30s, 40s, and older than 50 years were22.1%, 23.1%, 31.5%, and 23.3%, respectively, and63.6% were female. The healthcare workers including
doctors, nurses, and allied healthcare professionals
accounted for 65.0%, whereas the others were engaged
in basic research and investigation, general office duties,
and other nonclinical work. A total of 104 (16.5%)
participants were reported to have engaged in work
activities with high infection risks.
As shown in Table 1, among 631 participants, only
two were positive in two or more tests, indicating aseroprevalence of 0.32% (95% confidence interval:
0.04–1.14). One participant was positive in all tests,
with indices of 2.58, 13.9, 43.8, and 2.220 in the Abbott,
Sysmex-N, Sysmex-S, and Roche tests, respectively.
Another participant was positive in Abbott test (index:1.61) and Sysmex-N test (index: 22.8). Both individuals
were nonclinical workers. Meanwhile, four participants
were positive in one of the tests, two in the Abbott
test (indices: 1.52 and 1.56) and two in the Roche test
(indices: 1.340 and 1.500). No participant had a historyof PCR testing or close contact with patients diagnosed
with SARS-CoV-2. In addition, they claimed absence ofany symptom implying infection between January andJune 2020.
The Ministry of Health, Labor, and Welfare of Japan
conducted a survey of the general population; the results
showed that the seroprevalences in Tokyo, Osaka, andMiyagi were 0.10%, 0.17%, and 0.03%, respectively, in
June 2020 (2). During the same period, SoftBank Group
Corp. reported that 0.20% of their employees in Aichi
Prefecture, where NCGG is located, were positive in theanti-SARS-CoV-2 antibody test (4). Furthermore, 2.1%of the healthcare workers in Kanagawa Prefecture (nearTokyo) (5) and 0.16% of those in the National Center for
Global Medicine in Tokyo were antibody positive (6).
The antibody prevalence in the present study is similar
to that reported in these surveys, suggesting that theresidual serum of medical examinations can be used forthe rough estimation of seroprevalence.

In this study, discordant assay results were obtainedin five cases. Such discrepancies were observed insamples presumably with low antibody levels (7,8).
When the normalized values were compared between
assays, the Sysmex tests (both S and N) showed a clear
distinction between positive and negative values (Figure
S1, https://www.ghmopen.com/site/supplementaldata.
html?ID=25). The discordance among the tests
may have resulted from the difference in assay
characteristics. Antibodies reportedly cross-react withsome SARS-CoV-2 epitopes detected in the serum fromindividuals without SARS-CoV-2 infection or thosewith seasonally spreading human coronaviruses (HCoV),
possibly because the cross-reactivity persisted fromearlier HCoV infection (9). Cross-immunity is possible
in cases that show positivity in a single assay. Therefore,
multiple assays are needed to identify individuals withprior SARS-CoV-2 infection.
Acknowledgments
The authors thank Megumi Banno, Mayumi Taguchi,
Risa Nishijima, Koto Kamiji, Keiko Funatsu, and Yukari
Kido for their technical assistance.
Funding: This work was supported by the Japan HealthResearch Promotion Bureau Research Fund (2020-B-09).
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
References
1.
2.

3.

4.

(41)

Heymann DL, Shindo N, WHO Scientific and TechnicalAdvisory Group for Infectious Hazards. COVID-19: whatis next for public. Lancet 2020, 395:542-545.
Ministry of Health, Labour and Welfare of Japan. Aboutantibody prevalence survey. https://www.mhlw.go.jp/
content/10906000/000640184.pdf (accessed June 19,2021) (in Japanese).
Ministry of Health, Labour and Welfare of Japan. Aboutantibody prevalence survey. https://www.mhlw.go.jp/
content/000734482.pdf (accessed July 12, 2021) (inJapanese).
SoftBank Group Corp. About preliminary estimatesof antibody test results. https://group.softbank/system/

GHM Open. 2021; 1(1):40-42.

5.

6.

7.

8.

www.ghmopen.com

files/pdf/antibodytest.pdf (accessed June 19, 2021) (inJapanese).
Tanaka A, Yamamoto S, Miyo K, Mizoue T, Maeda
K, Sugiura W, Mitsuya, H, Sugiyama H, Ohmagari N.
Seroprevalence of antibodies against SARS-CoV-2 in alarge national hospital and affiliated facility in Tokyo,
Japan. J Infect. 2021; 82:e1-e3.
Matsuba, I, Hatori N, Koido N, Watanabe Y, Ebara
F, Matsuzawa, Nishikawa T, Kunishima T, Degawa
H, Nishikawa M, Ono Y, Kanamori A. Survey of thecurrent status of subclinical coronavirus disease 2019
(COVID-19). J Infect Chemother. 2020; 26:1294-1300.
The National SARS-CoV-2 Serology Assay Evaluation
Group. Performance characteristics of five immunoassays
for SARS-CoV-2: A head-to-head benchmark comparison.
Lancet Infect Dis. 2020; 20:1390-1400.
Manthei DM, Whalen JF, Schroede LF, Sinay AM, Li
SH, Valdez R, Giacherio DA, Gherasim C. Differences in

9.

performance characteristics among four high-Throughput
assays for the detection of antibodies against SARSCoV-2 using a common set of patient samples. Am J Clin
Pathol. 2021; 155:267-279.
Ng KW, Faulkner N, Cornish GH, Rosa A, Harvey R,
Hussain S, Ulferts R, Earl C, Wrobel AG, Benton DJ,
Roustan C. Preexisting and de novo humoral immunity to
SARS-CoV-2 in humans. Science. 2020; 370:1339-1343.

---Received June 29, 2021; Revised July 20, 2021; Accepted July27, 2021.
*Address correspondence to:
Masayo Kojima, Department of Frailty Research, ResearchInstitute, National Center for Geriatrics and Gerontology, 7-430
Morioka Obu Aichi 474-8511, Japan.
E-mail: masayok@ncgg.go.jp(42)

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GHM Open
National Center for Global Health and Medicine,
1-21-1 Toyama Shinjuku-ku, Tokyo 162-8655, Japan
URL: www.ghmopen.com
E-mail: office@ghmopen.com

Language Editing: Manuscripts prepared by authors whose
native language is not English should have their work

(P4)