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Volume 2, Number 1
August, 2022

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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).
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ii

CONTENTS		

Volume 2, Number 1, 2022

Policy Forum
1-11

Unfinished business: Lessons for future G20 meetings on a more inclusive understanding ofuniversal health coverage.
Aya Ishizuka, Mina Chiba, Hiroyasu Iso, Yasushi Katsuma

Review
12-24

Effects of self-management interventions with behavior-change support on long-term adherencein patients with chronic respiratory diseases: A systematic review.
Mihoko Fujii, Jiro Nakano, Yoshiharu Tanaka, Akiko Tonosaki

Original Article
25-30

Knowledge and practice for cervical cancer among female primary school teachers in Phnom
Penh, Cambodia: A cross-sectional phone-based survey.
Sann Chan Soeung, Tomoko Komagata, Chau Darapheack, Shikino Kikuchi, Hiromi Obara,
Rei Haruyama, Koum Kanal, Noriko Fujita, Nozomu Yanaihara, Aiko Okamoto, Tadashi Kimura

31-37

Association of atherogenic serum lipids and platelet activation with changes in arterial stiffnessin patients with type 2 diabetes.
Yuji Hirowatari, Hidekatsu Yanai

Brief Report
38-43

Safety of convalescent plasma therapy for COVID-19 patients and analysis of viral kinetics: A
single-center, open-label, single-arm, interventional study in Japan.
Satoshi Kutsuna, Sho Saito, Yuki Takamatsu, Mari Terada, Tomiteru Togano, Noriko Kinoshita,
Kenji Maeda, Akihiro Matsunaga, Masahiro Satake, Keiji Matsubayashi, Nelson Hirokazu Tsuno,
Makiko Kojima, Madoka Kuramitsu, Kenta Tezuka, Emi Ikebe, Kazu Okuma, Isao Hamaguchi,
Yumiko Shimanishi, Akira Hangaishi, Yukihito Ishizaka, Norio Ohmagari, Hiroaki Mitsuya

44-50

Global landscape of the COVID-19 vaccination policy: Ensuring equitable access to qualityassured vaccines.
Mami Wakabayashi, Satoshi Ezoe, Makiko Yoneda, Yasushi Katsuma, Hiroyasu Iso

Communication
51-53

Sensitivity of three antibody assays to SARS-CoV-2 nucleocapsid protein in relation to timing
since diagnosis.
Tetsuya Mizoue, Shohei Yamamoto, Akihito Tanaka, Yusuke Oshiro, Natsumi Inamura, Maki Konishi,
Mitsuru Ozeki, Norio Ohmagari

54-58

Development of the neurological simulation program e-learning version (Neuro Sim-e).
Mitsumi Masuda, Fumino Sugiyama, Junko Shogaki, Kyoko Matsumoto, Machiko Saeki Yagi,
Hidenori Oishi

iii

CONTENTS		

(Continued )Letter
59-62

Global extension of Japanese medical products related to COVID-19: A survey of WHO
Emergency Use Listing.
Mami Wakabayashi, Yasunori Ichimura, Eiichi Shimizu, Tomoko Nishioka, Yuzuru Kono, MasahikoDoi, Yuriko Egami, Tomoka Kadowaki, Hiroyasu Iso, Noriko Fujita

63-64

The state of foreigners living in Japan as gauged by people undergoing a comprehensive healthcheckup (Ningen Dock).
Jun Lu, Sachiko Kubo, Makiko Hashimoto, Yuko Hayashi, Hiroshi Kajio

iv

Policy ForumGHM Open. 2022; 2(1):1-11.
DOI: 10.35772/ghmo.2021.01006

Unfinished business: Lessons for future G20 meetings on a more
inclusive understanding of universal health coverage
Aya Ishizuka1,2,*, Mina Chiba1,3, Hiroyasu Iso1,4, Yasushi Katsuma1,5,6,7
1

Institute for Global Health Policy Research, National Center for Global Health and Medicine, Tokyo, Japan;
Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;
3
Organization for Regional and Inter-regional Studies, Waseda University, Tokyo, Japan;
4
Graduate School of Medicine, Osaka University, Osaka, Japan;
5
Graduate School of Asia-Pacific Studies, Waseda University, Tokyo, Japan;
6
Graduate Program in Global Leadership, Vietnam-Japan University, Hanoi, Vietnam;
7
Institute for the Advanced Study of Sustainability, United Nations University, Tokyo, Japan.
2

Abstract: The Group of 20 (G20) Osaka Summit in 2019 was a large step forward for global health diplomacy to build
consensus on universal health coverage (UHC). To strengthen multi-stakeholder UHC partnership, Japan involved theresearch and policy advice network for G20 (Think 20: T20), civil society (Civil 20: C20), private initiatives of medical
professional groups (H20), and the pharmaceutical sector. We attempted to identify UHC-related issues addressed andleft unaddressed at the G20 Osaka, to bring lessons for future G20. We reviewed the G20 Osaka Leaders' Declaration,
policy-related statements, and voices of the relevant G20 engagement groups and sectors. In July 2019, after the G20
Osaka Leaders' Summit, we organized an expert meeting convening Japan-based UHC-related key global healthstakeholders. This review provides record of main findings presented in form of classifying the voices expressed in themeeting by UHC-related topics, and definitional ranges of UHC summarized. The T20, H20, and the pharmaceuticalsector noted during our expert meeting that the ministerial-level health-finance collaboration was one of the key
agendas suggested at the G20. T20 and C20 called for a recognition of health needs of refugees, migrants and othervulnerable groups in achieving UHC. Sexual and reproductive health and rights (SRHR) with a human rights-based
approach through UHC was raised by the C20 as an issue unaddressed in G20 Osaka. Variation in operative purposes
between global health stakeholders led to a definitional difference in the scope of UHC. The definitional difference
could delay progress of UHC attainment. Addressing migrant and refugee health and SRHR within the context of UHC
is further needed. Understanding perspectives of various stakeholders will become increasingly important to wellcoordinate multi-actor cooperation with adequate social responsibility and transparency in UHC achievement andpublic-private partnership. In future G20, for UHC in the COVID-19 pandemic and post-pandemic worlds there is needof i) ensuring an integrated yet comprehensive multi-stakeholder approach towards UHC; ii) incorporating importantdimensions such as the marginalized population and gender; and iii) ensuring adequate investments toward healthinformation systems and governance to track health data for the vulnerable population and gender-responsive financing.
Keywords: G20, universal health coverage, global health, health policy, United Nations high-level meeting, global
health diplomacy

Introduction

health systems in 2017 (1), and no single paragraphexisted for UHC in the Leaders' Declarations agreed
by G20 countries in 2018 (2). During the 2019 G20
Summit, however, UHC was brought up clearly torecall its commitment for achievement according tonational contexts and priorities, in the G20 Osaka
Leaders' Declaration (3). Moreover, in recognizing
the importance of sustainable financing for health, theG20 Shared Understanding on the Importance of UHC
Financing in Developing Countries (4) was adopted

The Group of 20 (G20) Osaka Summit in May 2019was the last G20 meeting held before the coronavirus
disease 2019 (COVID-19) pandemic and was aremarkable milestone for global health diplomacy
to reach a consensus on promoting universal healthcoverage (UHC). Before then, UHC was only brought
up slightly in other G20 meetings, along with the content
on safeguarding against health crisis and strengthening(1)

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Identifying UHC related achievements and issues
unaddressed

to reaffirm commitment for UHC among the Financeand Health Ministers at their Joint Session, which wassimultaneously held during the G20 Osaka Summit (5).
Uniquely taking opportunity of the G20 presidency
in 2019, Japan took a whole-of-society approach in orderto strengthen partnerships and engage in policy dialogues
with G20 Engagement Groups. The official G20
Engagement groups include research and policy advice
network for the G20 (Think 20: T20) (6,7) and the civilsociety (Civil 20: C20) (4). The G20, T20, and C20 haveeach published their declaration in relations to G20 (68). In addition, private initiatives of medical professionalgroups from the Health Professional Meeting (H20)
organized by the World Medical Association (WMA)and Japan Medical Association (JMA) presented theirrespective memorandum (9), and the pharmaceuticalsector driven by the International Federation of
Pharmaceutical Manufactures and Associations (IFPMA)
including companies in Japan, the United States, andEurope published a statement (10) to Japan's Prime
Minister Shinzo Abe in order to accelerate progress
towards UHC among all United Nations (UN) member
states. Following the G20, the first-ever UN High Level
Meeting (UN-HLM) on UHC was held on September
23rd, 2019, where a political declaration on UHC was
adopted by all UN member states. This marked a turning
point in the history of global health diplomacy, placing
UHC as a major issue not only in global health but for
the entire global community.
Bloom and colleagues of the T20 called on next
steps to be taken for UHC in advance to the G20 Osaka
Summit, highlighting that the G20 have made an effort
to facilitate crucial actions for UHC (6). However,after the G20 Osaka Summit, issues remain awaited tobe addressed in subsequent G20 meetings, requiringstrengthened visibility for political momentum towards
UHC and further understanding of perspectives orvarious global health stakeholders. There is also alack of evidence regarding these remained issues inrelations to the voices and statements of the G20 Osaka
Summit Engagement Groups. Therefore, we attempt toidentify UHC-related issues that were either addressedor left unaddressed at the G20 Osaka Summit. We also
reflected upon outcomes of the first ever UN-HLM on
UHC in September 2019, which followed after G20
Osaka Summit. Since then, much of the world's focus
has shifted to pandemic preparedness and response withthe emergence of COVID-19, but UHC remains to be a
crucial issue to ensure health equity and prevent further
health crises. Lessons learnt in this study were initiallyto be applied for at the G20 Riyadh Leaders' Summit inNovember 2020, yet they still remain as important lessons
to be reflected in future G20, as many of the issues havebeen undealt with to date. We provide our review tosubstantially leverage effective UHC in its next miles ofpolitical history of global health diplomacy, including theG20 Rome taking place in October 2021 (11).

We reviewed the G20 Osaka Leaders' Declaration (3),and policy-related statements and voices of the relevant
G20 engagement groups and sectors (the T20, C20,
H20, and the pharmaceutical sector). In addition, an
expert meeting was held by authors from the Institutefor Global Health Policy Research (iGHP), National
Center for Global Health and Medicine (NCGM) under
the purpose of discussing the addressed and unaddressedissues at the G20 Osaka. This meeting was held on July
30th 2019, which was after the G20 Osaka and before
the 2019 UN-HLM on UHC. The main speakers wereJapan-based UHC-related key global health stakeholders
from the G20, T20, C20, H20, and the pharmaceuticalsector. Information obtained through this expert meetingwere also fed into this paper by summarizing the voicesfrom the discussion and answers to common questions(on what were "suggested and agreed by the 2019 G20","issues not discussed enough at the 2019 G20", "issues
to be discussed at the 2019 UN-HLM", and "issues to be
discussed at the 2019 G20 Health Ministers Meeting").
We then classified the voices of the T20, C20, H20,
and the pharmaceutical sector by UHC-related topics:
health systems financing, service quality and delivery;
inclusiveness; innovation; operational cooperationand partnership; and prioritization and sustainability,
monitoring and evaluation. In addition, based on the
stances taken by each of the stakeholders, we plotted thedefinitional ranges of UHC and perspectives in relations
to the 2019 G20 Health Ministers' Meeting and the 2019
UN-HLM.
Varying understandings of UHC
Alongside the strengthened ministerial-level
collaboration between health and finance sectors in theoccasion of the G20 Osaka Leaders' Summit, diversified
voices were heard among stakeholders, around issues
related to monitoring and evaluation of progress towards
UHC, actor cooperation between global health andmedical entities, and partnership building. To take afurther step into the discussion, stakeholders voiced thehealth needs of refugees, migrants and other vulnerable
groups in achieving UHC, and the importance forrealizing sexual and reproductive health and rights(SRHR) through UHC. Variation in operative purposes
among global health stakeholders has resulted in varying
scopes of key understanding behind UHC.
Diversified voices on UHC with health-financecollaboration agreed to be G20 Osaka's key agenda
While the G20 Osaka Leaders' Declaration called
for greater collaboration between health and financeauthorities, where its commitment was affirmed by the(2)

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G20 Finance and Health Ministers during their firstever joint session at the G20 (12), diversified voices on
UHC were heard among stakeholders. The T20, H20,
and the pharmaceutical sector noted during our expert
meeting that this health-finance collaboration was oneof the key agendas suggested to the G20 (Table 1).
However, according to the T20, the G20 failed to discuss
enough on monitoring tools for prioritizing primary
health care (PHC)-based health systems and a common
mechanism to monitor UHC. The H20 brought up
remaining challenges in cooperation among key global
health actors, medical doctors, and medical associations(Table 2). The pharmaceutical sector emphasized theneed to establish of a new public-private partnership(PPP) dialogue platform. In relations to partnerships,
T20 emphasized the importance of effective coordination
for sustainable UHC. C20 called for a comprehensive
and effective review mechanism including independent
evaluation of UHC by the civil society. Furthermore, theH20 raised further need in health-finance ministeriallevel collaboration to promote UHC in developing
nations, and the pharmaceutical sector requested toensure commitment for progress towards UHC not only
among G20 countries but among all UN member states.

a priority on funding for SRHR and clearly indicatesthat it is crucial that leaders recognize the central roleof UHC in health emergencies and the need for robust
health systems to save lives (16). The governmental levelstatement highlights the need for essential health workers
and resources to respond to maternal and child mortality,
unmet needs for reproductive health commodities
including contraception, sexually transmitted diseases,
and unsafe abortion (16,17).
Variation in definition and scope of UHC among
stakeholders
The purpose of the UN-HLM and the G20 Health
Ministers' Meeting have dimensional differentials
in terms of definitional range of UHC, as well as its
perspective regarding aid allocation, here simplified bya binomial dimension on the y-axis: whether it is donordriven or is based on the recipient countries' needs andperspectives (Figure 1). In addition to the countryspecific definition of UHC with an absence of global
standardization (18), variation in operative purposes
between global health stakeholders led to a definitional
difference in the scope of UHC. As plotted on the x-axis,
the narrowest definition of UHC would be in line with
the Sustainable Development Goal (SDGs) 3.8, referringto indicators of service coverage and financial risk
protection, namely the gold standards in monitoring andevaluating UHC (19,20). On the other hand, some global
health actors recognize UHC as a broader concept, i.e.,
inclusive approaches of health-related issues in the SDGs
or sometimes beyond (21).
The UN-HLM aims to prioritize accountability overresource efficiency, a clear distinction in comparison
to the G20 Health Ministers' Meeting that served as anopportunity to discuss more technical issues regarding
health resource allocation. While the importance of
health as an agenda remains a small part in comparison
to other G20 agendas. The G20 holds an inclusive stancein pinning the UHC definition and does not restrict its
meaning to the narrow definition in SDG 3.8. As G20 iscomposed of advanced economies, we see its perspective
closer to donor driven on the y-axis. On the contrary,
the C20 presented a less donor driven perspective, andemphasized a further need for UHC to meet the needs ofthe socially and politically marginalized population. H20
was relatively similar to C20 in terms of perspective but
was more technically oriented to promote cooperation
between ministries of finance and ministries of healthin recipient countries. They had a particular focus on
health system strengthening and capacity developmentof human resources. T20 had a narrower definitional
range of UHC compared to other stakeholders, as theyemphasized the need for multisector cooperation among
government, and their voices were centered around
operational cooperation, partnership, and innovation.
Objectively, T20 had a more donor driven perspective

Inclusive UHC to address migrant health and sexual andreproductive health and rights
In response to the last G20, both C20 and T20 called fora recognition of refugees, migrants and other vulnerable
groups in achieving UHC (4,8). Migration and migrants'
wellbeing are critical issues of the twenty first century(13). The T20 further called for data and statisticalmanagement of migrant health to understand their needs
better and to be able to provide evidence-based policy
to address the health needs of migrants (6), but the G20
Osaka left this issue unaddressed. While the Financeand Health Ministers' meeting in G20 Osaka recognized
the need for "high quality primary healthcare services,
including immunization, as well as essential medicines,[made] accessible to everyone", the document did not
specify whether this includes migrants, regardless oflegal and documentation status. The last G20 meeting
seemed to only address UHC as a narrower scope thatconcerned only its citizens. The G20 countries, instead,can approach UHC from a human security perspective.
Having this perspective would be the first step to ensure
primary healthcare at an affordable cost to all, including
migrants independent of their migratory or legal status.
Realization of SRHR through UHC was anotherissue proposed by the C20 but left unaddressed at
the G20 Osaka Summit. Post G20 Osaka, SRHR was
brought up in the political declaration of the UN-HLM
in 2019 (14,15), and its necessity was re-emphasized by
the joint press statement developed by 59 government
agencies in response to SRHR and COVID-19 (16). The
statement raises the need for sexual health services with(3)

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Table 1. Voices of the T20, C20, H20, and the pharmaceutical sector on achievement of the G20 and undiscussed issues
Thematic area
Health systems
financing,
service qualityand delivery

Inclusiveness

Suggested and agreed by the G20 2019
VoicesT20 C20

Issues not enough discussed at the G20 2019
H20

Emphasizing health systemstrengthening while focusing on thequality of services
Strong PHC systems that canharness increased ageing and NCD
related issues (integrated nursing
and medicine with a communitybased, life-course approach)

P

*1

X

X

Strengthening human resource
capacity for health and policy
makersX

Strengthening of health systems
with a focus on quality both bypublic and private sectors

X

VoicesT20 C20 H20

Health financing to achieve UHC

X

Domestic financing for health thatreach the 5% GDP target or 15%
of national budget, and elimination
or minimalization of out of pocket
payment

X

Due to emergence of large
multinational IT platform companies
etc., financial redistributions among
nations are decreasing, by factors
such as the globalization of profit
structure, or base erosion and profit
shifting (BEPS). The fact that
the G20 Shared Understanding
mentions "financial capacity" and"progressivity" can be evaluatedpositively to some extent, but doubts
remain on its effectiveness.

X

Countries with heavy disease
burdens as well as political
economic crises should not be left
out of achievement of UHC

X

PHC for all people, especially forthe marginalized population

X

UHC should be grounded on humanrights-based approach, prioritizing
PHC, ensuring SRHR, responding togender-based violence, and adopting
a holistic approach to healthincluding nutrition and WASH

X

Documentation of migrants
including health workforce mobility.
Health protection for migrants.

X

Ensure UHC that leaves noone behind, including the mostvulnerable and marginalized
populations such as migrants andrefugees, sexual minorities, MSM,
sex workers, etc.

X

UHC that leaves no one behind,including socially and politicallymarginalized and vulnerable
populations

X

Human rights and human security asa basis for UHC

X

Innovation

Promotion of innovation throughpublic private partnership/ costeffective and appropriate digital
healthX

Operational
cooperation andpartnership

Cooperation between health andfinance ministers

X

X

Call for an effective partnership,
Effective coordination forsustainable UHC

X

X

Recommending multilaterals
and stakeholders to coordinate
effectively
Prioritization and Recognizing the need for sustainable
health financing
sustainability,
monitoring andEach country should achieve 5%
evaluation
GDP for spending on heath, donor
countries should achieve 7% ODA
target and prioritize health. Ensuresustainability of GF, GAVI andother multilaterals through sufficient
replenishment

X

Role of physicians and theirassociations to advocate and ensure
UHC

P*1

X

Establishment of new platform for
public and private (and academia)
partnership

X

X

X

X

X

Commitment to ensure UHC in
accordance with each country
situation

Monitoring tools for PHC-based
health system

X

Support for UHC indicator
calculation. Common UHC
monitoring mechanisms

X

X

*1

P: Pharmaceutical sector. Abbreviations: UHC: universal health coverage; PHC: primary health care; SRHR: sexual reproductive health rights;
WASH: water, sanitation and hygiene; MSM: men who have sex with men; GDP: gross domestic product; ODA: official development assistance;
GF: Global Fund; GAVI: Gavi, The Vaccine Alliance.

(4)

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Table 2. Voices of the T20, C20, H20, and the pharmaceutical sector on remaining challenges for the UN High-level
Meeting and G20 Health Ministers' Meeting, 2019
Thematic area
Health systems
financing,
service qualityand delivery

InclusivenessOperational
cooperation andpartnership

Issues to be discussed at the UN High-level Meeting 2019
VoicesT20 C20

H20

Issues to be discussed at the G20 Health Ministers Meeting 2019
P

*1

VoicesT20 C20 H20

Financing for UHC, particularly on
securing domestic financing andachieving 5% GDP target

X

Health financing, (Each country
should achieve 5% GDP for
spending on heath, donor countries
should achieve 7% ODA for health,and prioritize health in their ODA
policy)X

Recognizing the importance ofequitable system for revenue
collecting

X

Access to essential medicines
in developing countries, lower
price setting and securing of new
incentives

X

Ensuring access to medicine, by
ensuring low or no out of pocket
payment

X

Development of a process which
minimizes the negative impact
for middle income countries
transitioning from donor funding todomestic funding for health financeresources to ensure UHC

X

Capacity development of healthhuman resources as well as ofpolicymakers

X

Securing sustainable healthfinancing to ensure UHC

XStrengthening of health systems
with a focus on quality

X

Talent development for humanresources for health to ensure UHC

X

Recognition for the importance andimplementation of sustainable healthfinance

X

Basis for UHC (human rights
and human security), as well as
achieving UHC that leaves no one
behindEffective coordination forsustainable UHC

Recognition of civil society
involvement in achieving UHC

X

XFurther coordination between healthand finance ministries to ensure
UHC in developing countries

X

Documentation of migrants
including health workforce mobility,
health protection for migrants

X

X

Establishment of new platform for
public and private (and academia)
partnership

X

X

Commitment to achieve UHC by
all UN member states, not just G20
countries

X

Further coordination between healthand finance ministries

X

Establishment of the Global Action
by G20X

Prioritization and Holistic review mechanism of
UHC that includes an independent
sustainability,
evaluation by CSOs
monitoring andevaluation

PHC for all people, especially forthe marginalized population

Partnership between physicians andtheir associations and governments
as well as with WHO to ensure
UHC
X

P*1

X

Monitoring tools for PHC based
health system

X*1

P:Pharmaceutical sector. Abbreviations: UHC: universal health coverage; PHC: primary health care; GDP: gross domestic product; ODA: official
development assistance; WHO: World Health Organization; CSO: chief sustainability officer.

than C20 and H20, as the T20 suggested a strong
PHC system to harness issues such as ageing and noncommunicable disease, and public-private partnership.
Based on policy-related documents and voicesfrom multi-stakeholders (Tables 1 and 2), we identified
a narrower definition of UHC among T20 and H20,
compared to G20 and C20, having a focus on monitoring
UHC rather than evaluation for accountability. The T20

and H20 had a higher motivation to seek for further
efficient resource allocation, through improvementof UHC indicators and partnerships. Issues on healthinformation systems, especially for migrant health andtheir social security, were brought up by T20 as an issue
undiscussed at G20. The C20 took an inclusive approachboth in terms of UHC definition and donor-recipient
perspective with attention on expanding the quality and(5)

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Figure 1. Definitional range of UHC and perspectives by key actors in relation to positions of high-level meetings.
Abbreviations: UHC: universal health coverage; SDGs: Sustainable Development Goals; UN: United Nations; PHC: primary healthcare; SRHR: sexual and reproductive health rights; MoF: Ministry of Finance; MoH: Ministry of Health.

quantity of financing development assistance for healthto reach the vulnerable and marginalized population suchas migrants.

integrated definition that harmonize the vision andphilosophy of UHC between stakeholders, may be a key
issue for comprehensive commitment towards UHC.
Given our results, all actors need to ensure the ownershipof both donor and recipient countries among multistakeholders as well as a clearer UHC definition.
Despite the varying dependence and acceptance of
migrants and refugees among the G20 countries, theyrecognized the growing migration trend as noted in theleader's declaration (3). With about one seventh of theworld's population currently living in a country outsideof where they were born (22), international effort isneeded to explicitly address the health needs of migrants
and refugees and to include them in the individual
national health policies and plans in advancing "healthfor all" for UHC. In particular, healthy inequity that arise
from economic, administrative, cultural and language
barriers to healthcare that migrants face regardless of thelegal or migratory status (23,24), should be addressed.
The World Health Organization (WHO) also recognizedthat the SDG 3.8 on UHC cannot be achieved unlessthe health needs of migrants and refugees are met andhealth inequity is reduced (25). Yet, migrants' healthstill remain as a challenging issue as border control andhealth protection policies often have differing goals(26). Despite two World Health Assembly resolutions
dedicated to the health of migrants in 2008 and 2017(27,28), the United Nations General Assembly High Level
Meeting on Large Movements of Migrants and Refugees
in 2016, and the Global Compacts on Refugees and Safe,
Orderly and Regular Migration adopted in 2018, many
countries, including some of the G20 countries, do not

Challenges and solutions for a holistic understandingof UHC
Definitional differences in the scope of UHC among
stakeholders were identified in our study. These
differences pose challenge in attaining harmonization
between aid agencies as well as alignment between
donors and recipients and could further delay theachievement of UHC and the movement towards
fulfillment of the SDGs. Addressing marginalized issues,
such as migrant and refugee health and SRHR, within
the context of UHC is needed. Nevertheless, they were
unfortunately not brought up clearly as part of the official
declarations in the event of the G20 Osaka Summit. In
the future, understanding perspectives of the G20, T20,
C20, H20, and the pharmaceutical sector will become
increasingly important to well-coordinate multi-actor
cooperation with adequate social responsibility andtransparency in UHC achievement, to build a stronger
PPP.
Migrant health and sexual and reproductive health andrights as a key issue for comprehensive commitment
towards UHC
Amid the increase in multi-stakeholder platforms andpartnerships, addressing vulnerable populations andissues such as migrant health and SRHR through an(6)

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share a shared understanding on migrants' rights and do
not recognize global frameworks for safe migration that
protects migrants' welfare, including migrants' health. As
for the Global Compact for Safe, Orderly and Regular
Migration, which explicitly stated that health needs of
migrants and refugees should be incorporated in national
and local healthcare policies and plans, it was also notsigned by several countries including the United States
under the Trump administration (29), primarily due toeconomic and national security issues. Public healthemergencies like COVID-19 may pose an opportunity
for countries to re-examine the importance of extending
access to healthcare to migrants and refugees to curve
health inequity and combat health crises. For example,
the United States and many other nations offered
COVID-19 vaccines for free to all individuals residingin the country regardless of the immigration status(30). Such an understanding on the impact of the healthprotection of the vulnerable population should extend tothe coverage of other essential health services to drive
forward UHC.
The lack of international consensus on the definitionof SRHR as well as family planning driven from its
sensitiveness, makes its realization via a concept like
UHC difficult. Reproductive health and rights were
defined and agreed during the International Conference
on Population and Development (ICPD) in 1994 among
179 states. However, ICPD neither defined sexual
health nor explicitly referred to sexual rights while theconference assumed that reproductive health embraces
sexual health. There have been several attempts to define
sexual rights by some organizations, e.g. WHO (31)and the World Association for Sexual Health, but nodefinition has yet to reach an international consensus. The
lack of international consensus regarding SRHR also liedin the family planning approach, principally in the rightto safe abortion. Different beliefs have existed among
the G20 member states where some members holdnegative stances against for abortion. For example, theUnited States during the Trump administration decided
to withdraw its support for federal funding for overseas
family planning and reproductive health organizations
that provide abortion services or counselling (32). The
key for reaching an agreement on SRHR is to highlightseveral components of SRHR in association to a more
widely recognized human rights that have definitionalalignments of SRHR and family planning. It remainsa challenge to standardize the definition in relation todiverse interpretation of safe abortion. However, giventhat there are also many components that the member
states have already admitted, e.g. women and girls' rights
and health care for women before and after pregnancy
and childbirth, shedding more light on these areas would
serve as the first step for member states to realize at least
some of the components of SRHR through UHC.

and evaluation system
The UHC monitoring framework indicators, composedof service coverage (19) and financial risk protection(20) suggested by the WHO and the World Bank (WB)
in 2013 (33), emphasizes the need to implement national
evidence-based monitoring and evaluation systems that
aim to attain country-comparability and national data
representativeness (34). At the G20 Osaka Summit,
this was reemphasized by countries of strong economy
agreeing that investing in health at an early stage ofdevelopment was important for sustainable and inclusive
growth, thus encouraging developing countries tomobilize their domestic resources for UHC (4). At thesame time, the digitalization of health data to track UHC
indicators is needed, especially for developing nations
that do not have a sufficient amount of quality data
(18,34). Multi-stakeholder platforms and partnerships
took a step to the next level where international
coordination became more important, especially foraid recipient countries. International coordination is a
crucial challenge in investment for global health due tothe increasing role of the private financial sector actors(35). Financial outcomes of long-term funding among
government institutions and multilateral agencies could
lead to risk sharing among health infrastructure projects,
for example, with better credit ratings and lower cost ofcapital (36).
Building further multi-stakeholder platforms andpartnerships for UHC
In order to follow a global action plan for healthy lives
and well-being for all, all relevant stakeholders needto collaboratively make effort for UHC through multistakeholder platforms and partnerships to support theefforts of member states, not only to achieve UHC but
other health-related SDG targets. Multiple perspectivesof the G20, T20, C20, H20, and the pharmaceuticalsector need to be understood in order to well-coordinate
its cooperation for higher participation and transparency
in UHC achievement.
Furthermore, despite the countries' growing
motivation towards UHC at the national level, there isan essential need for multi-stakeholder platforms andpartnerships that ensure all donor and recipient countries
to have ownership to further enhance UHC. The UHC
2030 serves as a knowledge hub to deliver experiencebased or evidence-based resources bridging between the
WHO and the WB. Through the UHC 2030, WHO andWB have the fundamental aim to further work together
to share their strong networks with health ministers andfinance ministers, as well as to exchange knowledge on
health expertise and financial operations that are uniqueto their institutions.
In addition, finances need to be well coordinated,with synergy of traditional and innovative financing

Strengthening the national evidence-based monitoring(7)

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mechanisms, including the Global Fund to Fight
AIDS, Tuberculosis and Malaria (GFATM), Gavi, theVaccine Alliance (GAVI), Global Financing Facility
for Women, Children, and Adolescents (GFF), andthe UN Trust for Human Security. Also, international
platforms with innovative financing mechanisms via
public-private partnerships, such as the Global HealthInnovation and Technology Fund (GHIT), the Coalition
for Epidemic Preparedness Innovation (CEPI), and therecently developed Access to COVID-19 Tool (ACT)
Accelerator, should facilitate and propel the researchand development of vaccines, pharmaceuticals andother essential medical commodities. In addition, theseplatforms should help with the knowledge sharing ofresource mobilization to implementation through the lensof UHC in order to expand the service delivery of theseessential commodities.
With limited public funding in health development
assistance, the need for strengthening the partnerships
among government institutions, the private sector,
academia, and the civil society require enhanced
emphasis on achieving UHC through traditional andinnovative financing mechanisms. The coordination
between the Secretary-General of the UN and theMember States to achieve synergistically UHC andall health-related targets of the SDGs would be a way
forward in ensuring political momentum to achieve UHC
by 2030, and to capture UHC-related targets outside
SDG 3.8. including migrant health and SRHR.

comprehensive multi-stakeholder approach towards
UHC, which could in some cases require efficient
specialization between actors to overcome its definitional
difference. Second, incorporating important dimensions
such as the marginalized population and gender, inorder for the progress of UHC to respond to structuralinequity and leave no one behind, is important. Third,
investments toward health information systems andgovernance to track health data for the vulnerable
population and gender-responsive financing are effective,
as demonstrated during the global spread of COVID-19.
Suggestions for future G20 Leaders' Summit beyond
Riyadh from experiences of G20 Osaka
In order to take better action for UHC through future
G20 summits, there is a need for ensuring an integrated
yet comprehensive multi-stakeholder approach towards
UHC. This could in some cases require efficient
specialization between actors to overcome its definitional
differences. Definitional alignment among various
stakeholders is needed to reach international consensus
on further promotion of UHC, as well as to address
marginalized issues that have not been addressed at the
G20 Osaka Summit. While between-country dialogue
is crucial to effectively achieve UHC, dialogue on
UHC between multi-stakeholders may also be a key inunderstanding how countries could together bring UHC
to its next step.
Second, incorporating important dimensions suchas the marginalized population and gender, in order to
respond to structural inequity and leave no one behind,is important. In doing so, we need further commitment
towards migrant and refugee health based on what has
been agreed at the UN-HLM 2019, and towards SRHR
stemming further upon the joint press statement on
SRHR and COVID-19 agreed by government agencies
of 59 countries calling for gender-responsiveness andmultilateral efforts to respond well to COVID-19 (16).

Way Forward
At the time of writing, no G20 meetings have yet tothoroughly address the definitional differences identified
in our study, including the G20 Riyadh Summit in 2020
and the Global Health Summit, which had taken place inRome on 21 May 2021 as a pre-event of the G20 Health
Ministers' Meeting 2021 and the G20 Rome Summit
2021. In midst of responding to the surging pandemic,
the Leader's Declaration of G20 Riyadh Summit in 2020
noted that "well-functioning, value-based, inclusive,and resilient health systems are critical to move towards
UHC achievement", and emphasized "the importanceof UHC financing in developing countries" (37). The
Rome Declaration, which was published as an output of
the Global Health Summit in May 2021, underlined theneed of "sustained investments in global health, towards
achieving UHC with primary healthcare at its centre,"amongst others, and listed principles as voluntaryorientation for current and future action for global healthincluding guiding commitments for UHC in its relations
with the current pandemic and future potential publichealth emergencies (38,39). In conclusion, we raise thefollowing three major points to be addressed throughfuture G20 meetings, including the upcoming Rome
Summit in October 2021.
First, there is need of ensuring an integrated yet

Further ways of coordination for leadership towards
digitalization of health data and optimal resource
allocation
Third, investments toward health information systems
and governance to track health data for the vulnerable
population and gender-responsive financing are effective,
especially with the global spread of COVID-19.
Investments toward better health information systems
and governance to track health data are solutions
for better migrant and refugee health (40). Whilst
COVID-19 is pushing forward investments in healthfor all amongst many countries (41), there is a need
for well-coordinated health governance and policies
with the social protection systems to protect the poorest
and the vulnerable population groups that are facing
further financial hardships due to the pandemic (42). For(8)

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example, with the COVID-19 pandemic, continuation ofcurrent lockdowns has increased gender-based violence
and unintended pregnancies that require carefully
thought-out preventive policies and actions to meet the
SRHR needs (43-45).
Leadership towards digitalization of health records orinfectious disease tracking mechanisms could be driven
further by the technologically advanced countries andactors with a well-established PPP (46). For instance,
rapid efforts to harmonize and digitalize personal healthrecords for COVID-19 vaccine and negative PCR test
results certification has been led separately by WHO, theEuropean Union, and the World Economic Forum andthe Commons Project in the past year (47-49).
Japan, being the host country of the G20 in 2019,is in place to take these lessons on unaddressed issues,
to alert the international community and apply themto ensure effective UHC among the marginalized andvulnerable population. Given the circumstance of low
priority on women and children in UHC strategies (50),G20 counties like Japan with a comparative advantage
in information technology face a great amount ofopportunity to collaboratively create new platforms andbusiness models for digital health locally, regionally,
and globally. This would lead to Japan and other G20
countries taking a further leadership role for UHC, inorder to make sure that the UHC concept is adapted toevery population and secures human rights for health.
The enhanced leadership could be enforced by different
key actors mentioned in this paper as well as by working
with the private sector.
Leadership towards digitalization of disease
comprehensive health records and its tracking
mechanisms via data linkage of individual health records
should be driven further not only by health authorities,
but also among coordination with humanitarian and nonhealth authorities, including agencies such as United
Nations High Commissioner for Refugees (UNHCR),
United Nations Relief and Works Agency for Palestine
Refugees in the Near East (UNRWA), or the International
Organization for Migration (IOM). Health systems
governance and financing require collaboration among
multi-stakeholders that quickly respond to healthemergencies and allow optimal allocation of existing
budgets simultaneously, which could be facilitated by
PPP, yet a good balance of input among other supporting
actors. From the G20 Osaka, the UN-HLM on UHC(September 2019), and G20 Health Ministers' Meetingin Okayama (October 2019), and the 2nd UHC Forumin Bangkok (January – February 2020), among others,
UHC has continued to be acknowledged and highlighted
as a key health issue globally. Along with future G20
summits, forthcoming milestones beyond G20 Riyadh
Leaders' Summit are nearing, including the G20
Rome Leaders' Summit in October 2021, along withconsecutive large events planned in Tokyo during 2021
and beyond. For better global health governance, Japan's

experiences in leading the 2019 G20 shows challenges
and future opportunities to align the definitional
disparities between various stakeholders to accelerate
inclusive political momentum for UHC, and to ensuresustainable commitment towards UHC from bothdeveloped and developing nations. These lessons should
be applied in the future G20 meetings, as the world
leaders convene in Rome in October 2021 to discuss
the health of the global community in the COVID-19
pandemic and post-pandemic worlds.
Acknowledgements
We would like to extend our gratitude to an anonymous
contributor for their invaluable inputs in theconceptualization, design, drafting and development of
the manuscript. We would also like to thank the membersof the expert meeting on UHC in Japan, including
those from the Government of Japan, think tanks, civilsociety organizations, Japan Medical Association, andthe pharmaceutical sector, as well as expert contributors,
for having participated in the meeting and offering
helpful comments and suggestions during the meeting.
The members of the expert meeting are listed in the
Supplementary Table 1 (https://www.ghmopen.com/site/
supplementaldata.html?ID=30).
Funding: None.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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---Received April 17, 2021; Revised August 19, 2021; Accepted
August 31, 2021.
Released online in J-STAGE as advance publication September
29, 2021.
*Address correspondence to:
Aya Ishizuka, Institute for Global Health Policy Research(iGHP), National Center for Global Health and Medicine, 1-211 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
E-mail: aishizuka@it.ncgm.go.jp(11)Review

GHM Open. 2022; 2(1):12-24.
DOI: 10.35772/ghmo.2022.01000

Effects of self-management interventions with behavior-change
support on long-term adherence in patients with chronic respiratory
diseases: A systematic review
Mihoko Fujii1,*, Jiro Nakano2, Yoshiharu Tanaka3, Akiko Tonosaki3
1

Doctoral Program in Nursing, National College of Nursing, Japan;
Faculty of Rehabilitation, Kansai Medical University, Osaka, Japan;
3
National College of Nursing, Japan.
2

Abstract: The aim of this systematic review is to determine the effects of self-management interventions withbehavior-change support on medication adherence and smoking cessation in patients with chronic respiratory
disease. We also describe the theories of health behavior change and behavior change techniques (BCTs) used todesign these interventions and their mode of delivery. The PubMed/MEDLINE, Cochrane Library, CINAHL, andPedro databases were systematically searched for relevant articles published up to November 2021. Randomized
controlled trials (RCTs) that evaluated the effect of self-management interventions with behavior change support
on medication adherence, correct inhaler use, and smoking cessation were included. Effect sizes (odds ratios) with
95% confidence intervals were calculated and pooled for random-effect meta-analysis. Of 5,223 articles identified,
15 were RCTs that met the inclusion criteria for the meta-analysis. Five of these RCTs were based on behavior
change theory, including social cognitive theory and a transtheoretical model. Between one and eight components
of BCTs in Behavior Change Technique (BCT) Taxonomy version1 were included in all interventions. The mostfrequent BCT components were social support (emotional) (n = 8), instruction on how to perform the behavior (n= 8), and goal setting (behavior) (n = 7). Meta-analysis showed that self-management interventions with behavior
change support have positive effects on medication adherence, correct inhaler use, and smoking cessation for morethan 6 months after their implementation. This indicates that individually tailored self-management interventions
with behavior change support are effective in improving long-term medication adherence and smoking cessation inpatients with chronic respiratory disease.
Keywords: behavior change theory, health science, behavior change techniques, self-care

Introduction

It has been suggested that interventions based on
behavior change theory are more effective in improving
adherence in people with chronic respiratory disease(4,5). Since the 1990s, studies in Japan and overseas
have reported that approaches for enhancing selfefficacy are effective in changing patients' behavior, andthe use of these approaches became more widespread in
the 2000s (6). The respiratory rehabilitation statement
published in Japan in 2018 stated that education on selfmanagement for patients with respiratory disease should
support behavior change to promote and maintain healthand increase adherence (7). COPD was one of the
major chronic respiratory diseases highlighted in HealthJapan 21 (second term) (8), and there is an increasing
focus on the importance of preventing exacerbations
and disease progression. However, there is limited
information on the long-term effects of behavior changeinterventions based on behavioral science on medication

Medication adherence and smoking cessation are
essential components of managing patients with chronic
respiratory disease. According to the World HealthOrganization, adherence to long-term therapy is definedas the extent to which a person's behavior – taking
medication, following a diet, and/or executing lifestyles
changes – corresponds to agreed recommendations
from a health care provider (1). However, adherence
is influenced by social and economic factors, thecharacteristics of the disease, and patient-related factors(1). Adherence to medication is less than 50% in many
patients with chronic obstructive lung disease (COPD)
because of patient-related factors, which include
depression and beliefs and concerns about medication(2). Lack of confidence in inhaler use is also associatedwith lower adherence in these patients (3).

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adherence and smoking cessation from meta-analysisof randomized controlled trials (RCTs). Moreover, there
are limited data on the components of behavior changeintervention that are effective.
This systematic review aimed to determine the longterm effects of self-management interventions withbehavior change support on medication adherence andsmoking cessation in patients with chronic respiratory
disease by meta-analysis of RCTs. We also aimed to
identify the extent to which behavior change theory and
BCTs have been implemented, the mode of delivery
used for the interventions (how: place of delivery,
provider, delivery format) and the components ofinterventions (what). We also investigated the effectsof correct inhaler use, which is another importantcomponent of medication adherence by meta-analysis.

who followed the steps for inhaling medication fromthe inhalation device correctly. Studies that reported
medication adherence and smoking cessation were
included even if these were not the primary outcomes.
The eligibility criteria were as follows: intervention
that can be implemented at home with selfmanagement; study participants aged 18 years or older;chronic respiratory disease diagnosed by a physician;
implementation of a psychological or behavioral selfmanagement intervention or mention of the term"behavior change", "health behavior" or "behavioral
intervention"; outcome assessment at more than 6months the start of intervention; and a full-text version
published in English.
Exclusion criteria
Studies that targeted a combination of respiratory andnon-respiratory diseases were excluded, as were thosepublished as quasi-randomized trials, systematic reviews,
letters, editorials, cross-sectional studies, and casereports.

MethodProtocol and objective
This systematic review is reported according to thePreferred Reporting Items for Systematic reviews andMeta-Analyses (PRISMA) 2020 statement (9) but was
not registered in advance.

Outcome measurements
Eligible studies from the literature search could use
self-report or objective measurements for medication
adherence, and self-report or biochemical verification
for smoking cessation.

Literature search and study inclusion process
Search strategy and databases
The PubMed/MEDLINE, Cochrane Library, CumulativeIndex to Nursing & Allied Health Literature (CINAHL),
and Pedro databases were searched to identify relevant
articles published up to November 2021. The searchstrategy was adapted to each database, and the searchterms are shown in Table 1.

Data extraction
Three reviewers (JN, AT, MF) independently screened
titles and retrieved abstracts to identify studies that met
the inclusion criteria. Full-text screening was performed
for studies that could not be confidently excluded. The
full texts of potentially eligible studies were retrieved
and assessed for eligibility by one reviewer (MF).
Disagreements and questions were resolved by consensus
at discussion meetings attended by all reviewers.
The individual components of the behavior changeintervention described in the included studies wereextracted and classified in accordance with the BCTTaxonomy version 1 (BCTTv1) (10,11), which wasdeveloped to identify individual components of behavior
change interventions and enable accurate reporting andreplication of content.

Inclusion criteria
RCTs (including feasibility and pilot studies) that
evaluated the effects of self-management interventions
supporting behavior change on medication adherence,correct inhaler use, and smoking cessation were sought.
Medication adherence was assessed by the numberof participants who were adherent. Correct inhaler
use was assessed based on the number of participants

Table 1. Search terms used in electronic database search
Search terms

PICs component
Patient"chronic respiratory disease", "chronic respiratory failure", "Respiratory Tract Disease", "Respiratory Tract Disorder","Respiratory Disease", "Lung Disease", "Chronic Lung Disease", "Pulmonary Disease"

Intervention"behavior therap*", "behaviour therap*", "behavior change", "behaviour change", "behavior modification", "behaviour
modification", "behavior intervention", "behaviour intervention", "behavioral intervention", "self manag*", selfmanagement, self-care, self-car*, self-report*, home-based, home

Comparison

trial, randomized, RCT*

the wildcard character.

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respectively (13). In the case of high heterogeneity (I2> 75%), a subgroup analysis was performed to identify
any valid causes. A sensitivity analysis was conducted
if necessary.

Quality assessment
The quality of the studies was assessed using the
Cochrane Collaboration's tool for assessing the risk ofbias (version 2.0). This tool includes five or six domainsof bias depending on the method used for randomization.
Five domains are used for parallel-group trials inwhich study participants are individually randomized:
bias arising from the randomization process, bias due
to deviations from intended interventions, bias due
to missing outcome data, bias in measurement of theoutcome, and bias in selection of the reported result. A
sixth domain, namely, bias arising from the timing ofidentification and recruitment of participants, is added forcluster-randomized trials. The risk of bias was assessedby two authors (YT, MF) working independently. Any
disagreements were resolved by discussion; if a decision
could not be reached, a final decision was made at aconsensus meeting attended by all the authors.

Results
Study selection
The literature search up to November 2021 identified
9,528 records, 4,305 of which were found to be
duplicates and were excluded. After screening of titles
and abstracts, 5,031 studies were excluded, leaving
192 for full-text review. From the results of the review,
158 studies were excluded based on the eligibility
criteria and 19 were excluded because their data werereported in an inappropriate format. Finally, data could
be extracted from 15 studies that met the eligibility
criteria. The outcome of the search process and study
selection is shown in Figure 1.

Statistical analysis
All statistical analyses were performed using Review
Manager (RevMan) version 5.4. (12). Odds ratio (OR)were calculated along with their 95% confidence
intervals (CIs). Assuming a degree of heterogeneity
between the interventions, the data were pooled usinga random-effects model. Statistical heterogeneity
between study outcomes was assessed using the I 2
statistic according to the method outlined by Higgins etal. (13). I2 values of 25%, 50%, and 75% are considered
to indicate low, moderate, and high heterogeneity,

Study characteristics
Overview of studies
The characteristics of the 15 studies are summarized inTable 2. All the studies were published between 2004
and 2021. Two studies each were performed in China(14,15), Israel (16,17), the Netherlands (18,19), and theUK (20,21); one study each was performed in Australia(22), Denmark (23), Iran (24), Jordan (25), Spain (26),Figure 1. PRISMA flow-diagram of the study selection process.

(14)

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Control:
Received standard informationon the benefits of smoking
Usual care:
Pharmacological prescriptions
and treatment followed thestandard protocols of the center

Usual care:
Continued to receive usual-carefrom GPs

Usual care:(Not described in detail)Control group:(Not described in detail)

Usual care:
Received a standard information
leaflet about self- managementof COPD

COPD (admitted with acute exacerbation)
FEV1 %: Male: Ex 35%, Con 36%
Mean Age: Ex 65, Con 67

COPD
FEV1 1.2 ± 0.5L
Male 86 %,Age 73 ± 8

Asthma, COPD or mixed
Pre-FEV1 % predicted:
Ex 81.9 ± 22.6
Con 84.7 ± 23.4
Male: Ex 35%, Con 28%
Age: Ex 49.9 ± 14.2, Con 44.7 ± 13.6

COPD
FEV1 %: Male: Ex 46.3%, Con 55.4%
Age: Ex 58.0 ± 12.1, Con 60.1 ± 11.5

COPD
FEV1 predicted (%)
Ex 53.7 ± 15.9, Con 52.8 ± 17.8
Male: Ex 39.4%, Con 41.8%
Age (median, IQR):
Ex 61(14), Con 64(15)COPD
meanFEV1 predicted (%): 71.6%
Male: EX 63%, Con 64%
Mean Age:
Ex 70.7 ± 8.8, Con 70.2 ± 7.8

Borglykke et al.,2008 (23)

Garcia-Aymerichet al., 2007 (26)Hesselink et al.,2004 (18)

Hilberink et al.,2005 (19)Jarab et al., 2012(25)

Jolly et al., 2018(20)

Telephone health coaching intervention:
Telephone coaching session for 35-60 min, 15-20 min telephonesessions at weeks 3, 7, and 11, providing standard written
prompts or information at weeks 16 and 24
Home; Nurses

Pharmaceutical care program:
Intensive education (no repeated process) making a medicationtable, discussion about the importance of exercise, symptom
control and techniques for expectoration, providing a booklet
Outpatient clinic; pharmacist

Smoking Cessation in patients with COPD (SMOCC):
A 4-h group training session, outreach visits and telephone
calls depending on the motivational stage, delivering support
materials
General practices and home; GP and nurses

Education program:
One to four 30-min semi-structured consultations (giving
information, individual training regarding inhalation technique,discussion about barriers in coping with the disease, a supportive
smoking cessation program, advice about when to consult adoctor, provide free booklets)
Primary care setting; general practice assistants

Integrated care (IC):A 2-h educational session at discharge, individually tailored careplan (visit patient's home within 72 h after discharge, weekly
phone calls during the first month after discharge, and one phone
call at 3 and 9 months after discharge), access through an ICT*2
platform
Primary care setting and home; physician, nurse, social worker

Smoking cessation groups (SCG):
Weekly 2-h sessions over 5 weeks, three sessions after thequitting date, follow-up session after 3 months
Hospitalized setting; nurses

Intervention
Component, delivery place, who delivered

SocialCognitive
TheoryNot
described

Trans
theoreticalmodel/

Not
described

Not
described

Not
described

TheoryAttempted to quit
smoking in past 6 month/self-report

Medication adherence(Morisky Scale)/self-report

Point prevalence/
self-report andbiochemical analysis

Inhalation technique/checklist developed by
the Dutch Asthma
Foundation,
medication use/threeitem checklist

Medication adherence
scale, Inhaler Adherence
Scale, observed skills foradministration of inhaled
drugs

Smoking cessation rate/
Self-report andcarboxyhemoglobin

Outcome/measurement

12M

6M

6M

2Y

12M

1Y

End
point

Abbreviations: Ex, experimental; Con, control; COPD, chronic obstructive pulmonary disease; ICT = information and communication technologies; NRT, nicotine replacement therapy; SPACE, Self-Management Programof Activity, Coping and Education; Y = years; M = months.

Comparison

Participants(illness, lung function, sex, age)

Author, year (Ref.)

Table 2. Characteristics of studies included

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(16)Received the usual or routine COPD
care

Usual care:
Arranged by the hospital without any
structured interventions

Usual care:
Continued to provide routine care,given the Lung Foundation Australia
booklet. Quitline referral was provided
to smokers.

Usual care:
Treated in the usual manner

COPD
FEV1 % predicted
Ex 37.8 ± 12.4, Con 36.4 ± 12.3
Male: Ex 69.4%, Con69.8%
Age: Ex 67.3 ± 8.9, Con 66.6 ± 9.6

AsthmaFEV1 %:Ex 72.4 ± 15.2, Con 69.2 ± 14.4
Male: Ex 43.2%, Con 38.6%
Age >60: Ex 25.2%, Con 21.6%

COPD
FEV1 % predicted
Ex 69.0 ± 20.5, Con 70.8 ± 19.3
Male: Ex 60.5%, Con 62.6%
Age: Ex 66.6 ± 10.8
Con 61.7 ± 10.1

COPD
FEV1 %: Male: Ex 48%, Con 48%
Age: Ex 61.6 ± 10.2
Con 61.5 ± 10.1

Kessler et al.,2018 (28)

Khdour et al.,2020 (16)Liang et al.,2019 (22)Lou et al.,2013 (14)Behavioral intervention program:
Brief smoking cessation advice and discussion for 5-8 min, home
visits at least once a week, follow-up once a week during the firstmonth and once a month until the end of the study, providing abookletHealthcare centers and home; general practitioners

Interdisciplinary primary care:
Individualized smoking cessation support consisted of briefcounseling and "quitline" referral, prescription medications for
smoking cessation, interview at home by pharmacist, education
focusing on medication use, an 8-week home-based pulmonary
rehabilitation consisting of one home visit and weekly follow-up
telephone calls.
General practitioners, clinic staff, pharmacist, physiotherapist

Pharmaceutical care in asthma management:
Adherence assessment and education on an individual basis,
inhaler techniques training, follow-up telephone calls, provide
action plans, written medication lists and an asthma manual
bookletOutpatient clinic and home; Pharmacist

Multicomponent home-based disease management intervention(COMET):
Four individual home sessions over 5 weeks, monthly group orindividual telephone sessions for 12-24 months, home monitoringat least once per week, an e-health telephone/web platform.
Home; case managers and hospital physician

Recommended care plus disease management
Disease management:
Face-to-face sessions during patients' visits, remote contacts
between visits, monitoring disease signs and symptoms,
educational sessions for caregivers
Community-based COPD centers; pulmonologists and nurses

Intervention
Component, delivery place, who delivered

Not
described

Not
described

Concernand beliefs

Not
described

Not
described

TheoryContinuous smoking
abstinence rates/
Self-report and expired
carbon monoxide level

7-day point prevalencesmoking abstinence/biochemical analysis

Medication adherence/
Morisky Scale, Inhaler
technique/Standardized
checklists

Smoking habits/
measurement: notdescribed in detail

Quit smoking/patients' reports

Outcome/measurement

4Y

6M

12M

12M

3Y

End
point

Abbreviations: Ex, experimental; Con, control; COPD, chronic obstructive pulmonary disease; ICT = information and communication technologies; NRT, nicotine replacement therapy; SPACE, Self-Management Programof Activity, Coping and Education; Y = years; M = months.

Recommended care alone:
Received selfcare education, followup by pulmonologists, treatment
with medication and oxygen, dietaryadvice, psychosocial support,
smoking cessation group sessions andprescriptions for smoking cessation
medications, physical exercise sessions

Comparison

COPD
FEV1 % predicted
Ex 43.8 ± 10.8
Con 44.1 ± 10.0
Male: Ex 69.0%, Con 73.3%
Age: Ex 66.7 ± 9.9
Con 68.3 ± 10.0

Participants(illness, lung function, sex, age)

Kalter-Leibovici
et al., 2018 (17)Author, year (Ref.)

Table 2. Characteristics of studies included (continued)

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Control group:
Mobile health application program:
Received routine care, which Knowledge and information support, visual aids to teach participants skills
included health education
to manage the disease, motivational support(Not described in detail)
Usual care:
Received resources provided
by their clinic

COPD
FEV1 % predicted
Ex 43.7 ± 13.2, Con 45.4 ± 11.5
Male: Ex 66.7 %, Con 74.4%
Age: Ex 63.2 ± 7.5, Con 64.4 ± 7.0

COPD
FEV1 % predicted: 58 ± 20
Male: 65.5%
Age: 61.3 ± 7.6

Wang et al.,2021 (15)Willard-Graceet al., 2020 (27)

(17)

Not
described

Not
described

Trans
theoreticalmodel

Readiness
to change

TheoryMedication adherence/patient-report,
inhaler use/
observation and checklist

Smoking abstinence/
self-report

Smoking abstinence/
self-report

Smoking status/
Self-report

Outcome/measurement

9M

12M

29W

6M

End
point

Abbreviations: Ex, experimental; Con, control; COPD, chronic obstructive pulmonary disease; ICT = information and communication technologies; NRT, nicotine replacement therapy; SPACE, Self-Management Programof Activity, Coping and Education; Y = years; M = months.

Health coaching intervention:
Accompanied to visits with clinicians, met individually in the community
or at their home, telephone calls at least once every three weeks
Primary care setting and home; health coaches, pulmonary specialists

Guided self change + NRT:
Five 1-h sessions over 5 weeks, including individual counseling, NRT,
telephone follow ups
Hospital and home; psychotherapist

NRT

COPD
FEV1 act:
Ex 1.91 ± 0.7, Con 1.94 ± 0.74
Male: 100%
Age: Ex 54 ± 8, Con 56 ± 10

Sharifpour et al.,2020 (24)Intervention
Component, delivery place, who delivered
SPACE for COPD:
Work with SPACE for COPD manual over 6 weeks, a 30-45 min
consultation, telephone calls at 2 and 4 weeks
Primary care settings and home; physiotherapist

Comparison

COPD
Usual care:
FEV1 % predicted(Not described in detail)Ex 56.04 ± 16.76, Con 59.60 ± 17.42
Male: Ex 60.6%, Con 49.4%
Age: Ex 69 ± 8.0, Con 69 ± 10.1

Participants(illness, lung function, sex, age)

Mitchell et al.,2014 (21)Author, year (Ref.)

Table 2. Characteristics of studies included (continued)

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and the US (27); and one study was a collaboration ofEuropean countries (France, Germany, Italy, and Spain)(28). The period between the start of the intervention
and the final follow-up ranged from 6 to 48 months. Theinterventions were delivered by various health-related
occupations.
Most commonly, in 12 studies, the intervention
was conducted on an individual basis from the start ofthe intervention or was group-based with follow-up
on an individual basis (14,15,16,18-22,24,26-28), andfollow-up was carried out by telephone in 10 studies(15,16,19,20-22,24,26-28). One of these studies also
used information and communications technology and a
web platform (28).

(14,19,22-26) did not use the GOLD classification.
Three of the studies, namely those by Garcia-Aymerichet al. (26), Borglykke et al. (23), and Wang et al. (15),included patients admitted with symptoms of acuteexacerbation; the remaining four studies did not report
the criteria used to determine severity.
Assessment of outcomes
The measurement methods used are summarized inTable 2.
Medication adherence was assessed by aquestionnaire in three studies (16,25,26), a standardized
checklist in one study (18), and by direct interview inanother study (27). For the purposes of this review,
the authors extracted the number of patients who werereported as adherent with medication from each study.
Correct inhaler use was evaluated by observation
using a checklist in two studies (16,27) and byobservation only in one study (26). Data for anotherstudy (20) that reported the number of participants who
received an inhaler check followed by recommendations
was also included in the meta-analysis.
Smoking status and abstinence rates were measured
by self-report in nine studies, four of which also included
biochemical verification (14,19,22,23). Only two of thesestudies defined smoking cessation (i.e., abstinence fromcigarettes during the previous 7 days) (19,22).

Illness and severity
The most common respiratory disease was COPD
(14,15,17,19-28) followed by asthma (16,18), and mixed
COPD-asthma (18) (Table 2). Five of the 11 studies
targeting patients with COPD (17,20,21,27,28) described
the severity of COPD according to the Global Initiative
for Chronic Obstructive Lung Disease (GOLD) guideline(29), which was used as the basis for the Guideline for
the Management of Chronic Obstructive Pulmonary
Disease published by the Japanese Respiratory Society(30). The study by Jolly et al. (20) targeted patients with
mild-to-moderate COPD. Mitchell et al. (21) included
all stages of COPD, with the majority (60.3%) ofpatients classified as having moderate disease. KalterLeibovici et al. (17) and Kessler et al. (28) only included
patients with severe COPD; severe exacerbations werealso included in the study by Kessler et al. (28). The
study by Willard-Grace et al. (27) targeted patients withmoderate-to-severe COPD. The remaining seven studies

Quality assessment
The results of the quality assessment using the Cochranerisk of bias tool are shown in Figure 2. An individually
parallel randomized tool was used in 12 studies anda cluster parallel randomized tool was used in threestudies. The most common types of bias identified were

Figure 2. Risk of bias of individual domains across included randomized trials. (A) Individually randomized trials; (B)Cluster-randomized trials.

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bias due to deviations from intended interventions, bias
in measurement of the outcome, and bias in selectionof the reported result. All methods used to measure
medication adherence and most of those used to measuresmoking cessation adherence were based on selfreported questionnaires. This is one of the limitationsof this review. However, bias arising from deviations
from intended interventions was unavoidable because
all study participants would have been aware of theirassigned intervention during the trial. Bias in terms of
selection of the reported result reflects the fact that mostof the details concerning the research protocols usedwere not available.

that the number of participants who quit smoking was
significantly higher in the intervention group than in thecontrol group (OR: 2.91, 95% CI: 1.20-7.06, p = 0.02;
Figure 3).
The statistical heterogeneity was high (I2 = 92%)
and was explored by sensitivity and subgroup analyses.
The sensitivity analysis was performed by removing
each study one by one and confirmed that the result was
not markedly affected by any single study. Subgroup
analyses were conducted to separate studies according
to severity of illness, differences in components of theintervention, outcome measurements, and duration offollow-up. When the studies were grouped by severityof illness, there was a distinction between studies that
included patients with severe or exacerbated COPD
(15,17,23,28) and those that included all stages of
COPD (14,19-22,24). The sub-group analyses showedthat the intervention improved adherence to smoking
cessation among only participants with severe orexacerbated COPD (OR: 2.57, 95% CI: 1.54-4.28, p= 0.0003; Figure 4). Other subgroup analyses did not
significantly change the heterogeneity.
ii) Medication adherence
Five studies were subjected to random-effects
meta-analysis (16,18,26,27). These studies included
725 participants (intervention groups, n = 353; control
groups, n = 372).
Pharmacological support was the only intervention
in three studies (16,25,27) and part of a multicomponent
intervention in two studies (18,26).
Meta-analysis showed that the number of adherent
participants was higher in the intervention group thanin the control group (OR: 2.27, 95% CI: 1.57-3.27, p <0.0001; Figure 5). The statistical heterogeneity was low(I2 = 0%).
iii) Correct inhaler use
Five studies were included in a random-effects
meta-analysis (16,18,20,26,27). These studies included
1,104 participants (intervention groups, n = 533; control
groups, n = 571). The meta-analysis showed that the
number of participants who used their inhalers correctly
was higher in the intervention group than in the control
group (OR: 4.07, 95% CI: 1.66-9.96, p = 0.002; Figure6). The statistical heterogeneity was high (I2 = 88%)and explored by sensitivity and subgroup analyses. A
sensitivity analysis, which was conducted by removing
a study one by one showed that the result was notmarkedly affected by any single study. Subgroup
analysis according to type and severity of disease did
not change the I2 value.

Behavior change theories or techniques used in selfmanagement interventions
One study used social cognitive theory (20), three useda transtheoretical model that included readiness tochange (19,21,24), and one mentioned considerationof participants' concerns and beliefs but did not reportapplication of a specific theory (16) (Table 2). Tenstudies did not mention behavior change theory.
Between one and eight BCTs categorized withreference to BCTTv1 were included in all interventions(Table 3). Overall, the most frequent BCT components
were social support (emotional) (n = 8), instruction on
how to perform the behavior (n = 8), and goal setting(behavior) (n = 7).
The most frequent components for promoting
behavior change and adherence with medication were
instruction on how to perform the behavior (n = 5)
(16,18,20,26,27), followed by goal setting (behavior) (n= 3) (16,20,27) and problem solving (n = 3) (18,20,27).
For smoking cessation, social support (emotional)(n = 6) (14,15,17,21,22,24) was used mostfrequently, followed by goal setting (behavior) (n= 5) (14,19,20,23,24) and pharmacological support(n = 5) (17,19,22-24). Of the five studies that usedpharmacological support, two also included thiscomponent for the purposes of comparison between
groups (17,24).
Effects of self-management based on behavior changeinterventions to promote adherencei) Smoking cessation
Ten studies were included in a random-effects metaanalysis (14,15,17,19-24,28). These studies included
5,406 patients with COPD (intervention groups, n= 2,838; control groups, n = 2,568). In four studies(14,19,23,24), all participants were smokers at baseline
and received self-management intervention specificallyfor smoking cessation. In the other six studies(15,17,20-22,28), not all participants were smokers;
in these studies, smoking cessation was included aspart of a multicomponent intervention and the only
data provided for smoking cessation was for patients
who were smokers at baseline. Meta-analysis revealed

Discussion
Previous systematic reviews in patients with chronic
respiratory diseases have shown that behavior change
support is effective in improving adherence (4,31).
However, the present systematic review is the first

(19)

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2.1. Monitoring of behavior byothers without feedback
2.6. Bio feedback

2.3. Self-monitoring of behavior

2.2. Feedback on behavior
2.3. Self-monitoring of behavior

2.2. Feedback on behavior

1.4. Action planning

1.1. Goal setting (behavior)
1.2. Problem solving

1.1. Goal setting (behavior)
1.2. Problem solving

2.1. Monitoring of behavior byothers without feedback
2.7. Feedback on outcomes of
behavior
2.6. Biofeedback

2.2. Feedback on behavior
2.3. Self-monitoring of behavior

2.5. Monitoring of outcomes of
behavior without feedback

2. Feedback and monitoring

1.1. Goal setting (behavior)

1.3. Goal setting (outcome)1.4. Action planning
1.1. Goal setting (behavior)
1.4. Action planning

1.1. Goal setting (behavior)
1.2. Problem solving
1.5. review behavior goal
1.4. Action planning

1.1. Goal setting (behavior)
1.2. Problem solving

1.2. Problem solving

The numbers are classification numbers of BcTTv1.

Mitchell et al.,2014 (21)Sharifpour et al.,2020 (24)
Wang et al.,2021 (15)Willard-Graceet al., 2020 (27)Kessler et al.,2018 (28)
Khdour et al.,2020 (16)Liang et al.,2019 (22)Lou et al.,2013 (14)Kalter-Leibovici
et al., 2018 (17)1.1. Goal setting (behavior)

Borglykke et al.,2008 (23)
Garcia-Aymerichet al., 2007 (26)Hesselink et al.,2004 (18)
Hilberink et al.,2005 (19)Jarab et al.,2012 (25)
Jolly et al.,2018 (20)1.4. Action planning

1. Goals and planning

Author, year (Ref.)

Table 3. Frequency of behavior change techniques identified in trials

4.1. Instruction on how to
perform the behavior
4.1. Instruction on how to
perform the behavior

3.3. Social support (emotional)

3.3. Social support (emotional)

4.1. Instruction on how to
perform the behavior

4.1. Instruction on how to
perform the behavior
4.1. Instruction on how to
perform the behavior

4.1. Instruction on how to
perform the behavior

4.1. Instruction on how to
perform the behavior
4.1. Instruction on how to
perform the behavior

4. Shaping knowledge

3.3. Social support (emotional)

3.1. Social support (unspecified)
3.3. Social support (emotional)

3.3. Social support (emotional)

3.3. Social support (emotional)

3.3. social support (emotional)

3.3. Social support (emotional)

3.1. Social support (unspecified)

3. Social support

5.4. Monitoring of
emotional consequences

5.1. Information about
health consequences
5.2. Salience ofconsequences

5.1. Information about
health consequences

5. Natural consequences

11.1. Pharmacologicalsupport11.1. Pharmacologicalsupport11.1. Pharmacologicalsupport11.1. Pharmacologicalsupport11.1. Pharmacologicalsupport

11. Regulation

12.4. Distraction

12. Antecedents

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Figure 3. Meta-analysis to estimate the effect of self-management interventions with behavior support on smoking
cessation.

Figure 4. Sub-group analysis of smoking cessation grouped by severity of illness.

Figure 5. Meta-analysis to estimate the effect of self-management interventions with behavior support on medication
adherence.

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Figure 6. Meta-analysis to estimate the effect of self-management interventions with behavior support on correct inhaler use.

to examine the long-term effects of self-management
interventions with behavior change support to improvemedication adherence, smoking cessation, and correct
inhaler use in patients with chronic respiratory disease.
It is also the first aiming to classify the contents ofinterventions by behavior change technique (BcTTv1).
All three components are essential for these patients tobe able to manage their disease. Our findings suggestthat interventions with behavior change support achieve
better rates of medication adherence and smoking
cessation than interventions without behavior support
and that these effects can persist for at least 6 months
after implementation. According to the transtheoreticalmodel of health behavior change, the maintenance stage
is estimated to last from 6 months to about 5 years(32), which suggests the importance of supporting thetransition to the maintenance stage in patients withchronic disease.
As reported elsewhere (4), many of the studies
included in our meta-analysis were not based on behavior
change theories for the development of the interventions
and none of the interventions were developed based on
BCTs. Several BCTs included in intervention strategies
were extracted by referring to the BCTTv1 (Table 3).
For smoking cessation, social support (emotional)(n = 6) (14,15,17,21,22,24) was used most frequently,
followed by goal setting (behavior) (n = 5)
(14,19,20,23,24) and pharmacological support (n = 5)
(17,19,22-24). Emotional support such as motivational
interviews may be important when self-efficacy isdiminished by chronic illness. There have been reportsof code classifications being devised for effective BCTs
that suggest behavioral support accompanied by BCTs
contributes to smoking cessation (33,34). Goal setting(behavior), pharmacological support, and information
about health consequences have been reported to be
the most promising BCTs for maintaining smoking
cessation after leaving a smoking cessation facility (34),which is in line with our findings.
When subgroup analysis was performed,
heterogeneity (I 2) was reduced when studies weredivided according to severity of COPD (degree of
airflow obstruction and acute exacerbation). Therefore,
behavior change interventions may be more effectivein patients with more severe airflow obstruction andin those who have experienced acute exacerbation of
COPD. However, some reports suggest an association
between the FEV1/FVC and the likelihood of successful
smoking cessation in patients with COPD (35), whileother researchers have found no association between
the severity of airflow obstruction and the effect ofpharmacological treatment on smoking cessation (5).
However, given the small number of studies included inthis review, further investigations are needed.
Interventions with behavior support were more
likely to achieve optimal long-term medication
adherence and correct inhaler use than those that did
not include behavior support. Subgroup analysis did notalter the high heterogeneity (I2) of the results for correct
inhaler use. This can be attributed to the small numberof studies and the different measurement methods usedin the studies. However, all studies found differences inoutcomes between the intervention and control groups,
suggesting that the intervention improved adherence.
Although there has been limited research on supporting
medication adherence with BCTs, there has been astudy in which 11 theory-based BCTs was selected to
improve medication adherence in older adults (36), andthe importance of taking into account each patient's
individual needs and adopting a tailored approach todelivery of BCTs has been noted (37).
With the exception of one study, all interventions
adopted repeated processes and patients in theintervention groups were followed up remotely by
telephone or via a website platform. The components of
the interventions were tailored individually according
to each patient's specific needs. The previous study
reported that person-centered support via telephone canmitigate worsening self-efficacy in patients with COPD
by supporting and strengthening their ability and selfesteem (38). Our analysis suggests that individually
tailored self-management interventions with healthbehavior change support were effective in improving
medication adherence and smoking cessation. However,
our review may contain a degree of bias toward BCTs
that are easier to provide remotely. Various remotedevices have been developed in recent years, so further
research is needed to confirm the elements of an(22)

GHM Open. 2022; 2(1):12-24.

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intervention that support self-management of patientswith chronic respiratory disease.
This review has several limitations. First, none of
the intervention strategies was developed in accordancewith the BCTTv1. We did not contact any authors
to obtain unpublished data, so we could not extract
information on behavior change theories that were notexplicitly stated but may have been used, and it wasalso difficult to code and classify the components of
BCTs according to the authors' intentions. Furthermore,
it was not possible to classify the BCTs used in thecontrol groups because too little detail was provided.
Second, medication adherence and smoking cessation
were assessed by self-report, which may haveintroduced a degree of reporting bias. Only one study
provided a definition of smoking cessation and not
all studies reported the duration of abstinence fromsmoking. Moreover, although we included the numberof participants reported to be adherent with medicationin each study in our meta-analysis, the assessment
criteria varied from study to study and may haveinfluenced our results. Third, we included studies witha duration of at least 6 months from the implementationof interventions and analyzed the data measured at the
final follow-up, so the measurement timing may haveaffected adherence. Fourth, although this review did not
impose limits on the types of respiratory disease that
could be included, most of the studies targeted patientswith COPD. Therefore, our findings may be biased
towards the characteristics of this patient population.

3.

Conclusion

10.

4.

5.

6.

7.

8.

9.

This review and meta-analysis demonstrated that
self-management interventions with behavior change
support improve adherence to smoking cessation,
medication, and correct inhaler use and that the
improvements can be maintained for at least 6 months
in patients with chronic respiratory disease.
When tailored to the patient's specific needs, behavior
change support is suggested to promote patient's selfmanagement and improve long-term adherence.

11.

12.

Funding: This work was supported by JSPS KAKENHI
Grant Numbers JP20H03991 and 19K22789.

13.

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

14.

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---Received January 8, 2022; Revised March 15, 2022; Accepted
March 28, 2022.
Released online in J-STAGE as advance publication April 8,
2022.
*Address correspondence to:
Mihoko Fujii, National College of Nursing, 1-2-1 Umezono,
Kiyose, Tokyo 204-0024, Japan.
E-mail: fujiim@d20.ncn.ac.jp(24)Original Article

GHM Open. 2022; 2(1):25-30.
DOI: 10.35772/ghmo.2022.01005

Knowledge and practice for cervical cancer among female primaryschool teachers in Phnom Penh, Cambodia: A cross-sectional phonebased survey
Sann Chan Soeung1, Tomoko Komagata2,*, Chau Darapheack3, Shikino Kikuchi2, Hiromi Obara2, Rei Haruyama2,
Koum Kanal1, Noriko Fujita2, Nozomu Yanaihara4, Aiko Okamoto4, Tadashi Kimura5
1

Cambodian Society of Gynecology and Obstetrics, Phnom Penh, Cambodia;
Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo, Japan;
3
National Institute of Public Health, Phnom Penh, Cambodia;
4
Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan;
5
Department of Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Osaka, Japan.
2

Abstract: Cervical cancer is a cancer with evidence-based and cost-effective preventive measures; Human
Papilloma Virus (HPV) vaccination for school girls and cancer screening for women. In Cambodia, cervical cancer
accounts for an estimated 11.4% and 10.4% of women's cancer and deaths in 2020, respectively. This study aimed to
identify the knowledge of cervical cancer, its information sources, and the experiences of cervical cancer screening
among female primary school teachers, who are key influencers of HPV vaccination. A cross-sectional study
was conducted using telephone interviews with 100 female primary school teachers in Phnom Penh, the capitalof Cambodia. All 100 participants had heard of cervical cancer, 94 (94%) had heard of screening, and 49 (49%)
had ever undergone a screening. When asked about their knowledge regarding cause(s), symptom(s), detection,and treatment(s) of cervical cancer, 31%, 44%, 35%, and 55% respondents said "Do not know". Those who did
not reply "Do not know" were asked open-ended questions. Many of their answers were judged as “incorrect” bygynecologists. Consequently only 1%, 38%, 63% and 28% of respondents replied with at least one correct answer
regarding cause(s), symptom(s), detection and treatment(s) respectively. The most common sources of information
were family and friends, followed by doctors, television, and the Internet. Among female primary school teacherswith an above-average educational level, their knowledge of cervical cancer was generally low. To promote
cervical cancer prevention, it is necessary to provide correct knowledge in a broad and accessible manner throughinvolvement of local medical doctors and healthcare providers.
Keywords: cervical cancer, screening, knowledge, attitude and practice, Cambodia

Introduction

through implementing these measures (4,5). In many
LMIC countries, where these preventive measures are
not available, women have little knowledge of cervicalcancer and its preventive measures (6-11). To promote
screening among women to prevent cervical cancer,
their own knowledge and understanding of cervicalcancer are essential.
In Cambodia, one of the LMICs in South-east Asia,
5.93 million women aged 15 years and older are at risk
for cervical cancer (12). In 2020, the number of cervicalcancer incidences and mortality were estimated to be
1,135 and 634, accounting for 11.4% and 10.4% offemale cancers, respectively (1). If no progress is madein cervical cancer prevention, the number of incidences
and mortality are expected to increase by 1,790 (1.6fold) and 1,090 (1.7-fold), respectively, 20 years
after 2020. (1). The Ministry of Health of Cambodia

Cervical cancer is a common public health problem
worldwide, ranking as the fourth most common cancer
among women (1). The highest incidence and mortality
rates for cervical cancer are consistently observed inlow- and middle-income countries (LMICs), where themajority of women are never screened for the disease(1-3). Without an urgent scale-up of services, thecervical cancer burden will increase to almost 460,000
deaths by 2040 in LMICs (2). Fortunately, cervicalcancer is a cancer with evidence-based and costeffective preventive measures. These include humanpapillomavirus (HPV) vaccination for girls as primaryprevention and cervical cancer screening for women
linked to treatment in the early stage as secondary
prevention. Cervical cancer can be avoided in the future(25)

GHM Open. 2022; 2(1):25-30.

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considers cervical cancer to be one of the mostimportant health issues and has attempted to establisha screening program since 2007 (13) in addition topreparing for HPV vaccination in 9-year-old school
girls (13-16). However, according to the 2016 STEP
survey, only 11.3% of Cambodian women aged 18-69
years have ever been screened, indicating that cervicalcancer screening is not yet widespread (17). Although
the knowledge and understanding of the target womenare essential to encourage them to undergo cervicalcancer screening, there is limited information regardingknowledge and practice concerning cervical cancer
among women in Cambodia (10,18,19). Since HPV
vaccination is planned to be introduced as a routine
immunization to 9-year-old girls in primary schools
in 2023, primary school teachers are considered key
influencers to school children and their parents whomake a decision for vaccination (20). Promoting theunderstanding of cervical cancer among primary school
teachers is indispensable to increase the acceptanceand uptake of the vaccine by children and their parents.
When female school teachers properly understand theimportance of screening, it would also contribute toincrease the administration of cervical cancer screening.
Because of the above reasons, female primary school
teachers were chosen as a target population.
This study aimed to identify the knowledge of
cervical cancer, its information sources, and theexperience of cervical cancer screening among female
primary school teachers in Phnom Penh, Cambodia.

public primary schools with 4,116 teachers, including
2,944 women. For the 2,944 study participants, theappropriate sample size was calculated to be 100, witha confidence interval of 95% and a standard error of
10%. In total, 100 study participants were recruitedfrom randomly selected primary schools in four urban
and four peri-urban districts of Phnom Penh.
Data collection method and instrument
To conduct the interviews, a structured questionnaire
was developed, which consisted of demographic
information, knowledge of cervical cancer, sourcesof information, and experience of cervical cancer
screening.
For knowledge, the participants were asked about
the cause, symptoms, detection, and treatment ofcervical cancer. The participants were asked if theyknew (yes or no) and, if yes, what they knew as an
open-ended form.
The questionnaire was finalized through a pilot test
using eight women to ensure that the questions are easy
to understand and have a logical order. All data werecollected via telephone interview conducted by trainedinterviewers. Each interviewer conducted three to four
telephone interviews per day for up to 20 min each.
Data analysis
The data collected by telephone interviews were written
down on the questionnaire sheet on the site, thensimultaneously entered into EpiData (version 3.1) by
two interviewers, and exported to Stata (version 16.1).
Descriptive statistical analysis was performed to assess
the frequencies of all variables.
Regarding the open-ended free responses onknowledge of cervical cancer (cause, symptoms,
detection, and treatment), a panel of four gynecology
specialists (two Cambodians and two Japanese)
independently judged each answer, real expression by
respondents, as "correct", "incorrect", or "unclassifiable",based on their clinical experiences and expertise.
When three or more gynecologists judged "correct"
or "incorrect", that answer was considered "correct"
or "incorrect", respectively by the panel. Others werecategorized as "unclassifiable".
A chi-square test was used to identify the association
between characteristics and cervical cancer screening
practices. Statistical significance was set at p < 0.05.

Methods
Study design
A cross-sectional phone-based survey was conducted inJuly 2020 among a sample of primary school teachers
in Phnom Penh, the capital of Cambodia. The survey
was initially designed to be conducted through face-toface interviews at schools; however, it was changed to aphone-based interview because schools were closed andmeetings and travel were restricted due to COVID-19.
Study population, sample size, and sampling
Our study was comprised of female teachers aged
over 30 years (i.e., the target age of cervical cancer
screening based on the Cambodian national operational
standard for cervical cancer screening (16) currently
working in primary schools in Phnom Penh. Prior to
conducting this study, full approval and cooperation
were obtained from the Ministry of Education Youthand Sports, Cambodia, and Phnom Penh Municipality
Department of Education Youth and Sports. Based on
the agreement, the latest list of public primary schools
and in-service teachers with their personal phone
numbers was provided. In Phnom Penh, there were 158

Ethical clearanceThis study was ethically approved by the Cambodia
National Ethics Committee for Health Research,
Ministry of Health, Cambodia (No. 161 NECHR)
and Institutional Review Board for Clinical Research,
National Center for Global Health and Medicine, Japan(26)

GHM Open. 2022; 2(1):25-30.

www.ghmopen.com(NCGM-G-003434-00).
Informed consent was obtained from all participants
before participation. The purpose of the study andassurance to withdraw at any step of the study without
any disadvantages were fully explained and telephoneinterviews were conducted privately.

in Supplemental Table S1 (https://www.ghmopen.
com/site/supplementaldata.html?ID=53). Then, perstudy subject, some women replied "correct answer(s)only", or "at least one correct and other answer(s)" or"incorrect and/or unclassifiable answer(s) only". "Other
answer(s) "here means either incorrect or unclassifiableanswer(s).
As shown in Figure 1, of those who did not reply"Do not know", 1.5% (1/67), 68% (38/56), 97% (63/65),
62% (28/45) replied at least one correct answer regarding
cause(s), symptom(s), detection, and treatment(s)respectively.
Consequently, among 100 study subjects, only 1,
38, 63, 28 respondents answered at least one correct
answer(s) to cause(s), symptom(s), detection, andtreatment.

Results
Characteristics of study participants
Table 1 presents the characteristics of the study
participants. A total of 100 women, 51 (51%) fromfour schools in urban districts and 49 (49%) from four
schools in peri-urban districts, participated in thisstudy. Their mean age was 47.9 ± 6.6 years, with 37
participants aged over 50 years. Of the 100 participants,
69 (69%) had graduated from high school or higher.
The mean number of years of teaching experience was
26.7 ± 7.3 years. Most women had been married (88%)
and had experience(s) of being pregnant (82%).

Sources of information on cervical cancer
Figure 2 shows the sources of information on cervicalcancer, screening, and vaccination to prevent cervicalcancer. Although these items were asked separately, thesources of information were generally similar. The mostcommon sources of information were relatives, friends,
and colleagues, followed by doctors, television, and theInternet. Less than 10 answered radios, conferences,and newspapers. A small number of respondents
reported that they actively obtained information frombooks, posters, and distributed leaflets.

Knowledge of cervical cancer
All the study participants had heard of "cervical cancer",
94 (94%) had heard of "cervical cancer screening" and91 (91%) had heard of "vaccination to prevent cervicalcancer". When asked if they knew about the cause,
symptoms, detection, and treatment of cervical cancer,"Don't know" was answered by 31 (31%) respondents
for the causes, 44 (44%) for symptoms, 35 (35%) for
detection, and 55 (55%) for treatment.
Among women who did not answer that they "Do
not know", open-ended questions were asked regarding
causes, symptom(s), detection, and treatment. One
respondent could answer at least one or multiple
answers to each open question. Each answer waslabeled correct, incorrect, and unclassifiable, as shown
Table 1. Characteristics of the study participants (n = 100)

Urban district
Peri-urban district
31-40
Age group
41-50
51-60
Secondary school
Educational level
High school
College or higher
Teaching experience ≤ 10
12-20
21-30
31-40
MarriedMarital status
Divorced/widowed
Not married
Yes
ParityNo
Location of school

Figure 1. Knowledge of causes, symptoms, detection andtreatment of cervical cancer.

n (%)

Contents
51
49
22
41
37
26
43
31
4
19
38
39
79
9
12
82
18

(51%)
(49%)
(22%)
(41%)
(37%)
(26%)
(43%)
(31%)
(4%)
(19%)
(38%)
(39%)
(79%)
(9%)
(12%)
(82%)
(18%)

Figure 2. Sources of information about cervical cancer,
screening, and vaccination (n = 100, multiple choice).

(27)

GHM Open. 2022; 2(1):25-30.

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Table 2. Number and proportion of women who reported ever undergoing cervical cancer screening
Total
Variables
Location of school
Age
Educational level
Marital status
Experience of health facility visit due to vaginal problem(s)Provided at least one correct answer on cause
Provided at least one correct answer on symptom
Provided at least one correct answer on detection
Provided at least one correct answer on treatment

Group
Urban
Rural
31-40
41-50
51-60
Secondary school
High school
Collage and higher
No
Yes
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No

Ever undergo cervicalcancer screening

n

n

(%)

51
49
22
41
37
26
43
31
12
88
64
36
1
99
38
62
63
37
28
72

25
24
13
21
15
9
22
18
0
49
45
4
0
49
20
29
34
15
17
32

(50.0)(49.0)(59.1)(51.2)(40.5)(34.6)(51.2)(58.1)(0)(55.7)(70.3)(11.1)(0)(49.5)(52.6)(46.8)(54.0)(40.5)(60.7)(44.4)

p value(χ2 test)
0.841
0.361
0.197
< 0.001< 0.001
0.325
0.570
0.195
0.144

who did not reply "Do not know" regarding cause(s),symptom(s), detection, and treatment(s) and revealed
that many of their answers were judged as "incorrect" bygynecologists. As hesitation to answering "no" or "don'tknow", is often observed in surveys in Southeast Asia(21), our results also indicate so-called Courtesy bias andneed to draw attention for a future similar study. All the
study participants in this study had received secondary or
higher education, and approximately 70% had received
high school or higher education, far more than the
average Cambodian woman (22). However, our results
showed limited knowledge on the cause, symptoms,
detection and treatment of cervical cancer, similar
to previous reports of women in general and factory
workers (10,18).
Experience of cervical cancer screening shows,unsurprisingly, those who are married and had experiencein health facility visits due to vaginal problems weresignificantly more likely to have undergone screening.
Although half of study participants had been screened
previously, there was no significant relation between theircervical cancer screening experiences and knowledge of
cervical cancer.
The sources of information were family and friends,
followed by doctors, television, and the Internet. The
main sources of information about cervical cancer
were the same for women in general, female factory
workers, and female elementary school teachers: family,
relatives/friends, doctors, and the Internet (10,18).
This suggests that these are the priority sources of
information on cervical cancer in Cambodia, and it isimportant that correct information emanates from allof these sources. Since the second largest source of
information was medical doctors, medical doctors andExperience of cervical cancer screening
Table 2 shows the number and proportion of study
participants who underwent cervical cancer screening
according to their sociodemographic characteristics.
Among the 100 study participants, 49 (49%) had
experience undergoing cervical cancer screening.
Participants who were married and had experiencein health facility visits due to vaginal problems weresignificantly more likely to have undergone cervicalcancer screening (p < 0.01). Although not statisticallysignificant, participants with higher educational levels
were also more likely to have undergone cervical cancer
screening. No particular tendency was observed between
experience in cervical cancer screening and knowledge
on cause, symptoms, detection, and treatment of cervicalcancer.
Discussion
In this study, 100 female primary school teachers inPhnom Penh, Cambodia, were surveyed about theirknowledge of cervical cancer, sources of information,and experiences of cervical cancer screening. A study
in a rural province in Cambodia involving 440 women
showed that 74 and 34% of women had heard about
cervical cancer and screening (10). In another study
on 443 female factory workers in Phnom Penh, 99%
had heard of cervical cancer, but none of them knew
about cervical cancer screening as a preventive measure(18). In contrast, in this study conducted among female
primary school teachers in the Cambodian capital, over
90% of respondents had heard of both cervical cancer
and screening. Open-ended questions were used for those(28)

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health care professionals might have a role in providing
correct knowledge of cervical cancer to the general
population of women. It is important for doctors andmedical personnel to be aware of their important role incervical cancer health education including the provisionof correct information on prevention as well as diagnosis
and treatment.
In Asian countries including Cambodia, there is astrong hesitation to publically talk about sexual andreproductive health, and education regarding sexual andreproductive health can be difficult (10,23-25). This
may relate to the fact that the most common source of
information on cervical cancer was family and friends.
To disseminate knowledge about cervical cancer to thegeneral female population, it is necessary to consider
effective methods that take into account the cultural
background, such as broadcasting of culturally tailored
video/sound (26-28) and culturally competent healtheducation by local doctors and healthcare providers (28).
On the other hand, it also suggests that correctknowledge does not necessarily lead directly to correct
behavior. One of the barriers is that the concept andpractice of prevention are not widely recognized insociety, and people do not consider it necessary to visit
health facilities unless they have serious symptoms(23,25,28). Some people do not want to be identified ashaving cervical cancer by screening for fear that having
cervical cancer will lead to social stigma and interferewith their daily lives due to discrimination and prejudicein the community (23). Moreover, lack of access totreatment has a direct association between cervical cancer
and death or giving up and is a factor that keeps people
away from seeking health care (11,29,30). Along with
the implementation of culturally and socially appropriate
health education, an improved understanding of cervicalcancer throughout society without discrimination andstigma is also essential, which will result in improved
access to health care that allows for cervical cancer
screening and subsequent treatment. At the same time,an environment that enables early treatment of cervicalcancer; medical facilities and equipment, quality healthpersonnel, and establishment of a medical insurance
system are needed.
The limitations of this study are that the sample size
was small (100 study participants), and that the target
population was a group of women living in the vicinityof the capital city and being educated at the secondary
school level or above, which is not representative of
the general female population in Cambodia. Although
it is difficult to generalize simply, this study provides
important basic information on the understanding ofcervical cancer among primary school teachers in Phnom
Penh.

cervical cancer, in accordance with the global initiative(5). However, our study revealed that among female
primary school teachers with above-average educational
level in Cambodia, their knowledge of cervical cancer
was generally low. It is important to improve theknowledge of primary school female teachers, who
are potential key influencers of HPV vaccination togirls. To disseminate knowledge to promote cervicalcancer prevention, it is necessary to provide correctknowledge in a broad and accessible manner throughthe involvement of local medical doctors and healthcare
providers. Appropriate health education by healthprofessionals may be an effective way to achieve this.
Acknowledgements
We are grateful to all study participants and the Ministryof Education Youth and Sports, Cambodia, and Phnom
Penh Municipality Department of Education Youthand Sports. We deeply appreciate the CambodianSociety of Gynecology and Obstetrics, especially the
Health Education Team, Prof. Leang Sim, Dr. Krouch
Rayonnette, Dr. Korn Aun, Dr. Kim Lumphiny, Dr. Chhit
Maryan, Dr. Kyna Uy, and Ms. Miwa Kanda, for theirsupport.
Funding: This study was supported by Japan
International Cooperation Agency Partnership Programand National Center for Global Health and Medicine
Intramural Research Fund (20A08).
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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---Received May 13, 2022; Revised July 25, 2022; Accepted
July 29,, 2022.
Released online in J-STAGE as advance publication August 1,
2022.
*Address correspondence to:
Tomoko Komagata, Bureau of International Health
Cooperation, National Center for Global Health and Medicine,
Toyama 1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan.
E-mail: aamnabibi@gmail.com(30)Original Article

GHM Open. 2022; 2(1):31-37.
DOI: 10.35772/ghmo.2021.01028

Association of atherogenic serum lipids and platelet activation withchanges in arterial stiffness in patients with type 2 diabetes
Yuji Hirowatari1,*, Hidekatsu Yanai2
1
2

Laboratory Sciences, Department of Health Sciences, Saitama Prefectural University, Saitama, Japan;
Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan.

Abstract: Pulse wave velocity (PWV) is a potential marker for atherosclerosis severity and/or predictor of futureatherosclerotic cardiovascular events. PWV is significantly correlated with carotid-intimal media thickness
in patients with diabetes. However, its significance as a surrogate marker for the treatment of atherosclerotic
cardiovascular risk in the management of type 2 diabetes has not been fully established. To elucidate the factors that
determine the improvement or deterioration of PWV, we studied the association of clinical parameters, parameters
for glucose metabolism, serum lipids including each lipoprotein fraction, serotonin as a marker for plateletactivation, and change in PWV in 54 patients with type 2 diabetes. Systolic blood pressure and serum levels of
non-high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol (LDL-C), and intermediate-density
lipoprotein-cholesterol significantly decreased in the PWV-improved group after 2 months compared with those in
the PWV-deteriorated group. The serotonin levels at baseline were significantly lower in the PWV-improved groupthan in the PWV-deteriorated group. The changes in systolic blood pressure and LDL-C levels were significantly andpositively correlated with those in PWV. The serotonin levels at baseline were significantly and positively correlatedwith changes in PWV. Therefore, amelioration of blood pressure, serum lipid level, and platelet activation might bebeneficially associated with PWV change. PWV-guided clinical practice for cardiovascular risk stratification could
be useful in type 2 diabetes management.
Keywords: atherosclerosis, diabetes, lipoprotein, pulse wave velocity, serotonin

Introduction

triglycerides (TG), low-density lipoprotein (LDL)cholesterol (LDL-C), small dense LDL, and oxidized
LDL as well as reduction of anti-atherogenic highdensity lipoprotein (HDL)-cholesterol (HDL-C) level
were observed in type 2 diabetes (9). Recently, attention
has been focused on the important contribution of TGrich lipoproteins, such as very-low-density lipoprotein(VLDL) and intermediate-density lipoprotein (IDL) toatherogenesis (10).
Serotonin is released from aggregating platelets
and mediates platelet-induced vasoconstriction (11).
In patients with diabetes, platelets are activated inendothelial injury promoted by atherosclerosis, andplatelets are hyperreactive with intensified adhesion
and aggregation (12,13). Activated platelets releaseserotonin stored in platelet-dense granules (13). It waspreviously reported that serotonin levels in platelet-poor
plasma (PPP) increased in patients with coronary heartdisease (CHD) (14-16). Platelet aggregatory response
to serotonin is modulated by the disparate effects oflipoprotein fractions, corresponding to the recognizeddifferences in the degree of atherogenicity of LDL and
HDL (11). Amplification of serotonin-induced platelet

Type 2 diabetes and dyslipidemia are significant
cardiovascular risk factors that should be managed (1,2).
Therefore, it is important to regulate atheroscleroticrisk factors and understand the progression ofarteriosclerosis in patients with type 2 diabetes. Aortic
pulse wave velocity (PWV) is an independent predictorof adverse cardiovascular events, including mortality(3). PWV reflects arterial stiffness and correlates withmarkers reflecting the severity of atherosclerosis, suchas carotid intima-media thickness (IMT) (4). PWV isthought to be applicable as a marker for the severity ofatherosclerosis and/or predictor of future atherosclerotic
cardiovascular events (4). PWV has been significantly
correlated with carotid IMT in patients with diabetes(5,6). Previous studies have reported that PWV can bebeneficial in the clinical practice for cardiovascularrisk stratification (7,8). However, its significance as asurrogate marker for the treatment of atherosclerotic
cardiovascular risk in the management of type 2
diabetes has not been fully established.
Elevated of levels of atherogenic lipids, such as(31)

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aggregation by LDL and its inhibition by HDL support
the hypothesis that serotonin-mediated effects represent
a mechanism clinically relevant to chronic progressionof atherosclerosis (11).
To elucidate the factors that determine theimprovement or deterioration of PWV, we studied
the association of clinical parameters, parameters forglucose metabolism, serum lipids including each type oflipoprotein fraction, and serotonin level with the change
in PWV.

and quantitatively.
Data are presented as mean ± standard deviation.
The Wilcoxon test was performed to compare the values
at baseline and that after 2 months. The Mann-Whitney
test and Fisher's exact probability test were performed toanalyze the differences in data between the two groups.
Correlations were estimated using the Spearman's rank
test. Statistical significance was set at P-values of < 0.05.
Results

Patients and Methods

The clinical characteristics of patients with type 2
diabetes are summarized in Table 1. The mean bodymass index and waist circumference were > 25 kg/
m2 and 0.9 m, respectively, suggesting that a relatively
greater proportion of overweight and obese patientswere included. Most patients were treated with insulin
or oral anti-diabetic drugs. Approximately 60% and 70%
of patients had used hypolipidemic and hypotensive
drugs, respectively.
PWV and clinical and metabolic parameters atbaseline and after 2 months of patients with type 2
diabetes are shown in Table 2. During the study periodof 2 months, no intentional change in drugs was
performed. No parameters, including PWV, showedsignificant changes. To determine the factors that
improve or deteriorate PWV, we divided patients into
PWV-improved (decreased) and PWV-deteriorated

A total of 54 patients with type 2 diabetes were recruitedfrom the outpatient clinics in Kohnodai Hospital,
National Center for Global Health and Medicine. We
measured PWV, parameters for glucose metabolism,
serum lipid profile, including each lipoproteincholesterol, and PPP serotonin at baseline and after
2 months. At 2 months, the treatments for diabetes,
dyslipidemia, and hypertension were not changed
intentionally. This study was conducted in accordancewith the principles of the Declaration of Helsinki
and approved by the Medical Ethics Committee of
the National Center for Global Health and Medicine(NCGM-G-000889). Written informed consent was
obtained from each patient.
PWV was measured using a noninvasive vasculardevice with four pneumatic pressure cuffs (BP-203RPE,
Omron Corp., Japan). Blood pressure levels and pulse
waves were measured in the bilateral brachial andradial arteries after 5 min of rest on the bed. PWV was
calculated as the transmission time and distance fromthe right or left arm to each ankle based on the bodyheight. The mean value of the right and left PWV wasused for analysis in this study.
Fasting plasma glucose, hemoglobin A1c (HbA1c),
C-peptide, and small dense LDL levels were measured
using commercial kits (HLC-723G and GA, Tosoh
Corp., Japan; Sekisui Medical Co., Ltd., Japan; andDenka Seiken Co., Ltd., Japan, respectively).
The analysis method for lipoprotein profile
using anion-exchange high-performance liquid
chromatography (AEX-HPLC) has been previously
reported (17,18). Briefly, major lipoprotein classes,
HDL, LDL, IDL, and VLDL, in the plasma samples
were separated using AEX-HPLC, and the cholesterollevels in the separated lipoprotein classes were measured
using post-column reaction with a reagent containing
cholesterol esterase and cholesterol oxidase. AEXHPLC can be used as a substitute for ultracentrifugation.
The PPP serotonin levels were measured using apreviously reported method (19). In brief, PPP serotonin
was separated in a column-switching system with
two octadecyl-bonded silica columns. The separated
serotonin was specifically converted into a fluorescentderivative with benzylamine and detected sensitively

Table 1.Clinical characteristics of studied patients with
type 2 diabetes (n = 54)
Variables
Age (years)
Sex (male/female)
Smoker (smoker/non-smoker)
Duration for diabetes (years)
Body mass index (kg/m2)
Waist circumference (m)Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Pulse wave velocity (cm/sec)
Anti-diabetic treatments (n)Insulin
Sulfonylurea
Glinides
Dipeptidyl peptidase-4 inhibitors
Thiazolidinedione
Metformin
a-glucosidase inhibitors
Hypolipidemic treatments (n)StatinFibrateEzetimibe
Anti-platelets treatments (n)Aspirin
Hypotensive treatments (n)Diuretics
Angiotensin converting enzyme inhibitors
Angiotensin II receptor blockers
b-blockers
Calcium antagonists(32)

Values65.3 ± 11.1
32/22
19/35
8.78 ± 9.72
25.6 ± 4.9
0.91 ± 0.12
141 ± 2180 ± 11
1,774 ± 380
10
9
5
15
13
31
9
27
3
2
5
1
2
19
2
17

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Table 2. Pulse wave velocity and metabolic parameters at baseline and after 2 months in patients with type 2 diabetes (n = 54)
Variables

Baseline

after 2 months

P value

Pulse wave velocity (cm/sec)
Clinical parameters
Body mass index (kg/m2)
Waist circumference (m)Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Parameters for glucose metabolism
Fasting plasma glucose (mg/dL)
Hemoglobin A1c (%)
Fasting serum C-peptide (ng/mL)
Serum lipids
Triglyceride (mg/dL)
Non-HDL-C (mg/dL)
LDL-C (mg/dL)
IDL-C (mg/dL)
VLDL-C (mg/dL)
HDL-C (mg/dL)
Small-dense LDL (mg/dL)
Oxidized LDL (U/mL)
Serotonin levels
PPP serotonin (nmol/L)

1,774 ± 380

1,777 ± 382

0.6421

25.6 ± 4.9
0.91 ± 0.12
141 ± 2180 ± 1125.5 ± 4.8
0.91 ± 0.11
139 ± 1979 ± 10

0.728
0.797
0.420
0.115

135 ± 287.2 ± 0.9
1.73 ± 0.7

134 ± 26
7.2 ± 0.8
1.92 ± 1.0

0.436
0.781
0.280

114 ± 47
128 ± 26116.3 ± 26.0
6.6 ± 2.1
12.1 ± 7.3
58.3 ± 16.0
27 ± 1192 ± 28112 ± 50123 ± 26
113 ± 25.3
6.7 ± 2.6
11.1 ± 7.0
58.1 ± 15.3
27 ± 1295 ± 24

0.390
0.091
0.240
0.607
0.155
0.904
0.801
0.740

20.9 ± 19.6

22.7 ± 17.2

0.196

Abbreviations: Non-HDL-C, non-high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; IDL-C, intermediate-density
lipoprotein-cholesterol; VLDL-C, very-low-density lipoprotein-cholesterol; HDL-C, high-density lipoprotein-cholesterol; PPP, platelet-poor plasma.

Table 3. Differences in clinical characteristics, parameters for glucose metabolism, serum lipids and serotonin between
PWV-improved group and PWV-deteriorated group
PWV-improved group(n = 25)
Variables
Baseline after 2 months
Clinical parameters
Body mass index (kg/m2)
26.1 ± 5.4
26.1 ± 5.1
Waist circumference (m)0.92 ± 0.13 0.92 ± 0.13
Systolic blood pressure (mmHg)
140 ± 21135 ± 17
Diastolic blood pressure (mmHg)
79 ± 1077 ± 8Treatments
Calcium antagonists (n)1212Parameters for glucose metabolism
Fasting blood glucose (mg/dL)
127 ± 23133 ± 23
Hemoglobin A1c (%)
7.1 ± 0.8
7.1 ± 0.7
Fasting serum C-peptide (ng/mL)
1.9 ± 0.8
2.1 ± 1.2
Serum lipids
Triglyceride (mg/dL)
112 ± 34
115 ± 56
Non-HDL-C (mg/dL)
140 ± 26
129 ± 28
LDL-C (mg/dL)
128.6 ± 26.6 118.2 ± 28.0
IDL-C (mg/dL)
6.6 ± 1.4
6.1 ± 1.7
VLDL-C (mg/dL)
11.1 ± 4.3
11.3 ± 7.3
HDL-C (mg/dL)
58.8 ± 14.9 55.8 ± 13.7
Small-dense LDL (mg/dL)
31.5 ± 10.7 30.6 ± 13.0
Oxidized LDL (U/mL)
97 ± 27
99 ± 24
Serotonin levels
PPP serotonin (nmol/L)
14.7 ± 9.3
19.0 ± 10.5

PWV-deteriorated group(n = 28)

Comparison between
2 groups

P values
vs.
baseline

Baseline

after 2 months

P values
vs.
baseline

P values atbaseline

P values
after
2 months

0.379
0.346
0.044
0.053

25.2 ± 4.5
0.91 ± 0.1
141 ± 2181 ± 1224.9 ± 4.5
0.90 ± 0.1
143 ± 2080 ± 11

0.223
0.288
0.235
0.392

0.521
0.726
0.470
0.762

0.368
0.368
0.076
0.184

NA

5

5

NA

0.020

0.020

0.029
0.354
0.173

141 ± 30
7.3 ± 1.0
1.6 ± 0.6

135 ± 297.2 ± 0.8
1.7 ± 0.9

0.197
0.489
0.308

0.149
0.438
0.250

0.817
0.464
0.107

0.495
0.014
0.016
0.010
0.404
0.069
0.295
0.371

116 ± 56
108 ± 47
117 ± 21118 ± 22104.9 ± 20.5 107.4 ± 22.5
6.6 ± 2.5
6.9 ± 2.9
12.8 ± 9.3
10.8 ± 7.0
58.8 ± 17.4 60.3 ± 16.7
23.1 ± 9.1
25.0 ± 10.3
88 ± 2891 ± 18

0.127
0.400
0.233
0.239
0.055
0.052
0.135
0.193

0.728
0.001
0.001
0.510
0.880
0.748
0.001
0.240

0.669
0.086
0.139
0.392
0.715
0.285
0.024
0.247

0.038

26.2 ± 24.3

0.477

0.032

0.466

23.6 ± 19.2

Abbreviations: Non-HDL-C, non-high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; IDL-C, intermediate-density
lipoprotein-cholesterol; VLDL-C, very-low-density lipoprotein-cholesterol; HDL-C, high-density lipoprotein-cholesterol; PPP, platelet-poor plasma;NA, not applicable.

(increased) groups and analyzed the differences between
both groups. Table 3 shows the differences in clinicalparameters, parameters for glucose metabolism, serum

lipid levels, and PPP serotonin levels between the PWVimproved and PWV-deteriorated groups.
Systolic blood pressure significantly decreased in the(33)

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PWV-improved group after 2 months. A significantly
greater number of patients had used calcium antagonists
at baseline and after 2 months in the PWV-improved
group than in the PWV-deteriorated group. Fastingblood glucose levels significantly increased in the
PWV-improved group. Serum levels of non-highdensity lipoprotein-cholesterol (non-HDL-C), LDL-C,
and IDL-cholesterol (IDL-C) significantly decreased
after 2 months in the PWV-improved group. Serumnon-HDL-C, LDL-C, and small-dense LDL levels atbaseline and small-dense LDL levels after 2 months
were significantly higher in the PWV-improved groupthan in the PWV-deteriorated group. PPP serotoninlevels significantly increased in the PWV-improved
group. However, PPP serotonin levels at baseline weresignificantly lower in the PWV-improved group than in
the PWV-deteriorated group.
We analyzed the correlation of parameters thatshowed a significant change with change in PWV. The
correlation of changes in systolic blood pressure andfasting blood glucose, non-HDL-C, LDL-C, IDL-C, and
PPP serotonin levels with changes in PWV is shownin Figure 1. Changes in the systolic blood pressureand LDL-C levels were significantly and positively
correlated with changes in PWV. However, changes in
the fasting blood glucose, non-HDL-C, IDL-C, and PPP
serotonin levels were not significantly correlated withchanges in PWV.
The parameters for clinical characteristics, glucose
metabolism, and serum lipids were not significantly
correlated with PPP serotonin levels at baseline or after
2 months. Furthermore, changes in any parameters
did not correlate with that in PPP serotonin levels.
The correlations of PPP serotonin levels with PWV atbaseline or after 2 months and with the change in PWV
are shown in Figure 2. PPP serotonin levels at baseline
were significantly and positively correlated withchanges in PWV.
Discussion
Since 2001, PWV measurement has been applied forthe risk stratification of patients with atherosclerotic
cardiovascular disease and/or its risk factors in Japan(4). Several cross-sectional studies have demonstrated
a significant correlation between PWV and known risk
factors for cardiovascular diseases. The treatment ofcardiovascular risk factors and lifestyle modifications
have been shown to improve PWV (4).
Several meta-analyses have demonstrated thatPWV reduces by antihypertensive treatments (20-23).
A significant reduction in systolic blood pressure in the
PWV-improved group and a significant and positive
correlation between changes in systolic blood pressure
and PWV suggest that a reduction in systolic bloodpressure is beneficially associated with PWV.

Figure 1. Correlation of changes in the systolic bloodpressure (A) and fasting blood glucose (B), non-high-density
lipoprotein-cholesterol (non-HDL-C) (C), low-density
lipoprotein-cholesterol (LDL-C) (D), intermediate-density
lipoprotein-cholesterol (IDL-C) (E), and platelet-poor
plasma (PPP) serotonin (F) levels with the change in pulse
wave velocity (PWV). R indicates the correlation coefficient.

Figure 2. Correlations of the platelet-poor plasma (PPP)
serotonin levels with pulse wave velocity (PWV) at baseline(A) and after 2 months (B) and with the change in PWV
at baseline (C) and after 2 months (D). R indicates thecorrelation coefficient.

(34)

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In a previous study with 4938 healthy adults, thesample was categorized into four groups using the 75 goral glucose tolerance test (24). PWV increased in thefollowing order: normal glucose tolerance, impaired
fasting glucose, impaired glucose tolerance, and newly
diagnosed diabetes (24). Another study showed thatPWV increased in the order of normal subjects, patientswith impaired fasting glucose, and patients with diabetes
and was positively correlated with fasting blood glucose
and HbA1c levels (25). Although fasting blood glucose
levels significantly increased in the PWV-improved
group, fasting blood glucose levels at baseline or after
2 months in the PWV-improved group were lower thanthose in the PWV-deteriorated group. Furthermore, nosignificant correlation between changes in fasting blood
glucose levels and PWV was observed. In our patients,
fasting blood glucose levels may not be associated withthe determination of PWV.
Atherogenic dyslipidemia comprises a triad ofincreased blood small dense LDL, decreased HDL, andTG levels (26). As a typical feature of type 2 diabetes,
atherogenic dyslipidemia has emerged as an important
coronary risk factor. The Framingham Heart Study(2,693 men, 3,101 women) has shown that non-HDL-C
level is a stronger predictor of CHD risk than LDL-C(27). An abundance of small dense LDL increases CHD
risk by three-fold (28). The metabolic milieu associatedwith small dense LDL includes insulin resistance,increased IDL, increased susceptibility to oxidative
damage, impaired reverse cholesterol transport, andincreased postprandial lipemia (28). A significant
decrease in non-HDL-C, LDL-C, and IDL-C levels
was observed in the PWV-improved group comparedwith in the PWV-deteriorated group. This decrease
might be beneficially associated with PWV. In ourstudy, low-density LDL levels in the PWV-improved
group at baseline or after 2 months were significantly
higher than those in the PWV-deteriorated group.
However, small dense LDL decreased in the PWVimproved group and increased in the PWV-deteriorated
group, thereby diminishing the negative impact ofhigh small dense LDL levels on PWV in the PWVimproved group. Otherwise, a significant reduction in
non-HDL-C, LDL-C, and IDL-C levels might havediminished the negative impact of high small dense
LDL levels on PWV in the PWV-improved group.
Accelerated atherosclerosis and increased risk ofthrombotic vascular events in patients with diabetes
may result from dyslipidemia, endothelial dysfunction,platelet hyperreactivity, impaired fibrinolytic balance,
and abnormal blood flow. The importance of platelets
in the atherothrombotic process has led to theinvestigation for the use of antiplatelet agents to reduce
cardiovascular risks. A meta-analysis conducted by the
Antiplatelet Trialists' Collaboration demonstrated that
aspirin reduced the risk of ischemic vascular events
as a secondary prevention strategy in numerous high-risk groups, including patients with diabetes (29).
Activated platelets release serotonin stored in plateletdense granules (13). In the present study, significantly
lower PPP serotonin levels were observed in the PWVimproved group than in the PWV-deteriorated group,suggesting a significant contribution of serotonin toatherogenesis. Furthermore, the PPP serotonin levels
at baseline were significantly and positively correlatedwith changes in PWV. The PPP serotonin levels havebeen reported to be increased in patients with CHD (1416), supporting our results.
Our study showed that a significantly greaternumber of patients had used calcium antagonists atbaseline and after 2 months in the PWV-improved groupcompared with that in the PWV-deteriorated group.
Calcium antagonists have been reported to inhibit theamplifying effect of LDL on serotonin-induced platelet
aggregation (11). In our study, the PPP serotonin levels
in patients receiving calcium antagonists (n = 16,
15.7 ± 13.2 nmol/L) were lower than those in patients
who were not receiving calcium antagonists (n = 36,
23.2 ± 21.6 nmol/L) (P = 0.057). Furthermore, PWV
decreased in patients using calcium antagonists (n =17, −57 ± 176 cm/s) but increased in patients who had
not used calcium antagonists (n = 37, 37 ± 149 cm/s) (P = 0.053). This suggested a possible beneficial
effect of calcium antagonists on PWV. A meta-analysis
showed that calcium antagonists significantly reduced
PWV compared with placebo in long-term trials (20).
However, calcium antagonists did not show superiority
in improving PWV compared with other types ofantihypertensive drugs. Further studies are needed toelucidate the influence of antihypertensive drugs on
PWV.
The Steno-2 study demonstrated that intensified
multifactorial intervention with tight glucose regulationand the use of renin-angiotensin system blockers, aspirin,
and lipid-lowering agents had sustained beneficial
effects with respect to vascular complications and on
mortality rates from any cause, including cardiovascularcauses (30). While no parameters improved in the PWVdeteriorated group, four parameters were significantly
improved in the PWV-improved group, suggesting thatthe improvement of multiple coronary risk factors led toan improvement in PWV.
This study has some limitations. First, the numberof participants was small. Second, since this was anobservational study, the causal relationship of the results
could not be explained clearly. To elucidate the influenceof metabolic parameters on PWV, a randomized
controlled trial using interventions is recommended in
the future.
In conclusion, a reduction in blood pressure; adecrease in the levels of atherogenic lipids, including
non-HDL-C, LDL-C, and IDL-C; and lower levels ofplatelet activation might be beneficially associated with
PWV. PWV-guided clinical practice for cardiovascular(35)

GHM Open. 2022; 2(1):31-37.

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risk stratification could be useful in the management oftype 2 diabetes.

Program. 2011; 2011:51-61.
14. Kurano M, Dohi T, Nojiri T, Kobayashi T, Hirowatari Y,
Inoue A, Kano K, Matsumoto H, Igarashi K, Nishikawa
M, Miyauchi K, Daida H, Ikeda H, Aoki J, Yatomi Y.
Blood levels of serotonin are specifically correlatedwith plasma lysophosphatidylserine among the glycerolysophospholipids. BBA Clin. 2015; 4:92-98.
15. Hirowatari Y, Hara K, Kamihata H, Iwasaka T, Takahashi
H. High-performance liquid chromatographic methodwith column-switching and post-column reaction for
determination of serotonin levels in platelet-poor plasma.
Clin Biochem. 2004; 37:191-197.
16. Odaka Y, Takahashi J, Tsuburaya R, Nishimiya K, Hao
K, Matsumoto Y, Ito K, Sakata Y, Miyata S, Manita D,
Hirowatari Y, Shimokawa H. Plasma concentration ofserotonin is a novel biomarker for coronary microvascular
dysfunction in patients with suspected angina andunobstructive coronary arteries. Eur Heart J. 2017;
38:489-496.
17. Hirowatari Y, Yoshida H, Kurosawa H, Doumitu KI, Tada
N. Measurement of cholesterol of major serum lipoproteinclasses by anion-exchange HPLC with perchlorate ioncontaining eluent. J Lipid Res. 2003; 44:1404-1412.
18. Hirowatari Y, Yoshida H. Innovatively established analysis
method for lipoprotein profiles based on high-performanceanion-exchange liquid chromatography. J Atheroscler
Thromb. 2019; 26:1027-1040.
19. Hirowatari Y, Hara K, Kamihata H, Iwasaka T, Takahashi
H. High-performance liquid chromatographic methodwith column-switching and post-column reaction for
determination of serotonin levels in platelet-poor plasma.
Clin Biochem. 2004; 37:191-197.
20. Ong KT, Delerme S, Pannier B, Safar ME, Benetos A,
Laurent S, Boutouyrie P; investigators. Aortic stiffness is
reduced beyond blood pressure lowering by short-termand long-term antihypertensive treatment: a meta-analysis
of individual data in 294 patients. J Hypertens. 2011;29:1034-1042.
21. Shahin Y, Khan JA, Chetter I. Angiotensin converting
enzyme inhibitors effect on arterial stiffness and wave
reflections: a meta-analysis and meta-regression of
randomised controlled trials. Atherosclerosis. 2012;
221:18-33.
22. Yen CH, Lai YH, Hung CL, Lee PY, Kuo JY, Yeh HI, Hou
CJ, Chien KL. Angiotensin receptor blockades effect on
peripheral muscular and central aortic arterial stiffness:a meta-analysis of randomized controlled trials andsystematic review. Acta Cardiol Sin. 2014; 30:98-107.
23. Niu W, Qi Y. A meta-analysis of randomized controlled
trials assessing the impact of beta-blockers on arterial
stiffness, peripheral blood pressure and heart rate. Int J
Cardiol. 2016; 218:109-117.
24. Li CH, Wu JS, Yang YC, Shih CC, Lu FH, Chang CJ.
Increased arterial stiffness in subjects with impaired
glucose tolerance and newly diagnosed diabetes but notisolated impaired fasting glucose. J Clin Endocrinol
Metab. 2012; 97:E658-E662.
25. Ohnishi H, Saitoh S, Takagi S, Ohata J, Isobe T, Kikuchi
Y, Takeuchi H, Shimamoto K. Pulse wave velocity as anindicator of atherosclerosis in impaired fasting glucose:
the Tanno and Sobetsu study. Diabetes Care. 2003;
26:437-440.
26. Musunuru K. Atherogenic dyslipidemia: cardiovascularrisk and dietary intervention. Lipids. 2010; 45:907-914.
27. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M,

Funding: None.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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Taniwaki H, Kawagishi T, Emoto M, Shoji T, Kanda H,
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SI, Panayiotou AG. Association of non-invasive measuresof subclinical atherosclerosis and arterial stiffness withmortality and major cardiovascular events in chronic
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Tada H, Nohara A, Inazu A, Mabuchi H, Kawashiri MA.
Remnant lipoproteins and atherosclerotic cardiovasculardisease. Clin Chim Acta. 2019; 490:1-5.
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Grundy SM. Non-high-density lipoprotein and very-lowdensity lipoprotein cholesterol and their risk predictive
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---Received August 25, 2021; Revised November 28, 2021;
Accepted December 28, 2021.
Released online in J-STAGE as advance publication January
16, 2022.
*Address correspondence to:
Yuji Hirowatari, Laboratory Sciences, Department of Health
Sciences, School of Health and Social Service, Saitama
Prefectural University, 820 San-Nomiya, Koshigaya-City,
Saitama 343-8540, Japan.
E-mail: hirowatari-yuji@spu.ac.jp(37)

Brief Report

GHM Open. 2022; 2(1):38-43.
DOI: 10.35772/ghmo.2022.01002

Safety of convalescent plasma therapy for COVID-19 patients andanalysis of viral kinetics: A single-center, open-label, single-arm,
interventional study in Japan§§
Satoshi Kutsuna1,2, ,*, Sho Saito1, , Yuki Takamatsu3, Mari Terada1,4, Tomiteru Togano5, Noriko Kinoshita1, Kenji Maeda3,
Akihiro Matsunaga6, Masahiro Satake7, Keiji Matsubayashi7, Nelson Hirokazu Tsuno8, Makiko Kojima7,8,
Madoka Kuramitsu9, Kenta Tezuka9, Emi Ikebe9, Kazu Okuma9, Isao Hamaguchi9, Yumiko Shimanishi1,

Akira Hangaishi5, Yukihito Ishizaka6, Norio Ohmagari1, Hiroaki Mitsuya3
1

Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan;
Department of Infection Control, Graduate School of Medicine Faculty of Medicine, Osaka University, Osaka, Japan;
3
Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan;
4Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan;
5
Department of Hematology, National Center for Global Health and Medicine, Tokyo, Japan;
6
Department of Intractable Diseases, National Center for Global Health and Medicine, Tokyo, Japan;
7Japanese Red Cross Central Blood Institute, Tokyo, Japan;
8Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan;
9Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan.
2

Abstract: Convalescent plasma therapy is an important treatment method for patients with severe coronavirus disease(COVID-19). This study was conducted to confirm the safety of this therapy. We conducted an open-label clinical trial
to administer convalescent plasma transfusion in a small Japanese cohort. Blood was collected from the recovered
COVID-19 patients with high anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) spike IgG
titer and high neutralizing activity and stored in the National Center for Global Health and Medicine Hospital until use.
Convalescent plasma was administered to COVID-19 patients who required supplemental oxygen within 3 days of
hospitalization. Convalescent plasma was administered to 11 patients with moderate to severe COVID-19. One patient
experienced an adverse event, such as redness of the skin around the intravenous injection site within 3 hours after
transfusion. Ten patients (91%) showed clinical improvement within 28 days, and one patient died of causes unrelated
to plasma therapy. The data suggest that patients with COVID-19 examined in the present study received convalescentplasma without having any significant adverse effects. We plan to conduct a randomized controlled trial to examine theclinical effectiveness of convalescent plasma transfusion in a large Japanese COVID-19 cohort.
Keywords: SARS-CoV-2, hospitalization, safety study, adverse event, Japan

Introduction

Argentine hemorrhagic fever (5), one of the SouthAmerican hemorrhagic fevers, revealed that the therapy
reduced the fatality rate. In recent years, convalescentplasma therapy has been used for severe infections suchas H5N1 avian influenza and Ebola hemorrhagic fever(6,7), as well as severe acute respiratory syndrome andMiddle East respiratory syndrome (8-10), which are
infections caused by the same coronavirus as the newcoronavirus.
Several clinical studies of convalescent plasma
therapy for COVID-19 have been reported in China (11),India (12), the United States (13), and South America(14), but it has never been implemented in Japan. This is
the first report on convalescent plasma therapy in Japan,

The coronavirus disease (COVID-19) epidemic began
in December 2019, and as of November 2021, morethan 250 million infections and 5 million deaths havebeen reported (1). Although some standard treatments
such as remdesivir and dexamethasone have been
established (2), resistance to remdesivir has beenreported (3), and therapeutic agents with antiviral
activity, in particular, continue to be in demand.
Convalescent plasma therapy was classically used
to treat patients with the Spanish flu and has beenreported to be effective (4). More than 40 years ago,
a randomized controlled trial conducted on cases of(38)

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and we conducted a safety evaluation and virologicalanalysis.

treatment studies for COVID-19, and those whose
physicians deemed inappropriate for inclusion in the
study were excluded. Eligible patients were given 200
mL plasma within 3 days of admission after providing
written consent. The plasma to be administered wasmatched to the blood type of the recipient patient.
Plasma was thawed spontaneously, cross-matching
was performed, and plasma was administered after
confirming the cross-matching results. Convalescentplasma was administered via a peripheral vein startingat 10 mL/15 min and then increasing the flow to 100
mL/h.
Initially, the primary endpoint was set as theabsence of ventilatory management or death by day
14 of treatment, but this was judged to be difficult toevaluate because of the small number of participantsin this study due to the planned start of a randomized
controlled trial, so the aim was changed to an
evaluation of the safety of convalescent plasma therapy.
The primary endpoint was the presence or absence ofadverse events within 28 days of plasma administration.
An adverse event was defined as any unwanted orunintended symptom (including abnormal laboratory
test results), condition, or illness that occurred within
28 days after convalescent plasma administration. The
presence of adverse events was assessed daily duringhospitalization and on days 3, 7, 14, and 28 after plasma
administration, which was the day of the outpatient
visit after discharge. Secondary endpoints included
changes in SARS-CoV-2 viral load in nasopharyngeal
swabs (pre-dose to day 14) and clinical improvement
was monitored up to 28 days using an 8-point scale andthe National Early Warning Score. Nasal swabs werecollected before and 3, 7, 14, and 28 days after plasma
administration. The SARS-CoV-2 viral copy number
in each sample was determined as previously described
and the threshold cycle (Ct) values were obtained (20).
To calculate the copy numbers of SARS-CoV-2 fromthe Ct values, a standard curve was generated with 10fold serial dilutions of a reference SARS-CoV-2 viral
RNA (19), and the Ct values for each sample wereconverted to SARS-CoV-2 copy numbers. The 8-point
scale was: 1. Dead; 2. Hospitalized and using invasive
mechanical ventilation or extracorporeal membrane
oxygenation; 3. Hospitalized and using noninvasive
ventilation or high-flow oxygenation; 4. Hospitalized
and needing oxygen supplementation; 5. Hospitalized
and needing no oxygen supplementation – requiringcontinuation of treatment (COVID-19-related or other);
6. Hospitalized and needing no oxygen supplementation– needing no continuation of treatment; 7. Not
hospitalized and needing limitation of activities and/or oxygen therapy at home; 8. Not hospitalized, and nolimitation of activities.
This study was approved as a specified clinical trial
in October 2020 in the NCGM and registered in theJapanese Register of Clinical Trials (jRCTs031200124).

Materials and Methods
This study was designed as an open-label, single-arm,
interventional study with only the convalescent plasmagroup and was conducted at the National Center for
Global Health and Medicine (NCGM) in Tokyo, Japan.
Recruitment of COVID-19 convalescent patientswas performed for plasma collection (15). Blood
samples were taken from COVID-19 recovering
patients who were at least 3 weeks from the date of
onset for measurement of laboratory data. Hemoglobin,
spike protein antibodies, and neutralizing activity were
examined at the National Center for Global Health andMedicine Research Institute. Screening for infectious
diseases (hepatitis B virus (HBV) surface antigen (Ag),HBV core antibody (Ab), HBV surface Ab, hepatitis
C virus (HCV) Ab, human immunodeficiency virus(HIV)-1 Ab, HIV-2 Ab, HBV DNA, HCV RNA,
hepatitis E virus RNA, HIV-1 RNA, HIV-2 RNA,
Treponema pallidum Ab, human T-cell lymphoma virus
1 Ab, human T-cell lymphoma virus 2 Ab, and humanparvovirus B19 Ag), blood type tests, and irregularantibody testing were performed at the Japanese Red
Cross Central Blood Institute, while severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2)
PCR tests in plasma were performed at the National
Institute of Infectious Diseases, Department of Safety
Research on Blood and Biological Products (16).
Spike protein was measured based on the methods
previously reported (17,18), and patients whose plasma
sample, absorbance value at optical density (OD) 450
nm was > 1, were considered to be eligible as donors.
As a neutralizing activity, the concentration of IgG
required for 50% inhibition of viral infection (IC50)
was evaluated according to the methods reported
previously (19). Plasma with less than 50 μg/mL of IC50
was considered eligible. Cases with positive infectious
disease screening tests or irregular antibodies were
excluded, as were cases with positive polymerase chain
reaction (PCR) tests for SARS-CoV-2 in serum. Four
hundred mL of plasma was collected from eligible
convalescent patients using a blood cell separator,
and the plasma was stored below -20°C in a freezer at
the National Center for Global Health and Medicine
Research Institute. Plasma to be administered to thepatient was obtained from plasma that was compatible
with the patient's and donor's blood types, starting withthe oldest date of collection.
The patients to whom plasma was administered werediagnosed with COVID 19 by PCR or antigen testing,and required supplemental oxygen. Patients aged under
20 years, pregnant or lactating women, those whose
religious beliefs do not allow for the administrationof blood transfusions, those participating in other(39)

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Table 1. The characteristics, COVID-19 treatment, plasma side effects and outcome of 11 COVID-19 patients who received
a convalescent plasma transfusion
Age
Sex(years)Underlying diseases

1
2

46
59

3
4

46
39

5

61

6
7
8

61
60
64

M HIV infection
M Diabetes,
hypertension, COPD,
hyperlipidemia
M Hypertension, obesity
M None(Previous history ofhepatitis B)
M Membranous
nephropathy, bronchialasthma, hyperuricemia,
dyslipidemia
M Interstitial pneumonia
M Hypertension
F Osteoporosis

9

90

F

10
11

66
86

Interstitial pneumonia,
hypertrophic heartdisease, hypertension
M Hypertension
F Hypertension,
dyslipidemia

Oxygen doseDays from
Oxygen doseat the worst
Treatment for COVID-19
at the time
Intubation
point of
Adverse event
COVID-19 onset to plasmaof plasmaor death
respiratory
administration administration
condition

OutcomeREM/DEXREM/DEX

10
8

1 L/minNHF

4 L/min
NHF

None
None

None
None

RecoveryRecoveryREM/DEXDEX

7
12

1 L/min2 L/min2 L/min5 L/min

None
None

None
None

RecoveryRecoveryREM/DEX

124 L/m

5 L/min

None

None

RecoveryREM/DEXREM/DEXREM/DEX

7
8
10

2 L/m
2 L/m
4 L/min2 L/min2 L/min
NHF

None
None
None

REM/DEX

95 L/min

NHF

Yes

REM/DEXREM/DEX

7
6

3 L/min1 L/minNHF
1 L/min

None
None

None
RecoveryNone
Recovery
Erythema at the Recovery
infusion site
None
Death
None
None

RecoveryRecovery

COVID-19, coronavirus disease; HIV, human immunodeficiency virus; COPD, chronic obstructive pulmonary disease; REM, remdesivir; DEX,
dexamethasone; F, female; M, male; NHF, nasal high-flow therapy.

Results and Discussion
From October 1, 2020, to December 31, 2020, 11 patientswere enrolled in the study (Table 1). Eight (72.7%)
patients were men, and the median age was 61 years. All
patients had underlying medical conditions. The median
day from onset to plasma administration was 8 days.
All patients received dexamethasone during the study,
and all but one received remdesivir. All patients wereon oxygen at the time of enrollment. One patient diedand the other ten were discharged. The data and safety
monitoring committee determined that the patient's death
was not causally related to the plasma administration.
One patient developed erythema at the puncture site theplasma transfusion. Of the 11 COVID-19 patients who
received convalescent plasma, five underwent infectious
disease screening tests 90 days after administration, andall were negative.
Figure 1 shows the relationship between the numberof days elapsed from the date of administration of theconvalescent plasma and the percentage of recovered
COVID-19 patients, defined as the criteria for category
6, 7, or 8 on the 8-point scale. Four patients (36%)
recovered within 7 days of treatment, 7 (64%) within 14
days, and 10 (91%) within 28 days.
Figure 2 shows the trend of SARS-CoV-2 viralload in nasal swabs as a function of the number of days
elapsed from the onset date. Counting from the date of

Figure 1. The relationship between the number of days
elapsed from the date of administration of the convalescentplasma and the percentage of COVID-19 patientsdischarged from the hospital. No, number; COVID-19,
coronavirus disease.

onset, none of the patients had the virus undetectablewithin 10 days of onset, three patients (27%) had thevirus below the detection limit within 20 days, 7 (64%)
patients within 30 days, and 9 (82%) patients within 40
days, and two patients (18%) did not disappear until 30
or 34 days after onset. Starting from the administrationof plasma, two patients (18%) disappeared within 7 days
after plasma administration, 7 (64%) within 14 days, 9(40)

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have shown that the administration of convalescentplasma to hospitalized patients who require oxygenationor who are severely ill with COVID-19 is not expected tobe effective (11,12,23). This may be because in patientswith advanced disease, viral replication has ceased andthe focus of the disease is on an excessive inflammatory
response, so the time when convalescent plasma, whosemechanism of action is to neutralize the virus, is nolonger effective.
In contrast, an RCT in which convalescent plasma
was administered within 3 days of disease onset to older
patients and patients at high risk of severe disease with
underlying disease showed that it prevented severe
disease (14). Furthermore, Sullivan et al. reported
that early administration of high-titer SARS-CoV-2
convalescent plasma reduced outpatient hospitalizations
by more than 50% (24). However, in another RCT,
convalescent plasma was administered within 7 daysof onset, but no efficacy was demonstrated (25). These
results suggest that convalescent plasma is unlikely
to be effective in already severe disease, and thatadministration of plasma with high antibody titers assoon as possible after the onset of disease is most likely
to be effective. In addition, in the RCTs conducted todate, the neutralizing activity of the collected plasma was
not assessed prior to administration, but only the IgG titer
was assessed. In fact, it has been reported that plasmas or
purified-IgG with high-neutralizing activity significantly
reduced the viral induced lung lesions in SARS-CoV-2
infected Syrian hamsters (26).
We have reported that IgG titer and neutralizing
activity can sometimes deviate in convalescent patients,
and neutralizing activity may not be accurately assessedby measuring IgG titers alone (19). In this study, we
assessed the neutralizing activity in the collected plasma,in order to assess the plasma quality more accurately.
In the future, the efficacy of convalescent plasma
therapy could be validated by conducting a randomized
controlled trial in high-risk patients with early onsetof disease, using plasma that has been previously
evaluated for neutralizing activity to be administered.
The antibodies possessed by the convalescent patientsare a wide variety of polyclonal ones, only a few ofwhich have neutralizing activity against the virus. A
homogeneous monoclonal antibody preparation withhigh neutralizing activity has been shown to be effectivein patients with early-onset COVID-19 (27,28). Now
that monoclonal antibody products are available, the roleof convalescent plasma therapy is limited, but it remains
a potential treatment option in developing countries
and could be a treatment option for the next emerging
infectious disease.
In this study, we also observed changes in the viralload of SARS-CoV-2 in the nasal swabs of 11 patients.
In a study analyzing the viral load of SARS-CoV-2
in 655 COVID-19 patients (40% of whom required
oxygen administration), the median time for the virus

Figure 2. The trend of SARS-CoV-2 viral load in nasal
swabs as a function of the number of days elapsed fromthe onset date. SARS-CoV-2, severe acute respiratory
syndrome coronavirus.

(82%) within 28 days, and two patients (18%) still had
detectable virus 28 days after administration.
Eleven COVID-19 patients received convalescentplasma, and no adverse events related to plasma
administration were identified, except for redness atthe site of intravenous injection after administration.
Although convalescent plasma therapy for COVID-19
has been used overseas, this is the first time that
this therapy has been implemented in Japan. The
establishment of a system for the safe administration ofconvalescent plasma in Japan is considered significant.
Although the number of COVID-19 patients towhom we have administered convalescent plasma
is small (11 patients), a larger number of patients
have been administered COVID-19 overseas, and thesafety of COVID-19 has been verified. In the UnitedStates, 22,000 COVID-19 patients have been treatedwith convalescent plasma and analyzed for adverse
effects (21). In this analysis, complications included
the following: transfusion reactions in 89 (< 1%),
thromboembolic complications in 87 (< 1%), cardiac
events in 680 (approximately 3%), and the majorityof thromboembolic and cardiac events were judged to
be unrelated to the plasma. These results show that theincidence of transfusion reactions with convalescentplasma appears to be comparable with that of standard
plasma when applied to a patient population with similar
illness severity.
In our study, 10 of 11 patients recovered, and one died(mortality rate 9.1%). According to data from COVID-19
Registry Japan (COVIREGI-JP) (22), a Japanese registryof COVID-19 hospitalized patients, the mortality rate
for patients requiring oxygen or ventilatory managementon admission is 17.7%. It is difficult to simply compare
the results of this study with those of COVIREGI-JP
because of the two studies used different definitions ofdisease severity. Randomized controlled trials (RCTs) todetermine the efficacy of convalescent plasma therapy
have been conducted in other countries, and the results ofsome RCTs have been reported to date. Multiple RCTs

(41)

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to fall below the limit of detection in patients older than
65 years was 16 days after onset, and 12 days in thoseyounger than 65 years (29). In our study, the median timefor viral load to fall below the detection limit in ninepatients was 21 days, and two patients virus was stilldetectable 28 days after transfusion. With these results,
it is not possible to show the effect of the administrationof convalescent plasma on the reduction of viral load.
The fact that the 11 patients in our study had a higher
severity of illness than the COVID-19 patients in the
study by Néant et al. may be related to the longer viraldisappearance time. In addition, since this study did
not examine the efficacy of convalescent plasma, butrather focused on evaluating safety, it is not possible todetermine the efficacy of convalescent plasma becauseof the disparate neutralizing activities of the plasma
administered.
In conclusion, this is the first study of plasma therapy
for COVID-19 patients to be conducted in Japan. No
treatment-related adverse events were observed in the
11 patients who received plasma therapy. A randomized
controlled trial using plasma with pre-evaluatedneutralizing activity is needed to determine the efficacy
of plasma therapy in patients with moderately severe
COVID-19.

6.
7.
8.

9.

10.

11.
12.

13.

Funding: This work was supported by the Health,
Labor, and Welfare Policy Research Grants, Researchon Emerging and Re-emerging Infectious Diseases and
Immunization (grant number 20HA1006) and NCGM
Intramural Research Fund (20A2003D).

14.
15.

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

16.

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MH, Chan P, Wong KC, Leung CB, Cheng G. Use ofconvalescent plasma therapy in SARS patients in HongKong. Eur J Clin Microbiol Infect Dis. 2005; 24:44-46.
Arabi Y, Balkhy H, Hajeer AH, et al. Feasibility, safety,
clinical, and laboratory effects of convalescent plasma
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Ko JH, Seok H, Cho SY, et al. Challenges of convalescentplasma infusion therapy in Middle East respiratory
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Agarwal A, Mukherjee A, Kumar G, Chatterjee P,
Bhatnagar T, Malhotra P. Convalescent plasma in the
management of moderate covid-19 in adults in India:
open label phase II multicentre randomised controlled trial(PLACID Trial). BMJ. 2020; 371:m3939.
Joyner MJ, Carter RE, Senefeld JW, et al. Convalescentplasma antibody levels and the risk of death from
Covid-19. N Engl J Med. 2021; 384:1015-1027.
Libster R, Pérez Marc G, Wappner D, et al. Early hightiter plasma therapy to prevent severe Covid-19 in older
adults. N Engl J Med. 2021; 384:610-618.
Terada M, Kutsuna S, Togano T, et al. How we secured a
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Nomoto H, Kutsuna S, Okuma K, et al. No SARS-CoV-2
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Kutsuna S, Asai Y, Matsunaga A. Loss of anti-SARSCoV-2 antibodies in mild Covid-19. N Engl J Med. 2020;
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S, Tsuchiya K, Hattori S, Matsuda K, Takamatsu Y,
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Simonovich VA, Burgos Pratx LD, Scibona P, et al. A
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severe pneumonia. N Engl J Med. 2021; 384:619-629.
24. Sullivan DJ, Gebo KA, Shoham S, et al. Randomized
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with high-titer convalescent plasma. medRxiv [Preprint].
2021; 2021.12.10.21267485.
25. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al.
Early convalescent plasma for high-risk outpatients with
Covid-19. N Engl J Med. 2021; 385:1951-1960.
26. Takamatsu Y, Imai M, Maeda K, Nakajima N, HigashiKuwata N, Iwatsuki-Horimoto K , Ito M, Kiso M,
Maemura T, Takeda Y, Omata K, Suzuki T, Kawaoka Y,
Mitsuya H. Highly neutralizing COVID-19 convalescentplasmas potently block SARS-CoV-2 replicationand pneumonia in Syrian hamsters. J Virol. 2022;
96:e0155121.
27. Weinreich DM, Sivapalasingam S, Norton T, et al.
REGEN-COV antibody combination and outcomes in
outpatients with Covid-19. N Engl J Med. 2021; 385:e81.
28 Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early
treatment for Covid-19 with SARS-CoV-2 neutralizing

29

antibody sotrovimab. N Engl J Med. 2021; 385:19411950.
Néant N, Lingas G, Le Hingrat Q, et al. Modeling SARSCoV-2 viral kinetics and association with mortality in
hospitalized patients from the French COVID cohort. Proc
Natl Acad Sci U S A. 2021; 118:e2017962118.

---Received February 9, 2022; Revised March 8, 2022; Accepted
March 12, 2022.
Released online in J-STAGE as advance publication March 18,
2022.
§

These authors contributed equally to this work.
*Address correspondence to:Satoshi Kutsuna, Department of Infection Control, Graduate
School of Medicine Faculty of Medicine, Osaka University, 2-2
Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail: kutsuna@hp-infect.med.osaka-u.ac.jp(43)Brief Report

GHM Open. 2022; 2(1):44-50.
DOI: 10.35772/ghmo.2021.01029

Global landscape of the COVID-19 vaccination policy: Ensuring
equitable access to quality-assured vaccines
Mami Wakabayashi1,2,*, Satoshi Ezoe2,3, Makiko Yoneda2, Yasushi Katsuma1,4,5,6, Hiroyasu Iso1,71Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo,
Japan;
2
Global Health Policy Division, International Cooperation Bureau, Ministry of Foreign Affairs, Tokyo, Japan;
3
Department of Global Health Policy, the University of Tokyo, Tokyo, Japan;
4
Graduate School of Asia-Pacific Studies, Waseda University, Tokyo, Japan;
5
Graduate Program in Global Leadership, Vietnam Japan University, Hanoi, Vietnam;
6
Institute for the Advanced Study of Sustainability, United Nations University, Tokyo, Japan;
7
Graduate School of Medicine, Osaka University, Suita, Japan.

Abstract: Ensuring equitable access to COVID-19 vaccines for all people has been challenging, hence, establishingrelevant vaccination policies is required. This study delineates how vaccination policies have affected equitable accessto COVID-19 vaccines. A situation survey was conducted in 201 countries and territories through 156 Japanesediplomatic missions abroad to capture the global state of COVID-19 vaccination policies. Questionnaire responses
were received from 159 states (79%) as of March 31, 2021, and data from Japan were incorporated into the analysis.
All questionnaire items were open-ended, covering the vaccines in use and five vaccination policies such as vaccine
eligibility. Results reveal that first, 81 states (51% out of 160) had not started vaccinations as of February 24, 2021,
but by March 31, this number had decreased dramatically to 37 (23%); in particular, the number of states in Africa
without vaccination decreased from 40 to 16. Second, 43 (27%) states did not recommend the vaccine for pregnant
women. Third, the vaccine was free of charge to the public in 116 states (73%), and 43 states (27%) offered no-fault
compensation. Finally, vaccination was voluntary in 124 states (78%). In conclusion, the number of countries that had
started vaccination increased by March 2021, especially in Africa, although many African countries seemed to lackaccess to the mRNA vaccine. To fix the uneven distribution, dose donations were accelerated since middle of July.
Reviewing worldwide vaccine policies is useful not only for this pandemic but also to strengthen vaccination systems
for preparedness for the next pandemic.
Keywords: vaccine policy, equity, COVAX Facility, mRNA, no-fault compensation, voluntary inoculation

Introduction

equitable access to vaccines with guaranteed safety,
efficacy, and quality for all nations, including developing
countries. With this study, we aimed to assess the state ofvaccine delivery worldwide and vaccine policy in eachcountry as of March 31, 2021, using survey data; weselected the end of March because the COVAX Facility
had begun delivering vaccines approximately one
month earlier. Our aim was to understand the directionof vaccine policies and how to expand equitable accessto vaccines both as an effective countermeasure against
COVID-19 and to prepare for future global pandemics.

The year 2020 brought a global pandemic caused by the
new coronavirus infection; on January 30, the World
Health Organization (WHO) Director-General declared
the virus a Public Health Emergency of International
Concern (PHEIC) (1). In response to what was later
declared a pandemic, vaccine development beganworldwide, and pre-purchase negotiations for COVID-19
vaccine candidates heated up among developed countries
from the early stages. To ensure equitable access to
the COVID-19 vaccine for all regardless of national
economic power, Gavi, the Vaccine Alliance (Gavi),
Coalition for Epidemic Preparedness Innovations (CEPI),
and WHO established a global mechanism known as"COVID-19 Vaccine Global Access Facility (COVAX
Facility)" for pooled procurement and distribution of
vaccines (2). The COVAX Facility aimed to ensure

Methods
Generating the data
To determine the status of the global COVID-19
vaccination policy, the Ministry of Foreign Affairs in(44)

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Japan sent a survey request to the Japanese diplomatic
missions abroad, which covered 201 countries andterritories. As of March 31, 2021, the questionnaires
were returned by 159 (79%) states. Besides incorporatingthese responses, we also include the status of thevaccination policy in Japan as of March 31, 2021. All
survey items were open-ended questions on topics that
had been developed by the International Affairs Division,
Minister's Secretariat of Ministry of Health, Labourand Welfare and the Global Health Policy Division,
International Cooperation Bureau, Ministry of Foreign
Affairs. For this study, we selected several responses toquestions that could be categorized into quantitative datafrom qualitative responses, such as which vaccine thecountry used and the start date of vaccination.

The vaccines: The vaccines were identified using thedevelopers' names taken from the COVID-19 candidate
vaccine landscape and tracker (3). Items and responses
were based on the date from when the vaccine wasavailable to public-facing essential workers, such as
healthcare workers, who were usually prioritized for
vaccination in each country, not by the clinical trial
dates. The vaccine developed by Astra Zeneca and the
University of Oxford and the vaccine licensed by theSerum Institute of India, Covishield, were categorized
as Oxford-AstraZeneca. Vaccines developed by
Sinopharm with the Wuhan Institute of Biological
Products or the Beijing Institute of Biological Products
were not separately identified in this study.
The regional categories: The regional categories
were based on countries and territories classified by the
Ministry of Foreign Affairs of Japan (4).
The analysis items: We collected data on thevaccines used in each country and on the following
five key policies: the option of vaccine type based on
people's preference; vaccine eligibility for children,
pregnant women, foreigners, and dignitaries underlimited supply; vaccine cost; no-fault compensation
programs; and regulations regarding immunization,such as voluntarily inoculation. For states that had not
begun vaccination as of March, we used information
about their planned or current policies or categorized
them as "Do not know".

in the E.U. and the U.S. (5). Although Pfizer/BioNTech
was more expensive, in March 2021, it was in use in
71 states; this might reflect that it received the earliest
approval besides reflecting higher efficacy; Pfizer/
BioNTech was approved on December 2, 2020, by
national regulatory authorities, such as the Medicinesand Healthcare products Regulatory Agency in the U.K.
(6).
The WHO assessed that sufficient data on Pfizer/
BioNTech were available for an Emergency Use Listing(EUL) recommendation on December 31, 2020 (7). The
EUL is a procedure for assessing unlicensed vaccines,
therapeutics, and in vitro diagnostics during PHEIC, withthe goal of expediting the availability of these products topeople who need them (8). Also, the EUL was one of the
COVAX Facility's product eligibility criteria for vaccine
use recommendation (9).
At that time, Pfizer/BioNTech required storage at-90°C to -60°C for a six-month shelf life (10), which
required expensive freezers to maintain the ultra-coldtemperature. Conversely, Oxford-AstraZeneca could be
stored under ordinary conditions at 2-8°C (11). Basedon its price and storage advantages, the COVAX Facility
had expected that Oxford-AstraZeneca would be on EUL
in the early stages.
There was uneven distribution of Pfizer/BioNTechby region. Specifically, it was used primarily in North
America and Europe, where the Moderna vaccine wasalso in high use; both Moderna and Pfizer/BioNTech
are mRNA vaccines. In December 2020, the COVAX
Facility made available limited funding to support
ultra-cold freezers in cases of emergency, but only 10
million USD was initially allocated (12). Therefore,
it is highly possible that Pfizer/BioNTech was only in
use in countries that could afford the vaccines and thefreezers.
The U.S. government announced a donation of
500 million Pfizer/BioNTech doses for low-income
countries through either the COVAX Facility or othermechanisms on June 10, 2021 (13), and on June 23, the
COVAX Facility increased the funding for ultra-coldfreezers to 775 million USD (14). These supports willcontribute to reducing the inequitable distribution of the
Pfizer/BioNTech vaccine and to increasing choice andavailability in low- and middle-income countries that
could not afford certain vaccines themselves.

Results and Discussion

Expanding vaccine availability

Uneven distribution of vaccine use

Figure 2 presents the changes in vaccine use byregion from February 24, the first day the COVAX
Facility delivered vaccines, to March 31. During thatapproximately one month, the number of states that
had not started vaccination decreased from 81 to 37,
and particularly in Africa, the number of states with novaccine decreased from 40 to 16.
The COVAX Facility began vaccine delivery in

Measures

Figure 1 displays the vaccines by region that were in
use worldwide as of March 31. Oxford-AstraZeneca
was in widest use, in 112 states over 6 regions; it wasmuch cheaper by dose, approximately 3 to 4 USD, thanthe vaccines based on mRNA, such as Comirnaty by
Pfizer/BioNTech, which costs approximately 19 USD(45)

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Figure 1. Nations' selected vaccines by region as of March 31, 2021.
Footnote: The figure described the number of countries or territories each vaccine was used by.

Figure 2. Changes in vaccine type and number by region between February 24 and March 31, 2021.
Footnote: The figure described the number of countries by the number of available vaccines in two time lines.

Ghana on February 24 and had reached over 100
states by April 8, 42 days later (15). To receive thevaccine supported by donor funding through the
COVAX Facility, the states had to prepare a national
vaccination plan; 92 states were eligible based on
income. To develop an overall vaccination policy, a
regional committee, including Gavi Independent Review
Committee members, reviewed the vaccination plansof the 92 eligible economies (16), and because of these
preparations, the vaccine administration progressedsmoothly. The findings here clearly indicate that without
the COVAX Facility, many more countries would nothave started COVID-19 vaccination by March 31.

policies. In most of the states (87%), people did nothave a choice regarding the vaccine type they would
receive, when several vaccine types were available in the
country. Concerning eligibility, children were eligible
for vaccination in six states as of March 2021, and 43
states recommended against COVID-19 vaccination
for pregnant women. In 59 countries, foreigners could
receive the vaccine under the same conditions as
domestic citizens, and political leaders in 31 states
had begun discussing easing quarantine restrictions
for vaccinated residents. Dignitaries had received thevaccine in approximately 50% of the states. Vaccination
was voluntary in 78% of the states. Only one country
required residents to pay for vaccination. Forty-threestates had no-fault compensation programs.

Overview for five vaccination policies
Supplemental Table S1 (https://www.ghmopen.com/site/
supplementaldata.html?ID=31) presents the findings
from our analyses regarding key COVID-19 vaccination

Vaccine eligibility and prioritization
The WHO Strategic Advisory Group of Experts on(46)

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Immunization used available clinical data to provide
guidance for overall vaccine program strategy, including
prioritization by subpopulation. Children take priority
for routine immunizations; however, COVID-19 rarely
causes severe illness or death in children (17), and in
our study, six states were administering the vaccine
to children as of March 2021, although some clinicaldata on children were available on May (18). Evidence
showed that pregnancy was associated with increased
rates of hospitalization, ICU care, and mechanicalventilation (17); however, the available data on vaccine
use in pregnant women of the first EUL vaccine,
Pfizer/BioNTech, were insufficient to assess vaccineassociated risks in relation to pregnancy as of December
2020, and the WHO was not recommending pregnancy
testing prior to vaccination at that time (10). The
initial recommendations for the COVID-19 vaccine
influenced how national plans prioritized vaccination;
as of March 2021, 43 states recommended that pregnant
women not receive the vaccine; however, 40 states wereadministering the vaccine with a doctor's consultation.
In June 2021, the initial recommendations for several
vaccines were updated with relevant data; for example,
based on its benefits, the WHO recommended the use of
Pfizer/BioNTech in pregnant women (19).
Each country has had to prioritize vaccine
distribution given limited supplies despite sufficient
data showing their safety and effectiveness. Considering
the inequities in vaccination rates between high- andlow- to middle-income countries, countries accelerated
donating vaccines through the COVAX Facility since
middle of July (20,21). Countries with high vaccination
rates, in particular, should increase dose-donation forvulnerable countries before administering booster shots
for the general population in the countries, because there
was limited data that booster doses were efficient in
September 2021 (22).

especially important because the COVID-19 vaccines
were developed at unprecedented speed, and there wereuncertainties concerning severe adverse events or longterm effects.
COVID-19 vaccine fees
In the acute phase of an infectious disease, it isreasonable for any vaccine to be free of charge for all
to promote vaccine access and prevent severe disease
and death. In most of the surveyed countries, 72%, thegovernments administered the vaccines at no cost to the
public. The COVAX Facility decided that the pledge for
vaccine procurement by donors would cover at least 20%
of a nation's population, excluding India because of its
large population, during the acute phase of COVID-19
for the 92 eligible lower-income countries and that it
would then introduce a cost-sharing mechanism bothto ensure sustainability of vaccine distribution andencourage a sense of ownership (26,27). It is possiblethat COVID-19 vaccination will require a yearly booster
shot in the same way as seasonal influenza vaccinationand that people might need to pay for it. To avoid thesituation where low-income individuals hesitate to get
vaccinated or low-income countries do not purchasethe vaccine, careful consideration should be given to
covering out-of-pocket costs for the COVID-19 vaccine.
Vaccination regulations
The WHO stated that either governments or institutional
policymakers or both should encourage voluntary
vaccination against COVID-19 before contemplating
mandatory vaccination (28). In our survey, the
COVID-19 vaccination was voluntary in most states(78%). The ongoing COVID-19 pandemic is sufficiently
dire that it necessitated drastic restrictions on social
activity, including national lockdowns, but securing
the public health had tremendous economic impacts,
and the lockdowns were controversial. There werehigh expectations for vaccines to control COVID-19,
and some national leaders focused on expanding theirvaccinated populations.
For instance, most of the WHO EUL-approved
vaccines, except for that of the Janssen Pharmaceutical,
need two doses at intervals recommended according toclinical trial data; however, to extend access with limited
supplies, some countries emphasized administering thefirst dose to as many people as possible before giving thesecond shot. For example, leaders in the U.K. elected toextend the interval between doses for Pfizer/BioNTech
from 3 weeks to 12 (29), and similar decisions weremade for Oxford-AstraZeneca, for which a longer gap
between doses had shown improved efficacy in some agegroups (30). We found only five countries prioritized to
expand first shots before second shots were completed.
Although governments attempted to maximize the public

No-fault compensation
Before the pandemic, no-fault compensation programs
were set up in a few high-income countries; we identified
39 states with such programs for vaccine injuries, and3 had established the programs for the COVID-19
vaccine. In a prior study in 2018, only 25 states had nofault compensation programs for vaccine injuries, with
programs administered at the central government levelin 15 states (23). The COVAX No-Fault Compensation
Program started in April 2021 to protect the 92 eligible
economies (24,25), and the COVAX Facility requested
that all participating countries make indemnification andliability agreements with each manufacturer before they
shipped the vaccine (16). The aims of vaccine injury
compensation were to promote vaccination with faircompensation for individuals in the event of harm andto accelerate vaccine research and development while
protecting manufacturers from liability. The latter was(47)

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health impact of the vaccine and the WHO recommended
longer between-dose intervals given the limited supplyof vaccine (10,11,19), most governments seemed hesitant
to deviate from the recommended protocol and expand
administration of single shots.
There was high demand from industries to reduce
the COVID-19 restrictions on international mobility,
especially from aviation industries, because international
tourism fell by around 80% in 2020, and up to 174
million jobs were estimated to be at risk globally (31).
However, easing restrictions carries risk of transmission,and indeed, some outbreaks occurred after quarantine
restrictions were eased (32,33). Our survey only showed
the eligibility of foreigners who were living withina given country, but some countries also offered thevaccine to foreign travelers (34,35). For example, the U.S.
government offered travelers the Janssen Pharmaceutical
vaccine, owned by Johnson & Johnson, which required
only one shot (36). This type of vaccine tourism could
increase the inequities in global vaccination because only
countries with surplus vaccines can offer such services
for rich people who can travel oversea given the limited
global supply. Accelerating vaccination rates with
policies such as longer intervals between doses before
completing second shots was a sound decision with
scientific evidences; however, we recommend against
encouraging vaccine tourism or only easing regulations
for vaccinated individuals. Such policies will only extend
vaccine inequity given that few states had over 50% of
their populations fully vaccinated by the end of June
2021 (37).

the vaccines free of charge. The COVAX Facility
comprehensive global system and relevant vaccine
policies established in each country were highly effectiveat ensuring equitable access to the COVID-19 vaccine
and protecting people. From February 24, 2021, when
the COVAX Facility distributed the first vaccines to a
low-income country, to the end of March, the numberof countries that had not started vaccination decreased
substantially, especially in Africa; the COVAX Facility
supported 46 African nations in expanding vaccine
access as 92 eligible low-income countries. This review
of policies worldwide and accumulated data could
make substantive contributions to countries' vaccination
policies. The systems for adjusting uncertainties andmaking justifiable policies, such as emergency use
approval mechanisms and no-fault compensation
programs, for vaccine injuries are of great use during thisongoing pandemic and will contribute to preparedness
for the next one.
Acknowledgements
The authors appreciate the efforts of the Ministry ofForeign Affairs for collecting the initial data and sharing
them.
Funding: None.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
Declarations: This manuscript was written based on thedata as of the end of March. Additionally, it was writtenby the authors using their personal ideas; it does notreflect their respective organizations' views and positions.

Strengths and limitations
For this study, we relied on information reported in
the media and in press releases that was available by
the end of March 2021 and COVID-19 conditions
are changing dramatically from country to country
depending on date; however, a particular strength of
this study is that information was collected from people
who understood the languages of original information.
Although we could not produce a holistic view of
the COVID-19 vaccination policies, we were able tohighlight how these policies contributed to promoting
and extending vaccination.

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Accepted September 29 , 2021.
Released online in J-STAGE as advance publication November
8, 2021.
*Address correspondence to:
Mami Wakabayashi, Institute for Global Health Policy Research,
Bureau of International Health Cooperation, National Center
for Global Health and Medicine, 1-21-1, Toyama Shinjuku-ku,
Tokyo, 162-8655 Japan.
E-mail: mwakabayashi@it.ncgm.go.jp(50)

Communication

GHM Open. 2022; 2(1):51-53.
DOI: 10.35772/ghmo.2021.01030

Sensitivity of three antibody assays to SARS-CoV-2 nucleocapsid
protein in relation to timing since diagnosis
Tetsuya Mizoue1,*, Shohei Yamamoto1, Akihito Tanaka2, Yusuke Oshiro2, Natsumi Inamura2, Maki Konishi1,
Mitsuru Ozeki2, Norio Ohmagari3
1

Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Toyko, Japan;
Department of Laboratory Testing, Center Hospital of the National Center for the Global Health and Medicine, Tokyo, Japan;
3
Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.
2

Abstract: The sensitivity of immunoassay for antibodies to SARS-CoV-2 may decrease over time. We compared
three serology assays against SARS-CoV-2 nucleocapsid protein using serum samples of 20 health care workers witha history of mild PCR-confirmed coronavirus disease 2019 (COVID-19) at various timing since diagnosis. Overall,
the sensitivity (95% confidence interval) was 95.0 (75.1-99.9), 60.0 (36.1-81.0), and 45.0 (23.1-68.5) for the Roche,
Sysmex, and Abbott assays, respectively. The sensitivity of all these assays exceeded 80 for those diagnosed within
6 months, whereas it varied considerably for those diagnosed more than 6 months ago: 88.9 (Roche) versus 0 (Abbott).
The present data provide a reference for researchers planning serological studies and interpreting these data. Suchassay difference in terms of detection durability can be used, if used in combination, for the estimation of the timingof previously undetected infection.
Keywords: COVID-19, SARS-CoV-2, immunoassay, antibody, sero-epidemiologic studies, Japan

Introduction

CoV-2 nucleocapsid protein among health care workers
with a history of COVID-19 in a Japanese hospital.

Epidemiological data on the spread of SARS-CoV-2
infection are helpful for planning strategies to control
coronavirus disease 2019 (COVID-19). The number of
COVID-19 cases confirmed by reverse-transcription
polymerase chain reaction (RT-PCR), which has
been performed mainly for symptomatic cases, does
not represent the whole picture of this infection. In
this context, serological study has been performed toassess the undiagnosed infection of SARS-CoV-2 in a
population (1).
Several immunoassays for antibodies to SARSCoV-2 have been developed and proved to be highly
sensitive in detecting recently diagnosed cases (2). Dueto the waning of antibodies within months, especiallyamong those without symptoms (3), however, a concern
has been raised about the increasing gap between
seroprevalence and cumulative infection over time.
Following an earlier report that showed a variationin sensitivity among assays after 3-4 months sincedisease onset (4), several serological studies with alonger period of follow-up have demonstrated an evenlarger between-assay variation in sensitivity (5-7). Dataon this issue is scarce in Asians, who recorded higher
maximum anti-nucleocapsid levels after infection (3).
Here we compared three immunoassays against SARS-

Sero-epidemiological study among health care
workers
A repeat serological study has been conducted since
July 2020 among workers of National Center for
Global Health and Medicine (NCGM) (8), which has
accepted many patients with severe COVID-19. We
asked participants about COVID-19 related information
including a history of COVID-19 and the date ofdiagnosis, which were confirmed against records
kept by the infection control department. The current
study included participants who reported a history of
COVID-19 at the third survey (June 2021). Written
informed consent was obtained from each participant,and the study procedure was approved by the ethics
committee of NCGM.
Assessment of three antibody assays
We measured antibodies against SARS-CoV-2
nucleocapsid protein, which increased after SARSCoV-2 infection but not after vaccination, using threecommercially available kits; namely, Elecsys® AntiSARS-CoV-2 immunoassay (Roche diagnostic),(51)

GHM Open. 2022; 2(1):51-53.

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Figure 1. SARS-CoV-2 antibody titers of the Roche (A), Abbott (B), and Sysmex (C) assays with time since diagnosis of
COVID-19.
Table 1. Sensitivity of three SARS-CoV-2 antibody assays according to time since diagnosis of COVID-19
Timing of COVID-19 diagnosis with RT-PCR
Items

Roche
SysmexAbbottOver 6 months (24 weeks) ago

Within 6 months (24 weeks)No. of positives /Total number

Sensitivity (95% CI)

No. of positives /Total number

Sensitivity (95% CI)

8/9
3/9
0/9

88.9 (51.8 - 99.7)
33.3 (7.5 - 70.1)
0 (0 - 33.6)

11 / 119 / 11
9 / 11100 (71.5 - 100)
81.8 (48.2 - 97.7)
81.8 (48.2 - 97.7)

Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; RT-PCR, reverse transcription-polymerase chain reaction; SARSCoV-2, severe acute respiratory syndrome coronavirus 2.

SARS-CoV-2 IgG assay (Abbott), and HISCL antiSARS-CoV-2 immunoassay (Sysmex). We plotted
immunoglobulin titer/assay signal against time since
COVID-19 diagnosis and calculated the proportion of
detecting COVID-19 confirmed cases (sensitivity) for
each assay according to time since diagnosis.

ago showed negative (n = 6/9) (Figure 1C).
Comparison of sensitivity according to the timing
since diagnosis
Overall, the sensitivity (95% confidence interval) was
95.0 (75.1-99.9), 60.0 (36.1-81.0), and 45.0 (23.1-68.5)
for the Roche, Sysmex, and Abbott assays, respectively.
The sensitivity of these assays exceeded 80 for
those diagnosed within 6 months, whereas it varied
considerably for those diagnosed more than 6 months
ago: 88.9 (Roche) versus 0 (Abbott) (Table 1).

Identification of individuals with a history of
COVID-19
Of 2,763 participants (89%) of the third survey, 20 selfreported a history of RT-PCR confirmed COVID-19,
which was confirmed against the hospital record.
Of these, 5 (25%) were admitted to a hospital while
contracting COVID-19, but none received mechanicalventilation; 14 (70%) received Pfizer-BioNTech vaccine
twice.

Careful evaluation of assay is needed when planning
serological studies and interpreting data in the laterstages of a pandemic
In a cross-sectional analysis of health care staff witha history of COVID-19, we found a remarkabledifference in the sensitivity over time among the threecommercially available assays, with sensitivity being
the highest in the Roche assay, followed by the Sysmex
and Abbott assays.
The three assays showed a sensitivity of over 80 for
the samples taken from patients who were diagnosed
within 6 months. However, the Abbott and Sysmex
assays, both of which are targeted for IgG SARS-CoV-2
nucleocapsid protein, showed a considerably low
sensitivity for the samples taken more than 6 months
after diagnosis. Similarly, long-term repeat serologicalstudies have reported a high sensitivity of the Roche

Comparison of seropositive rate according to thetiming since diagnosis
In the Roche assay, 19 of 20 previously diagnosed
COVID-19 cases showed positive, and the titer appears
not to be related to the timing of diagnosis (Figure 1A).
In the Abbott assay, only 9 of 20 cases were positive,
and the proportion of positive cases dramaticallydecreased over time, with all 9 cases diagnosed morethan 6 months ago being negative (Figure 1B). The
Sysmex assay also showed a decreasing trend of
positivity over time; 12 of 20 cases were seropositive,
and two-thirds of cases diagnosed more than 6 months(52)

GHM Open. 2022; 2(1):51-53.

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References

assay but a considerably low sensitivity of the Abbott
assay toward the end of follow-up (5-7).
The population studied was comprised of individuals
with a history of mild COVID-19, which has been
associated with lower antibody titers than severe one (6).
Given that mild cases explain a major portion of thisdisease, the large between-assay difference in sensitivity
observed in the present as well as previous studies
highlights the need for careful evaluation of assay whenplanning serological studies and interpreting data in thelater period of the pandemic.
We should acknowledge study limitations. First, due
to the small size of the study (n = 20), the estimatedsensitivities have wide confidence intervals. Second,as mentioned above, our study included only patientswith mild COVID-19. The result may not be applied
to severe or asymptomatic cases. Third, the crosssectional design of the study limits our inference about
the change of antibody status over time for each case.

1.

2.

3.

4.

5.

Conclusions and future directions

6.

The present data provide a reference for researchersplanning serological studies and interpreting these data.
Further, such large difference among assays in terms ofdetection durability can be used, if used in combination,
for the estimation of the timing of previously undetected
infection. More research is required to examine whether
the use of multiple assays can help differentiate theimpact of the recent epidemic from earlier ones.

7.

8.

Acknowledgements
We thank Haruka Osawa for her contribution to datacollection.

Kalish H, Klumpp-Thomas C, Hunsberger S, et al.
Undiagnosed SARS-CoV-2 seropositivity during thefirst 6 months of the COVID-19 pandemic in the UnitedStates. Sci Transl Med. 2021; 13:eabh3826.
National SARS-CoV-2 Serology Assay Evaluation
Group. Performance characteristics of five immunoassays
f o r S A R S - C o V- 2 : a h e a d - t o - h e a d b e n c h m a r k
comparison. Lancet Infect Dis. 2020; 20:1390-1400.
Lumley SF, Wei J, O'Donnell D, et al. The duration,
dynamics, and determinants of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) antibody
responses in individual healthcare workers. Clin InfectDis. 2021; 73:e699-e709.
Muecksch F, Wise H, Batchelor B, et al. Longitudinal
serological analysis and neutralizing antibody levels incoronavirus disease 2019 convalescent patients. J InfectDis. 2021; 223:389-398.
Schallier A, De Baets S, De Bruyne D, Dauwe K, Herpol
M, Couck P. Assay dependence of long-term kinetics of
SARS-CoV-2 antibodies. Diagn Microbiol Infect Dis.
2021; 100:115403.
Peluso MJ, Takahashi S, Hakim J, et al. SARS-CoV-2
antibody magnitude and detectability are driven by
disease severity, timing, and assay. Sci Adv. 2021;
7:eabh3409.
Kerr C, Allen N, Hughes G, Kelly M, O'Rourke F,
Lynagh Y, Dunne J, Crowley B, Conlon N, Bergin C.
SARS-CoV-2 anti-nucleocapsid assay performance inhealthcare workers at baseline and 6 months. Ir J Med
Sci. 2021; doi: 10.1007/s11845-021-02700-5.
Yamamoto S, Tanaka A, Oshiro Y, Ishii M, Ishiwari
H, Konishi M, Matsuda K, Ozeki M, Miyo K, Maeda
K, Mizoue T, Sugiura W, Mitsuya H, Sugiyama H,
Ohmagari N. Seroprevalence of SARS-CoV-2 antibodies
in a national hospital and affiliated facility after thesecond epidemic wave of Japan. J Infect. 2021; 83:237279.

---Received October 12, 2021; Revised November 1, 2021;
Accepted November 25, 2021.

Funding: This work was funded by the NCGM
COVID-19 Gift Fund (19K059) and the Japan HealthResearch Promotion Bureau Research Fund (2020-B09). Antibody assay reagents of Elecsys® Anti-SARSCoV-2 immunoassay and SARS-CoV-2 IgG assay
were provided by Abbott Japan and Roche Diagnostic,
respectively.

Released online in J-STAGE as advance publication
November 30, 2021.
*Address correspondence to:
Tetsuya Mizoue, Department of Epidemiology and Prevention,
National Center for Global Health and Medicine, 1-21-1,
Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
E-mail: mizoue@hosp.ncgm.go.jp

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

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Communication

GHM Open. 2022; 2(1):54-58.
DOI: 10.35772/ghmo.2022.01006

Development of the neurological simulation program e-learning
version (Neuro Sim-e)
Mitsumi Masuda1,*, Fumino Sugiyama2, Junko Shogaki3, Kyoko Matsumoto4, Machiko Saeki Yagi5, Hidenori Oishi61

Department of Critical Care Nursing, Graduate School of Nursing, Nagoya City University, Aichi, Japan;
Department of Adult Nursing, School of Nursing, National College of Nursing, Tokyo, Japan;
3
Graduate School of Health Science, University of Kobe, Hyogo, Japan;
4
Nursing Division, Department of Neurosurgery, Kansai Rosai Hospital, Hyogo, Japan;
5
SimTiki Simulation Center, University of Hawaii at Manoa, USA;
6
Department of Neurosurgical, School of Medicine, Juntendo University, Tokyo, Japan.
2

Abstract: It is difficult to coordinate the working hours of busy clinical nurses and provide lectures, but e-learning
can be used during their spare time. Therefore, this study aimed to share our experience in developing andimplementing the neurology simulation program e-learning version (Neuro Sim-e). Needs analysis was conducted,
and the Neuro Sim-e was developed. Four evaluation questionnaires: attention, relevance, confidence, andsatisfaction (ARCS) etc., were examined. We developed the Neuro Sim-e, which consists of three scenarios. The
subjects were 20 nurses. Regarding the "attention", "relevance", "reliability", and "satisfaction" of the Neuro Sim-e,
70.0%, 95.0%, 65.0%, and 90.0% of the respondents answered "rather agree" or higher, respectively. The Neuro
Sim-e obtained positive feedback via ARCS evaluation and provided adequate results as an overall assessment.
It is too early to conclude whether it is as effective as or better than a mannequin-based simulation, but this study
provided learning materials that nurses could use in their spare time.
Keywords: neurological nursing, simulation-based learning, e-learning

Introduction

when learners wish to learn. Moreover, in e-learning
so far, the learning methods, such as the confirmationof knowledge, have been the mainstream, but are
insufficient in improving the clinical practice ability.
To compensate, Goal-Based Scenario (6,7) proposedby Schank is appropriate. Goal-Based Scenario (GBS)
is the acquisition of necessary knowledge and skills
while repeating training and error for the achievementof a given goal in the educational material using theexperience of learning by failing a subject. Based on
GBS, learners can learn how to make decisions by not
only remembering knowledge they wish to acquire but
also using that knowledge in practice.
Therefore, the aim of this short communication is toshare our experience in developing and implementing a
GBS-based the neurology simulation program-e-learning
version (Neuro Sim-e).

Simulation training is rapidly being incorporated
into health professional education and, recently, has
ascertained efficacy as a way to foster clinical judgment
capabilities (1,2). It is common for physicians andnurses in the field of neurology to encounter suddenchange cases. A delay in response can directly lead toa life-threatening situation for the patient, so a prompt
and accurate response is required. Therefore, educationis required in neurology to learn various techniques,
behavioral patterns, communication skills, and logicalthinking in a real-world context. Conversely, in
addition to the skill training, such as cardiopulmonary
resuscitation, the Simulation-Based learning in theemergency field (3,4) and cardiovascular field (5),which often provide treatment for emergency changes
and severe diseases, is applied sporadically. However,similarly, there is training specific to the neurology field,
where the possibility of sudden patient changes is high.
It is also difficult to coordinate the working hours ofbusy clinical nurses and provide lectures simultaneously.
Therefore, e-learning can be used "anytime andanywhere" during their spare time and can be applied

Research design for developing the Neuro Sim-e
Flow of scenario creation
To develop the Neuro Sim-e, a semi-structured interview
learning needs survey was administered to 10 second(54)

GHM Open. 2022; 2(1):54-58.

www.ghmopen.com

year or older nurses in the neurology department of A
University Hospital to determine their learning needs.
The data collection period was from September 1, 2020
to March 31, 2021. The survey comprised of questions
about frequent diseases and situations in clinical settings,
learning needs, and barriers and needs in skill upgrading.
The results of the interview survey were analysed
qualitatively and inductively.
Based on need analyses, the diseases, situations, andlearning components used in the case are consideredamong researchers. Next, seven components (mission,
coverage story, roles, learning goals, scenario
manipulation, feedback, and source) of GBS (8) areconsidered. The created content is set for online learning
using Moodle, a learning management system. Then,
researchers and three nurses with clinical experience inthe neurology domain or intensive care unit confirmed
content validity. Finally, a test run was performed tocheck whether the learning goal could be achieved andwhether there was confusion or inadequacy.

the ID and password were prepared and shared with thesubject.

The Neuro Sim-e evaluation

Core elements of the Neuro Sim-e

Subjects
The selection criteria for the study subjects werestaff nurses who were assigned to the Departmentof Neurology at the University Hospital B in Japanand were in their second year or older who agreed
to participate in this study. Exclusion criteria werequalified nurses such as certified nurse specialists.

The Neuro Sim-e development

Data analysis
The ARCS evaluation questionnaire and the Neuro
Sim-e evaluation sheet were used to perform descriptive
statistics. The Neuro Sim-e was used for learning
analysis. Moreover, free description of the Neuro
Sim-e evaluation sheet was analysed qualitatively andinductively.
Ethical considerations
This study was conducted with approval from the
Research Ethics Committee of the Graduate School of
Nursing, Nagoya City University (approval number:
18034). The subjects received verbal and written
explanations about the purpose, methods, protecting
personal information, e-learning, and responding to thequestionnaire to ensure that individuals are not identified
by their shared IDs and passwords.

As a result of the learning needs analysis, eightcategories regarding the most frequent diseases andsituations in clinical settings, and eight categories
regarding barriers and necessities for skill upgradingwere extracted (Table S1, https://www.ghmopen.com/
site/supplementaldata.html?ID=52).
Based on the results, it was determined that thecase needed to include the situations of "response to
endovascular surgery" and "deterioration of condition
after surgery", and was classified into three events: i)carotid artery stenting (CAS) in the posterior carotid
sinus reflex, ii) CAS in posterior hypoperfusion
syndrome, and iii) post-craniotomy cerebral infarction.
The three situations were classified as observation,
implementation of nursing care, and evaluation.
Moreover, seven components of GBSs were considered.
As an example, the GBS component of Case 1 isshown in Table S2 (https://www.ghmopen.com/site/
supplementaldata.html?ID=52). The contents wereset for online learning using Moodle, a learning
management system.

Survey contents
The survey consisted of the attention, relevance,
confidence, and satisfaction (ARCS) (9) evaluationquestionnaire of Kirkpatrick's four-level training
evaluation model (10). For level 1 response, four items
were investigated. The answers were measured on afour-point Likert scale: 4 for "I think so" and 1 for "I donot think so".
M o r e o v e r, t h e N e u r o S i m - e e v a l u a t i o nquestionnaires consisting of five items (including
one free-text), and learning time and rate of correct
answers, as Kirkpatrick's four-level training evaluation
model level 2 learning were investigated. The degree ofdifficulty, amount of questions, whether knowledge thatcan be used in practice was acquired, and whether theyfelt that they could use it in practice were asked in the
Neuro Sim-e evaluation questionnaire. It also included
an open-ended section for the user to express positive
feedback and areas for improvement.

Overview of study subjects
Requests were sent to 25 nurses, and 20 responses wereobtained (80.0% response rate) from 18 women and2 men in the neurology department at B University
Hospital. The educational background of the subjects
was as follows: junior college for 2 subjects, university
for 16 subjects, and master's degree for 2 subjects. A
total of 12 subjects had 3-5 years of nursing experience,
4 had 6-10 years, and 4 had ≥ 11 years. The Neuro

Survey method
The researcher asked all 25 candidates to participate
in this study verbally and in writing. Consent toparticipate in this study was obtained by accessing the
Neuro Sim-e on Moodle and responding to the presenceor absence of consent. When accessing the Neuro Sim-e,(55)

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Table 1. ARCS evaluation questionnaire
Items

Attention
Relevance
Confidence
Satisfaction

Four-level training evaluation
1
I do not think so
n (%)

2
I somewhat do not think so
n (%)

3
I somewhat think so
n (%)

4
I think so
n (%)

1 (5.0)0 (0.0)1 (5.0)0 (0.0)5 (25.0)
1 (5.0)6 (30.0)
2 (10.0)

12 (60.0)
17 (85.0)
0 (0.0)15 (75.0)

2 (10.0)
2 (10.0)
13 (65.0)
3 (15.0)n = 20Mean ± SD

2.75 ± 0.72
3.05 ± 0.40
2.60 ± 0.60
3.05 ± 0.41

ARCS: attention, relevance, confidence, and satisfaction.

Sim-e and the ARCS evaluation questionnaire wereadministered to all 20 subjects who agreed to participate
in the study.

Table 2. Neuro Sim-e evaluation questionnaire
Items
Degree of difficulty
Difficulty
A little difficulty
Just right
A little easy
Easy
Amount of questions
Many
A little more
Just right
A little few
Few
Whether knowledge that can beused in practice was acquired
Acquired
A little acquired
Not acquired a little
Not acquired
Whether they felt that they could
use it in practice
I think so
I somewhat think so
I somewhat do not think so
I do not think so

The Neuro Sim-e evaluation
Kirkpatrick's four-level training evaluation model: Level
1 response
In terms of "Attention", "Relevance", "Confidence",and "Satisfaction" for the Neuro Sim-e the number of
respondents that answered "I somewhat think so" or
more, "Confidence" was slightly low (Table 1).
"Degree of difficulty", "Amount of questions" of
five-item questions for the Neuro Sim-e evaluation were
negatively answered. "Whether knowledge that canbe used in practice was acquired" and "whether theyfelt that they could use it in practice" were positively
answered (Table 2).
Free-text results were also summarized in 30 codesand 9 categories. Below, categories are indicated by thestrongest quote. On the case used in the Neuro Sim-e,
the opinion of "It was real cases and practice contents"
was obtained. In addition, positive answers such as "I
was able to deepen my knowledge", "I was able to learn
how to report", "I want to put learning into practice",and "I learned how to deal with sudden changes" werereported. On the other hand, there were opinions oncontent and methods, such as "The descriptive test wasdifficult", "The number of free descriptions were manyand it took a lot of time", "Difficult to see test", and"Difficult to perform with devices other than PC".
The ARCS evaluation for the Neuro Sim-e showed
positive results. Therefore, it can be said that thelearning motivation for the Neuro-Sim-e was effective.
In a previous study on self-learning of neurologicale-learning conducted in Korea (11), it was found that
nurses' neurological assessment skills were improved.
From this, it can be said that e-learning materials arean effective method for improving nurses' judgment
and assessment skills. Moreover, the Neuro Sim-e is a
GBS-based program, intended to not only remember
the knowledge to be acquired but also to learn how
to judge by utilizing that knowledge. From the resultof this study, it was not only possible to deepen the

n

%

11
3
4
2
0

55.0
15.0
20.0
10.0
0.0

16
4
0
0
0

80.0
20.0
0.0
0.0
0.0

6
10
0
4

30.0
50.0
0.0
20.0

2
16
2
0

10.0
80.0
10.0
0.0

Mean ± SD
1.85 ± 1.01

1.20 ± 0.41

3.10 ± 0.72

3.00 ± 0.46

knowledge but also to learn how to deal with and report
the sudden change. It was evaluated that the learningwhich reflected the philosophy of GBS was possible andconsidered to be a great achievement.
However, it was suggested that the following
points need to be improved. First, of the four itemsof the ARCS evaluation, "Confidence" was lower
than the other three items, so further improvement isneeded. High results are obtained for "Confidence" inWestern studies (12), but "Confidence" tends to be low
in previous studies in Japan (13,14). Therefore, it isconsidered that there is a Japanese cultural backgroundof humility. Second, regarding the evaluation of the
Neuro Sim-e, the difficulty level was high. This finding
should be improved, and the high difficulty level
may have influenced the inadequate "Confidence" of
ARCS evaluation. Finally, participants also reported
many questions and difficulty in inputting descriptive
questions about reporting methods. As has been pointed(56)

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out, the circumstances used by learners have a major
effect on e-learning; it will be improved by considering
the ease of answering on various devices and asking
multiple-choice questions. Particularly, the feature ofthis study is that busy clinical nurses can apply e-learning"anytime and anywhere" during their spare time and canobtain knowledge when they wish to. Therefore, it isimportant for it to be easily accessible on devices otherthan PCs.

evaluation of the Neuro Sim-e, it was suggested to refine
the high degree of difficulty, quantity of questions, andconvenience for use on various devices.
Acknowledgements
We would like to offer our heartfelt appreciation to thenurses who participated in this study.
Funding: This study was supported by Grants-inAid from the Ministry of Education, Science, Sports
and Culture of Japan and by JSPS (Grant Number:
17K12219).

Kirkpatrick's four-level training evaluation model: Level
2 learning
The correct answer rates for the total scores of cases
1 to 3 were 73.0%, 87.5%, and 80.4%, respectively, andCase 1 was slightly lower. The average response time
(range) was 34.22 (9.12-120.55) min, 30.58 (6.30-60.85)
min, and 30.35 (11.12-90.25) min, respectively.
Since this is a basic study prior to intervention
research, and the goal was not to perform a prepost comparative test of the mean points of eachcase, this result was an appropriate outcome as an
overall overview. In Kirkpatrick's four-level training
evaluation model, level 2 learning, is likely to exhibit
an example of what has been experienced so far and thepossibility of obtaining new findings and adapting theknowledge gained to practice. Merrill's first principle of
instructional design states that "Learning is facilitatedin situations where new knowledge can be used inpractice" (14). In addition to learning content based on
previous experiences, new findings and learning that canbe used in actual clinical settings have been reflected in
the total rating. Based on the above, the Neuro Sim-e
had a certain effect on the improvement of knowledge
and clinical judgment ability required for nursing in theneurology domain in Kirkpatrick's four-level training
evaluation model level 1 response and level 2 learning.

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

Kim J, Park JH, Shin S. Effectiveness of simulation-based
nursing education depending on fidelity: A meta-analysis.
BMC Med Educ. 2016; 16:152.
2. Laschinger S, Medves J, Pulling C, McGraw R, Waytuck B,
Harrison MB, Gambeta K. Effectiveness of simulation on
health profession students' knowledge, skills, confidence,and satisfaction. Int J Evid Based Healthc. 2008; 6:278302.
3. Chen J, Yang J, Hu F, Yu SH, Yang BX, Liu Q, Zhu XP.
Standardized simulation-based emergency and intensive
care nursing curriculum to improve nursing students'
performance during simulated resuscitation: A quasiexperimental study. Intensive Crit Care Nurs. 2018; 46:5156.
4. Johnson KD, Alhaj-Ali A. Using simulation to assess
the impact of triage interruptions. J Emerg Nurs. 2017;
43:435-443.
5. Stueben F. Implementation of a simulation-based cardiac
surgery advanced life support course. Clinical Simulationin Nursing. 2017; 13: 432-435.
6. Schank RC. What we learn when we learn by doing.
Technical Report #60 (1995). https://web-archive.
southampton.ac.uk/cogprints.org/637/1/LearnbyDoing_
Schank.html (accessed January 15, 2022)
7. Schank RC. Goal-Based Scenarios: Case-based
reasoning meet leaning by learning by doing. In: CaseBased Reasoning: Experience, Lessons & Future
Directions (Leake D, Ed.). AAAI Press/ The MIT Press,
Massachusetts, USA, 1996; pp.1-39.
8. Nemoto J, Suzuki K. A checklist development for or
instructional design based on goal-based scenario theory.
Japan Society for Educational Technology. 2006; 29: 309318. (in Japanese)
9. Keller MJ. Motivational design for learning andperformance: the ARCS model approach. Springer,
Florida, USA, 2010.
10. Alzahrani AR. Kirkpatrick's four-level training evaluation
model. International Journal of Scientific & Engineering
Research. 2016; 7:66-69.
11. Shin JY, Issenberg SB, Roh YS. The effects of neurologic
assessment e-learning in nurses. Nurse Educ Today. 2017;57: 60-64.
12. Ellis B, Winn S, MacMillan D, Bouthillet K, Purcell C.

Limitations
In this study, the pre- and post-comparison wereinsufficient, and levels 3 and 4 of Kirkpatrick's fourlevel training evaluation model were not evaluated. In
the future, it will be necessary to add results, such aslevel 3 behavior and level 4 learner behavioral changes
and clinical outcomes, to the evaluation items to conduct
an effect confirmation study.
Conclusion
It is too early to conclude whether it is as effective as or
better than a mannequin-based simulation because this isan exploratory study, but it provided learning materials
that busy nurses could use in their spare time; thus, thisstudy was meaningful.
As a result of levels 1 and 2 in Kirkpatrick's fourlevel training evaluation model, the effectiveness ofthe program could be confirmed. Conversely, from the(57)

GHM Open. 2022; 2(1):54-58.

www.ghmopen.com

Simulated learning experience in advance care planning
conversations. J Hosp Palliat Nurs. 2021; 23:339-345.
13. Kimura N, Masuda M, Nakagaki A. Development andeffect of simulation materials for sudden changes inpatients' conditions in basic nursing education. Journal ofJapan Academy of Nursing Science. 2021; 41:79-87. (inJapanese)
14. Hirakawa Y, Yahiro Y, Fukano K, Nakamura M,
Maruyama T, Usui Y, Aoki N. Student's evaluation on
simulation learning in perioperative nursing. Journal ofJapan Association for Simulation-based Education in
Healthcare Professionals. 2018; 6:36-40.

---Received May 1, 2022; Revised June 15, 2022; Accepted June27, 2022.
Released online in J-STAGE as advance publication July 9,2022.
*Address correspondence to:
Mitsumi Masuda, Department of Critical Care Nursing,
Graduate School of Nursing, Nagoya City University, 1
Kawasumi, Mizuo-cho, Mizuho-ku, Nagoya 467-0005, Japan.
E-mail: m.masuda@med-nagoya-cu.ac.jp(58)Letter

GHM Open. 2022; 2(1):59-62.
DOI: 10.35772/ghmo.2021.01032

Global extension of Japanese medical products related to COVID-19:
A survey of WHO Emergency Use Listing
Mami Wakabayashi1,*, Yasunori Ichimura2, Eiichi Shimizu2, Tomoko Nishioka2, Yuzuru Kono2, Masahiko Doi2, Yuriko
Egami2, Tomoka Kadowaki3, Hiroyasu Iso1,4, Noriko Fujita2
1

Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine,Tokyo, Japan;
2
Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo, Japan;
3
Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan;
4
Public Health, Department of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.

Abstract: The World Health Organization (WHO) has been utilizing Emergency Use Listing (EUL) to expand accessto medical products during the COVID-19 pandemic. EUL is a risk-based procedure for assessing and listing unlicensed
vaccines, medicine, and in vitro diagnostics. To determine whether Japanese medical products acquired EUL relating to
COVID-19, we conducted desk research as a part of a new project. Results showed that thirteen of twenty-eight in vitro
diagnostic products were from China and three of ten vaccines on EUL were from India. However, only one vaccine
manufactured in Japan was on EUL. A common weakness of Japanese companies in the global public procurement
market was a lack of knowledge on qualification systems for medical products. We hypothesized holistic approaches
from private companies and systematic supports from public sectors are required for a response to an emergency. These
activities could lead to contribute to global health issues through sustainable businesses.
Keywords: global public procurement, vaccines, medicine, in vitro diagnostics, public-private partnership,
international cooperation

The World Health Organization (WHO) declared
coronavirus disease 2019 (COVID-19) as a Public
Health Emergency of International Concern (PHEIC)in January 2020 (1). In response to the pandemic,
the development of medicines, vaccines, and in vitro
diagnostics for COVID-19 began worldwide. The
Emergency Use Listing (EUL) is a WHO procedure forassessing unlicensed medicines, vaccines, and in vitro
diagnostics during a PHEIC to expedite the availabilityof these products to people who need them (2). The
EUL was established and reformed by the Emergency
Use Assessment and Listing mechanism which wasdeveloped to respond to the 2014-2016 Ebola virus
disease outbreak (3). The EUL indicates certain
standards for interim use of unlicensed products underemergencies. Therefore, pharmaceutical companies
were competing for the development of COVID-19
products and submitting their product documentation
for EUL to supply their products worldwide. However,before submitting documentation, the establishment ofan assessment platform is necessary among the WHO,
external experts, and the national regulatory authority(NRA) where the products produce. The EUL procedure
is based on a public-private partnership.

The number of new COVID-19 cases in Japan wasvery low on the week of December 22, 2021, with
about 0.9 per 100,000 and no cases in some regions(4). However, Japan also had the first report of a new
SARS-CoV-2 variant belonging to the Pango lineage
B.1.1.529 (Omicron variant) on December 6, which
has spread rapidly in January (5). The number of new
COVID-19 cases in Japan increased to 41 per 100,000
on the week of January 13, 2022 (6). The Omicron
variant has been spreading rapidly around the world
and 20 million new cases globally were confirmed on
the week of January 10 (7). Considering the ongoingpandemic, the EUL should be continuously used to
expand access to COVID-19 medical products.
The Bureau of International Health Cooperation,
National Center for Global Health and Medicine(NCGM) conducted the preliminary result of a desk
research to examine whether Japanese medical products
acquired EUL relating to COVID-19.
By January 17, 2022, the Pharmaceutical andMedical Devices Agency (PMDA) responsible forapproval of medicine or medical devices relating to
COVID-19 in Japan approved 71 in vitro diagnostic
products, 3 vaccines, and 5 medicines including special(59)

GHM Open. 2022; 2(1):59-62.

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approval which distributed by companies in Japan(8). Meanwhile, 28 in vitro diagnostic products, 10
vaccines, and no medicines were listed on the EUL(Figure 1).
Table 1 shows the countries of origin of developers
who applied to EUL and were accepted on the list. In
Table 1, we counted vaccines by the number of national
authorities instead of the number of countries thatdeveloped the product because if the same vaccine was
manufactured in other countries, a different application

to EUL with each national authority's platform wasstill needed. In vitro diagnostic products by Chinesecompanies were the most frequently accepted among 74
applications to EUL, followed by American companies.
Vaccines by Indian companies were the most frequently
accepted among 29 applications on EUL, followedby China, the U.S., Korea, and the Netherlands. Half
as many vaccine applications compared to in vitro
diagnostics for EUL were listed by January 17, 2022.
This may reflect the complexity of products and theassessment process for vaccines (9), while there were
140 vaccine candidates in clinical trials in the world (10).
Forty-eight products from China underwent
application for the EUL, which is four times that fromthe U.S., although the acceptance proportion in China
was much lower than that for U.S. products (Table1). This may be a result of the "Made in China 2025
(MIC25)" policy (11). The MIC25 policy was launchedin 2015 by Xi Jinping, the party and state leaderof China. The strategy defined ten core industries,
including biomedicine and high-performance medical
equipment aimed at boosting local capabilities.
Furthermore, more than 1,800 government industrial
investment funds were invested in MIC25 with 3
trillion CNY in March 2018 (11). MIC25 encourages
the development of key biopharma clusters to accelerateinnovative research and clinical trials (12).

Figure 1. The number of medical products related to
COVID-19 by qualification as of January 17, 2022 (dateof data accession). Data are updated irregularly. PMDA:
Pharmaceutical and Medical Devices Agency of Japan; EUL:
Emergency Use Listing by World Health Organization.

Table 1. The number of products categorized by the countries of origin of product developers on Emergency Use Listing
as of January 17, 2022 (date of data accession)
Countries

Diagnostics (Total: 74)

Vaccines (Total: 29)

Accepted

Not accepted

Accepted (The name of vaccine)

In process

Total

Acceptance proportion (%)

China
United States
India
Korea
Germany
United Kingdom
Japan
Netherlands
TurkeyVietnam
Italy
RussiaSpain
Australia
SwedenFranceCuba
CanadaMexicoArgentina

13
7
1
3
2
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0

28
2
3
3
3
1
1
0
1
2
2
0
0
0
0
0
0
0
0
0

2 (Coronavac, ShinophamBIBP)
2 (Comirnary, Spikevax)
3 (Covishield, Covaxin, Covovax)
2 (Vaxzevria, Spikevax)
1 (Comirnaty)0
1 (Vaxzevria)
2 (Ad26.COV2-S, Nuvacovid)00001 (Spikevax)
1 (Vaxzevria)
1 (Vaxzevria)
00
1 (Vaxzevria)
1 (Vaxzevria)
1 (Vaxzevria)

5
0
1
0
0
0
0
0
0
0
0
2
0
0
0
1
1
0
0
0

48
11
8
8
6
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1

31
82
50
63
50
50
50
100
50
0
0
0
100
100
100
0
0
100
100
100

Total

28

46

19

10

103

Footnote: Comirnaty was developed by BioNTech (Germany) and Pfizer (United States). Vaxzevria was developed by AstraZeneca and Oxford
University in the United Kingdom. Spikevax was developed by Moderna Biotech (United States). We assigned each vaccine to its respective
national authority listed on Emergency Use Listing. Vaccines approved by the European Medicines Agency (EMA) were assigned to the country
or countries which applied to the EMA. There were many in vitro diagnostic products under review, which numbers were not counted in Table 1.
We calculated the acceptance proportion based on our definition for this survey based on the latest available data from January 17, 2022. Data are
updated irregularly.

(60)

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Japanese companies rarely competed to apply
for EUL, although there are 71 PMDA-approved invitro diagnostic products in Japan. Only one vaccine
produced by Japanese companies was on the EUL
list, which was developed by AstraZeneca and Oxford
University (13). Recent surveys showed that one of
the common weaknesses of Japanese companies in
the global public procurement market was a lack ofknowledge about the qualification procedure for medical
products (14) and a lack of understanding of global
public procurement systems (15). Language barriers
should also be considered. To fill the gap, the NCGM
has implemented a series of seminars to introduce thequalification procedure, focusing on "prequalification"(PQ) as defined by the WHO. PQ is a systematic process
to determine the capacity of a manufacturer to produce
medical products of consistent quality in accordance withWHO specifications (16), which is utilized for generalprocurement. Compared with PQ, EUL focuses on only
three categories of products (vaccines, medicines, invitro diagnostics) for emergency procurement. The seriesof seminars related PQ is a part of activities supportedby the projects for the global extension of medical
technologies which have implemented since 2015 underthe "Japan Revitalization Strategy" by the Government ofJapan (17). These projects aim to disseminate Japanese
medical technologies, high-quality medicines, medical
devices, and health services in a way that suits local
needs and to improve health and medical care in lowand middle-income countries. The project detail wasavailable on the other paper (17).
Under the project newly granted from 2021 to 2023,
we have analyzed the process for both global public
procurement and emergency procurement related to
COVID-19 and hypothesized that seven steps basedon "the access and delivery partnership" approach areessential for both means of procurement (18). The sevensteps are as follows: i) analysis of needs, ii) research anddevelopment, iii) regulatory approval, iv) selection andprioritization, v) procurement or bidding, vi) distribution
and storage, and vii) service delivery. The integrated
approach across the seven steps by private companies isnecessary to drive successful global public procurement.
We are continuing analysis of case studies to find out
root causes and possible solutions or public-privateinterventions for joining the global public procurement
and for quickly responding to global emergency
procurement.
Only one vaccine produced by Japanese companies
had EUL, which was developed by AstraZeneca andOxford University. Moreover, Japanese companies
seem to not be successful when applying for general
global public procurement related to COVID-19 (19).
Several successful Japanese companies for global public
procurement under COVID-19 were continuously
preparing before the pandemic. To encounter current andfuture public health emergencies, basic preparation for

global public procurement will help during emergency
procurement procedures including applying to EUL.
Further systematic supports from the public sectors
to private companies are needed to enter the global
public procurement market. The Government of Japanestablished the "Global Health Strategy Promotion
Council" under the Prime Minister of Japan and the
Cabinet to strengthen global health strategy in 2021 (20).
Japan will determine how they can contribute to global
health issues through enhancing sustainable business andpublic-private partnerships.
Acknowledgements
The authors wish to thank Ms. Chiaki Hashimoto and
Mr. Yoshinori Ariyasu for collecting basic data. We also
acknowledge our colleagues responsible for the projectsof global extension of medical technologies, the project
to promote acquiring prequalification of the WHO, andthe project to support "Access & Delivery" of medical
products to developing countries by the Bureau ofInternational Health Cooperation in the NCGM, whoprovided insight and expertise that greatly assisted thisresearch.
Funding: This work was supported by a Ministry of
Health, Labor and Welfare (MHLW) research grant ofJapan (JPMH21BA1001) and the promoting project forJapanese companies to acquire WHO prequalification,
WHO recommendation, and WHO compendium of
innovative health technologies for low-resource settings.
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
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Pharmaceuticals and Medical Devices Agency. Approved
Medical Products for COVID-19. https://www.pmda.go.jp/
english/about-pmda/0002.html (accessed January 17, 2021).
Plotkin S, Robinson JM, Cunningham G, Iqbal R, Larsen
S. The complexity and cost of vaccine manufacturing – Anoverview. Vaccine. 2017; 35:4064-4071.
World Health Organization. COVID-19 vaccine tracker
and landscape version 18 Jan 2021. https://www.who.
int/publications/m/item/draft-landscape-of-covid-19candidate-vaccines (accessed January 20, 2021).
Zenglein MJ, Holzmann A. Evolving Made In China
2025: China's industrial policy in the quest for global techleadership. https://merics.org/sites/default/files/2020-04/
MPOC_8_MadeinChina_2025_final_3.pdf (accessed
November 30, 2021).
L.E.K. Consulting. Innovation in China, "Made in China2025" and implications for healthcare MNCs. https://www.
lek.com/sites/default/files/insights/pdf-attachments/ChinasHealthcare-Innovation-by-Made-in-China-2025-andImplications-for-MNCs_JUL06.pdf (accessed November
11, 2021).
World Health Organization. WHO recommendation
AstraZeneca/MHLW approved sites COVID-19 vaccine(ChAdOx1-S) [recombinant]. https://extranet.who.int/
pqweb/vaccines/who-recommendation-astrazeneca-mhlwapproved-sites-covid-19-vaccine-chadox1-s-recombinant(accessed November 30, 2021).
Fujita N. Projects of Global Extension of Medical
Technologies of Japan – an overview, achievement, andfuture outlook. Jpn Fed Med Devices Assoc J. 2021;
115:42-48. (in Japanese)

15. MUFG Consulting. A survey for the Japanese companies'
needs to enter the global public procurement market ininternational organizations and emerging economies. https://www.murc.jp/sp/1712/picturesi/report-06.pdf (accessed
November 30, 2021). (in Japanese)
16. World Health Organization. Prequalification. https://www.
who.int/rhem/prequalification/en/ (accessed January 17,2022).
17. Nozaki I, Sugiura Y, Fujita N, Iso H, Umeda T. Businessmodels for sustainable development: Projects of global
extension of medical technologies of Japan. Glob HealthMed. 2021; 3:6-10.
18. The Access and Delivery Partnership. Approach. https://adphealth.org/approach/ (accessed January 12, 2022).
19. United Nations Office for Project Services (UNOPS). 2020
Annual Statistical Report on UN Procurement. https://www.
ungm.org/Shared/KnowledgeCenter/Document?widgetId=
4826&documentId=1144853 (accessed January 17, 2022).
20. Global Health Strategy Promotion Council. The Meetingfor Global Health Strategy Expert Task Force. http://www.
kantei.go.jp/jp/singi/kenkouiryou/global_health/pdf/tf_
konkyo20211104.pdf (accessed November 30, 2021). (inJapanese)---Received December 10, 2021; Revised January 25, 2022;
Accepted February 15, 2022.
Released online in J-STAGE as advance publication February
26, 2022.
*Address correspondence to:
Mami Wakabayashi, Institute for Global Health Policy Research,
Bureau of International Health Cooperation, National Center
for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku,
Tokyo 162-8655, Japan.
E-mail: mwakabayashi@it.ncgm.go.jp(62)Letter

GHM Open. 2022; 2(1):63-64.
DOI: 10.35772/ghmo.2022.01004

The state of foreigners living in Japan as gauged by people undergoinga comprehensive health checkup (Ningen Dock)
Jun Lu*, Sachiko Kubo, Makiko Hashimoto, Yuko Hayashi, Hiroshi Kajio
Department of Medical Examination Center, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan.

Abstract: Benefiting from the Japanese Government's welcoming of foreign visitors, our facility was able to accept
and respond to large number of foreign tourists (1,493) to undergo a comprehensive health checkup (Ningen Dock)
in 2019. However, coronavirus disease 2019 (COVID-19) completely precluded the acceptance of tourists for two
years starting in from 2020. In August 2020, our hospital policy was changed to actively accept foreign residents
in Japan for comprehensive health checkups. In this article, we analyzed the foreign residents who use our facility
in detail and we investigated the characteristics of foreign residents from the viewpoint of a comprehensive healthcheckup.
Keywords: Ningen Dock, foreign residents, female consultation rate

The number of foreigners residing in Japan was 2,760,635(1) at the end of 2021, and it has decreased every year
since 2019. Dividing the number of foreign residents
by the current latest total population of Japan (2) gives
approximately 2.20%. Foreign residents accounted for
2.32% of the population in Japan in 2019 but gradually
decreased to 2.29% in 2020 and 2.20% in 2021.
This suggests that the number of foreign residents isdecreasing. In 2019, the number of foreign residents
reached its peak, and the tourism industry was at its peak.
However, the COVID-19 pandemic that started in the
beginning of 2020 has presumably affected the numberof foreign residents.
Looking at the number of foreign residents bynationality, most are Chinese, but that proportion islower than it was in 2017. The number of Vietnamese
living in Japan is on the rise, surpassing Koreans in 2020
and accounting for the second largest proportion after
Chinese.
Benefiting from the Japanese Government's
welcoming of foreign visitors, the authors’ facility
was able to accept and handle a large number offoreign tourists (1,493) undergoing a comprehensive
health checkup (Ningen Dock) in 2019 (3). However,
COVID-19 completely precluded the acceptance of
tourists for two years starting in 2020. Therefore, hospital
policy was changed in August 2020 to actively accept
foreign residents in Japan for comprehensive healthcheckups, and the collection of statistics on foreign
residents started at the same time.
Here, the foreign residents visiting this facility havebeen analyzed in detail while referring to data from the
Immigration Bureau and the Statistics Bureau, and thecharacteristics of foreign residents have been investigatedfrom the viewpoint of a comprehensive health checkup.
This facility accepted 159 foreign residents living
in Japan from August 2020 to December 2021. The
159 foreigners included 96 Chinese, 24 Koreans, 8
Vietnamese, 6 Americans, 4 French, 3 Canadians, 2
Bangladesh, 2 British, 2 Philippines, 2 Bulgarians, 2Germans, 1 Thai, 1 Swiss, 1 Israeli, 1 Mongolian, 1
Kenyan, 1 Brazilian, 1 Singaporean, and 1 Peruvian(Figure 1). Foreigners were from a total of 19 countries.
According to statistics from the Immigration Bureau(1), the largest proportion of foreign residents in Japanis from China (26.0%), followed by Vietnam (15.7%),
South Korea (14.8%), Philippines (10.0%), and Brazil(7.4%). People undergoing a comprehensive healthcheckup at the authors’ facility were from China (60.4%),
South Korea (15.1%), Vietnam (5.0%), the United States(3.8%), and France (2.5%). Although these numbers areroughly proportional to the foreign population, many ofthe people undergoing a comprehensive health checkup
were Chinese, suggesting that Chinese are highlyinterested in comprehensive health checkups or theirhealth.
Foreign residents undergoing a comprehensive healthcheckup consisted of 52.2% males and 47.8% females,with an average male age of 43.6 years and an average
female age of 43.0 years. The male-female ratio of all
the people undergoing a comprehensive health checkup(almost 96% Japanese) in 2021 was 57.7% males with(63)

GHM Open. 2022; 2(1):63-64.

www.ghmopen.com

Figure 1. Number of foreigners undergoing a comprehensive health checkup (Ningen Dock) in Japan by their country oforigin (Aug. 2020 – Dec. 2021).

an average age of 54.6 years and 42.3% females withan average age of 53.5 years. Compared to all of thepeople undergoing a comprehensive health checkup, thefemale consultation rate was higher for foreign residents
and those residents were 10 years younger on average.
This suggests that young female foreign residents are
more interested in comprehensive health checkups thanJapanese.
Of the total of 4,178 people undergoing acomprehensive health checkup, 159 (3.8%) were foreign
residents and 51 (32.1%) needed language support. By
country, 32 (33.3%) of the 96 Chinese needed language
support. One (4.2%) of the 24 Koreans and 5 (62.5%)of the 8 Vietnamese needed language support. Of the
31 foreigners from 16 countries other than China, South
Korea, and Vietnam, 13 (41.9%) needed English support.
Koreans are less likely to need language support and arelikely to be more familiar with Japanese society. Thatsaid, the number of Vietnamese residents has increased
rapidly, and many of the residents needed language
support during a consultation. About 30% of foreign
residents appear to be fluent in Japanese and they canfunction in everyday life but they are worried about
medical terms and need a medical interpreter.
Since medical terms in specialized fields arecomplicated and informed consent is important inmedicine, the demand for medical interpreters is expected
to increase in the future. In order for foreign residents inJapan to safely and comfortably receive medical care,many issues need to be addressed, such as training,

evaluation, and employment of medical interpreters.
Funding: This work was supported in part by JSPS
KAKENHI grant number JP20K07439 (to Jun Lu).
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
References
1.
2.
3.

Immigration Services Agency of Japan. https://www.
moj.go.jp/isa/content/001370057.pdf (accessed April 11,2022). (in Japanese)
Statistics Bureau of Japan. https://www.stat.go.jp/data/
jinsui/pdf/202203.pdf (accessed April 11, 2022). (inJapanese)
Lu J. Ningen Dock: Japan's unique comprehensive healthcheckup system for early detection of disease. Glob HealthMed. 2022; 4:9-13.

---Received April 15, 2022; Revised June 2, 2022; Accepted June27, 2022.
Released online in J-STAGE as advance publication July 9,2022.
*Address correspondence to:
Jun Lu, Department of Medical Examination Center, Center
Hospital of the National Center for Global Health andMedicine, 1-21-1 Toyama, Shinjuku-Ku, Tokyo 162-8655,
Japan.
E-mail: j-lu@hosp.ncgm.go.jp(64)Information for Authors

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Suggested Reviewers: A list of up to 3 reviewers whoare qualified to assess the scientific merit of the study iswelcomed. Reviewer information including names, affiliations,addresses, and e-mail addresses should be provided at thesame time the manuscript is submitted online. Please do notsuggest reviewers with known conflicts of interest, including
participants or anyone with a stake in the proposed research;
anyone from the same institution; former students, advisors,
or research collaborators (within the last three years); or close
personal contacts. Please note that the Editor-in-Chief may
accept one or more of the proposed reviewers or request areview by other qualified persons.

(As of January 2022)

GHM Open
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