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Acknowledgements
We thank Drs. Daisuke Kobayashi, Ryota Ito, Mitsuru Odate, Hiroshi Morioka, Yuka Tomita, and Nancy Thabet
for data acquisition and their comments on results. We are indebted to the clinical research coordinators (Kyoko
Kazeto and Sumiyo Tanaka), laboratory staff (Yukari Osada, Teruko Okura, Nami Shimaoka, Toshi Nada, Mariko
Mochizuki, Miho Saito, and Nobuya Sakagami), and all health-care professionals who participated in data collection. We would like to thank Enago (www.enago.jp) for the English language review.
Author contributions
All authors meet the ICMJE authorship criteria. Y.S., M.S., Y.M., and Y.H. designed this study. Y.M., Y.S., H.K.,
T.S., J.O., M.S., and M.I. participated in data acquisition. Y.M., Y.S., K.T., and S.M. created the statistical analysis
plan, which was reviewed by all authors. Y.M., Y.S., H.K., T.S., J.O., and M.S. contributed to data interpretation.
T.Y. and Y.H. contributed to study supervision. Y.M. wrote the initial draft of the manuscript. Y.S., K.T., S.M.,
and Y.H. contributed to the critical revision of the manuscript for important intellectual content. All authors
approved the final draft.
Funding
This work was partially supported by the Japan Society for the Promotion of Science KAKENHI (Grant Number
20K08517).
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Competing interests The following information describes relevant financial activities outside of the submitted work. YS reports personal fees (payment for lectures, including service on speakers bureaus) from KYORIN Pharmaceutical Co.,
Ltd., AstraZeneca K.K., DAIICHI SANKYO COMPANY, LIMITED, Nippon Boehringer Ingelheim Co., Ltd.,
GlaxoSmithKline plc, and Gilead Sciences Inc. and participates as a member of the case adjudication committee of GlaxoSmithKline Biologicals SA. TY reports grants and personal fees (payment for lectures, including
service on speakers bureaus) from Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., and MSD
K.K. SM reports personal fees (payment for consultations in other studies) from Takeda Pharmaceutical Co.,
Ltd. YH reports grants and personal fees (payment for lectures, including service on speakers bureaus) from
Chugai Pharmaceutical Co., Ltd., MSD K.K., GlaxoSmithKline plc, KYORIN Pharmaceutical Co., Ltd., Pfizer
Japan Inc., Meiji Seika Pharma Co, Ltd., Sanofi K.K., and Daiichi Sankyo, Inc. All other authors have nothing
to declare. The funders had no roles in the design and conduct of the study; collection, management, analysis,
and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the
manuscript for publication.
Additional information
Supplementary Information The online version contains supplementary material available at https://doi.org/
10.1038/s41598-022-18794-5.
Correspondence and requests for materials should be addressed to Y.S.
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