| |

Received: 29 May 2020    Revised: 6 August 2020    Accepted: 25 September 2020

DOI: 10.1002/osi2.1088

CASE REPORT

Actinomycotic osteomyelitis of the mandible with bone

destruction: Two case reports with a review of the Japanese
literatures

Yoshiko Yamamura1  | Yasusei Kudo2 | Keiko Kudoh1 | Youji Miyamoto1

1
Department of Oral Surgery, Institute of
Biomedical Sciences, Tokushima University Abstract
Graduate School, Japan Mandibular actinomycosis, which is mainly caused by Actinomyces israelii, is char-
2
Department of Oral Molecular Pathology,
acterized by trismus and multiple abscesses. The associated destruction of the jaw
Institute of Biomedical Sciences, Tokushima
University Graduate School, Japan bone in cases of mandibular actinomycosis is rare. As the clinical symptoms and imag-
ing findings of this disease are similar to those in malignant tumors, a biopsy should
Correspondence
Yoshiko Yamamura, Department of Oral be performed at an early stage to facilitate a definitive diagnosis. To date, no stud-
Surgery, Institute of Biomedical Sciences,
ies have reported on the incidence and management of actinomycotic osteomyelitis.
Tokushima University Graduate School,
3-18-15 Kuramoto-cho, Tokushima 770- Here, we report two cases of actinomycotic osteomyelitis with bone destruction, and
8504, Japan.
review the literature for similar cases that have been reported in Japan.
Email: yamamura.yoshiko@tokushima-u.ac.jp

KEYWORDS

actinomycosis, bone destruction, mandible, osteomyelitis

1 |  I NTRO D U C TI O N of mandibular actinomycosis with bone destruction in the Japanese

Osteomyelitis in the mandible caused by Actinomyces is uncommon,
and often underappreciated by many clinicians during the assess-
ment of head and neck infections. Most cases can be traced to an
odontogenic source, with periapical abscesses and posttraumatic (or
surgical) complications being key antecedent events. Actinomyces is
an anaerobic Gram-positive filamentous organism, commonly found
at high concentrations in tonsillar crypts and gingivodental crev-
ices. While over 30 species of Actinomyces have been described,
Actinomyces israeli is the most prevalent species in human infections,
and is responsible for most cases of actinomycosis.1
Mandibular actinomycosis is mainly caused by A israelii and is
characterized by trismus, a plate-like induration, as well as multiple
2
abscesses. In recent years, the typical clinical features of actino-
mycosis have become less prominent owing to the frequent use of
antibiotics. In general, most cases show no bone destruction. Cases
with bone destruction, however, are difficult to distinguish from
malignant tumors due to similar clinical symptoms and imaging find-
ings.3-5 Here, we report two cases of actinomycosis with extensive
bone destruction, which initially resembled malignant tumors; one
case was caused by A odontolyticus. Additionally, we review cases
literature.
2 | C A S E R E P O RT
2.1 | Case 1
A 68-year-old man was referred to a general dental clinic because
of pain induced on drinking cold water, which was localized to the
lower right second premolar region. Pulpitis was diagnosed in the
lower right second molar and endodontic treatment was performed.
However, trismus and swelling of the right mandible later appeared.
Accordingly, there was a possibility that a cold water induced pain
had been one of Vincent's symptom.
A subsequent clinical examination at the Tokushima University
Hospital found a swelling in the right cheek, and a limited range of
mouth opening (12 mm between the upper and lower incisors). The
lower right second premolar was mobile, and pus discharge was noted
from the gingival sulcus. Panoramic radiography revealed a radiolucent
lesion with an irregular border involving the root of the lower right
second premolar, and the marginal alveolar bone and the periodontal

© 2021 Japanese Stomatological Society     1

Oral Sci Int. 2021;00:1–7. wileyonlinelibrary.com/journal/OSI |
 |
2       YAMAMURA et al.

cavity (Lamina dura) around it and white line of the mandibular canal
were not revealed (Figure 1A). Bone resorption in the mandibular
ramus was observed on a computed tomography (CT) scan (Figure 1B).
On a T2-weighted magnetic resonance (MR) image, the outer cortex
of the right mandible ramus had resorbed, and the bone marrow sig-
nal intensity was slight high and non-uniform, from the lower right
second premolar to the mandibular ramus (Figure 1C). Moreover on a
T2-weighted MR image, masseter muscle and internal pterygoid mus-
cle showed thickened and slight high and non-uniform signal.
The pathological diagnosis of a biopsy specimen from the man-
dibular ramus was actinomycotic osteomyelitis. A odontolyticus,
Streptococcus constellates, and obligatory anaerobes were identified in
the biopsy specimen. A mass of actinomycetes was observed under
hematoxylin and eosin (H&E) and Grocott staining (Figure 2). The lower

(A)

F I G U R E 1   (A) Panoramic radiograph

showing a radiolucent lesion that extends
(B) (C) around the right lower second premolar
(an arrow). (B) Computed tomography
scan showing bone resorption in the
mandibular ramus (a bold arrowhead). (C)
T2-weighted magnetic resonance image
showing loss of the right outer cortex of
the mandible ramus (an arrow), and the
non-uniform bone marrow signal from
the lower right second premolar to the
mandibular ramus. The masseter muscle
and internal pterygoid muscle showed
thickened and slight high and non-uniform
signal (bold arrowheads)

F I G U R E 2   (A) Histopathology of the

(A) (B) biopsy specimen (Hematoxylin and eosin
stain, bar 50 µm). (B) Histopathology of
the biopsy specimen (Grocott stain)

50 μm
YAMAMURA et al. |
      3

right second premolar and first molar were extracted under general
anesthesia, and the cortical bone of mandibular ramus and cortical
bone around extraction sockets were removed; curettage was then
performed. An indwelling drain was placed in the wound. Irrigation
from the drain tube was carried out for 1 month after the surgery. The
patient was prescribed penicillin antibiotics for 3 months post-opera-
tively, along with cephem antibiotics, which were shown to be active
against the cultured bacteria. After 1 month, A odontolyticus was no
longer detected. The intravenous infusion of antibiotics was discon-
tinued, and oral penicillin antibiotics were prescribed for 56 days. No
recurrence of inflammation was observed 2 years later (Figure 3).

2.2 | Case 2

A 61-year-old woman was referred to a general dental clinic because

of pain and swelling at the lower left second molar region (Figure 4A).
A diagnosis of chronic apical periodontitis was made for the lower left
second molar, and the tooth was subsequently extracted. However,
the swelling was not relieved after tooth extraction. A clinical exami-
nation at Tokushima University Hospital revealed a mild swelling in
her left cheek. The extraction socket was not epithelialized, and the
F I G U R E 3   Two-year post-operative panoramic radiograph
buccal gingiva remained edematous and inflamed.

F I G U R E 4   (A) Panoramic radiograph

showing before tooth extraction of (A) (B)
the left second molar. (B) Panoramic
radiograph showing a radiolucent lesion
with an irregular border that extends
from the lower left second molar to the
left mandibular ramus. (C) Computed
tomography scan showing a wide region
of bone destruction, from the lower left
mandibular body to the mandibular ramus.
(D) T2-weighted magnetic resonance
image showing a high signal intensity
in the bone marrow, conforming to the
region of bone destruction observed in
the CT image

(C) (D)
 |
4       YAMAMURA et al.
(B)
(A)
50 μm
F I G U R E 6   Panoramic radiograph taken at 2 years and
11 months, post-operatively
A radiolucent lesion, with an irregular border that extended from
the lower left second molar to the left mandibular ramus, was ob-
served on a panoramic radiograph (Figure  4B). On the CT scan, there
was a wide region of bone destruction, extending from the lower
left mandibular body to the ramus (Figure  4C). On a T2-weighted
MR image, a high signal intensity was observed in the bone marrow,
which conformed to the region of bone destruction observed on the
CT image (Figure 4D).
The pathological diagnosis of the biopsy specimen from the
extraction socket was actinomycotic osteomyelitis. Under H&E
and Grocott staining, the bacterial colonies showed characteristic
club-shaped filaments that formed radiating rosette patterns, with
F I G U R E 5   (A) Histopathology of the
biopsy specimen (Hematoxylin and eosin
stain, bar 50 µm). (B) Histopathology of
the biopsy specimen (Grocott stain)
peripheral basophilic filaments and eosinophilic club-shaped ends
(Figure 5). Curettage and decortication were performed under general
anesthesia, and the wound was opened. Washing of the wound and
replacement of a gauze impregnated with fradiomycin sulfate were
performed for 2 weeks after the surgery. Penicillin antibiotics were ad-
ministered for 9 days. Lincomycin (for which bacterial sensitivity was
previously demonstrated) was simultaneously administered for 7 days.
No recurrence of inflammation was observed after 3 years (Figure 6).
3 | D I S CU S S I O N
Actinomycotic osteomyelitis is a communicable disease caused by A
israelii, and is characterized by clinical symptoms such as trismus and
multiple abscesses. 2 Approximately 60% of all actinomycotic infec-
tions occur in the cervicofacial area. Diagnosis is often difficult be-
cause of the absence of typical symptoms, which may be attributed
to the use of antibiotics.
The details of 28 patients with actinomycotic osteomyelitis with
bone destruction, including the present cases and those from previ-
ous Japanese reports, are shown in Table 1. The male-to-female ratio
was 1.8 to 1, with a mean age of 55.2 years (range, 14 to 87 years).
The frequently affected sites were the mandibular body (12 cases:
42.9%) and mandible ramus (9 cases: 32.1%). Approximately 70% of
the patients had symptoms such as induration, trismus, and an abscess
at the first visit. However, eight cases (28.6%) did not have any symp-
toms, which possibly increased the difficulty of the diagnosis. In gen-
eral, the fungal filament of Actinomyces or a bacterial mass must be
observed in the pus or granulation tissue for an accurate diagnosis.3
Asada et al reported that it was often difficult to demonstrate the pres-
ence of Actinomyces using culturing methods.6 Among 28 cases, the
causative species (A israelii and A odontolyticus) were identified in only
two cases (7.1%). Thus, in the majority of cases, the inability to detect
Actinomyces may be attributable to the use of antimicrobial agents.
In case 1 (Case No. 28 in Table 1), a bacterial mass was observed
on pathological examination, and the presence of Actinomyces was
TA B L E 1   Actinomycotic osteomyelitis of the jaws with bone destruction and a review of the Japanese literature

Treatment Published Reference

No. Age Sex Site Pathogenesis Induration Trismus Abscess Species Treatment Antibiotics Outcome duration Authors year No.

1 18 M Mandibular ramus None ＋ ＋ ＋ Unknown Curettage Penicillin, Healing 86 days Ioroi et al 1988 13
YAMAMURA et al.

quinolone,
tetracycline
2 61 M Mandibular ramus None － ＋ ＋ Unknown Curettage Penicillin, cephem Healing 38 days Shibata et al 1988 14
3 18 M Mandibular angle Extraction ＋ ＋ ＋ Unknown Pus discharge Penicillin, cephem Healing 14 days Ouchi et al 1994 15
4 59 M Mandibular condyle Extraction ＋ ＋ － Unknown Pus discharge Penicillin Unknown 87 days Ohhira et al 1998 16
5 57 M Mandibular ramus None ＋ ＋ ＋ Unknown Curettage Penicillin Healing 16 days Yamamoto et al 1998 17
6 53 M Maxilla Extraction － － － Unknown Biopsy Cephem Healing 14 days Sato et al 1999 18
7 51 F Maxilla None － － － Unknown Excision Unknown Unknown Unknown Yamada et al 2000 10
8 21 M Mandibular body Extraction － ＋ ＋ Unknown Unknown Unknown Unknown Unknown Kimura et al 2001 19
9 45 M Mandibular ramus None － － － Unknown Unknown Unknown Unknown Unknown
10 51 M Mandibular ramus None － ＋ ＋ Unknown Unknown Unknown Unknown Unknown
11 14 M Mandibular ramus None ＋ ＋ ＋ A israelii Cortical bone Cephem, Healing 150 days Suzuki et al 2002 20
removal, curettage lyncomycin
12 58 M Mandibular body None ＋ ＋ － Unknown Biopsy Unknown Unknown Unknown Hasebe et al 2002 21
13 30 F Mandibular body Extraction － ＋ － Unknown Excision Penicillin Healing 45 days Koyama et al 2004 22
14 74 M Mandibular angle None ＋ － ＋ Unknown Curettage Cephem Healing 21 days Takaku et al 2005 23
15 48 M Mandibular body None ＋ ＋ ＋ Unknown Excision Penicillin Healing 42 days Nagashima et al 2006 24
16 82 F Mandibular body Extraction － － ＋ Unknown Curettage Penicillin, Healing 35 days
lyncomycin
17 58 M Mandibular body None ＋ ＋ ＋ Unknown Pus discharge Cephem, Healing 30 days Mizutani et al 2007 25
carbapenem
18 66 F Mandibular body None － － － Unknown Pus discharge Penicillin, cephem, Healing 29 days
carbapenem
19 87 F Mandibular ramus None ＋ ＋ ＋ Unknown Excision Penicillin Healing 25 days Iijima et al 2008 26
20 70 M Mandibular body None ＋ － ＋ Unknown Biopsy Penicillin Healing 69 days Abe et al 2008 27
21 71 F Maxilla Extraction － － － Unknown Biopsy Penicillin Healing 7 days Fujii et al 2009 28
22 54 M Maxilla Loss of a tooth － － － Unknown Curettage Cephem Healing Unknown Mukai et al 2010 29
23 65 M Mandibular body Extraction － － － Unknown Curettage Penicillin Healing 137 days Kou et al 2010 30
24 51 F Mandibular ramus None － － ＋ Unknown Curettage Penicillin, cephem Healing Unknown Harada et al 2012 31
25 69 F Mandibular ramus Root canal treatment － ＋ ＋ Unknown Curettage Penicillin, cephem Healing Unknown Kikuta et al 2012 32
26 85 F Mandibular body Extraction ＋ ＋ － Unknown Biopsy Penicillin Healing 139 days Obata et al 2017 33
27 68 M Mandibular body Root canal treatment ＋ ＋ － Odontolyticus Cortical bone Penicillin, cephem Healing 89 days Yamamura et al present
removal, curettage case
|

28 61 F Mandibular body Extraction － － － Unknown Curettage Penicillin, Healing 16 days

      5

lyncomycin
 |
6       YAMAMURA et al.
demonstrated on culturing. Although A israelii was the predominant
2
bacteria detected, A odontolyticus was also identified. A israelii has
been reported in 52% of all oral infections, while the isolation of A
odontolyticus has been substantially lower at 2%.4 The detection of
A odontolyticus in case 1 was a rare finding. A odontolyticus is usually
7-9
found in periodontal pockets or root canals. The routes of infec-
tion of actinomycosis in the jaw include the dental pulp chambers,
periodontal pockets, and extraction sockets. In case 2 (Case No. 27
in Table 1), it was suspected that actinomycetes invaded the alveolar
bone through the extraction socket. In case 1, it was considered that
actinomycetes invaded through the root canal following endodontic
treatment. Indeed, 13 (46.4%) of the 28 cases of actinomycotic osteo-
myelitis occurred after either tooth extraction or root canal treatment.
Actinomycotic osteomyelitis is associated with destruction
of the cortical bone, and spreads into the soft tissues. CT imaging
may show a slight bone puncture and a small punched-out appear-
ance.4,10 MRI imaging also shows punctate defects in the cortical
bone, and an image of breaking the cortical bone from the outside of
the bone to reach the inside of the bone is observed. The destruc-
tion of cortical bone was also observed in our 2 cases. The clinical
symptoms of actinomycotic osteomyelitis are similar to those of ma-
lignant tumors, making a differential diagnosis difficult. In the two
cases presented in this report, malignant tumors were considered
because of extensive bone destruction. Therefore, we made a defin-
itive diagnosis only after performing a biopsy and histopathological
examination for each case.
The first-line treatment for actinomycotic osteomyelitis involves
long-term administration of high doses of penicillin antibiotics.4
Miller et al recommended that patients with more severe conditions
should receive penicillin G at doses of 12 to 20 million units daily
in four equal doses, with the treatment lasting from 2 to 6 weeks.
While there are reports of actinomycotic osteomyelitis being suc-
cessfully treated solely with antibiotics, 2 some investigators have re-
ported healing with concurrent surgical treatment such as scraping
of the granulation tissue and removal of cortical bone.3,11 Sixteen
(57.1%) of the 28 cases were managed with surgical measures, in-
cluding curettage, cortical bone removal, and tooth extraction. In
both our cases, surgical treatment and antibiotic administration
were performed, and no relapse was observed over 2 years after
treatment. Eighteen of 24 cases used penicillin antibiotics. The drug
was administered for 7 to 150 days, and the average administration
period was 54 days, which is considered to be a relatively long pe-
riod. The prognosis was good in each case.
In conclusion, it is difficult to distinguish between actinomy-
cotic osteomyelitis and malignant tumors owing to the similarity in
clinical symptoms. It is important to perform a biopsy in the early
stages of infection and establish a histopathological diagnosis. The
combination of surgical management and antibiotic administration
has been shown to result in a favorable treatment outcome. As
actinomycetes in the oral cavity can potentially spread to the brain
and cranium,12 careful observation and follow-up with CT or MRI
may be necessary until wound closure and the resolution of sub-
jective symptoms.
AC K N OW L E D G E M E N T S
None.
C O N FL I C T O F I N T E R E S T
The authors declare that they have no competing interests.
ORCID
Yoshiko Yamamura  https://orcid.org/0000-0002-5735-6652
REFERENCES
1. Valour F, Sénéchal A, Dupieux C, Karsenty J, Lustig S, Breton P, et al.
Actinomycosis: etiology, clinical features, diagnosis, treatment, and
management. Infect Drug Resist. 2014;7:183–97.
2. Bartkowski SB, Zapala J, Heczko P, Szuta M. Actinomycotic osteo-
myelitis of the mandible: review of 15 cases. J Craniomaxillofac
Surg. 1998;26:63–7.
3. Shindo J. The situation of oral actinomycosis–analysis of 140 cases
in 45 facilities. Jpn J Oral Maxillofac Surg. 1983;29:1879–89.
4. Miller M, Haddad AJ. Cervicofacial actinomycosis. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod. 1998;5:496–508.
5. Sa'do B, Yoshiura K, Yuasa K, Ariji Y, Kanda S, Oka M, et al.
Multimodality imaging of cervicofacial actinomycosis. Oral Surg
Oral Med Oral Pathol. 1993;76:772–84.
6. Asada K, Nakagawa Y, Maruyama T, Ochiai M, Ishibashi K. Oral
and maxillofacial infections isolated Actinomyces–in relation to
the criteria of actinomycosis and its pathogenesis. Jpn J Oral Surg.
1985;31:580–4.
7. Tang G, Samaranayake LP, Yip HK, Chu FC, Tsang PC, Cheung BP.
Direct detection of Actinomyces spp. from infected root canals in a
Chinese population: a study using PCR-based, oligonucleotide-DNA
hybridization technique. J Dent. 2003;31:559–68.
8. Bhatawadekar S, Bhardwaj R. Actinomycotic bacteraemia after
dental procedures. Indian J Med Microbiol. 2002;20:72–5.
9. Topazian RG, Goldberg MH. Oral and maxillofacial infections, 2nd
ed. Philadelphia: WB Saunders; 1987. p. 403–7.
10. Yamada M, Hayatsu Y, Mizugaki Y, Shinozaki F. A case of osteo-
myelitis of the maxilla caused by actinomycosis. Jpn J Oral Surg.
2000;46:59–61.
11. Meethal AC, Pattamparambath M, Balan A, Kumar NR, Sathyabhama
S. Actinomycotic osteomyelitis of the maxilla – a delusive presenta-
tion. J Clin Diagn Res. 2016;10:ZJ01-ZJ03.
12. Shafer WG, Hine MK, Levy BM. A textbook of oral pathology, 3rd
edn. Philadelphia: WB Saunders; 1974. p. 346–9.
13. Ioroi K, Oomine T, Kobayashi C, Matsumoto M, Kumimoto Y,
Shibahara T, et al. Actinomycosis associated with idiopathic throm-
bocytopenic purpura: report of a case. Iryo. 1988;42:861–5.
14. Shibata Y, Kitayama S, Nagao T, Toyota T, Oda H, Uno Y.
Actinomycosis of the mandible which doubted as parotid gland
tumor: report of a case. Jpn J Oral Surg. 1998;34:2600–3.
15. Ouchi O, Yagi M, Fukuta Y, Ohya T, Kudo K, Satoh M. A case of ac-
tinomycosis occurred in the mandibular angle area. Jpn J Oral Surg.
1994;40:287–9.
16. Ohhira A, Sugiyama Y, Sekiyama S, Shozushima M, Satoh M. A case
of actinomycosis accompanied by bone absorption in coronoid pro-
cess. J Jpn Stomatol Soc. 1998;47:141–6.
17. Yamamoto S, Ishii Y, Kitagawa Y, Ogasawara T. MRI diagnosis of
mandibular actinomycosis. J Jpn Stomatol Soc. 1998;47:500–9.
18. Sato H, Miyate H, Yokota M, Koizumi H, Kudo K, Sato H. A case
of actinomycosis arising in the maxilla. Jpn J Oral Surg. 1999;45:
354–6.
19. Kimura Y, Araki K, Hanasawa T, Sakamaki K, Okano T. CT and US
appearances of osteomyelitis of the mandible with actinomycosis.
Dent Radiol. 2001;41:231–9.
YAMAMURA et al.
20. Suzuki H, Takagi R, Imai N, Nagashima K. A case of actinomycosis
in a child with allergies to many kinds of medicines. Pediatr Oral
Maxillofac Surg. 2002;12:15–20.
21. Hasebe H, Jinbu Y, Noguchi T, Kusama M, Kobayashi K. A case
of mandibular actinomycosis accompanied by remarkable bone
absorption in panoramic radiograph. Dent Radiol. 2002;42:
234–5.
22. Koyama H, Shinbata T, Yamamori I, Ouchi T, Yoshizawa N. A case
of actinomycosis in the pregnant woman after the extraction of
wisdom tooth. Jpn Soc Dent Med Compromised Patient. 2004;13:
15–9.
23. Takaku S, Mori K, Sano T, Kurita Y, Shinoda C, Shimada J. Mandibular
osteomyelitis caused by Actinomyces report of a case. Jpn J Oral
Diagn/Oral Med. 2005;18:106–9.
24. Nagashima H, Asada K, Yamamoto H, Nakayama A. Two cases
of mandibular osteomyelitis caused by Actinomyces. Oral Ther
Pharmacol. 2006;25:47–52.
25. Mizutani M, Mukai T, Azuma K, Shigenori M. Two cases of oral and
maxillofacial actinomycosis with bone destruction. Jpn J Oral Surg.
2007;53:150–4.
26. Iijima K, Kurita H, Tokita R, Nisizawa R, Kurashina K. A case of a
dentigerous cyst in the mandibular notch associated with actinomy-
cosis. Jpn J Oral Surg. 2008;54:674–8.
27. Abe T, Imai K, Sakata Y, Nakamoto N, Kobayashi A, Yoda T. A case
of Actinomycosis of the mandible with bone destruction. Jpn J Oral
Diagn/Oral Med. 2008;21:49–54.
|
      7
28. Fujii T, Nagano M, Taniike N, Takenobu T, Usami Y. A case of actino-
mycotic osteomyelitis of the maxilla suspected of malignant tumor.
J Jpn Stomatol Soc. 2009;58:64–8.
29. Mukai T, Takano K, Matsuura R, Yamada C, Yoshioka H. A case of
maxillary osteomyelitis involving Actinomyces infection after loss
of a tooth. Jpn J Oral Surg. 2010;56:428–31.
3 0. Kou N, Kakurai J, Omura K. A case of actinomycotic osteomyelitis of
the mandible with bone destruction. Jpn J Oral Surg. 2010;56:90–4.
31. Harada S, Tsuyama Y, Kimura Y, Okano T. Actinomycotic osteomyelitis
of the mandible with lower lip paralysis. Dent Radiol. 2012;52:30–4.
32. Kikuta T, Seto M, Takahashi H, Umemoto J, Otani T, Kita R, et al.
Actinomycotic osteomyelitis of the mandible following hemodialy-
sis: report of a case. Med Bull Fukuoka Univ. 2012;39:205–10.
33. Obata Karagi S, Yao M, Shibata A, Yoshioka N, Shimo T, Sasaki A.
A case of mandibular actinomycotic osteomyelitis: a review of the
comparison between the past and the present case of actinomyco-
sis in Japan. J Jpn Soc Oral Mucous Membr. 2017;23:23–7.
How to cite this article: Yamamura Y, Kudo Y, Kudoh K,
Miyamoto Y. Actinomycotic osteomyelitis of the mandible
with bone destruction: Two case reports with a review of the
Japanese literatures. Oral Sci Int. 2021;00:1–7. https://doi.
org/10.1002/osi2.1088