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Journal of Evidence-based Complementary & Alternative Medicine logoLink to Journal of Evidence-based Complementary & Alternative Medicine
. 2016 Jun 8;22(2):324–333. doi: 10.1177/2156587216650302

Natural Treatments for Fissure in Ano Used by Traditional Persian Scholars, Razi (Rhazes) and Ibn Sina (Avicenna)

Ali Reza Derakhshan 1,
PMCID: PMC5871188  PMID: 27279645

Abstract

Most cases of chronic fissure do not respond to medical treatment. Razi and Ibn Sina were 2 of the best-known scientists of ancient Persia. The purpose of this study was to find out new scientific evidence in modern medicine about their recommendations, in order to find certain clues to conduct useful researches in the future. First, treatments of anal fissure mentioned by Razi and Ibn Sina were reviewed. Then, literature search was made in electronic databases including PubMed, Scopus, and Google Scholar. Management of anal fissure according to Razi’s and Ibn Sina’s practices is done based on 3 interventions: lifestyle modifications, drug treatments, and manual procedures. Almost all remedies suggested by Razi and Ibn Sina have shown their effects on fissure in ano via several mechanisms of action in many in vitro and in vivo studies; Still there is lack of human studies on the subject.

Keywords: fissure in ano, Persian medicine, traditional medicine, Avicenna, Rhazes


Fissure in ano is a linear tear in the anoderm usually extending distally from the dentate line to the anal verge.1 It is one of the most common anorectal problems. It is reported that 1 in every 5 people will suffer from anal fissure during their lifetime. It is more common in teenagers and young adults although it can be seen in all ages.2 Although the exact etiology of anal fissure is unknown, the initiating factor is thought to be trauma from the passage of hard stool with painful bowel movement.3

Most anal fissures are acute and heal spontaneously or with conservative care in less than 2 weeks.2 Although there is no defined time period distinguishing acute from chronic fissures, some articles suggest that if a fissure fails to heal within 6 weeks, it is considered to be chronic.1,2,4

Acute anal fissures can be managed by conservative methods such as stool softeners and improvement of local hygiene, but the treatment of chronic anal fissures is usually more difficult, therefore they are treated by surgery.3 The procedure of choice is lateral internal sphincterotomy.5

Fissures often recur after medical therapy.6 On the other hand, surgical treatment of chronic anal fissure is associated with complications such as ecchymosis, hematoma,7 pain, postsurgical secondary infection,8 abscess and fistula formation,9 long hospital stay,10 and a degree of incontinence, which has been reported to be in up to 30% of patients.11

Nowadays, the use of nonsurgical method as the first-line treatment of chronic anal fissure is well accepted. Because of possibility of failure and complications after surgery, research for the nonsurgical treatment of chronic fissure continues.10

Complementary and alternative medicine is a branch of medicine based on the holistic concept of health that can improve the quality of life along with the treatment of the ailment.12 The philosophy behind complementary and alternative medicine is different from that of Western medicine. Today traditional medicines as a part of complementary and alternative medicine are being practiced in large parts of Asia, Africa, and Latin America due to the availability and affordability.13

Traditional Persian medicine, also known as Unani medicine or Hikmat,14 is a type of complementary and alternative medicine with more than 4000 years of history that has been widely used in ancient Persia and has flourished in Muslim countries.15 Traditional Persian medicine is a medical system consisting of all the measures to prevent, diagnose, and treat the various ailments in Persia from ancient times to present.

The principles of traditional Persian medicine are based on 4-fold elements, namely fire, air, water, and earth and each one has its specific quality: fire is hot and dry, air is hot and moist, water is cold and moist, and earth is cold and dry. The entire world is made up of these elements and the different ratios of them in every object is responsible for the diversity present in our universe. Elements combine with each other to create an object and based on the dominant element(s) and its quality the object will possess a new quality in all of its particles known as Mezaj (temperament). For instance, if fire is dominant the object has hot and dry temperament. Accordingly, traditional Persian medicine practitioners believe that each disease has its own temperament and it should be managed by its opposite quality.16

There is information and data in traditional Persian medical books about natural products and medicinal plants that are used by Persian scientists for the treatment of fissure in ano. Scientists like Razi,17 Majusi Ahwazi,18 Ibn Sina,19 Jorjani,20 Ibn Nafis,21 Samarghandi,22 Muhammad ibn Muhammad Abdullah,23 and Arzani24 have devoted a chapter of their books to fissure in ano disease.

In this article, we represent the opinion of 2 Persian hakims (practitioners), Abu Bakr Muhammad ibn Zakariya Al-Razi known to the West as Rhazes (born circa 854, Rayy, Persia [now in Iran]—died 925/935, Rayy) and Abu Ali Al-Hussain Ibn Abdullah Ibn Sina better known as Avicenna (born 980, near Bukhara, Persia [now in Uzbekistan]—died 1037, Hamadan, Iran) on the treatment of fissure in ano.25,26 In light of their teachings we have investigated the modern medical findings as well in the field of fissure in ano.

Materials and Methods

We reviewed Razi and Ibn Sina’s books Kitab al-hawi (Liber Continens) and Qanoon fi al-teb (The Canon of Medicine), which are considered as major references in traditional Persian medicine, and also among the central texts in Western medical education from the 13th to the 18th centuries.27 These books were originally written in Arabic and for this reason we studied their Arabic editions.28,29 Then scientific names of the proposed plants were extracted from a Persian plant encyclopedia30 and were matched with an English textbook.31 We considered the scientific name(s) and common name(s) of their suggestions as the key words and based on these key words, we established the next phase of our study, that is, literature search in Medline, Scopus, Google Scholar, and text books. We tried to find out new scientific documents in modern medicine about Razi’s and Ibn Sina’s recommendations, in order to find certain clues to conduct useful researches in the future.

Background Info

Razi was one of the most important physicians and chemists who discovered alcohol and sulfuric acid and more than 184 texts in medicine attributed to him with 40 of them currently available.32 He is best known for making the first description of smallpox and measles. Also, he was the first chief physician of the great hospital at Baghdad. Al-Hawi fi al-tibb (also known as Liber Continens or The Comprehensive Book) is the most renowned manuscript of Razi. It was a compilation of Greek, Persian, and Arabic medicine, as well as some Indian medical knowledge. Razi added his own clinical observations and case studies, his personal medical experiments and his own considered judgment to this book. Razi finished this medical encyclopedia in 15 years. It has 23 volumes and fissure in ano is discussed in volume 11. Also the 20th and 21st volume is devoted to the pharmacopoeia of Mufradat (single-drugs).26,33,34

Ibn Sina is considered a great Muslim philosopher and physician who had a major role in development of medicine in early medieval times through his innovative ideas. He has written more than 400 books and treaties about astronomy, philosophy, and many other branches of science, especially medicine.35 Al-qanoon fi al-tibb (The Canon of Medicine) is the preeminent work of Ibn Sina, which is divided into 5 books. The first book contains 4 treatises that explain basic theories of traditional Persian medicine like 4-elements’ theory and humors, anatomy, etiology, symptoms, hygiene, health and sickness, classification of disease and general overview of regimens and nutrition. The second book is Materia Medica. The third book covers diseases from head to toe and fissure in ano is discussed in this book. The fourth book examines diseases that are not specific to certain organs like fevers. The fifth book presents compound drugs. Indeed, Ibn Sina summarized the medical knowledge of the time in Qanoon. It is considered one of the great classics in the history of medicine and remained the most popular medical textbook in the world over the subsequent 6 centuries.25,36,37

Results

In traditional Persian medicine, the term denoting fissure in ano is Shiqaq (rift). Shiqaq is defined as anal margin ulcer.20 In Al-Hawi and Al-Qanoon, independent parts of the books have been devoted to Shiqaq disease. In addition, some treatments for Shiqaq are expressed in the pharmacopoeia of these books. Shiqaq can be caused by several reasons. The most prevalent cause is the warmth and dryness of anus. When this condition is associated with passage of dense stool, anal fissure develops. Other causes are warm swelling in anus, fissure with hemorrhoid, and congestion of rectal arteries.

There are several treatments for fissure in ano in traditional Persian medicine texts, which are classified as: (1) lifestyle modifications, (2) drug treatments, which include treatment with Mufradat (single natural drugs) and treatment with Qarabadin (pharmaceutical formulation of 2 or more bioactive substances), and (3) manual procedures.

It is important to know that according to Razi’s principles, lifestyle modifications takes priority over single-drug management and single-drug management takes priority over combination-drug management.38

Lifestyle modifications are series of administrations often nutritional for fissure in ano including persistence on eating laxative foods and drinks, avoidance of eating sour, astringent and dry foods and drinks and several dietary advices like eating soft-boiled egg yolk, cabbage soup, coconut, almond, brown sugar, and so on, and topical usage of animal fats like those of hen, goose, goat, and camel.39 Warm water sitz bath, sitting on soft surfaces, avoid sitting on hard surfaces, such as horseback riding, and avoiding scratching of the anal area is also recommended.

There are many Mufradah (single-drug) mentioned in traditional Persian medicine books for treatment of anal fissure. Among them, those that are expressed in Al-Hawi and Al-Qanoon with their common and scientific name(s), plant family and type of application in traditional Persian medicine have been shown in Table 1 alphabetically. Moreover, details of recent research findings that support their efficacy in treatment of anal fissure have been demonstrated in Table 2.

Table 1.

Single Natural Substances Used by Traditional Persian Medicine (TPM) Practitioners to Treat Anal Fissure52,5355 , a

Scientific Name Synonyms Family Common English Name TPM Name(s) Application in TPM for Fissure Related Function in TPM for Fissure Part Used in TPM for Fissure Prescribed by
Allium cepa L Allium angolense Baker Amaryllidaceae Onion Basal / Piyaz Oral Laxative Bulb Ibn Sina19,56
Althaea officinalis L Malvaceae Marshmallow Khatmi Sitz bath Anti-inflammatory Laxative Flower / Root Razi57 Ibn Sina58
Artemisia absinthium L Absinthium vulgare Gaertn Absinthium officinale Lam. Asteraceae (Compositae) Wormwood / Absinthium Afsantin Oral (drink) Anti-inflammatory Wound healing Flower Ibn Sina59
Commiphora mukul (Hook ex Stocks) Engl Commiphora wightii (Arn) Bhandari Balsamodendron mukul Hook ex Stocks Burseraceae Guggul / Indian bdellium-tree / Mukul myrrh tree Muql Oral / Topical Anti-inflammatory Laxative Resin Razi60 Ibn Sina61
Daemonorops draco (Willd) Blume Calamus draco Willd Arecaceae Dragon’s blood Dammul-Akhwain / Khun-siavashan Oral Wound healer Resin Ibn Sina62
Hen egg yolk Yolk Safrat al-bayz / Zardeh Topical Anti-inflammatory Wound healer Egg yolk Razi63 Ibn Sina64
Malva sylvestris L Malva mauritiana L Malvaceae High mallow / Common mallow Khobbazi / Panirak Sitz bath Anti-inflammatory Wound healer Laxative Flower Razi65 Ibn Sina66
Trigonella foenum-graecum L Trigonella tibetana (Alef) Vassilcz Fabaceae (Leguminosae) Fenugreek Hulba / Shanbalileh Oral / Topical Anti-inflammatory Laxative Seed / leaves Razi67 Ibn Sina68
Vitex agnus-castus L Vitex verticillata Lam Lamiaceae Chasteberry / Chaste Tree / Vitex Panjangosht Topical / Oral / Sitz bath Anti-inflammatory Fruit Razi69 Ibn Sina70

aAll plants named in the table except Commiphora mukul and Daemonorops draco are cultivated in Iran. It should be noted that ancient Persia had broader boundaries.

Table 2.

Pharmacological Activities Attributed to Natural Substances Used in Traditional Persian Medicine (TPM) for the Management of Anal Fissure.a

Natural Substance Part / Extract Extract Dosage Active Constituent Model Species Result Reference
Allium cepa L Sprout Aqueous extract In vitro Anti-inflammatory activityb 71
Bulb Alcoholic extract 300 mg/kg In vivo Rats Wound healing effectc 72
Bulb Fresh juice 7.5 mL/kg In vivo Mice rats Analgesic effectd Anti-inflammatory activitye 73
Bulb Aqueous extract In vivo Mice Anti-inflammatory activityf 74
Althaea officinalis L Root Aqueous extracts In vitro Anti-inflammatory activityg 75
Flower Aqueous extract 50, 100, and 250 mg/kg body weight In vivo Rats Anti-inflammatory activityh Antiulcerogenic activityi 47
Artemisia absinthium L Derived herb Methanol extract 5,6,3′,5′-Tetramethoxy 7,4′-hydroxyflavone (p7F) In vitro In vivo — Mice Anti-inflammatory activity Anti-inflammatory activityj 76
Flowers Methanol extract Cardamonin 2′,4′-dihydroxy-60-methoxychalcone In vitro Anti-inflammatory activityk 77
Flower Aqueous extracts 50, 100, and 200 mg/kg/d In vivo Mice Anti-inflammatory activityl 78
Seed and stem Methanolic extract 300, 500, and 1000 mg/kg In vivo Mice Rats Analgesic effectm Anti-inflammatory activityn 79
Leaves and inflorescence Dried extract of the plant in normal saline 4% and 6% weight/volume In vivo Mice Antinociceptive effecto 80
Dried powder 3 × 750 mg for 6 weeks Clinical trial Anti-inflammatory activityp 81
Seed Chloroform fraction 0.05, 0.1, and 0.5 mg/kg body weight 11-Deoxocucurbitacin-I-2-O-b-D-glucoside In vivo Mice Rats Peripheral analgesic activityq Anti-inflammatory activityr 82
Seed and fruit Acetone and methanol extracts 0.05 to 1 mg/kg 0.5 to 1 mg/kg In vivo Mice Rats Peripheral analgesic activitys Anti-inflammatory activityt 83
Commiphora mukul (Hook ex Stocks) Engl Resin In vitro Anti-inflammatory activityu 84
Resin 0, 2.5, 5, 10, 25, or 50 µM for 4 hours Guggulsterone In vitro Anti-inflammatory activityv 85
Resin Ethyl acetate extract In vitro Anti-inflammatory activityw 86
Resin 30 mg/kg/d for 5 days Guggulsterone In vivo Mice Anti-inflammatory activityx 87
Resin Alcoholic extract In vivo Rats Anti-inflammatory activityy 88
Resin 200 mg/kg for 2 weeks In vivo Rats Antinoniceptive effectz 89
Resin Ethyl acetate extract gel Gugulipid In vivo Rats Anti-inflammatory activityaa 90
Resin 3 g/d for 4 weeks Randomized controlled trial Analgesic and laxative effectsbb 91
Daemonorops draco (Willd) Blume Resin Ethanol extract In vitro Anti-inflammatory activitycc 92
Resin Ethyl acetate extract In vitro Anti-inflammatory activitydd 93
Resin 0.14, 0.56, and 1.12 g/kg Cochinchinenin B(CB) In vitro In vivo — Rats Anti-inflammatory and analgesic effectsee anti-inflammatory and analgesic effectsff 94
Resin Powder 0.9 g spread on the wound Case report Wound healing effect 95
Hen egg yolk Egg yolk Phosvitin Phosvitin In vitro Anti-inflammatory activitygg 96
Egg yolk Direct heat extracted oil 100, 200, 300 mg/kg In vivo Mice Rats Analgesic effecthh Anti-inflammatory activityii 97
Egg yolk Extracted oil In vivo Rat Wound healing effectjj 98
Malva sylvestris L Dried leaves Alcoholic extracts In vitro Anti-inflammatory activitykk 99
Dried leaves Hydroalcoholic extract 0.01–3.0 mg/ear Malvidin 3-glucoside In vivo Mice Topical anti-inflammatory activityll 100
Leaves Hydroalcoholic extracts 300 µg/cm2 In vivo Mice Topical anti-inflammatory activitymm 101
Leaves Aqueous extract 10 mg/kg In vivo Mice Antinociceptive activitynn 102
Flowers Diethyl ether extract 200 mg/kg/d In vivo Rats Wound healing activityoo 103
Trigonella foenum-graecum L Seeds Hexane extract, ethyl acetate extract, and methanolic extract 250 µg/mL In vitro Anti-inflammatory activitypp 104
Leaves Aqueous extract 1000 and 2000 mg/kg In vivo Rats Anti-inflammatory activityqq 105
Leaves Aqueous extract 1000 and 2000 mg/kg In vivo Rats Antinociceptive activityrr 106
Vitex agnus-castus L Fruit Methanol extract In vitro Analgesic effectss 107
Fruit Methanol extract and defatted extract In vitro Analgesic effecttt 108
Aerial parts Methanol extract Methyl 3,4-dihydroxybenzoate 5-hydroxy-2-methoxybenzoic acid 3,4-dihydroxybenzoic acid In vitro Anti-inflammatory activity 109
Fruit Hydroalcoholic extract 265, 365, 465, 565, and 665 mg/kg 225-565 mg/kg body weight In vivo Mice Antinociceptive activityuu Anti-inflammatory activityvv 110

aEmpty cells were not mentioned in the original article.

bWith a dose-related response in the lipoxygenase inhibitor screening assay.

cIn excision, incision, and dead space wound models.

dIn Hot plate and formalin tests in both pain phases.

eIn carrageenan-induced paw edema test.

fInhibited mouse ear oedema induced by arachidonic acid.

gStimulated phagocytosis, and the release of oxygen radicals and leukotrienes from human neutrophils. Also induced the release of cytokines, interleukin-6, and tumor necrosis factor from human monocytes.

hIn acute and chronic inflammation induced by carrageenan and formalin, respectively.

iIn ethanol-induced gastric ulcer.

jP7F inhibited the expression or production of pro-inflammatory mediators such as cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) and inducible nitric oxide synthase/nitric oxide (iNOS/NO) in lipopolysaccharide (LPS)–stimulated RAW 264.7 cells. P7F also suppressed the serum level of tumor necrosis factor-α (TNFα) in mice treated with collagen and inhibited nuclear factor κB (NFkB) activation as well as NFκB promoter activity in RAW 264.7 cells stimulated with LPS.

kInhibits LPS-induced TNFa production in THP-1 human monocytes.

lIncrease of the levels of important pro-inflammatory mediators TNF-α and interleukin-1 (IL-1) was significantly suppressed by aqueous extracts of Artemisia absinthium pretreatment.

mIn tail immersion method.

nIn hind paw edema test.

oShowed antinociceptive effect at 4.6% concentration but did not show antinociceptive effect in lower doses in tail flick test.

pSuppresses TNF-α and improvement in Crohn’s disease symptoms.

qIn writhing test.

rInhibition of carrageenan-induced rat paw edema.

sIn writhing test.

tInhibition of carrageenan-induced rat paw edema without inducing side effects.

uInhibits COX-1 and COX-2 enzymes.

vInhibits LPS-induced TNF-α, COX-2 expression and COX-2 production in human middle ear epithelial cells in a dose-dependent manner.

wDownregulation of inflammatory mediators such as interferon-γ (IFN-γ), IL-12, TNF-α, IL-1h.

xIn murine models of inflammatory bowel disease, effectively attenuated the severity of wasting disease and the fecal score and colon inflammation, also attenuated generation of IL-2 and IL-4 and IFN-γ assessed by measuring the macroscopic- and microscopic-damage scores.

yIt possessed a highly significant activity in formaldehyde-induced arthritis as compared with hydrocortisone and butazolidin as reference standards.

zModulated neuropathic pain as observed from the increased hot-plate and tail-flick latencies, and decreased paw withdrawal duration in acetone test.

aaInhibition of carrageenan-induced paw edema.

bbSignificant improvement in the rate of constipation and proctorrhagia.

ccInhibits LPS-stimulated NO, PGE2, IL-1, and TNF-α release, and iNOS and COX-2 expression.

ddInhibited the production of NO, reactive oxygen species (ROS), PGE2, TNF-α, IL-8, and IL-6 in LPS-treated human aortic smooth muscle cells and RAW 264.7 macrophages.

eeBlocking the synthesis and release of substance P through inhibition of COX-2 protein induction and intracellular calcium ion concentration.

ffIntragastric administration of dragon’s blood (DB) inhibited paw edema, hyperalgesia, COX-2 protein expression, or preprotachykinin-A mRNA expression in carrageenan-inflamed or sciatic nerve–injured (chronic constriction injury) rats, respectively. Short- and long-term exposure of cultured rat dorsal root ganglion (DRG) neurons to DB reduces substance P release.

ggReduced the production of IL-8.

hhIn writhing test and hot plate test.

iiInhibition of carrageenan-induced paw edema.

jjYolk oil–treated burned animals showed abundant re-epithelialization without any tissue scar in comparison with 1% silver sulfadiazine group.

kkSignificantly reduced the desferrioxamine-induced release of PGE2 and PGD2.

llReduced ear inflammation caused by 12-O-tetradecanoylphorbol acetate.

mmInhibition of the croton oil–induced ear edema.

nnEffect against acetic acid–induced abdominal constrictions, formalin-induced pain, and capsaicin-induced pain.

ooStimulates wound contraction in alloxan-induced diabetic rats.

ppStrong lipid peroxidation (LPO), COX-1 and COX-2 enzyme inhibitory activities.

qqReduce formalin-induced edema.

rrIn a dose-dependent manner in both phases of formalin and tail-flick tests.

ssActivating opioid receptors.

ttActivating µ-opiate receptors.

uuIn formalin test.

vvTopical application of 225 to 565 mg/kg body weight doses resulted in potent suppression of acute mouse ear edema induced by xylene.

More than 40 Qarabadin (multidrug formulations) are mentioned in Hawi and Qanoon for treatment of fissure in ano. The constituents, the preparation and usage method and the dosage are comprehensively discussed by Razi and Ibn Sina. They are used in a variety of forms, including oral preparations, ointments, medicated oils, sitz baths, and fumigation.

Manual interventions are generally not recommended as a treatment plan although in some cases Fasd (blood letting through vein) can be used in anal fissures.

It is noteworthy that the treatment of anal fissure in traditional Persian medicine is based on lifestyle modification and use of natural single drugs. Multidrug therapy and manual interventions are considered as the second line of treatment.

Discussion

The purpose of this study was to investigate the opinions of Razi and Ibn Sina about the treatment of fissure in ano. They have designed a chapter about fissure in ano etiology and treatment under the heading of diseases of the anus in their books Al-Hawi and Al-Qanoon. According to Razi’s and Ibn Sina’s medical practices the first step in treatment is lifestyle modification. Orders related to lifestyle modification mostly focused on diet and improving patient’s constipation. Findings of modern medicine confirmed the role of relieving the constipation and use of stool softeners in treatment of fissure in ano.1 Warm water sitz bath is another recipe of these scholars for fissure in ano, which is also recommended by modern medicine.40

Razi and Ibn Sina have introduced some natural remedies for this condition beside principles of lifestyle modification. All the medicinal plants and natural foods claimed to be efficacious in the management of fissure in ano were collected from Al-Hawi and Al-Qanoon, and any scientific evidence that prove their efficacy was retrieved from electronic databases. These remedies have shown their effectiveness on fissure in ano via several mechanisms of action including anti-inflammatory, analgesic, wound healing, and laxative effect. Most of these natural remedies asserted their effect through more than one of the mentioned mechanisms.

Despite many pieces of in vitro and in vivo evidence, only 1 clinical trial and 1 case report were found to confirm the effectiveness of investigated remedies. As shown in Table 1, the plants used by Razi and Ibn Sina for management of fissure in ano are from different families, and there is no exact relationship between the family of plants investigated and their efficacy.

Among the listed medicinal herbs, Allium cepa,41 Althaea officinalis,42,43 Malva sylvestris,44 Trigonella foenum-graecum,45 and Vitex agnus-castus 46 contain flavonoid compounds that can be responsible for their anti-inflammatory effects. On the other hand, mucilaginous compounds of Althaea officinalis,47 Malva sylvestris,48 and Trigonella foenum-graecum,49 in addition to anti-inflammatory activity, can be involved in the relief of symptoms through laxative effects.

There are a limited number of studies that have investigated natural therapies for fissure in ano. The effects of clove oil topical cream,3 Aloe vera topical cream,50 and a mixture of honey, olive oil, and beeswax51 on fissure in ano were interpreted as significantly positive in separate studies.

Overall, there are various natural remedies prescribed by Razi and Ibn Sina for the management of fissure in ano whose efficacy has been established through various in vitro and in vivo studies. Because of lack of human studies, it is recommended that clinical trials are conducted in the future to prove their efficacy and obtain more conclusive results.

Acknowledgments

The author would like to thank Dr Rasool Choopani for his time and advice in the development of this work and Dr Sohrab Dehghan for proofreading the manuscript.

Footnotes

Declaration of Conflicting Interests: The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval: This study did not warrant institutional review board review as no human subjects were involved.

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