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ABSTRACT
In the article of genetic studies of patients with post-covid maxillofacial complications. The condition after COVID-19
is considered a life-threatening disease, ranging from mild symptoms to serious complications. Candidiasis is the most
common type of superficial purulent infection. The Candida species is a frequent inhabitant of the oral mucosa, but its
growth is inhibited by other organisms in the div, which prevents any pathological change in the mucous membrane
of this fungus. Candida albicans is the most common yeast, followed by Candida glabrata, Candida krusei, Candida
tropicalis and Candida stellatoidea. According to this systematic review, 57 cases of oral candidiasis and one case of
retinitis candidiasis were reported in patients undergoing treatment for COVID-19. Single-cell RNA-seq analysis of
angiotensin-converting enzyme II (ACE2) expression and serologic examination of samples indicates that ACE2 may
be the cellular receptor for SARS-CoV-2, suggesting that ACE2-expressing cells are likely to be the main target cell type
that vulnerable to SARS-CoV-2 infection. As a rule, there is a high expression of ACE2 r on the epithelial cells of the oral
mucosa, enrichment is enriched in epithelial cells of the tongue. There were few reports prior to this study.
KEYWORDS
Post-covid maxillofacial complications, COVID-19, oral mucosa, Candida.
Research Article
COMPARATIVE ANALYSIS OF THE FREQUENCY OF RS1801133
POLYMORPHISM OF THE MTHFR GENE IN THE GROUP OF PATIENTS
WITH POSTCOVID COMPLICATIONS OF MAXILLOFACIAL AREA
Submission Date:
December 25, 2021,
Accepted Date:
January 05, 2022,
Published Date:
January 15, 2022 |
Crossref doi:
https://doi.org/10.37547/TAJMSPR/Volume04Issue01-02
Sh.A. Boymuradov
Tashkent Medical Academy, Uzbekistan
Y.Kh. Kurbonov
Tashkent Medical Academy, Uzbekistan
J.A.Djuraev
Tashkent Medical Academy, Uzbekistan
Journal
Website:
https://theamericanjou
rnals.com/index.php/ta
jmspr
Copyright:
Original
content from this work
may be used under the
terms of the creative
commons
attributes
4.0 licence.
10
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INTRODUCTION
Mucormycosis
is
an
angioinvasive
infection
characterized by tissue necrosis and blood vessel
infarction [1]. Mucormycosis is caused by saprophytic
fungi belonging to the order Mucorales [2,3].
Compared to global data, the incidence of
mucormycosis in India has been estimated to be 70
times higher than the COVID-19 pandemic originated
[4,5]. A multicountry study of mucormycosis
associated with COVID-19 found that 53% of cases occur
in India, followed by the United States of America
(10%), Pakistan (6.3%), France (5%), Mexico (5%) , Iran
(5%) and Russia (2.5%) [6]. During this pandemic, the
number of cases of mucormycosis in India increased
significantly (> 40,000 cases), prompting the Indian
health authorities to declare mucormycosis a notifiable
disease [7]. The situation is exacerbated by the limited
availability of first-line antifungals such as liposomal
amphotericin or amphotericin B deoxycholate.
Whereas, the European Confederation for Medical
Mycology (ECMM) and the International Society for
Human and Animal Mycology (ISHAM) have proposed
guidelines for the treatment of mucormycosis in low to
moderate income level [7]; in addition, they also
offered global guidelines for the management of
mucormycosis [8]. Prior to the COVID-19 pandemic,
diabetes mellitus was considered the most frequent
risk factor for mucormycosis in India, followed by
hematologic malignancies and solid organ transplant
recipients [4,5]. Mucormycosis has also been reported
in patients without any disease [4,5]. A multicenter
study in India identified diabetes, inappropriate steroid
therapy (6 mg dexamethasone daily for 7-10 days is
recommended; higher dose and longer duration of
treatment are considered impractical) and COVID-19
virus as risk factors for increased incidence of
mucormycosis during the first wave COVID-19 in 2020
[9]. During this outbreak, the most common
manifestation
was
rhino-orbital-cerebral
mucormycosis (ROCM), followed by pulmonary
mucormycosis [6,9].
An ecological study of the ecology of Mucorales in
Indian soils has shown a high prevalence of clinically
significant Mucorales [2]. Mucorales spores are also
widespread in indoor and outdoor air in the same
country [10]. Patients become infected by inhalation,
ingestion,
or
traumatic
contamination
of
environmental spores. The causes of this CAM
outbreak can be multifactorial. In addition to
environmental factors, uncontrolled diabetes mellitus,
inappropriate
steroid
therapy,
increased
iron
accumulation and damage caused by the COVID-19
virus may be the cause of this outbreak [9,11-13]. This
review attempts to elucidate the interaction of risk
factors or possible pathogenic mechanisms in the
onset of CAM.
Humans contract mucormycosis by inhalation,
ingestion, or traumatic inoculation of environmental
mucorales sporangiospores [2,3]. Mucorales are
ubiquitous; however, the number of spores is higher in
tropical countries [2.14]. Spores of Mucorales have
been isolated from indoor and outdoor air in Europe
[10,14]. Rhizopus arrhizus, the main pathogenic
species, is also the predominant species isolated from
the environment [2,4,14,15]. The number of CAM cases
is very high in Europe compared to the rest of the
world during this COVID-19 pandemic [6,11], and this
high number may be due to the high environmental
burden of pathogenic Mucorales spores. The study
reported the isolation of rare species such as
Apophysomyces variabilis and Rhizopus homothallicus
in the Indian environment [2]. Infections caused by
these rare species are also widespread in India [4,5].
Rhizopus homothallicus was isolated from clinical
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specimens in many centers even during the current
outbreak, in addition to the usual species, R. arrhizus
(unpublished data). During this outbreak, systematic
environmental research is needed; further comparison
of ecological and clinical isolates may provide a
plausible explanation for the emergence of SAMs. The
high burden of CAM cases in India may also be related
to the emergence of virulent strains of the order
Mucorales. Genome analysis of Mucorales isolated
prior to COVID-19 and the pandemic, as well as in vivo
animal experiments, may reveal a possible role for
Mucorales virulence factors in the onset of CAM.
Host factors are likely to play a more important role in
increasing the burden of CAM cases. Patients with
diabetes mellitus and hematologic malignancies, as
well as transplant recipients, were at high risk of
contracting mucormycosis in the pre-COVID-19 era
[5,16,17]. By comparison, patients with diabetes
mellitus and inadequately high doses of corticosteroids
are at increased risk of contracting mucormycosis
during
the
COVID-19
pandemic
[6,9,11,14].
Hyperglycemia in COVID-19 patients can be caused by
four reasons: (a) pre-existing diabetes mellitus, (b)
damage to COVID-19 pancreatic beta cells, leading to
decreased insulin production [13,15], (c) corticosteroid
therapy [1.12] and (d) increased cortisol levels
associated with stress [3,4]. Hyperglycemia and
treatment with glucocorticoids impair phagocytic
functions without stopping the germination and
growth of spores and leading to the progression of the
disease [5,16]. receptors have been found in patients
with COVID-19 [14]. Thus, these factors
In addition, patients with diabetes mellitus and COVID-
19 have elevated ferritin levels, such as preexisting
endothelial damage and upregulation of endothelial
receptors (hyperferritinemia), resulting in altered iron
homeostasis
[17].
In
addition,
endothelial
glucocorticoid
therapy,
hyperglycemia-related
complications such as damage and overexpression of
endothelial receptors have been observed in COVID-19
hyperferritinemia and immune dysfunction of innate
immune cells, likely to homeostasis [15]. In addition,
endothelial damage and increased endothelial
expression.
Thus, the factors mentioned above, such as preexisting
endothelial damage, contribute to the pathogenesis of
CAM and upregulation of endothelial receptors,
glucocorticoid therapy, complications associated with
hyperglycemia such as hyperferritinemia, and immune
dysfunction of innate immunity.
COVID-19 turns a blind eye to the angiotensin-
converting enzyme 2 (ACE2) receptor on endothelial
cells, followed by internalization of viral particles
leading
to
coagulation,
endotheliitis
and
internalization of viral particles, resulting in
coagulation, endotheliitis and endothelial cell death. In
addition to the ACE2 receptor, glucose regulates
protein cell death. In addition to the ACE2 receptor,
glucose-regulated protein 78 (GRP78) 78 (GRP78) acts
as a coreceptor for the recognition of the SARS-CoV-2
spike protein and acts as a coreceptor for the
recognition of SARS-CoV-2. protein spike and increases
the internalization of the virus. GRP78 is a 78 kDa heat
shock protein, also known as heat shock protein A5
(HSPA5). GRP78, 78 kDa, also known as heat shock
protein A5 (HSPA5). GRP78 is a molecular chaperone
localized in the endoplasmic reticulum (ER), has a
significant molecular chaperone localized in the
endoplasmic reticulum (ER), and plays an important
role in the regulation of the unfolded protein response
(UPR), protein stability, the role of calcium
homeostasis in the regulation of unfolded protein
response (UPR), protein stability, calcium homeostasis
and autophagy. Elevated serum GRP78 levels have
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been observed in autophagic patients. Elevated serum
GRP78 levels have been observed in patients with
COVID-19 infections compared to healthy controls.
Hence, suppression of COVID-19 infections versus
healthy controls. Therefore, inhibition of the GRP78
receptor GRP78 can reduce the internalization of SARS-
CoV-2 by decreasing the receptor, it can reduce the
internalization of SARS-CoV-2 by reducing the
expression of ACE2 receptors, which will further lead
to a decrease in viral binding and infection of the ACE2
receptors, which in further leads to a decrease in the
binding of the virus and the severity of the infection
[8]. severity. Like the ACE2 receptor, GRP78 also
mediates the endothelial cell barrier. Like the ACE2
receptor, GRP78 also mediates endothelial cell barrier
disruption and inflammation.
The aim of this work
is to study the features of genetic
studies in the diagnosis and prognosis of patients with
postcoid complications of the maxillofacial region.
From 2020 to 2021, we carried out a comprehensive
examination and treatment of 118 patients with COVID-
19 and its purulent-necrotic complications in the
maxillofacial area, who were being treated at the post-
COVID center of the Multidisciplinary Clinic of the
Tashkent Medical Academy.
All patients were divided into three groups (Figure 1).
Figure 1. Distribution of groups.
Molecular genetic studies were performed in the
Hematology Department of the TMA Multidisciplinary
Clinic.
This part of the work consisted of several stages:
1.
Blood sampling (Figure 2).
2.
Isolation of DNA from peripheral blood
lymphocytes.
3.
Carrying out PCR.
4.
Carrying out electrophoresis and visualization of
results.
all examined persons
Group 1 (COVID-19
118 patients with
purulent-necrotic
complications)
Control group (20
practically healthy
people)
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Figure 2. Blood sampling
In the course of the work, 4 polymorphic variants of genes were investigated (table 1).
Table 1
List of studied gene polymorphisms
Gene (abbreviation)
Localization
Polymorphism
A source
MTHFR
1p36.22, 677 C>T
rs1801133
Morrison N.A. et all.
1992
MTHFR
1p36.22, 1298 A>C
rs1801131
Braun N. et all 1996
MTR
1q43, 2756 A>G
rs1805087
Um J.Y., et all. 2004;
50: 647-650.40
MTR
5p15.31, 66 A>G
rs1801394
Vincenti V. et all. 1996
RESULTS AND DISCUSSION
In patients with postcoid complications of the PMO,
the unfavorable C allele of the rs1801133 677C> T
polymorphism in the MTHFR gene occurs slightly more
often than in healthy individuals. There is a high
frequency of occurrence of this allele with a
predominance of the homozygous T / T variant,
especially at stage 3 of the course of the disease (from
2.3 to 5.3 times). At the same time, the differences
between 1 and the control sample were noted at the
level of the trend, and the trend had a borderline level
of statistical significance. These data allow us to
conclude that the C allele and the T / T genotype of the
rs1801133 677C> T polymorphism in the MTHFR gene,
associated with a decrease in MTHFR production, have
an
insignificant
predisposing
effect
on
the
development and clinical course of postcoid
complications of MCL. Since this polymorphism is
located in the promoter region of the gene and
belongs to functional polymorphisms, it can be argued
that its presence affects the rate of expression of the
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gene encoded by MTHFR. The pattern of the
inflammatory response gene is capable of modifying
the implementation of the immune and inflammatory
response in the direction of an inappropriate
hyperinflammatory
response,
leading
to
the
progression and development of a more severe degree
of postcoid complications of MCL. According to the
odds ratio, the risk of postcoid complications of MCL in
carriers of this genotype is increased by 1.17 times (χ2 =
3.423; P = 0.068; RR = 5.271; OR = 5.902; 95% CI: 3.166 -
8.774).
Summarizing the obtained results, we can conclude
that there are insignificant differences in the frequency
of detection of allelic and genotypic variants of the
rs1801131 polymorphic locus in the MTHFR gene in 1 and
the control group. In patients with postcoid
complications of MCL, compared with the control
group, there is a slight tendency to an increase in the
frequency of the C / C genotype. According to the odds
ratio, the risk of postcoid complications of MCL in
carriers of this genotype increased by 1.17 times (χ2 =
0.017; P = 0.898; RR = 1.171; OR = 1.176; 95% CI: 0.238 -
5.762).
Thus, we have found that in patients with postcoid
complications of the PMO, the unfavorable G allele of
the 66A> G rs1801394 polymorphism in the MTR gene
is more common than in healthy individuals. There is a
high frequency of occurrence of this allele with a
predominance of the homozygous variant G / G (from
2.3 to 7.02 times). At the same time, the differences
between group 1 and the control sample were noted at
the level of the trend, and the trend had a borderline
level of statistical significance. These data allow us to
conclude that the G allele and the G / G genotype of the
66A> G rs1801394 polymorphism in the MTR gene have
a predisposing effect on the risk of development and
severe clinical course of postcoid complications of
MCL. Since this polymorphism is located in the
promoter region of the gene and refers to functional
polymorphisms. The presence of the G allele in patients
with postcoid complications of the PMO is
accompanied by a decrease in the production of the
MTR gene in the presence of the G / G genotype. The
pattern of the inflammatory response gene is capable
of modifying the implementation of the immune and
inflammatory response in the direction of an
inadequate hyperinflammatory response, leading to
the progression and development of a more severe
form of postcoid complications of MCL.
The MTHFR gene is located in the promoter region of
chromosome 1 at locus 1q36-22 and has 5 exons and 4
introns []. Several polymorphisms are found in the
gene, the most famous of which are the transition - at
the C \ T point 677 (rs1801133). This polymorphism plays
an important role in inflammatory and infectious
diseases [].
This part of the work is devoted to the study of the
distribution
frequencies
of
the
rs1801133
polymorphism of the MTHFR gene, as well as to the
analysis of the contribution of this polymorphism to
the formation, development and clinical course of
postcoid complications of MCL.
The study of the frequencies of detection of alleles and
genotypes of 677C> T polymorphism in the MTHFR
gene showed the presence of differences in their
distribution between the main and control groups
(Table 2).
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Table 2
Frequency of distribution of alleles and genotypes of rs1801133 polymorphism (gene localization on chromosome
lp36.22) 677C> T in the MTHFR gene in patient and control groups
Num
Group
Allele frequency
Genotype distribution frequency
C
T
C /C
C /T
T /T
n
%
n
%
n
%
n
%
n
%
1
Main group (n =
70)
105
75
35
25
45 64,29 16 22,86 9 12,86
2
Control group (n
= 41)
72
87,8 10
12,2
31
75,61
9
21,95
1
2,44
In the course of the study, it was possible to establish
the frequency of detection of the C allele, which was
3.0 times higher than the frequency of detection of the
T allele in the main group and 7.19 times in the control
group. The C \ C genotype in the main group, in
comparison with the C \ T and T \ T genotypes, was
detected more often by 2.8 and 4.9 times, respectively,
and in the population sample by 3.4 and 30.9 times,
respectively (diagram 1).
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Diagram. 1.
Frequency of distribution of alleles and genotypes rs1801133 (gene localization on chromosome lp36.22) 677C> T in
the MTHFR gene in patient and control groups
The results of a comparative analysis of the
frequencies of detection of alleles and genotypes of
the rs1801133 677C> T polymorphism in the MTHFR
gene in group 1 of patients with postcoid complications
of the PMO and in the population sample are
presented in Table 3.
Table 3
Differences in the frequency of allelic and genotypic variants of the rs1801133 677C> T polymorphism in the MTHFR
gene in patient groups
0
20
40
60
80
100
Main group
Control group
75
87.8
25
12.2
64.29
75.61
22.86
21.95
12.86
2.44
allele Т\Т
allele С\Т
allele С\С
allele Т
allele С
Alleles
and
genotypes
Number of examined alleles
and genotypes
Хi2
p
RR
95%CI
OR
95%CI
Main group Control group
n
%
n
%
C
105
75
72
87,8
5,25
0,02
0,85
0,579 -
1,259
0,42
0,197 -
0,881
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Allele C among practically healthy people in the control
group in the study group 2 than in group 1 met with a
slightly higher frequency (1.17). Allele T among patients
with postcoid complications of PMO in the study group
1 than in the control group met a slightly higher
frequency (2.04). It was possible to note only a slight
prevalence of the frequency of detection of the
genotype T 1 group among patients with postcoid
complications of the PMO. There was also a slightly
more significant, but still statistically insignificant, 0.9
times, excess of the frequency of genotype C, among
patients with postcoid complications of PCO, relative
to the frequency of detection of this genotype in the
control sample (χ2 = 5.25; p = 0 , 02; RR = 0.85; OR =
0.42; 95% CI: 0.579 - 1.259). The frequency of detecting
the C / C genotype of the rs1801133 677C> T
polymorphism in the MTHFR gene, by 1.17 times,
prevailed in the control group, relative to its values in
group 1 of patients with postcoid complications of
PMO (χ2 = 1.536; p = 0.219; RR = 0, 85; OR = 0.581; 95%
CI: 0.49 - 1.473). The frequency of occurrence of the C /
T genotype was slightly higher among patients with
postcoid complications of PMO compared to the
control group, amounting to 1.04 and 22.86%,
respectively (χ2 = 0.012; p = 0.916; RR = 1.041; OR =
1.053; 95% CI : 0.539 - 2.011). The frequency of detection
of the Gln / Gln genotype was 3.23% among
patients with postcoid complications of the PMO,
which was statistically significant, 5.27 times higher
than in the population sample, where its occurrence
was at the level of 8.4% (χ2 = 3.423; p = 0.068; RR =
5.271; OR = 5.902; 95% CI: 3.166 - 8.774) (Table 3).
Thus, we have established that the unfavorable allele C
of the rs1801133 677C> T polymorphism in the MTHFR
gene occurs insignificantly more often in patients with
postcoid complications of BLO than in healthy
individuals. There is a high frequency of occurrence of
this allele with a predominance of the homozygous T /
T variant, especially at stage 3 of the course of the
disease (from 2.3 to 5.3 times). At the same time, the
differences between 1 and the control sample were
noted at the level of the trend, and the trend had a
borderline level of statistical significance. These data
allow us to conclude that the C allele and the T / T
genotype of the rs1801133 677C> T polymorphism in the
MTHFR gene, associated with a decrease in MTHFR
production, have an insignificant predisposing effect
on the development and clinical course of postcoid
complications of MCL. Since this polymorphism is
located in the promoter region of the gene and
belongs to functional polymorphisms, it can be argued
that its presence affects the rate of expression of the
gene encoded by MTHFR. The pattern of the
inflammatory response gene is capable of modifying
T
35
25
10
12,2
5,25
0,02
1,17
0,38 - 3,612
2,40
1,135 -
5,077
C /C
45
64,29
31
75,61
1,536
0,219
0,85
0,49 - 1,473 0,581
0,246 -
1,371
C /T
16
22,86
9
21,95
0,012
0,916
1,041
0,539 -
2,011
1,053
0,418 -
2,653
T /T
9
12,86
1
2,44
3,423 0,068 5,271
3,166 -
8,774
5,902
0,9 -
38,706
18
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SJIF
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the implementation of the immune and inflammatory
response in the direction of an inappropriate
hyperinflammatory
response,
leading
to
the
progression and development of a more severe degree
of postcoid complications of MCL. According to the
odds ratio, the risk of postcoid complications of MCL in
carriers of this genotype is increased by 1.17 times (χ2 =
3.423; P = 0.068; RR = 5.271; OR = 5.902; 95% CI: 3.166 -
8.774).
CONCLUSION
Thus, our data confirm the complexity of the genetic
mechanism for the development of polyposis
processes in patients with postcoid complications of
PCO and indicate the need and importance of
understanding complex gene interactions in the
analysis of the development and clinical stage of the
studied pathology. Analyzing the prevalence of
genotypic variants of this polymorphism, we revealed
a direct association of the T / T monogenotype of the
677C> T rs1801133 polymorphism in the MTHFR gene,
the C / C monogenotype of the 66A> G rs1801394
polymorphism in the MTR gene with the development
of postcoid complications of the PLC.
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1.
Van Der Made C. I. et al. Presence of genetic
variants among young men with severe COVID-
19 //Jama. – 2020. – Т. 324. – №. 7. – С. 663-673.
2.
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19
Volume 04 Issue 01-2022
The American Journal of Medical Sciences and Pharmaceutical Research
(ISSN
–
2689-1026)
VOLUME
04
I
SSUE
01
Pages:
9-19
SJIF
I
MPACT
FACTOR
(2020:
5.
286
)
(2021:
5.
64
)
OCLC
–
1121105510
METADATA
IF
–
7.569
Publisher:
The USA Journals
15.
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comprehensive literature review on the clinical
presentation, and management of the
pandemic coronavirus disease 2019 (COVID-19)
//Cureus. – 2020. – Т. 12. – №. 4.
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coronavirus
(severe
acute
respiratory
syndrome coronavirus 2) pandemic: A joint
american college of academic international
medicine-world
academic
council
of
emergency medicine multidisciplinary COVID-
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global infectious diseases. – 2020. – Т. 12. – №.
2. – С. 47.
17.
Syamal
M.
Literature‐guided
recommendations for otolaryngologists during
the COVID‐19 pandemic: A contemporary
review
//Laryngoscope
Investigative
Otolaryngology. – 2020. – Т. 5. – №. 3. – С. 432-
437.
