1

MODES OF TRANSMISSION OF COVID 19 VIRUS

By
Mandeep Pundir1, Manjinder Kour2, Darshdeep Singh3
1. Assistant Professor S. Lal Singh Memorial College of Pharmacy, Desh Bhagat University,
Mandi Gobindgarh
2. Assistant Professor S. Lal Singh Memorial College of Pharmacy, Desh Bhagat University,
Mandi Gobindgarh
3. Assistant Professor S. Lal Singh Memorial College of Pharmacy, Desh Bhagat University,
Mandi Gobindgarh

Introduction :-
On 31 December 2019, Chinese authorities notified the World Health Organization of
the emergence of a novel corona virus in patients in Wuhan, Hubei province [1]. At the
moment, the virus is referred to as extreme acute respiratory syndrome corona-virus 2
(SARS-CoV-2), and the disease is referred to as corona virus disease 2019. (COVID-19).
This virus is more lethal than other endemic viruses, and it is also more lethal to humans than
the SARS-CoV-1 outbreak in 2003 and the Middle East respiratory syndrome coronavirus
(MERS-CoV) outbreak in 2012. Both SARS-CoV-1 and MERS-CoV share a common
ancestor with bat-borne viruses. Both viruses are transmitted through intermediate hosts:
palm civets for SARS-CoV-1 and dromedary camels for MERS-CoV.
SARS-CoV-2 is responsible for the latest pandemic. It, like the previous two
coronaviruses, is a member of the Corona-viridae family. Corona viruses have wide (30 kb)
single-stranded, positive-sense RNA genomes; the genome is approximately 80% similar to
the genomes of other coronaviruses [2]. The coronaviruses contain the following structural
protein-coding genes: spike protein (S), envelope protein (E), membrane protein (M), and
nucleocapsid protein (N)[3]. SARS-spike CoV-2's protein utilises angiotensin-converting
enzyme 2 (ACE2) as its cell surface receptor, which has an effect on the virus's tropism.
COVID-19 is a virus that affects people of all ages. However, two distinct classes are at an
increased risk of developing serious illness: the elderly and those with underlying
comorbidities such as diabetes mellitus, hypertension, cardiopulmonary conditions, chronic
liver disease, or renal failure. Cancer patients, those taking immunosuppressive drugs, and
pregnant women are all considered to be at an increased risk of contracting serious disease if
infected [4]. The following chart illustrates the progression of COVID-19 infections. The first
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confirmed cases occurred in December 2019 [5]. Between December 18 and December 29,
2019, five patients were admitted to the hospital with acute respiratory distress syndrome,
one of whom died [6]. By January 2, 2020, 41 hospitalised patients with laboratory-
confirmed COVID-19 infection had been identified; less than half of these patients had
underlying diseases such as diabetes, hypertension, or cardiovascular disease [7]. These
patients were assumed to have contracted the infection in that hospital, most likely as a result
of nosocomial infection. It was concluded that the COVID-19 virus is not a super-hot
spreading virus (infected one patient and spread to several others), but rather spreads by
unknown mechanisms to a large number of patients in different locations in the hospital.
Additionally, since only patients who were seriously ill were examined, there were almost
certainly several more patients who were presumably infected. As of January 22, 2020, a total
of 571 new coronavirus (COVID-19) cases had been registered in China's 25 provinces
(districts and cities) [8]. China's National Health Commission released information on the
first 17 deaths that occurred between January 22, 2020 and January 22, 2020. On January 25,
2020, a total of 1975 cases of COVID-19 infection were reported in mainland China, with 56
deaths [9]. On January 24, 2020, another study estimated the total incidence in China to be
5502 cases [10]. As of January 30, 2020, 7734 cases had been confirmed in China, with 90
additional cases registered in Taiwan, Thailand, Vietnam, Malaysia, Nepal, Sri Lanka,
Cambodia, Japan, Singapore, Republic of Korea, United Arab Emirates, United States, The
Philippines, India, Australia, Canada, Finland, France, and Germany. The fatality rate in this
case was estimated to be 2.2 percent (170/7824) [11]. The discovery of the first reported case
of COVID-19 infection in the United States resulted in the classification, identification,
diagnosis, clinical course, and management of this case. This involves the patient's initial
mild symptoms and progression to pneumonia on day 9 of the illness [12]. Additionally, the
first case of COVID-19 transmission from person to person was identified in the United
States on January 30, 2020 (https://www.cdc.gov/media/releases/2020/p0130).

Pathogenesis:-

SARS-CoV-2 infections reaches host cells via the S spike protein, where it is assisted
in internalisation by the TMPRSS2 protease. The virus's high infectivity is due to mutations
in the receptor binding domain and the S spike protein acquiring a furan cleavage site. In
predisposed patients, the virus-ACE2 interaction can reduce ACE2's anti-inflammatory role
and increase angiotensin II's effects [13]. With the difficulty we face with COVID-19, others
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have advocated for the use (or discontinuation) of Angiotensin II receptor type 1 (AT1
receptor) blockers and ACE inhibitors in patients with hypertension receiving COVID-19.
Currently, the European Society of Cardiology's Council on Hypertension recommends that
patients continue their antihypertensive care unchanged, since there is no evidence to support
its cessation [14]. However, additional study is needed to substantiate these
recommendations.
The virus's invasion of lung cells, myocytes, and endothelial cells of the vascular system
causes inflammatory changes such as oedema, degeneration, and necrosis. These
modifications are primarily due to pro-inflammatory cytokines such as interleukin (IL)-6,
interleukin (IL)-10, tumour necrosis factor, granulocyte colony stimulating factor, and
monocyte. Chemoattractant protein 1, macrophage inflammatory protein 1, and increased
expression of programmed cell death 1, T-cell immunoglobulin, and mucin domain 3 (Tim-3)
were identified [15]. These changes contribute to the pathogenesis of lung injury, myocyte
injury caused by hypoxia, the body's immune response, increased myocardial cell damage,
and intestinal and cardiopulmonary changes.
Hypoxaemia has also been linked to SARS-CoV-2 infection. These changes result in the
accumulation of oxygen free radicals, altered intracellular pH, lactic acid accumulation,
electrolyte changes, and additional cellular damage.
SARS-CoV-2 is mainly a lung, vasculature, and immune system virus [16]. The initial
step in viral replication is viral protein spike (S) binding to the surface of respiratory cells
[17]. It was previously hypothesised that SARS-CoV-2 may use angiotensin-converting
enzyme 2 (ACE2, EC 3.4.17.23) found in a variety of mammals, except mice and a few birds,
such as pigeons [18]. SARS-CoV-2 has a 10–20-fold higher affinity for ACE2 than SARS-
CoV [19].
ACE2 is a metalloproteinase with approximately 60% homology to the angiotensin-
converting enzyme carboxy-peptidase (ACE, EC 3.4.15.1). ACE2 is a type I transmembrane
glycol-protein with a single extracellular catalytic domain. It contains 805 amino acids [20].
It has been documented to be expressed in the lungs, cardiovascular system, gut, kidneys,
central nervous system, and adipose tissue [21]. It is the central active peptide of the renin–
angiotensin system (RAS) or the renin–angiotensin–aldosterone system (RAAS) [21].
Angiotensin II (Ang II) is the primary effector of the RAAS, promoting hypertension in part
by decreasing baro-receptor sensitivity necessary for heart rate maintenance and increasing
vasoconstriction, sodium retention, oxidative stress, inflammation, and fibrosis. Numerous
studies indicate that ACE2 plays a critical role in efficiently degrading Ang II to Ang-(1-7),
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which neutralises Ang II's impact (Fig.1) [21]. Ang-(1–7) acts on the Mas-receptor, lowering
blood pressure slightly via vasodilation, promoting sodium and water excretion by the
kidney, and also attenuating inflammation via nitric oxide output (Fig.1) [19]. On the other
hand, ACE transforms Ang I to Ang II, which acts on the type 1 angiotensin receptor (AT1R)
and elevates blood pressure by inducing vasoconstriction, increasing sodium and water
reabsorption by the kidney, and inducing oxidative stress, which promotes inflammation and
fibrosis (Fig.1) [19].

Fig. 1 Functional scheme of the renin-angiotensin system. The protease renin converts the
precursor angiotensinogen to Angiotensin I (Ang I) and subsequently converted to Ang II by
dipeptidyl carboxypeptidase angiotensin converting enzyme (ACE). Ang II binds to the AT1
receptor (AT1R) to stimulate inflammation, fibrosis, oxidative stress and an increase in blood
pressure. Ang II are converted to Ang-(1-7) via endopeptidases (NEP) and the moncar-
boxypeptidase ACE2, respectively. Ang-(1-7) binds to the Mas-R to exert anti-inflammatory
and anti-fibrotic actions, stimulate the release of nitric oxide and reduce blood pressure.
SARS-CoV-2 binds to ACE2 to stimulate internalization of both the virus and peptidase caus-
ing deleterious effects. Angiotensin converting enzyme inhibitors (ACEIs)/Angiotensin recep-
tor blockers (ARBs) regulate the metabolic pathway.

The SARS-S1 CoV's domain binds to the host cell's ACE2 receptor [22]. The binding
of the SARS-CoV-2 spike protein to ACE2, followed by a conformational change in the S-
glycoprotein that allows ACE2 to be proteolyzed by transmembrane serine protease 2
(TMPRSS2) to generate the S1 and S2 subunits, is a critical step in S2-induced membrane
 5

fusion and virus internalisation through endocytosis in the pulmonary epithelium. The virus's
entrance into cells stimulates virus replication and cell-to-cell transmission further [22], and
is thought to suppress ACE2 expression. This inhibition of ACE2 results in a decrease in
tissue level and a decrease in Ang- (1–7) development, as well as an increase in Ang II levels.
Further conversion of Ang-(1–7) by ACE results in the formation of less biologically active
peptides. This process has the potential to initiate an Ang II–AT1R-mediated inflammatory
response in the lungs and to stimulate parenchymal injury in the future [19]. The
pathogenesis is complex and includes two interconnected processes: lung inflammation and
immune deficiency, both of which are associated with an abnormal immune response and
excessive development of pro-inflammatory cytokines [16], as well as an altered redox
balance in infected cells due to NAD? Deficiency. Biosynthesis, poly (ADP-ribose)
polymerase (PARP) action, and proteasome and mitochondrial dysfunction all contribute to
the escalation of inflammation and lipid peroxidation, resulting in cell harm [23].
Additionally, the activation of apoptosis and the p53 signalling pathway in lymphocytes
caused by SARS-CoV-2 results in lymphopenia in these patients [24]. SARS-CoV-2 exhibits
neurotropic properties and has the potential to induce neurological diseases. CoV are often
detected in the brain or cerebrospinal fluid, according to reports [25]. Another characteristic
of extreme COVID-19 is coagulopathy, as measured by elevated Plasmin (ogen) levels in
these patients. Plasmin and other proteases have been shown to cleave the furin site in the S
protein of SARS-CoV-2 extracellularly, increasing its infectivity and virulence, and is
associated with hyperfibrinolysis [26].

PATHOPHYSIOLOGY:

Transmission of infection: -
Infection is primarily transmitted person to person through respiratory droplets. The faecal-
oral route is also an option. The virus has been detected in sputum, pharyngeal swabs, and
faeces [27]. Vertical transmission of SARS-CoV-2 has been identified [28] and verified by
the presence of COVID-19 on a nasopharyngeal swab. COVID-19 has a median incubation
time of 5.2 days; the majority of patients experience symptoms between 11.5 and 15.5 days.
As a result, it has been recommended that those exposed to infection be quarantined for 14
days.
As 2019-nCoV enters the human body, it interacts with ACE2 receptors and releases
 6

its RNA into epithelial cells (ECs), where it replicates and spreads to adjacent cells, spreading
from the nasal passage to the alveolar region of the lung [29]. Alveoli mediate gaseous
exchange, but infection with 2019-nCoV results in a vascular integrity defect (increased
permeability and leakage), which results in pulmonary oedema, activation of disseminated
intravascular coagulation (DIC), pulmonary ischaemia, hypoxic respiratory failure, and
progressive lung harm [30]. Additionally, it reaches the bloodstream through infected ECs
and spreads throughout the body, including the brain, gastrointestinal tract, heart, kidney, and
liver, causing cerebral haemorrhage, neural disorder, ischemic stroke, coma, paralysis, and
ultimately death [31]. Additionally, the vulnerability and incidence of 2019-nCoV infection
in individuals are strongly influenced by co-morbidities such as hypertension, diabetes, and
lung diseases, as well as by age and dysregulation of the innate immune response. This may
be because the ACE2 receptor (an integral membrane protein) is overexpressed on the surface
of many organs, including the lung, heart, kidney, and intestine, as well as host ECs [32]. By
binding to ACE-2, the 2019-nCoV infects ECs and causes localised inflammation,
endothelial activation, tissue damage, and disordered cytokine release. The extreme
aggravation of the "cytokine storm" through secretion of vascular endothelial growth factor
(VEGF), monocyte chemoattractant protein–1 (MCP-1), and IL-8, as well as decreased E-
cadherin expression on ECs, contribute to increased vascular permeability and leakage, which
contribute to the pathophysiology of hypotension and pulmonary dysfunction in acute
respiratory distress syndrome (ARDS). The majority of COVID19 patients die as a result of
ARDS, which pulmonary ECs contribute to by altering vessel barrier integrity, promoting
coagulation, inducing vascular inflammation, and reconciling inflammatory cell infiltration
[33]. Thus, it is important to consider the multiple complications associated with 2019-nCoV
infection of the vasculature. When compared to ECs from other organs, lung ECs exhibit
greater immunomodulatory signatures, including increased expression of genes involved in
major histocompatibility complex (MHC) class II-mediated antigen processing, loading, and
presentation. This indicates that a subset of lung ECs functions as semi-professional antigen-
presenting cells in the presence of respiratory pathogens. Additionally, it has been proposed
that ECs play a critical role in the pathogenesis of acute respiratory distress syndrome
(ARDS) and multi-organ failure in patients with COVID-19. In extreme COVID-19
infection, coagulation pathways are activated, potentially leading to the production of DIC.
As a result of DIC and inflammatory cell clogging/congestion of small capillaries, as well as
possible thrombosis in larger vessels, lung tissue ischaemia occurs, triggering angiogenesis
and possible EC hyperplasia [34,35]. Numerous mechanisms for increased vascular
 7

permeability and leakage have been suggested in extreme COVID-19 patients, as Teuwen et
al. explain in detail (2020). 61 In brief, the 2019- nCoV will directly affect ECs, causing EC
dysfunction, lysis, and death; ii) Additionally, in order to reach the host cells, the 2019-
nCoV binds to the ACE2 receptor, inhibiting its activity and thus activating the kallikrein–
bradykinin pathway, resulting in increased vascular permeability. iii)activated neutrophils
recruited to pulmonary endothelial cells (ECs) generate histotoxic mediators such as reactive
oxygen species iv) immune cells, inflammatory cytokines, and vasoactive molecules increase
the contractility of ECs and the loosening/gap of inter-endothelial junctions; v) the cytokines
IL-1 and TNF activate glucuronidases that degrade the glycocalyx but also unregulated
hyaluronic acid synthase 2, resulting in increased hyaluronic acid deposition in the
extracellular matrix [36,30]. Additionally, elevated cytokine levels accelerate the destructive
process, resulting in additional EC dysfunction, DIC, inflammation, and vasodilation of the
pulmonary capillary bed. When these conditions are combined, they eventually result in
multi-organ failure and death as a result of alveolar dysfunction and ARDS with hypoxic
respiratory failure. Additionally, it has been suggested that denudation of the pulmonary
vasculature can activate the complement system, promoting the accumulation of neutrophils
and pro-inflammatory monocytes that contribute to the cytokine storm, as was observed
during influenza virus infection, where pulmonary ECs induce an amplification loop
involving interferon-producing cells and virus-infected pulmo [37]. Normalization of the
vascular wall by metabolic interventions can be considered an additional route of action,
paving the way for potential therapeutic opportunities in addition to anti-inflammatory, anti-
cytokine, and ACE inhibitors, among others [36]. Additionally, some indirect evidence
indicates a link between ECs, pericytes, and COVID-19. As a result, the effects of 2019-
nCoV on the entire vasculature need additional attention [29]
Modes of transmission:
Human-to-human transmission occurs through common routes such as direct transmission,
contact transmission and airborne transmissions through aerosols and during medical
procedures (figure 1). Cough, sneeze, droplet inhalation, contact with oral, nasal and eye
mucous membranes are the common modes of spread. Viral shedding occurs from respiratory
tract, saliva, faeces and urine resulting in other sources of virus spread.[38,39,40] The viral
load is higher and of longer duration in patients with severe COVID-19.[41] Spread of
COVID-19 from patients to health workers and flight attenders who were in close contact
with the infected patients are also reported.[42] COVID-19 has a very high infectivity rate.
Two modes of transmission exist—direct and indirect. The direct mode includes transmission
 8

via aerosols, anal (feco-oral) secretions, tears, saliva, semen, and mother-to-child. Indirect
modes include transmission via fomites. Several of these modes may be underestimated and,
thus, risk the spread of virus.
Transmission through Saliva, urine, semen, and tears
Less data is available on body fluids and secretions (other than respiratory secretions) of
infected patients testing positive for the virus. These include saliva, urine, semen, and tears.
In the study by Azzi et al., salivary samples of two patients proved positive, while their
respiratory swabs showed negative results on the same day [43]. Virus may migrate from the
nasopharynx but may be present in the oral cavity as the epithelial cells of the oral mucosa
show a high expression of angiotensin-converting enzyme-2 (ACE-2) receptors [43]. Ren et
al. found that urine of an asymptomatic patient was positive for viral nucleic acid and
concluded that urine may serve as a mode of virus transmission [44]. Valente et al. identified
conjunctival swabs from three of the 27 patients, with ocular manifestations, tested positive
for COVID-19, while Güemes-Villahoz et al. identified only one patient with the presence of
viral RNA in the tears [45, 46]. Despite the low prevalence and rapid regression of viral
presence in the conjunctiva, SARS-CoV-2 transmission through tears may be possible, even
in patients without apparent ocular involvement. Of note, Li et al. found that semen of 6 cases
tested positive for SARS-CoV-2 [47]. Thus, the authors suggest that the presence of virus in
semen may raise suspicion of sexual transmission of virus.
In a study by Yu et al., one of the seven neonates tested positive for SARS-CoV-2 after 36 h
of birth [48]. On the contrary, all the neonates born to 14 pregnant women, included in the
two studies by Khan et al. and Li et al., tested negative for virus and, thus, could not find any
evidence of vertical transmission [49, 50]. Authors conclude that transmission from mother-
to-child may be rare, but not completely absent.Transmission through mother to neonates
through breast feeding can be further studied on different stages of lactation.
Transmission through sweat

In this study, twenty-five infected patients, all of whom had clinical symptoms and high viral
load in respiratory samples, were examined for the presence of SARS-CoV-2 in sweat sam-
ples. All of them were negative and only two positive cases were found. By asking patients
who tested positive, we found that they had touched their foreheads during the test and that
their hands may have been contaminated with oral secretions or mucosa, so the positive result
was actually due to contamination of the sampling site with the secretions of other parts
(https://doi.org/10.1016/j.micpath.2020.104556) Unfortunately, very little study has been
 9

done on the possible role of sweat in the transmission of any of the betacoronaviruses, espe-
cially with regard to other deadly viruses that can be transmitted through the sweat of an in-
fected person [51]. In 2015, a report was presented that a Korean healthcare worker infected
with the MERS coronavirus during cardiopulmonary resuscitation (CPR) of a MERS patient.
According to the report, during CPR, a large amount of fluid was splashed and the nurse be-
comes infected by touching the mask and wiping the sweat from her face. Although this is
not certain, one of the possible ways that this person became infected was through mucosal
exposure to sweat contaminated with MERS coronavirus [52]. The presence of the SARS-
CoV-2 in eccrine glands indicates that sweat can be a source of transmission [53].

From a theoretical point of view, one way of transmission can be path skin-object-mucosa so
that contaminated sweat may remain on objects, which in turn may cause infection if touched
by non-infected people [54]. The receptor for SARS-CoV-2 to enter human cells is human
angiotensin converting enzyme 2 (ACE2), and it is thought that organs with high levels of
this receptor will be able to accept more viruses and therefore be more likely to become in-
fected [55]. ACE2 is itself exist in the skin, eccrine glands and smooth muscles around the se-
baceous glands as well as within these glands [56]. The fact that the number of ACE2 recep-
tors in the skin can absorb the SARS-CoV-2 raises concerns about how the SARS-CoV-2 is
transmitted. Therefore, it is possible that not only inhaling or touching the oral and respira-
tory secretions and mucosa alone does not cause infection, but also simpler routes such as
touching the sweat-soaked objects of the infected person can cause the infection. However,
the results of this study refute the hypotheses about the possibility of transmitting SARS-
CoV-2 through sweat, but still more research in this case with more samples and sweat sam-
pling of other parts of the body are recommended to ensure this result.

Feacal Transmission
In a short Research Letter published in the Journal of the American Medical Association,
different tissues of patients with COVID-19 (n=1,070 specimens from 205 patients of mean
age 44 years) were tested by RT–PCR. 32% of pharyngeal swabs (126 of 398) and 29% of
faecal samples (44 of 153) tested positive. Electron microscopy of four SARS-CoV-2-
positive faecal specimens detected live virus in stool samples from two patients who did not
have diarrhoea.
The precise mechanisms by which SARS-CoV-2 interacts with the gastrointestinal tract
remain unknown. SARS-CoV-2 is thought to use ACE2 as a viral receptor, and ACE2 mRNA
is highly expressed in the gastrointestinal system. In preliminary findings published in
 10

Gastroenterology, researchers examined clinical specimens from 73 hospitalized patients with

SARS-CoV-2 infection. 39 patients tested positive for SARS-CoV-2 RNA in stool samples.
In addition, 17 patients remained positive for SARS-CoV-2 in stool after becoming negative
in respiratory samples. Viral host receptor ACE2 stained positive mostly in gastrointestinal
epithelial cells. [57]
Transmission through breast milk

Most neonates born to mothers diagnosed with COVID-19 by RT-PCR tests during their
pregnancy were negative for viral infection. One neonate was reported to be negative for
COVID-19 by RT-PCR tests in throat swabs but had elevated IgM and IgG levels at birth.
[58] These findings may suggest that vertical transmission does not appear to occur during
the peripartum period. It is possible that passive immunity from the mother to the infant could
be protective against infection. This was also suggested in the context of severe acute respira-
tory syndrome coronavirus (SARS-CoV) infection.[59] Breast milk is not homogenous and
its composition changes through the lactation period. In the future studies, it will be important
to determine if the risk of transmission changes with the stage of lactation. In this review,
most of the breast milk samples (43 out of 46) were negative for SARS-CoV-2 RNA pres-
ence, and the majority were tested during the first 48 h postpartum. This early period usually
has a higher concentration of immune factors in milk compared with the composition of ma-
ture milk after the first month postpartum. There were few samples at different stages indicat-
ing the need to further characterize the risk of SARS-CoV-2 transmission in the context of
breast milk composition, especially considering the immunomodulating components of breast
milk, including antibodies, growth factors, and otherproteins, with critical roles in sustaining
healthy neonatal intestinal epithelium and with antimicrobial properties.[60] Lactoferrin, an
iron-binding protein present in breast milk, for example, has been found to inhibit SARS-
coronavirus infection in cell culture conditions.[61]

Conclusion: The recent COVID-19 outbreak in China has raised serious concerns about the
threat it poses to the global public health. Despite its lower mortality rate as compared to pre-
vious coronavirus outbreaks, such as the 2002 SARS-CoV and the 2012 MERS-CoV out-
breaks, the SARS-CoV-2 has shown patterns of higher transmissibility. To date, limited stan-
dardized techniques, including PCR-based detection of specific SARS-CoV-2 genes and
complementary radiological and serological tests, are available to detect the disease. To in-
crease testing capacity and allow for point-of-care COVID-19 infection detection, multiple
robust kits have been developed and are currently in use in diagnostic laboratories and in
 11

home-based settings worldwide. Currently, there is an absence of specific vaccines and an-
tiviral therapeutics against COVID-19. In the meantime, the demand for urgent COVID-19
control and prevention has led to testing the efficacy of existing approved vaccines and drugs
known to be safe for human immunization/consumption, as vaccines and antiviral therapeu-
tics designed specifically against the COVID-19 may take years before entering the market.
In addition, it is suggested that future studies focus on different modes of transmission and
steps should be taken to reduce the transmission of COVID-19.

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