The role of peripheral serotonin in SARS-CoV-2 infectivity, COVID-19 treatment and long COVID

The role of peripheral serotonin in SARS-CoV-2 infectivity, COVID-19 treatment and long COVID | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 21 May 2025 V1 Latest version Share on The role of peripheral serotonin in SARS-CoV-2 infectivity, COVID-19 treatment and long COVID Authors : Daniel Thorpe 0000-0002-5644-6170 , Lauren Jones A , Alyce Martin M , Rosemary Amelia Coleman 0009-0009-1494-871X , Caitlin Allman , Rochelle Peterson A , and Damien Keating J [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174781126.60677247/v1 Published Immunology & Cell Biology Version of record Peer review timeline 621 views 201 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Gastrointestinal symptoms have emerged as a common, but underappreciated, cause of morbidity in relation to SARS-CoV-2 infection and the COVID-19 pandemic. This manifests as a range of indications including diarrhea, anorexia, nausea, vomiting and abdominal pain. In addition, the gastrointestinal tract may represent a route of viral entry via the epithelial cell layer lining the gut wall. This route of entry could be a significant component of disease pathogenesis, including effects on the nervous system via the gut-brain axis. In this review we provide an assessment of the effects of COVID-19 on the gastrointestinal system, its involvement in disease severity and potential pathways for viral entry and infection in the gastrointestinal tract. We also examine evidence that gut-derived serotonin is affected by SARS-CoV-2 infection, how this may link to symptoms and disease pathogenesis, and the potential link to the efficacy of selective serotonin reuptake inhibitors in reducing COVID-19 severity. REVIEW: The role of peripheral serotonin in SARS-CoV-2 infectivity, COVID-19 treatment and long COVID. Daniel W Thorpe 1 , Lauren A Jones 1 , Alyce M Martin 1 , Rosemary A Coleman 1 , Caitlin Allman 1 , Rochelle A Peterson 1 , Damien J Keating 1 * Gut Sensory Systems Group, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Australia. *Author for correspondance: Prof Damien J Keating, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042 Email: [email protected] Short tile : Serotonin in COVID-19 Word count: 3451 Daniel W Thorpe: https://orcid.org/0000-0002-5644-6170 Lauren A Jones: https://orcid.org/0000-0003-4841-8847 Alyce M Martin: https://orcid.org/0000-0003-1631-8307 Damien Keating https://orcid.org/0000-0002-0154-8305 Abstract Gastrointestinal symptoms have emerged as a common, but underappreciated, cause of morbidity in relation to SARS-CoV-2 infection and the COVID-19 pandemic. This manifests as a range of indications including diarrhea, anorexia, nausea, vomiting and abdominal pain. In addition, the gastrointestinal tract may represent a route of viral entry via the epithelial cell layer lining the gut wall. This route of entry could be a significant component of disease pathogenesis, including effects on the nervous system via the gut-brain axis. In this review we provide an assessment of the effects of COVID-19 on the gastrointestinal system, its involvement in disease severity and potential pathways for viral entry and infection in the gastrointestinal tract. We also examine evidence that gut-derived serotonin is affected by SARS-CoV-2 infection, how this may link to symptoms and disease pathogenesis, and the potential link to the efficacy of selective serotonin reuptake inhibitors in reducing COVID-19 severity. Keywords: SARS-CoV-2, COVID-19, gastrointestinal, serotonin, SSRI. Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; GI, gastrointestinal; ICU, intensive care unit; ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane serine protease 2; NRP1, neuropilin-1; BSG, Basigin, BSG; LY6E, lymphocyte antigen 6 complex, locus E; IFITM1, interferon-induced transmembrane proteins-1; IFITM3, interferon-induced transmembrane proteins-3; IFNRA1, interferon type I receptor A1, IFNRA1; interferon type I receptor A1, IFNRA2; NRP1, neuropilin-1; EE, enteroendocrine; 5-HT, 5-hydroxytryptamine or serotonin; EC, enterochromaffin; CgA, chromogranin-A; SSRI, selective serotonin reuptake inhibitors; SERT, serotonin-reuptake transporter. Introduction The coronavirus disease 2019 (COVID-19) pandemic has had a profound impact on global health, health care systems, and economies and has resulted in significant loss of life. COVID-19 arises following infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and, while multi-organ manifestations exist 1 , initial symptoms are largely associated with the respiratory system and significant effects on the gastrointestinal (GI) tract. The GI symptoms associated with COVID-19 are complex and varied and present a significant new challenge in relation to clinical management of COVID-19. Additionally, there is significant interest regarding the potential for COVID-19 to be transmitted via feces and for infection to occur through the GI tract itself. This review will focus on the pathogenic pathways related to acute and chronic GI symptoms identified in relation to COVID-19 infection, evidence supporting the GI tract as a route of infection, and the future challenges related to this infectious disease, the GI tract, and its related physiological pathways. Gastrointestinal symptoms related to COVID-19 infection While COVID-19 is predominantly a respiratory virus, GI symptoms are reported in 10-60% of hospitalized patients 2-4 . These symptoms include diarrhea, anorexia (loss of appetite), nausea, vomiting, abdominal pain, acid reflux, abdominal distention, and bloody stool 25, . The most frequently reported are diarrhea (2–55%), anorexia (10.1–39.7%), and nausea (1.0–27.5%) 6 . While GI symptoms typically occur alongside respiratory symptoms, early reports from China indicated that as many as 23% of patients only experienced GI symptoms 27-9, . Patients with severe SARS-CoV-2 infection or ICU admission are more likely to experience diarrhea, abdominal pain and anorexia 810, , while those with diarrhea reported an increased prevalence of other common COVID-19 symptoms such as headaches, fatigue, cough and sputum production 11 . These patients also experienced longer periods of fever and dyspnea (shortness of breath), took longer to produce a negative throat swab and spent more time in hospital 11 . However, this finding was not linked with differences in improvement or deterioration of symptoms during follow up 11 . Similarly, patients with GI symptoms were found to experience a longer duration of illness, but that this was not linked to increased severity, as indicated by no difference in intensive care unit (ICU) admissions 12 . Conversely, while the study by Greco et al . on patients in Italy found no difference in disease severity between those with and without GI symptoms, it found that those with GI symptoms spent less time in hospital overall 13 . GI symptoms appear linked with fecal viral load, a longer period between symptom onset and viral clearance, and feature in the presentation of long-COVID 9 . A meta-analysis of findings from 4243 patients with COVID-19 found that 17.6% of patients had GI symptoms, with viral RNA detected in stool samples from 48.1% of patients, even in stool collected after respiratory samples gave negative test results 14 . Patients presenting with diarrhea are more likely to produce stool samples that test positive for viral SARS-CoV-2 RNA compared to those without diarrhea 2911, . Similarly, patients with digestive symptoms are more likely to have a longer delay before viral clearance, taking an average of 42 days between onset and clearance compared to 33.5 days 9 . Long-COVID has been used to describe a variety of symptoms that persist after COVID-19 infection, including GI symptoms 15 . As many as 44% of hospitalized patients have reported experiencing GI symptoms over 90 days from discharge, and up to 8% report GI symptoms after 6 months 515, . The most reported of these were anorexia (24%), nausea (18%), acid reflux (18%) and diarrhea (13%). While these trends do not necessarily translate into COVID severity, they may be indicative of a subgroup of COVID-19 patients that experience persistent mild GI symptoms of long-covid. Potential routes of SARS-CoV-2 entry The digestive tract is an established route of SARS-CoV-2 infection 16-18 . Although gut-related symptoms alone do not appear to be a predictor of COVID-19 clinical outcomes or mortality 19 , the presence of SARS-CoV-2 within the gut and degree of GI symptoms is positively correlated with overall prevalence and duration of other COVID-19 symptoms 2320, . Infection of human small intestinal organoids with SARS-CoV and SARS-CoV-2 demonstrates that epithelial cells, especially enterocytes, support viral replication 21 . In similar organoid experiments from human ileum, most gut epithelial cell types were capable of SARS-CoV-2 infection, with hormone-secreting enteroendocrine cells having the greatest proportion of cells infected at 12 hours after viral exposure 22 . Infection via the gut epithelial cell layer may therefore act as a route of infection as well as contribute to the prolonged fecal viral shedding seen in a proportion of infected individuals 23 . There is now a good understanding of SARS-CoV-2-host interactions, particularly relating to host proteins which are important for viral entry and infection. In this regard angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), neuropilin-1 (NRP1), FURIN, and Basigin (BSG) have all been implicated 24 . Conversely, lymphocyte antigen 6 complex, locus E (LY6E), interferon-induced transmembrane proteins-1 (IFITM1) and 3 (IFITM3), and interferon (IFN) type I receptors (IFNRA1 and IFNRA2) have been associated with a resistance to SARS-CoV-2 infection 2425, . ACE2 has been identified as the most predominant receptor pathway for multi-organ infection 26 . Within the GI tract, co-expression of ACE2 and TMPRSS2 facilitate infection of differentiated enterocytes in the small and large intestine 1621, . Selective expression of only TMPRSS2 or another key SARS-CoV-2 target receptor, neuropilin-1 (NRP1), is associated with low to no viral infection, indicating that cellular entry requires ACE2 co-expression 2728, . Co-expression of two or all these facilitatory proteins results in increasing viral loads within cells, highlighted by SARS-CoV-2 infection in lung cells enriched in NRP1, TMPRSS2 and the protease enzyme FURIN, compared to non-infected bystander cells 27 . Recently, a suite of SARS-CoV-2 targets involved in viral docking, processing and viral defense such as ACE2, TMPRSSR, and BSG have been identified as potential mechanisms of viral entry into the brain to cause downstream neurological manifestations 2429, . Expression of SARS-CoV-2 receptors and related proteins in gut epithelial cells For COVID-19 to have direct effects on the GI tract, we hypothesised that receptors for the virus are intrinsically expressed within the mucosal layer of cells lining the gut wall. To identify the expression pattern of SARS-CoV-2 receptors within different cell-types of the GI tract, we explored a single-cell RNA-seq database for mouse small intestinal mucosa 30 . Our focus was on gene expression for proteins implicated or known to be involved as COVID-19 receptors for efficient cell entry; ACE2, BSG and NRP1 28 , associated proteins involved in intracellular trafficking and breakdown; TMPRSS2, TMPRSS11A, TMPRSS11B, FURIN, CTSB and CTSL, and proteins associated with viral protection; LY6E, IFITM1-3, and IFNAR1-2. We identified that the genes encoding for all of these proteins are expressed within the intestinal epithelium 31 but that the Sars-Cov2 receptor, NRP1, is only expressed in serotonin-producing enterochromaffin (EC) cells. NRP1 protein expression is highly co-localized in the gastrointestinal wall in cells that express chromogranin-A (CgA), a marker of EC cells 32 . Peripheral serotonin in COVID-19 EC cell-derived serotonin (5-hydroxytryptamine, 5-HT) is by far the major source of peripheral, non-brain serotonin 33 and co-ordinates an array of non-neuronal roles including regulation of fat mass 34 and blood glucose levels 35 as well as coordinating signals from the gut microbiome to modify host physiology 36 37 , . Gut-derived serotonin plays a key role in GI function, including gut motility 38 for which abnormalities in serotonin levels are associated with various gut disorders, including irritable bowel syndrome 39 and gastroparesis 40 . EC cell serotonin is modulatory of gut transit, with a constipation phenotype occurring in models lacking EC cell-derived serotonin 40-42 , and an excess known to cause diarrhea 43 . A considerable number of COVID-19 patients report experiencing GI symptoms, with diarrhea being the most common 244, . Circulating plasma serotonin is significantly higher in patients with COVID-19 compared to healthy patients 45 46 , . Furthermore, plasma serotonin levels correlate strongly with increasing COVID-19 symptom severity, and is significantly higher in COVID-19 patients with diarrhea compared to those without diarrhea 45 . Peripheral serotonin and immune response The expression of SARS-CoV-2 receptors by EC cells highlights a potential mechanistic pathway not only underlying GI symptomology, but also increased severity of COVID-19 through its role in the innate and adaptive immune response. The roles of gut-derived serotonin and serotonin receptors as activators of immune responses and inflammation are well characterized. Innate immune cells responding to pathogens or infection, such as eosinophils, mast cells, natural killer cells, monocytes, macrophages and dendritic cells, all have the capacity to respond to circulating serotonin through serotonin receptors, while monocytes, macrophages, mast cells and dendritic cells can uptake and store serotonin via SERT 47 . Exogenous serotonin increases mast cell accumulation via 5-HT 1A receptors and uptake through SERT 48 . Mast cells release pro-inflammatory mediators such as histamine, proteases, cytokines and chemokines and facilitate the recruitment of other serotonin-responsive immune cells, such as eosinophils, natural killer cells, neutrophils and adaptive immune cells (dendritic cells and T-cells) 49 . Circulating serotonin is thought to contribute significantly to eosinophil infiltration, mediated via 5-HT 2A receptors 50 . Serotonin increases macrophage production of pro-inflammatory cytokines, such as interleukin-1 and interleukin-6, and enhances their phagocytic capacity 4748, . Additionally, serotonin promotes chemotaxis of monocytes to sites of inflammation by working through serotonin receptors expressed on alveolar macrophages 49 . The relationship between serotonin and inflammation is complex, as several pro-inflammatory cytokines and immune mediators, including interleukin 1β and interleukin 13 also appear to increase EC cell serotonin release 50-52 . Release of several pro-inflammatory cytokines by mature dendritic cells is enhanced in the presence of serotonin, through activation of 5-HT 4 and 5-HT 7 receptors 53 . This leads to the accumulation of immature cells at the site of inflammation and the secretion of inflammatory cytokines which influence downstream T-cell signalling. As such, serotonin signalling to dendritic cells can have longer-term consequences for immune function and inflammation, due to their ability to signal cells in the adaptive immune response. Adaptive immunity involves the destruction of invading pathogens through recognition of specific antigens by T and B-cells 54 . Immunological staining of primate intestinal mucosa shows serotonin containing cells are in very close proximity to, and in some cases in direct contact with both T-cell and B-cells 55 , suggesting a close relationship between these cell types may exist. Immune cells express a number of serotonin receptors, with 5-HT 7 expressed in naïve cells and 5-HT 1A and 5-HT 2A in activated T-cells 5657, . Similar to T-cells, adaptive immune B-cells responsible for antigen presentation and antibody production also contain 5-HT 1A receptors, which are upregulated following cell activation 57 . Expression of SERT has also been found on B-cells, indicating uptake and potential storage of serotonin may play a role in modulating B-cell activity 58 . This is also demonstrated in mouse models of colitis and intestinal inflammation, with IL-13 mediating an increase in EC cell number and mucosal 5-HT content, which is prevented in mice lacking IL-13 cytokine production and increased with exogenous IL-13 administration 5051, . This was also associated with an increase in infiltrating macrophages, consistent with the activity of serotonin on immune cells. Gut-derived serotonin worsens intestinal inflammation in animal models of gut inflammatory disorders 59 due to its effects on increasing macrophage infiltration and production of proinflammatory cytokines through a process dependent on nuclear factor κB signaling in immune cells 47 . The association between serotonin and inflammation is not limited to the gut, however, with alterations in serotonin levels having also been reported in allergic airway inflammation and rheumatoid arthritis patients 54 . The role of EC cell serotonin in modulating the immune system and peripheral inflammation is evidently complex, with serotonin both contributing to the immune defense system while also being increased by inflammatory cytokines. The latter may be a positive driver to further increase the activity of several immune cells as a means of overcoming infection, however, this may also contribute significantly to diseases associated with increased inflammation, as a heightened response to IL-1β is seen in EC cells derived from patients with Crohn’s disease 52 . Selective serotonin reuptake inhibitors and COVID-19 treatment Several recent studies indicate that the use of selective serotonin reuptake inhibitors (SSRI), normally prescribed to treat mental health conditions such as depression, as being highly effective in mitigating COVID-19 infection in vitro 60 61 , and reducing COVID-19 severity in humans 62-65 . Such drugs act to inhibit the function of the serotonin-reuptake transporter (SERT) protein. Two such studies demonstrated the ability for SSRIs to either prevent or reduce infection with SARS-CoV-2 in vitro, using human nasal epithelial cells 60 and human lung tissue 61 . Furthermore, a recent double-blind, placebo-controlled, randomized clinical trial found that fluvoxamine, a common SSRI, significantly reduced clinical deterioration of patients with COVID-19 compared to placebo 64 . Clinical deterioration, described as dyspnea, hospitalisation, or a decrease in oxygen saturation , occurred in 0 of 80 patients in the fluvoxamine group and 6 in 72 (8.3%) patients in the placebo group. In addition, the placebo group reported more GI symptoms (such as nausea and vomiting) compared with those in the fluvoxamine group 64 . Similar results were subsequently reported, in which a randomised, placebo-controlled, adaptive platform trial found that fluvoxamine treatment resulted in an absolute risk reduction of 5%, and a 32% relative risk reduction of hospitalisation due to COVID-19 62 . Other observational retrospective studies also indicated an association between SSRI (including escitalopram, fluoxetine, and paroxetine, and the SNRI venlafaxine ) use and a reduction in both intubation requirement and mortality among hospitalised COVID-19 patients 63 65-67 , . A open-label, randomized, outpatient, controlled trial assessed whether SSRI fluvoxamine in combination with; bromhexine, cyproheptadine (antagonist of 5-hydroxytryptamine), and niclosamid within 48-h of symptom onset of 1900 participates (995 participants completed the trial), would improve clinical deterioration outcomes by 9, 14, or 28 days 68 . Fluvoxamine, fluvoxamine and bromhexine, and fluvoxamine and cyproheptadine had significantly less clinical deterioration at all time points than standard care participants 68 . With combination treatments resulting in significantly decreased viral loads at day 5 of treatment, decreased levels of serum cytokines and lower incidence of long COVID-19 symptoms 68 . This suggests that SSRI treatment for COVID-19 may have significant benefits in terms of clinical outcomes. In this regard a recent meta-analysis of randomized controlled trials and observational studies found medium-dose fluvoxamine (100 mg twice a day) was associated with reduced mortality, hospitalization, and composite of hospitalization/emergency room visits, while a lower dose of fluvoxamine (50 mg twice a day) did not 69 . However, this was met with debate due to the confounding factors such as differences in the major mutated strains at different times, baseline risk of population progression, and vaccination rates 70 .The original authors subsequently agreed that factors beyond differences in fluvoxamine dose should be considered when interpreting there results and that further investigations, including the Fluvoxamine 100 arm of the ACTIV-6 platform trial would shed light on these issues 71 . Indeed, that randomized clinical trial of 1175 US participants demonstrated that Fluvoxamine, 100 mg twice daily, does not shorten the duration of symptoms in outpatient adults with mild to moderate COVID-19 72 . Therefore, in adequately vaccinated populations, there appears minimal evidence that SSRIs are beneficial for patient mortality in COVID-19. Long COVID-19 and serotonin. A recent study identified a link between lower plasma serotonin and Long-COVID and provides this as an explanation for multiple symptoms including hypercoagulation and cognitive decline 73 . However, there is debate regarding some of the measurements linking serotonin to long COVID with Anderson, et.al. insisting that the plasma serotonin levels were much higher than expected for platelet free plasma, potentially invalidating the insight of lower plasma serotonin in long COVID 74 . While the findings from this study remain to be replicated some interesting questions arise. SSRI usage would be expected to be associated with a reduction in plasma serotonin levels, given absence of plasma serotonin is observed in SERT KO mice and rats 7576, . This raises the interesting question of whether Long COVID is more prevalent in individuals consuming SSRIs. Indeed this has been addressed in a small study in which researchers from the Netherlands investigated the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of 95 patients with post-coronavirus disease 2019 (COVID-19) syndrome (PCS) 77 . They explored the neurobiological mechanisms underlying the response 77 . They found that all the patients showed improved well-being and decreased symptoms, and about two-thirds of the patients showed a good-to-strong response to SSRIs 77 , providing some preliminary evidence of SSRIs’ efficacy in treating PCS. Interestingly a retrospective study conducted using real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of long COVID 78 . Agonism of this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of Post-acute sequelae of COVID-19 78 . Such data provide a significant issue in aligning the proposed efficacy of SSRIs in benefitting long COVID, with the proposed observations that low plasma serotonin, which SSRIs should exacerbate, is a significant factor in worsening long COVID frequency and outcomes. We determine that either one of these outcomes is not correct, or that the observed effects do not occur at the level of plasma serotonin levels, but at a more nuanced cell or tissue-specific role that peripheral serotonin is playing in long COVID. This may include in immune cells, specific brain regions affected via the gut-brain axis or within platelets to alter thrombotic changes in this disorder. Conclusions Gastrointestinal symptoms are a well characterized component of COVID-19 and diarrhoea is the most common GI symptom in patients with COVID-19. In addition, circulating levels of serotonin are increased in COVID-19 and correlate with gastrointestinal symptoms such as diarrhoea. All circulating serotonin is produced by EC cells in the gut epithelium and EC cells are the only cell type in the gut wall to express all 3 receptors for the SARS-CoV-2 virus. Peripheral serotonin has well characterized effects on the immune system and immune responses and early data suggested that SSRIs may be efficacious in treating the symptoms and progression of COVID-19. However, it now appears that larger studies do not support this proposition, especially in those immunized to the virus. While gut serotonin is also implicated in long COVID, significant debate remains on this matter. Conflict of interest The authors have no conflicts of interest to disclose. Author Contributions All authors contributed to the original draft and the writing and editing. References1. Gavriatopoulou M, Korompoki E, Fotiou D , et al. Organ-specific manifestations of COVID-19 infection. Clinical and Experimental Medicine 2020; 20 : 493-506.2. Lin L, Jiang X, Zhang Z , et al. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut 2020; 69 : 997-1001.3. Mao R, Qiu Y, He J-S , et al. 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Information & Authors Information Version history V1 Version 1 21 May 2025 Peer review timeline Published Immunology & Cell Biology Version of Record 8 Mar 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords covid-19 enterochromaffin cell gastrointestinal sars-cov-2 serotonin ssri Authors Affiliations Daniel Thorpe 0000-0002-5644-6170 Flinders University College of Medicine and Public Health View all articles by this author Lauren Jones A Flinders University College of Medicine and Public Health View all articles by this author Alyce Martin M Flinders University College of Medicine and Public Health View all articles by this author Rosemary Amelia Coleman 0009-0009-1494-871X Flinders University College of Medicine and Public Health View all articles by this author Caitlin Allman Flinders University College of Medicine and Public Health View all articles by this author Rochelle Peterson A Flinders University College of Medicine and Public Health View all articles by this author Damien Keating J [email protected] Flinders University College of Medicine and Public Health View all articles by this author Metrics & Citations Metrics Article Usage 621 views 201 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Daniel Thorpe, Lauren Jones A, Alyce Martin M, et al. 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