key: cord-0753269-x87qh1xb
authors: Elkazzaz, M. R.; Esam-Eldin Abo-Amer, Y.; Ahmed, A.; Hayadar, T.
title: 13 cis retinoic acid improved the outcomes of COVID-19 patients. A randomized clinical trial
date: 2022-03-08
journal: nan
DOI: 10.1101/2022.03.05.22271959
sha: 8346b4a3738669eeebb6e519f64f793c8c4360ff
doc_id: 753269
cord_uid: x87qh1xb

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. Given the urgency of the COVID-19 pandemic, the clinical investigation of approved drugs is a promising alternative to find a timely effective treatment. In this randomized trial, we investigated the activity of both oral and aerosolized 13 cis retinoic acid in the treatment of SARS-COV-2 added to standard of care treatment in patients with COVID-19 versus standard of care treatment alone. This was a randomized controlled trial conducted at Kafrelsheikh Universitys Quarantine Hospitals, Egypt. After obtaining informed consent, forty patients with a confirmed diagnosis of COVID-19 were enrolled in the study. They were randomly assigned to one of two groups: Group I; 20 patients received aerosolized and oral 13 cis retinoic acid plus standard of care treatment (13 cis RA group) and Group II; 20 patients received only standard care treatment as a control group. The two groups were age and gender matched. There was no statistically significant difference between them in any of the baseline characteristics or laboratory parameters. The results showed that there was a high significant difference between the two groups regarding intensive care unit (ICU) admission, mortality and improvement (P<0.05). Only 10.52 % of patients in the 13 cis retinoic acid group needed ICU admission compared to 28.57 % in the control arm. There was no mortality in the 13 cis retinoic acid group, whereas about 14.35% were died in the group II. All patients who received 13 cis retinoic acid noticed a high improvement (P<0.001), and the mean value for clinical improvement was 16 days. There was no significant difference regarding the laboratory parameters before and after 14 days of treatment in the group of patients received the standard of care treatment (P=0.66). Univariate logistic regression analysis showed overall mortality was significantly related to the patients age, serum ferritin, C-reactive protein, oxygen saturation, the presence of diabetes mellitus, obesity, and abdominal pain. We conclude that 13 cis retinoic acid is a promising drug in the treatment of patients with COVID-19 infection, when added to the standard of care treatment.

been elucidated at the atomic level, and the efficiency of ACE2 usage was found to be a key determinant of COVID-19 transmissibility (5). As the effective immune response in viral infections depends on the activation of cytotoxic T cells that can clear infection by killing virus-invaded cells, boosting the numbers and function of T cells in COVID-19 patients are needed for successful recovery. CD8 T cells produce very important and effective factors, such as Interferon gamma (IFN-g) and granzyme, to clear MERS-CoV (6). Also, low circulating lymphocyte counts in 82.2% of COVID-19 cases were showed by a recent study (7). A COVID-19 infects macrophages, and after that macrophages present COVID-antigens to T helper (Th0) cells. This process leads to T cell stimulation and activation, including the production of cytokines associated with the different T cell subsets (i.e., Th1, Th2, and Th17), followed by a huge release of cytokines for immune response amplification. The continued secretion of these immune factors due to viral persistence has a negative and unwanted effect on Th0 and cluster of differentiation 8 (CD8) T cell activation by inhibiting IL12 and IFN-g production (8). However, CD8 T cells produce very effective mediators, such as IFN-g and granzyme, to clear COVID-19. It is still unclear whether long-term or short-term protective antibodies are produced during neutralizing antibody production against COVID-19 (2). Attachment of COVID-19 to ACE2 on the host cell through S protein leads to the appearance of viral genomic ribonucleic acid (RNA) in the cytoplasm. An immune response to double-strand RNA (ds RNA) can be partially generated during COVID-19 replication. Toll-like receptor 3 (TLR-3) sensitized by dsRNA and cascades of signaling pathways (IRFs and NF-kB activation) are activated to produce type I IFNs and proinflammatory cytokines. Type I Interferon (IFNs) is important to support the release of antiviral proteins for the protection of uninfected cells. Accessory proteins of COVID-19 can interfere with TLR-3 signaling and bind the dsRNA of COVID-19 during replication to inhibit TLR-3 induction and activation and evade the immune response. Cell-virus interactions lead to high production of immune mediators. The secretion of large quantities of chemokines and cytokines is promoted in infected cells in response to MERS-CoV infection. These chemokines and cytokines in turn recruit lymphocytes and leukocytes to the site of infection (8). In a recent study of 522 COVID patients and 40 healthy controls from two hospitals in Wuhan, China showed a negative correlation between T cells numbers and the serum IL6, IL-10, and TNF-a concentration, on the other hand, patients in decline period showing reduced IL-6, IL-10, and TNF-a concentrations and restored T cell counts (9). Significantly higher levels of the exhausted marker programmed cell death protein (PD-1) in comparison to health controls, were expressed by T cells from COVID-19 patients. Moreover, as the patients progressed from prodromal to overtly symptomatic stages, it was reported that increasing PD-1 and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) expression on T cells, which further indicates T cell exhaustion. T cell exhaustion is a progressive loss of effector function due to prolonged antigenic stimulation, which is a characteristic of chronic infections (9). COVID-19 is World's biggest challenge since World War II, says United Nations (UN) Secretary General. The emergence of coronavirus disease-2019 (COVID-19) pandemic and its catastrophic consequences resulted in extreme demand for treatment. This article investigates the potential effect of 13 cis retinoic acid , a potential metabolite of Vitamin A in the treatment of SARS-CoV-2 owing to its ability to downregulate angiotensin Converting Enzyme (ACE2) receptor and angiotensin II expression and its impact on immunity, androgen receptors, inflammatory IL-6, thrombin and respiratory diseases. Moreover, our recent molecular docking based analysis showed that spike protein Receptor Binding Domain (RDB) of COVID-19 strongly and efficiently binds to STRA6 receptor, definitely to the RDB vital residues of RBP-binding motif located in STRA6 receptor(10). STRA6 receptor expressed in many organs and immune cells, upregulated by retinoic acid 6 (STRA6), which was the first protein to be identified in a novel category of proteins, cytokine signaling transporters, due to its ability to function as both a cell surface receptor and a membrane protein that binds to retinol binding protein facilitating cellular uptake of retinol (10). The primary ligand of STRA6 (vitamin A/retinol) was shown to be drastically reduced during COVID-19 infection, which support the role of retinoic acid in COVID-19 treatment (10).

We conducted a randomized interventional comparative trial a 1:1 ratio randomized (Two groups) using a computerized random number generator using simple randomization with an equal allocation ratio, comparing and investigating the efficacy of aerosolized and oral 13 cis retinoic acid plus Standard Therapy vs Standard Therapy including for treating COVID-19 among hospitalized adults with respiratory illness admitted to Kafrelsheikh University's Quarantine Hospitals with suspected or confirmed COVID-19 in the period between June and August 2020 . The trial was limited to include only laboratory-confirmed cases (Adult patients with COVID-2019 infection confirmed by PCR; Absolute value of lymphocytes < 1.0x 109/L). According to WHO interim guidelines released on March 13, 2020. Adults (aged ≥ 18 years) who had been hospitalized for less than 48 hours, patients were classified in to; i) Mild cases: represented patients with uncomplicated upper respiratory tract viral infection, ii) moderate cases: represented patients with pneumonia but without need for supplemental oxygen; iii) Severe respiratory failure: within 48 hours and requires admission to ICU and severe respiratory failure :was defined as PaO2/FiO2 < 200 mmHg and was supported by positive pressure mechanical ventilation (including noninvasive and invasive mechanical ventilation, PEEP>5cmH2O). This clinical trial was approved by the Research Ethics Committee of the Faculty of Medicine , Kafrelsheikh University. Informed and signed consent was obtained from patients or legally authorized representatives. The study was registered on clinicaltrials.gov with Clinical Trials.gov Identifier NCT04353180, It worth mentioning that this clinical trial of aerosolized 13 cis retinoic acid therapy was initially submitted on April 10, 2020, met QC Criteria on April 17, 2020, and was first published on April 20, 2020 (https://clinicaltrials.gov/ct2/keydates/NCT04353180).

In this study, a total of forty patients were included, and divided randomly in two groups as following: Group I;The 13 cis retinoic acid : This group included 20 patients who received aerosolized 13 cis retinoic acid for 14 days divided doses increased gradually in concentration and oral 13 cis retinoic acid with constant concentration (one dose increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy) plus oral 13 cis retinoic acid 20 mg/day added to the standard therapy adopted according to treatment protocol by the national MOH for 14 days. Group II; This group included 20 patients who received only the standard therapy adopted according to treatment protocol by the national MOH for 14 days.

The Egyptian Ministry of Health (MOH) adopted a standard of care treatment protocol for COVID-19 patients. It included (Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily and invasive mechanical ventilation with hydrocortisone for severe cases if PaO2 < 60 mmHg, O2 saturation < 90% despite oxygen or noninvasive ventilation, progressive hypercapnia, respiratory acidosis (pH < 7.3), and progressive or refractory septic shock.

The history of all patients and also the appropriate clinical examination were done prior to the treatments. All the participants were subjected to thorough history taking and full clinical examination including age, gender, weight and height measurements, and calculation of body mass index (BMI); medication history; and investigations in the form of complete blood picture and computed tomography of the chest (CT chest).

Statistical analysis: Data were analyzed statistically using R programming, and were expressed the mean ± standard deviation (SD) or percentage (%). For normality investigation, the Shapiro-Wilks test was used for numerical data, and the Chi-square test (χ2) was used for categorical data. The means of samples with normal distribution and of sufficient size were compared by Student's t test and one-way ANOVA. Differences between abnormal scatterings and the medians were compared by Mann-Whitney U and Kruskal-Wallis test. A p value < 0.05 was considered significant.

The clinical examinations of all patients in two groups were done, and the results showed that, Persistent fever was found in 26.3 %, intermittent fever was present in 37%, cough was present in 68.5 %, anosmia was found in 32 %, Abdominal pain and diarrhea was present in 22% of the included patients. With regards to oxygen saturation, Oxygen saturation between 95 and 90 was present in 52.63%, 90-85 in 15.7%, and less than 85 in 31.57% of all the participants. The computed tomography chest scans were normal in 31.57%, ground-glass opacities in 21.05%, confluent opacities in 15.5%, consolidation in 15.78%, and extensive consolidation in 15.7%. (Table1) showed that, there were no significant difference between both groups regarding all laboratory parameters Before treatment. The results revealed that in the first group of patients who received 13 cis retinoic acid , there was a highly significance difference before and after 14 days regarding laboratory parameters ( Table 2) . On the other hand, in the patients group who received standard of care treatment, there was no significance difference after 14 days of treatment compared to at the start of treatment ( Table 3) . The results of laboratory examination after 14 days of treatments revealed a high significance difference between the two groups (Table 4) . With regards to the clinical outcomes, in the 13 cis retinoic acid group, only 10.52 % of patients needed intensive care unit (ICU) admission compared to 28.57 % in the other group. In the 13 cis retinoic acid group, duration to achieve negative PCR was 13.36± 1.49 compared to 23.85±4 in the other group.

.The 13 cis retinoic acid group had a mean of 16.3±4.5 days to show clinical improvement and 21.57±4.97 days to hospital discharge, whereas the control group had a mean of 25.23±4.72 to clinical improvement and 33.04±2.72 to hospital discharge (P < 0.01). After 28 days, there was significant difference between the two groups regarding the clinical outcome (P < 0.05). Complete recovery was achieved in all cases (100%) of the 13 cis retinoic acid group, and there were no deaths in this group, While 52.38 % of patients who treated with standard of care treatment were recovered, 14.28 % mild, 4.76 % moderate 14.35% were died (Table 5) . By logistic regression, the overall mortality was not significantly associated with 13 cis retinoic acid therapy. On the other hand, it was significantly related to the C-reactive protein (P<0.001), D-dimer (P<0.001), ferritin (P<0.001), Oxygen saturation (P<0.05), obesity (P<0.001), the presence of diabetes mellitus (P<0.001), and abdominal pain and diarrhea (p<01) ( Table 6 ). (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 8, 2022. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

The emergence of new SARS-CoV-2 mutants and recombinant strains unfortunately reduces the effectiveness of vaccines in the fight against the pandemic. For this reason, it is necessary to return to the beginning every 5-6 months in the fight against the epidemic. Although there is a vaccine, the number of patients who have had severe COVID-19 and have died is not All rights reserved. No reuse allowed without permission.

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small. Therefore, the importance of drug development and drug repositioning options is increasing in the fight against COVID-19. The development of effective treatment options against COVID-19 will only be possible with a clear understanding of the pathogenesis of COVID-19. Retinoic acid metabolism is defective in COVID-19 (cytokine storm), sepsis, ARDS and SIRS(10). Therefore, reconstitution of the signaling of retinoid may prove to be a valid strategy for COVID-19 management. Vitamin A is of special interest in the field of infectious diseases, especially for pulmonary infections(11). It is crucial for the development of normal lung tissue and tissue repair after injury due to infection [11]; therefore, it may play a role in recovery after severe COVID-19 pneumonia. Vitamin A has immune regulatory functions [12] and positively affects both the innate and adaptive immune cell response [13, 14, 15] . Several studies revealed increased risks of severe illness due to respiratory tract infections in vitamin A-deficient individuals, whereas vitamin A supplementation can reduce the risks of severe illness and death, as was shown for children with measles and in influenza pneumonia in mice models [16] [17] [18] . The occurrence of severe infections and inflammation can also negatively affect vitamin A status, and several mechanisms such as urinary loss of vitamin A [19], decreased vitamin A hepatic mobilization [20], and reduced intestinal vitamin A absorption [21] . A recent study showed In hospitalized patients, the vitamin A plasma levels of critically ill patients were significantly reduced compared to patients with moderate disease (p < 0.05) (22) . In patients with COVID-19, plasma levels of vitamin A decrease during acute inflammation, and severely reduced plasma levels of vitamin A are significantly associated with ARDS and mortality (35) . Serum retinol levels were low in patients with severe COVID-19(36). Therefore, it is not surprising that ATRA exhibited antiviral effect against SARS-CoV-2 3CLpro cell culture (58) In addition to 13 CIS retinoic acid was found to protect against COVID-19 disease severity (59, 60) . 13 cis retinoic acid ( isotretinoin) , along with other retinoids, was found to inhibit SARS-CoV-2 replication in Vero E6 cells. According to Shoemark et al, 13 cis retinoic acid ( isotretinoin) may bind to the SARS-CoV-2 spike protein at the SARS-CoV-2 spike fatty acid site, influencing the conformational changes required for receptor binding and stabilising the spike protein's locked ACE2 conformation. In this way, isotretinoin may influence viral entry, especially in the early stages of infection (74).In our clinical study we selected 13 cis retinoic acid to be our candidate of investigation owing to its ability to inhibit Angiotensin II,IL-6, DHT, Platelet aggregation, thrombin production and ACE2. In addition to its ability to induce CD4 cells, IgA antibodies. 13-cis-retinoic acid is a member of the retinoid class of compounds which are structural analogues of vitamin A and include both natural and synthetic compounds. Naturally occurring retinoid compounds such as all trans retinoic acid ("ATRA"), 9-cis -retinoic acid, trans 3-4 didehydroretinoic acid, 4-oxo retinoic acid and retinol are pleiotrophic regulatory compounds that influence a large number of inflammatory, immune and structural cells(38). Here 13 cis retinoic acid was formulated as a powder aerosol, and its delivery to the lungs of COVID-19 patients was studied as well as oral 13 cis retinoic acid with the aim to explore its efficacy in treating COVID-19 . This clinical study is the first clinical submitted on April 10, 2020, met QC Criteria on April 17, 2020, and was first published on April 20, 2020 (https://clinicaltrials.gov/ct2/keydates/NCT04353180). According to our clinical findings, 13 cis retinoic acid, a synthetic vitamin A analogue, is effective in the treatment of COVID-19 with no mortality. All patients who received 13 cis retinoic acid noticed a high improvement (P<0.001), and the mean value for clinical improvement was 16.3±4.5 days. There was no significant difference regarding the laboratory parameters between before and after 14 days of treatment of patients had the standard of care treatment (P=0.66). After treatment with Aerosolized and oral 13 cis retinoic acid there were significant decrease in Ang II level. Most of our patients were obese, conversely, adipose tissue is an important source of angiotensin, and obesity results in increased systemic RAS. ACE-Ang-II-AT1R axis, which has proinflammatory, profibrotic, prothrombotic, and vasoconstrictive effects, is potential mechanism of more severe SARS-CoV-2 infection(39). Plasma Ang II is associated with body weight, decreases during weight loss, and is associated with markers of insulin resistance in obese subjects with T2D(39). This agrees with our study, which revealed that obesity and diabetes were found to be risk factor for COVID-19 severity and mortality. Also, comes in agreement with many studies, which found that obesity is associated with severe disease and mortality in patients with coronavirus disease 2019 (COVID-19)(40,41,42,43). In the present study, TNF-a concentration was significantly higher in the 13 cis retinoic acid group in comparison to the other group after 14 days of treatment.this agrees with a recent study, which included 522 COVID patients and 40 healthy controls from two hospitals in Wuhan, China, which showed a negative correlation between T cells numbers and the serum IL6, IL-10, and TNF-a concentration, on the other hand, patients in decline period showing reduced IL-6, IL-10, and TNF-a concentrations and restored T cell counts (9). Severe patterns of COVID-19 ARDS are characterized by thrombin burst and consequent coagulation activity(66).It was documented that retinoic acid significantly inhibit thrombin activity (65 ) . This comes in agreement to our study, which revealed that thrombin activity significantly decreased in both groups, however, the reduction was significantly in the13 cis retinoic acid group than the other group. The reduced vitamin A plasma levels were found to be associated with higher levels of inflammatory markers of acute SARS-COV-2 infection (CRP,ferritin). So,this comes in agreement to our study, which revealed that higher levels of inflammatory markers of acute SARS-COV-2 infection (CRP,ferritin) were significantly decreased after treatment in both groups, however, the reduction was significantly in the13 cis retinoic acid group than the other group. Vitamin A deficient Mice has decreased numbers of IgA+ ASCs in site of the small bowel lamina propria. Consequently, mice deficient in retinoic acid(RA) precursor vitamin A lacked IgA antibodies-secreting cells in the small intestine (85, 86) . In addition, RA is considered to possess an activity of IgA isotype switching (87). Furthermore, retinoic acid, performing as a highly specific IgA isotype switch factor, cooperates with transforming growth factor beta 1 (TGFb1) to enhance the overall IgA response(88). Therefore, it is not surprising that isotretinoin (13-cis-retinoic acid) repair the function of IgA antibodies in submucosal pustular dermatosis patients(92). This agrees to our results, which showed that IgA significantly increased in both groups, however, the increase was significantly in the13 cis retinoic acid group than the other group.

Our study showed that decreased serum lymphocytes and the cholesterol levels of COVID-19, which responded to the treatment and increased significantly in both groups, however, the increase was significantly in the13 cis retinoic acid group than the other group.

Also,it was founded that decreased serum lymphocytes responded to the treatment and increased (134 ) .Also, Researchers from Wenzhou, China looked at clinical laboratory investigations in patients with COVID-19. They showed a marked reduction in the cholesterol levels of COVID-19(93). Also, during the early stages of infection, it was found that cholesterol levels decline rapidly and increase as the patient starts to recover. Intracellular cholesterol level is regulated by two competing pathways, cholesterol uptake and efflux, and ATP-binding cassette transporter (ABCA1) plays a major role in the cholesterol efflux pathways. Retinoic Acid induces macrophage cholesterol efflux and inhibits atherosclerotic plaque formation in apoEdeficient mice, was reported in a study(95). All trans-retinoic acid (ATRA) and 13-cis-RA may play an important role in immune response(97). Increased ANG II levels in COVID-19 has been reported (44) . A study by Liu and colleagues (2020), observed markedly high ANG II levels in COVID-19 patients when compared to healthy controls. Many studies found that plasma ACE 2 increased in COVID-19 patients (48,49,50). In our study plasma ACE2 was significantly decreased after treatment in both groups, but, it was significantly reduced after treatment in the13 cis retinoic acid group than the other group. Dihydrotestosterone (DHT) was found to be a potent activator of TMPRSS2 (118) and this activation may be followed by processing and activation of COVID-19 spike protein to bind to its ACE2 receptors in the lung, kidney, other organs. A study demonstrated that 13-cis-retinoic acid competitively and reversibly inhibits dihydrotestosterone (124) . Also, in the current study Dihydrotestosterone (DHT) was significantly decreased after treatment in the13 cis retinoic acid group only, also, it was significantly reduced after treatment in the13 cis retinoic acid group than the other group. AngII via AT1 receptors upregulates many proinflammatory genes, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL6) (54), but 13-cis-RA specifically downregulated the AT1 protein in a dose-and time-dependent manner. Deregulation of the AT1 expression results in reducing AngII-mediated intracellular calcium release. Similarly with receptor downregulation, treatment with 13cRA resulted in a significant reduction in AT1 mRNA (55) . In our study soluble ACE2 was found to be decreased after treatment with 13 cis retinoic acid . This is similar to a study, which investigated the effects of the 672 clinically approved drugs in CMAP found that (13cRA) is the strongest down-regulator of ACE2 suggesting its therapeutic potential in preventing the entry of COVID-2019 to the host cell (56) . Serum interleukin-6 is one of the most important factor implicated in cytokine storm and is an indicator for severity in patients with SARS-CoV-2 infection (57) . Our results agreed many results in which 13 cis retinoic acid (Isotretinoin) therapy significantly decreased the secretion of IL-1b, IL-6, IL-10, and IL-12p70 by monocytes from acne patients in response to P. acnes compared with pretreatment levels. Cytokine secretion decreased as early as 1 week after 13 cis retinoic acid(isotretinoin) therapy and continued to decrease through 20 weeks of therapy (58). A recent study reported that retinoic acid have preventive effects on pulmonary fibrosis by inhibiting IL-6-dependent proliferation and TGF-b1-dependent trans differentiation of lung fibroblasts (59) . Also, another study reported that 13-cisretinoic acid and other retinoid analogs inhibit IL-1-induced IL6 production and that this effect is analog-specific and, at least partially, transcriptionally mediated (60) . This is agreement to our study, which revealed that IL-6 were significantly reduced after the treatment. The previous results, explains our results, which revealed that, mortality and need of ICU were significantly lower and also, the mean duration to clinical improvement and hospital discharge were lower in the13 cis retinoic acid. Lastly, we conclude that 13 cis retinoic acid, will be a promising drug in the treatment of COVID19.

The small number of patients and the fact that the study was conducted in a single center. Therefore, we need multicenter studies on a large patient scale. Due to the potential teratogenic effect of 13-Cis retinoic acid, pregnant female patients were not included in the study. RAs are the most potent teratogenic agents. RA is not given to a patient who is planning pregnancy regardless of the dose, even 6 months before. and pregnancy is prevented for 6 months, sometimes up to a year, after the treatment is stopped. The reason for this is the understanding that RAs are stored in adipose tissue. Pregnancy allowed after RA's are cleared from the body

The authors report no conflict of interest in this work. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 8, 2022. ; https://doi.org/10.1101/2022.03.05.22271959 doi: medRxiv preprint

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