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REVIEW ARTICLE |
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Year : 2020 | Volume
: 4
| Issue : 5 | Page : 25-32 |
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Mini-review on recent update on coronavirus disease 2019: Clinical outcome and largest pharmaceutical companies
Pooja Shivappa1, Ashfaque Hoosain1, Padma G.M. Rao2
1 Department of Microbiology & Immunology, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE 2 Department of Clinical Pharmacy & Pharmacology, RAK College of Pharmaceutical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
Date of Submission | 03-May-2020 |
Date of Acceptance | 29-Jun-2020 |
Date of Web Publication | 13-Aug-2020 |
Correspondence Address: Dr. Pooja Shivappa Rak Medical and Health Sciences University, Ras Al Khaimah 11172 UAE
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/bbrj.bbrj_67_20
The current worldwide outbreak of the novel coronavirus disease 2019 (COVID-19); the pathogen called SARS-CoV-2; previously 2019-n CoV), which originated from Wuhan in China and has now spread worldwide. This current review includes information regarding treatment and, clinical outcomes of COVID-19 patients with diabetes, liver injury, rheumatic diseases, respiratory issues, kidney problems, and breast malignant growth. The various international companies supporting the findings in the treatment/vaccine for COVID-19. There are currently no specific antiviral drugs, however, several antiviral drugs and repurposed drugs are under serious scrutiny. We encourage all readers to continue to assess clinical data as it emerges and shares their experience within our community in a well-controlled and, adequately powered fashion.
Keywords: Coronavirus disease 2019, clinical outcomes, pandemic, SARS-CoV-2, treatment
How to cite this article: Shivappa P, Hoosain A, Rao PG. Mini-review on recent update on coronavirus disease 2019: Clinical outcome and largest pharmaceutical companies. Biomed Biotechnol Res J 2020;4, Suppl S1:25-32 |
How to cite this URL: Shivappa P, Hoosain A, Rao PG. Mini-review on recent update on coronavirus disease 2019: Clinical outcome and largest pharmaceutical companies. Biomed Biotechnol Res J [serial online] 2020 [cited 2022 May 19];4, Suppl S1:25-32. Available from: https://www.bmbtrj.org/text.asp?2020/4/5/25/292089 |
Introduction | |  |
The current worldwide outbreak of the novel coronavirus disease 2019 (COVID-19), now known as the severe acute respiratory syndrome coronavirus 2 (SARSCoV2), originated from Wuhan in China,[1] has now spread to 210 countries and territories around the world and two international conveyances. As of April 21, 2020, over 3,014,895 confirmed cases, 207,931deaths, and 8,88,543 recovered cases attributable to this disease have been reported.[2] In wake of this global health crisis, stringent public health measures have been implemented to curtail the spread of COVID-19.[1] Research groups have found that SARS-CoV-2, which is the virus causing COVID-19, uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells and is mainly transmitted through the respiratory tract. It is imperative to demonstrate the progressive spreading from person to person, with many cases reported worldwide. Clinical symptoms of COVID-19 patients include fever, cough, exhaustion, diarrhea, and gastrointestinal side effects. Elderly people and people with diseases are highly prone to get infected and are vulnerable to outcomes associated with acute respiratory distress syndrome and cytokine storm. There are currently no specific antiviral drugs; however, several antiviral drugs and repurposed drugs are under intense scrutiny.[3]
The current stage, preparedness, transparency, and sharing of information are crucial to risk assessments and beginning the outbreak control activities. This information includes reports from treatment/vaccine, clinical outcomes from pandemic sites, and laboratories supporting the investigational drugs. This paper aggregates and consolidates the clinical management strategies.
Methodology | |  |
Study design
Using the methodological framework suggested by Arksey and O'Malley,[4] “the following five steps were followed to conduct this scoping review:
- Objective and strategy: identifying a clear research objective and search strategies
- Content search: identifying relevant research articles
- Content selection: Selection of research articles
- Data representation: extraction and charting of data
- Analysis and evaluation: analyzing, reporting, discussing, and summarizing the data.”
Study methodology
The current article is a review of the existing literature on treatment and clinical trials relevant to the COVID-19 pandemic by various drug companies. A search of the PubMed and Google Scholar was undertaken using the search terms “COVID-19,” “review, treatment, and clinical outcome” in various permutations and combinations. We also searched for referenced papers to identify further studies. A total of 188 review papers on COVID19 out of which 17 papers extending back to the last year using MeSH terms. Out of 17 papers, one was excluded because it was available in the German language while 16 included because they dealt with updates on COVID-19.
Careful literature searches were conducted by Rollin et al.,[5] on 34 largest pharmaceutical companies through Google Scholar on the basis of each company's updates to COVID19, related to drug therapy and preclinical trials, that will help healthcare systems.
Results | |  |
For this review article, 188 papers on COVID19 were reviewed out of which 17 papers covering the last 1 year, COVID19, review, treatment, and clinical outcomes using MeSH terms. A randomized multicenter-managed scientific trial through a few biotechnology and pharmaceutical groups is presently underway to evaluate the efficacy and safety in patients with COVID-19. The present review is based on the current research on the benefits of understanding the clinical outcome and various companies trial on to the treatment/vaccine of COVID-19
Literature-based on treatment and clinical outcomes related to updating on COVID-19
Treatment
At present, no viable antiviral treatment or immunization is accessible for COVID-19. First-line treatment for fevers incorporates antipyretic drugs.[6] Medications against COVID-19 suggestions are arranged in four classes: antiviral and anti-inflammatory drugs, antimalarial drugs, traditional Chinese drugs, and other treatments/drugs. All examined medicines, despite the fact probability viable against COVID-19, need either proper drug development or clinical trial for clinical use.[7] At present, the advantage of lopinavir and ritonavir tablets in the treatment of coronavirus is not self-evident. The course of treatment is long and inclined to cause liver and kidney damage. Those with respiratory side effects were treated with interferon nebulized inward breath and Chinese medication antiviral treatment.[8]
Remdesivir
This (GS-5734™) is an antiviral medication that is a potential agent for COVID-19 worldwide, multisite clinical preliminaries. At present, accessible proof on the antiviral impacts of remdesivir against coronaviruses is essentially found onin vitro andin vivo examinations (remembering some for a synthetically related compound, GS-441524™), which have exhibited to great extent ideal discoveries.[9]
Chloroquine and hydroxychloroquine
Antimalarial agents with mitigating anti-inflammatory and immunomodulatory activity have increased critical enthusiasm as a potential restorative alternative for the administration of COVID-19.[10]
Lopinavir/ritonavir
Lopinavir, an human immunodeficiency virus (HIV)-1 inhibitor of protease controlled in a fixed-portion mixture with ritonavir (LPV/r), a potent inhibitor of CYP3A4 “helps” lopinavir = fixing. Lopinavir appears to obstruct the fundamental protease of SARS-CoV-1, hindering viral replication.[11] There are 10 continuous enrolled clinical trials in China, Korea, Thailand, and Hong Kong assessing LPV/r as monotherapy or in blend with different antivirals (e.g., ribavirin and interferon beta-1b) or conventional Chinese medication for the treatment of COVID-19. Certifiable information for the treatment of COVID-19 with LPV/r is developing.[12]
Nitazoxanide
Phase 2 randomized controlled trials with nitazoxanide in patients with severe acute respiratory diseases requiring hospitalization prevalently reduced respiratory infections. Even though thein vitro activity of nitazoxanide against SARS-CoV-2 is empowering, more information is expected to decide the management of COVID-19.[13]
Tocilizumab
Immunotherapy with tocilizumab is recorded as a treatment choice for serious or critical instances of COVID-19 with elevated IL-6; this is reported in the Seventh Release of the National Health Commission of the People's Republic of China COVID-19 Diagnosis and Treatment Guide.[14]
Information on corticosteroids as an adjunctive consideration for severe coronavirus. The ongoing articulation of the agreement from the Chinese Thoracic Society suggests a lower dose of ≤0.5–1 mg/kg methylprednisolone daily for ≤7 days in selected patients, Consideration on the basis of risks and advantages.[15]
Favipiravir
RNA-dependent RNA polymerase inhibitor with a wide range of antiviral actions exhibited high EC50 (diminished intensity) against SARS-CoV-2; however, it was powerful in ensuring mice against Ebola infection despite comparatively high EC50 values. NCT04273763 is presently being assessed in clinical trials for patients with COVID-19. This drug is not FDA approved or accessible in the United States.[10] Fujifilm's influenza drug favipiravir is being tested to treat COVID-19[16] (Fujifilm's influenza). Additional medications that are under examination incorporate emtricitabine/tenofovir and ribavirin.[17],[18]
Oseltamivir and baloxavir
Antiviral drugs against influenza, significant consideration to oseltamivir, and a lesser degree to baloxavir, as potential alternative treatment for COVID19. This was exacerbated by the underlying report from China.[19]
Azithromycin
Based on the study report on patients with infection of COVID-19 were treated with hydroxychloroquine, and the combination of hydroxychloroquine with azithromycin was related with a higher likelihood of demonstrating a negative reverse transcriptase-polymerase chain response to infection from the third day after the start of the treatment, in compared to the first day and with the individuals who got hydroxychloroquine alone.[20]
Clinical outcomes of coronovirus disese 2019-treating patients with diabetes, liver injury, rheumatology, respiratory issues, kidney problems, and breast malignant growth
Diabetes mellitus
An increase in incidence and mortality due to COVID-19 is associated with diabetes mellitus. Persistent exacerbations, increased coagulation, decreased immune response, and possible direct damage to the pancreas SARS-CoV-2 are the most important pathological conditions that arise due to this association. Compared with ACE inhibitors or angiotensin receptor blockers in people with diabetes and COVID-19, clinical evidence does not suggest to replace angiotensin. Precautions must be taken to avoid cases of hypoglycemia that may be associated with the use of chloroquine to treat COIVD-19 in people with diabetes.[21]
Liver injury
There is increasing evidence of continuous episodes of liver damage in patients with COVID-19, regularly showing an increase in serum aminotransferase. In all cases, patients occasionally have impaired liver function and distinct intrahepatic cholestasis, unless previously noted liver infections. COVID-19's hidden liver injury system includes psychological stress, systemic reactions to inflammation, drug toxicity, and previous liver disease movements. However, there is currently insufficient evidence of hepatocytes infected with SARS-CoV-2 or liver damage associated with COVID-19 infection.[18]
Rheumatic diseases
Routine antirheumatic drugs used in the treatment of COVID-19. The hypothesis for the condition, perhaps the immediate response to antivirals is focusing for a safer response. Antimalarial drugs commonly used for arthritis can adjust lysosomal proteases that mediate the viral division of the cell and show adequacy in treating the disease. As seen in previous coronavirus contamination, cytokine exacerbation has been observed in patients with fatal complications. Anti-IL-1 and anti-IL-6, in extreme cases and the use of tocilizumab, can impair cytokine repression. Barisitinib has antiviral and sedative properties. Checkpoint inhibitors, anti-CD200, and anti-PD1 may play a role in the treatment of COVID-19. Arthritis patients should continue taking immunosuppressants so that they can continue normal treatment, avoid social contact, forest pollution, and stop immunization if the disease occurs. A national and worldwide vault is being established to collect information on patients with arthritis who have COVID-19.[22]
Lung disease
The management of COVID-19 is unclear, but consent is moving toward a biphasic approach. During the main period of the disease (7–10 days after the onset of symptoms), the effect of the virus is significant, and one has the opportunity to plan antiviral treatment. During the second inflammatory phase of the disease, immunomodulating strategies (e.g., glucocorticoids or anticytokine drugs) may be considered. This last stage is described as an improvement in the lung condition associated with an increased need for oxygen and sometimes a sign of impaired hemophagocytosis.[3],[23],[24] TRPV1 connection (efferent/efferent neurons) of the lung TRPV1 cells are pain cytokines throughout the pulmonary system and generally control the processes associated with rapid progression of the disease. TRPV1-mediated repair mechanisms, including pulmonary neurofilaments, control inflammation, and immune signaling activity, lead to a reduction in mortality and improvement in the overall outcome. Besides, in the clinical setting of malignant neoplasm, TRPV1-positive pulmonary pathways in patients with COVID-19, currently, the most effective TRPV1 agonist, resiniferatoxin is explored for its use as a potential clearance operator.[25],[26],[27] COVID-19 presents as acute respiratory disease and pneumonia. However, the adult population is at higher risk of infection by SARS-CoV-2, which can also cause aging in newborns and children.[3] Further, abnormal infections of inpatients and humanitarian workers and viral infections by nondisease carriers have been estimated. The chest image results for patients with pneumonia include glass opacities with bilateral lesions. Patients with mild cases have more such lesions. Disease severity may be linked to COVID-19 results. So far, the treatment has not been successful. Clinical trials are underway to investigate the therapeutic effect of various drugs including chloroquine. Currently, mixed infection control interventions are the best way to prevent the spread of SARS-CoV-2.[3],[28],[29]
Kidney disease
Renal replacement therapy (RRT) should be initiated in patients with severe renal impairment. Renal function and fluid balance should be used to identify patients in need of RRT.[30]
RRT is needed in patients with kidney disease, especially those with a strong immune system or severe complications. The rehabilitation method used in Brescia (Italy) was for the care of COVID-19-infected patients who underwent kidney transplant and hemodialysis. Besides, it provides information on medical and physiopathological basis, including the underlying consequences, to explain all possible etiologies of the disease and clinical administration.[24]
Breast malignant growth
Breast radiation therapy represents a significant range of patient numbers in modern radiation oncology practice. Concerning anticipated asset requirements during the COVID-19 epidemic and extensive network contamination of SARS-CoV-2, countermeasures must be considered by suppliers to coordinate both patient infection and tumor risk.[31] There are evidence-based rules to ignore or discontinue radiation therapy for breast disease, with the ultimate goal of reducing patient risk and improving resource utilization. If one is seeking care resources and can identify sick patients in general health conditions in an emergency, breast radiation therapy can reduce clinical load without compromising tumor outcome. Appropriate and personal use of research data is appropriate in the context of the probability of death associated with this epidemic.[32],[33]
Literature addressing the few biotechnology and pharmaceutical companies update on the impact of coronovirus disease 2019
A randomized multicenter-managed scientific trial through the largest pharmaceutical groups is presently underway to evaluate the efficacy and safety in patients with COVID-19.
There is a wide spread collaboration between various international companies to fight this pandemic. Largest Companies review based on the Rollins et al.[5] while nine other companies are progressing toward a definitive treatment and/or vaccine for COVID-19 that has caused the present pandemic. Following are the 32 (23 + 9) different companies mentioned: Johnson and Johnson, Pfizer, Teva, Roche, Merk, Vertex, Abbvie, Abbott, Eli Lilly and Co, Astra Zenca, GlaxoSmithKline, Sanofi, Bristol-Myers Squibb, Celgene, Gilead Sciences, Biogen, Bayer, Takeda, BioSig, Regeneron, Alexion, BioMarin, Mylan, Novartis, Jakafi, Incyte, Invivo, CanSino, Innovax, Neurimmune, Ethris and Moderna; a few companies are tabulated in [Table 1]. | Table 1: Tabular representation of companies progressing toward a definitive treatment and/or vaccine for coronavirus disease 2019
Click here to view |
The remaining 11 companies that are supporting but not carrying out clinical trials for COVID-19 are listed below.
Amgen
An increasing number of clinical trial sites are restricting on-site visits and prohibiting continuing studies and patient visits to protect staff and patients from the potential risk of COVID-19. Safety concerns related to COVID-19 and study decisions, and to reduce the risk to patients and facilities. Continued recruitment/screening studies in clinical trials with significant benefits.[63]
Eisai
Support of the development of novel coronavirus remedies, ensuring a stable supply of medicines, and the support of aid conducted in different countries. This company supplied active pharmaceutical ingredients to the National Institute of Infectious Diseases in response to a request “for the provision of active pharmaceutical ingredients applicable for screening of remedies for the novel coronavirus” through the Ministry of Health, Labor, and Welfare toward the Federation of Pharmaceutical Manufacturers Association of Japan and the Japan Pharmaceutical Manufacturers Association. This consortium aims for the fast delivery of potentially relevant research results, relating to vaccines, medicines, and diagnosis techniques to people affected by COVID-19 across the world.[64]
Novo Nordisk
It is leveraging experience, resources, and global reach to support research efforts and urgent medical needs. When new problems arise, it works with health officials and international organizations to consider the COVID-19 epidemic and discover how it can make meaningful contributions. Community support efforts with new people are ongoing and up to date.[65]
Illumina perspective on the novel coronavirus SARS-CoV-2
Ensuring safety of employees and expertise to control and manage the pandemic. Further, Alumina has provided worldwide technology to Chinese health officials and similar applications to improve and enhance SARS-CoV-2 epidemiology, development, and virulence detection. The modern technology has identified the virus and sequenced its entire genome, to explain the genetic evolution of the virus.[66]
Shire
The Shire had been a leading company in plasma-derived therapies and had advanced expertise in developing albumin and immunoglobulin preparations. Takeda's acquisition of Shire thus caused to join the pursuit of COVID-19 treatment.[67]
Perrigo
It has a unique opportunity to respond to the COVID-19 crisis as a global provider of wellness solutions when families need it most, as well as a corporate partner in a regional organization.[68]
Allergan
The Allergan Foundation's 2020 donations are dedicated to 70 agencies responding to the local effect of the COVID-19 pandemic. The goal of those rapid tune grants is to position a good deal needed for financial help inside the palms of companies and provide healthcare services.[69]
Stryker
Stryker's anticipates generating emergency relief bed in low cost and ready to serve healthcare facilities during the COVID-19 pandemic.[51]
Daiichi Sankyo Company
This contributes to relief efforts for countermeasures in opposition to COVID-19.[70]
Astellas
In recent COVID-19 cases, Astellas is suspending start-up sports involving study sites for brand spanking new interventional clinical research. Astellas remains centered on shielding sufferers, employees, and our enterprise while retaining regulatory compliance and information integrity throughout medical improvement applications.[71]
Zoetis Inc
According to Rollins et al.,[5] Zoetis Inc is one among other companies that have no much contribution to the pandemic. This company focuses on variable dynamics and is believed to motivate marketing and promote animal genetics.[72]
Conclusion | |  |
The current review focused on the impact of treatment, clinical outcomes of different COVID-19 therapeutic approaches, and the contributions of biotechnology/pharmaceutical companies. There are currently no specific antiviral drugs; however, several antiviral drugs and repurposed drugs are under serious scrutiny. So far, there are few large-scale observational studies ongoing, but it is clear that the COVID-19 pandemic produced a vigorous and multifunctional response.
Acknowledgment
We thank Dr. S. Gurumadhva Rao, President, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates, for his support and encouragement.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References | |  |
1. | Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review. Infect Dis Poverty 2020;9:29. |
2. | |
3. | Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – An update on the status. Mil Med Res 2020;7:11. |
4. | Arksey H, O'Malley L. Scoping studies: Towards a Methodological Framework. Int J Soc Res Methodol 2005;8:19-32. |
5. | Rollin G, Lages J, Serebriyskaya TS, Shepelyansky DL. Interactions of pharmaceutical companies with world countries, cancers and rare diseases from Wikipedia network analysis. PLoS One 2019;14:e0225500. |
6. | Deng SQ, Peng HJ. Characteristics of and public health responses to the coronavirus disease 2019 outbreak in China. J Clin Med 2020;9:575. |
7. | Md Insiat Islam Rabby. Current drugs with potential for treatment of COVID-19: A literature review. J Pharm Pharm Sci 2020;23:58-64. |
8. | Li J, Fan JG. Characteristics and mechanism of liver injury in 2019 coronavirus disease. J Clin Transl Hepatol 2020;8:13-7. |
9. | Amirian ES, Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health 2020;9:100128. |
10. | Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71. |
11. | Ratia K, Pegan S, Takayama J, Sleeman K, Coughlin M, Baliji S, et al. A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc Natl Acad Sci U S A 2008;105:16119-24. |
12. | Young BE, Ong SW, Kalimuddin S, Low JG, Tan SY, Loh J, et al. epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020;323:1488. |
13. | Gamiño-Arroyo AE, Guerrero ML, McCarthy S, Ramírez-Venegas A, Llamosas-Gallardo B, Galindo-Fraga A, et al. Efficacy and safety of nitazoxanide in addition to standard of care for the treatment of severe acute respiratory illness. Clin Infect Dis 2019;69:1903-11. |
14. | |
15. | |
16. | |
17. | |
18. | |
19. | |
20. | Lover AA. Quantifying Treatment Effects of Hydroxychloroquine and Azithromycin for COVID-19: A Secondary Analysis of an Open Label non-Randomized Clinical Trial (Gautret et al., 2020); 2020. |
21. | Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract 2020;162:108142. |
22. | Ceribelli A, Motta F, De Santis M, Ansari AA, Ridgway WM, Gershwin ME, et al. Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy. J Autoimmun 2020;109:102442. |
23. | |
24. | Alberici F, Delbarba E, Manenti C, Econimo L, Valerio R, Pola A, et al. Management of Patients on Dialysis And With Kidney Transplant During SARS-COV-2 (COVID-19) Pandemic In Brescia, Italy. Kidney Int Rep 2020;(5):580-585. |
25. | |
26. | |
27. | Nahama A, Ramachandran R, Cisternas AF, Ji H. The role of afferent pulmonary innervation in ARDS associated with COVID-19 and potential use of resiniferatoxin to improve prognosis: A review. Med Drug Discovery 2020;5:100033. |
28. | |
29. | Lai CC, Liu YH, Wang CY, Wang YH, Hsueh SC, Yen MY, et al. Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths. J Microbiol Immunol Infect 2020;53:404-12. |
30. | Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061. |
31. | Shurell E, Olcese C, Patil S, McCormick B, Van Zee KJ, Pilewskie ML. Delay in radiotherapy is associated with an increased risk of disease recurrence in women with ductal carcinoma in situ. Cancer 2018;124:46-54. |
32. | Gunderson LL, Tepper JE, editors. Clin Radiat Oncol 2012. 3rd ed, Philadelphia: Elsevier saunders; 2012. p.1339-53. |
33. | Braunstein LZ, Gillespie EF, Hong L, Xu A, Bakhoum SF, Cuaron J, et al. Breast radiotherapy under COVID-19 pandemic resource constraints – Approaches to defer or shorten treatment from a Comprehensive Cancer Center in the United States. Adv Radiat Oncol 2020;1-7. |
34. | |
35. | |
36. | |
37. | |
38. | |
39. | |
40. | |
41. | Fujifilm Tests Favipiravir as COVID-19 Treatment. C EN Global Enterprise 2020;98:11. |
42. | |
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44. | |
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48. | |
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63. | |
64. | |
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66. | |
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72. | |
[Table 1]
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