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      Personalised health education against health damage of COVID-19 epidemic in the elderly Hungarian population (PROACTIVE-19): protocol of an adaptive randomised controlled clinical trial

      research-article
      1 , 2 , 1 , 3 , 1 , 4 , 1 , 4 , 1 , 4 , 1 , 4 , 1 , 4 , 1 , 4 , 1 , 4 , 1 , 4 , 1 , 2 , 5 , 1 , 6 , 1 , 4 , 1 , 4 , 5 , 7 , 1 , 4 , 5 , 7 , 1 , 4 , 1 , 4 , 6 , 1 , 4 , 6 , 8 , 9 , 4 , 10 , 11 , 12 , 13 , 14 , 15 , 1 , 1 , 16 , 1 , 1 , 1 , 1 , 1 , 1 , 17 , 9 , 4 , 10 , 4 , 10 , 6 , 6 , 6 , 1 , 2 , 4 , 5 ,
      Trials
      BioMed Central
      COVID-19, SARS-CoV-2, nCov-2019, Public health, Randomised controlled trial, Prevention

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          Abstract

          Background

          Early reports indicate that COVID-19 may require intensive care unit (ICU) admission in 5–26% and overall mortality can rise to 11% of the recognised cases, particularly affecting the elderly. There is a lack of evidence-based targeted pharmacological therapy for its prevention and treatment.

          We aim to compare the effects of a World Health Organization recommendation-based education and a personalised complex preventive lifestyle intervention package (based on the same WHO recommendation) on the outcomes of the COVID-19.

          Methods

          PROACTIVE-19 is a pragmatic, randomised controlled clinical trial with adaptive “sample size re-estimation” design. Hungarian population over the age of 60 years without confirmed COVID-19 will be approached to participate in a telephone health assessment and lifestyle counselling voluntarily. Volunteers will be randomised into two groups: (A) general health education and (B) personalised health education. Participants will go through questioning and recommendation in 5 fields: (1) mental health, (2) smoking habits, (3) physical activity, (4) dietary habits, and (5) alcohol consumption. Both groups A and B will receive the same line of questioning to assess habits concerning these topics. Assessment will be done weekly during the first month, every second week in the second month, then monthly. The composite primary endpoint will include the rate of ICU admission, hospital admission (longer than 48 h), and mortality in COVID-19-positive cases. The estimated sample size is 3788 subjects per study arm. The planned duration of the follow-up is a minimum of 1 year.

          Discussion

          These interventions may boost the body’s cardiovascular and pulmonary reserve capacities, leading to improved resistance against the damage caused by COVID-19. Consequently, lifestyle changes can reduce the incidence of life-threatening conditions and attenuate the detrimental effects of the pandemic seriously affecting the older population.

          Trial registration

          The study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (IV/2428- 2 /2020/EKU) and has been registered at clinicaltrials.gov ( NCT04321928) on 25 March 2020.

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          Most cited references12

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          Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

          Summary Background In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding National Key R&D Program of China.
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            WHO Declares COVID-19 a Pandemic

            The World Health Organization (WHO) on March 11, 2020, has declared the novel coronavirus (COVID-19) outbreak a global pandemic (1). At a news briefing, WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, noted that over the past 2 weeks, the number of cases outside China increased 13-fold and the number of countries with cases increased threefold. Further increases are expected. He said that the WHO is “deeply concerned both by the alarming levels of spread and severity and by the alarming levels of inaction,” and he called on countries to take action now to contain the virus. “We should double down,” he said. “We should be more aggressive.” Among the WHO’s current recommendations, people with mild respiratory symptoms should be encouraged to isolate themselves, and social distancing is emphasized and these recommendations apply even to countries with no reported cases (2). Separately, in JAMA, researchers report that SARS-CoV-2, the virus that causes COVID-19, was most often detected in respiratory samples from patients in China. However, live virus was also found in feces. They conclude: “Transmission of the virus by respiratory and extrarespiratory routes may help explain the rapid spread of disease.”(3). COVID-19 is a novel disease with an incompletely described clinical course, especially for children. In a recente report W. Liu et al described that the virus causing Covid-19 was detected early in the epidemic in 6 (1.6%) out of 366 children (≤16 years of age) hospitalized because of respiratory infections at Tongji Hospital, around Wuhan. All these six children had previously been completely healthy and their clinical characteristics at admission included high fever (>39°C) cough and vomiting (only in four). Four of the six patients had pneumonia, and only one required intensive care. All patients were treated with antiviral agents, antibiotic agents, and supportive therapies, and recovered after a median 7.5 days of hospitalization. (4). Risk factors for severe illness remain uncertain (although older age and comorbidity have emerged as likely important factors), the safety of supportive care strategies such as oxygen by high-flow nasal cannula and noninvasive ventilation are unclear, and the risk of mortality, even among critically ill patients, is uncertain. There are no proven effective specific treatment strategies, and the risk-benefit ratio for commonly used treatments such as corticosteroids is unclear (3,5). Septic shock and specific organ dysfunction such as acute kidney injury appear to occur in a significant proportion of patients with COVID-19–related critical illness and are associated with increasing mortality, with management recommendations following available evidence-based guidelines (3). Novel COVID-19 “can often present as a common cold-like illness,” wrote Roman Wöelfel et al. (6). They report data from a study concerning nine young- to middle-aged adults in Germany who developed COVID-19 after close contact with a known case. All had generally mild clinical courses; seven had upper respiratory tract disease, and two had limited involvement of the lower respiratory tract. Pharyngeal virus shedding was high during the first week of symptoms, peaking on day 4. Additionally, sputum viral shedding persisted after symptom resolution. The German researchers say the current case definition for COVID-19, which emphasizes lower respiratory tract disease, may need to be adjusted(6). But they considered only young and “normal” subjecta whereas the story is different in frail comorbid older patients, in whom COVID 19 may precipitate an insterstitial pneumonia, with severe respiratory failure and death (3). High level of attention should be paid to comorbidities in the treatment of COVID-19. In the literature, COVID-19 is characterised by the symptoms of viral pneumonia such as fever, fatigue, dry cough, and lymphopenia. Many of the older patients who become severely ill have evidence of underlying illness such as cardiovascular disease, liver disease, kidney disease, or malignant tumours. These patients often die of their original comorbidities. They die “with COVID”, but were extremely frail and we therefore need to accurately evaluate all original comorbidities. In addition to the risk of group transmission of an infectious disease, we should pay full attention to the treatment of the original comorbidities of the individual while treating pneumonia, especially in older patients with serious comorbid conditions and polipharmacy. Not only capable of causing pneumonia, COVID-19 may also cause damage to other organs such as the heart, the liver, and the kidneys, as well as to organ systems such as the blood and the immune system. Patients die of multiple organ failure, shock, acute respiratory distress syndrome, heart failure, arrhythmias, and renal failure (5,6). What we know about COVID 19? In December 2019, a cluster of severe pneumonia cases of unknown cause was reported in Wuhan, Hubei province, China. The initial cluster was epidemiologically linked to a seafood wholesale market in Wuhan, although many of the initial 41 cases were later reported to have no known exposure to the market (7). A novel strain of coronavirus belonging to the same family of viruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as the 4 human coronaviruses associated with the common cold, was subsequently isolated from lower respiratory tract samples of 4 cases on 7 January 2020. On 30 January 2020, the WHO declared that the SARS-CoV-2 outbreak constituted a Public Health Emergency of International Concern, and more than 80, 000 confirmed cases had been reported worldwide as of 28 February 2020 (8). On 31 January 2020, the U.S. Centers for Disease Control and Prevention announced that all citizens returning from Hubei province, China, would be subject to mandatory quarantine for up to 14 days. But from China COVID 19 arrived to many other countries. Rothe C et al reported a case of a 33-year-old otherwise healthy German businessman :she became ill with a sore throat, chills, and myalgias on January 24, 2020 (9). The following day, a fever of 39.1°C developed, along with a productive cough. By the evening of the next day, he started feeling better and went back to work on January 27. Before the onset of symptoms, he had attended meetings with a Chinese business partner at his company near Munich on January 20 and 21. The business partner, a Shanghai resident, had visited Germany between January 19 and 22. During her stay, she had been well with no signs or symptoms of infection but had become ill on her flight back to China, where she tested positive for 2019-nCoV on January 26. This case of 2019-nCoV infection was diagnosed in Germany and transmitted outside Asia. However, it is notable that the infection appears to have been transmitted during the incubation period of the index patient, in whom the illness was brief and nonspecific. The fact that asymptomatic persons are potential sources of 2019-nCoV infection may warrant a reassessment of transmission dynamics of the current outbreak (9). Our current understanding of the incubation period for COVID-19 is limited. An early analysis based on 88 confirmed cases in Chinese provinces outside Wuhan, using data on known travel to and from Wuhan to estimate the exposure interval, indicated a mean incubation period of 6.4 days (95% CI, 5.6 to 7.7 days), with a range of 2.1 to 11.1 days. Another analysis based on 158 confirmed cases outside Wuhan estimated a median incubation period of 5.0 days (CI, 4.4 to 5.6 days), with a range of 2 to 14 days. These estimates are generally consistent with estimates from 10 confirmed cases in China (mean incubation period, 5.2 days [CI, 4.1 to 7.0 days] and from clinical reports of a familial cluster of COVID-19 in which symptom onset occurred 3 to 6 days after assumed exposure in Wuhan (10-12). The incubation period can inform several important public health activities for infectious diseases, including active monitoring, surveillance, control, and modeling. Active monitoring requires potentially exposed persons to contact local health authorities to report their health status every day. Understanding the length of active monitoring needed to limit the risk for missing infections is necessary for health departments to effectively use resources. A recent paper provides additional evidence for a median incubation period for COVID-19 of approximately 5 days (13). Lauer et al suggest that 101 out of every 10 000 cases will develop symptoms after 14 days of active monitoring or quarantinen (13). Whether this rate is acceptable depends on the expected risk for infection in the population being monitored and considered judgment about the cost of missing cases. Combining these judgments with the estimates presented here can help public health officials to set rational and evidence-based COVID-19 control policies. Note that the proportion of mild cases detected has increased as surveillance and monitoring systems have been strengthened. The incubation period for these severe cases may differ from that of less severe or subclinical infections and is not typically an applicable measure for those with asymptomatic infections In conclusion, in a very short period health care systems and society have been severely challenged by yet another emerging virus. Preventing transmission and slowing the rate of new infections are the primary goals; however, the concern of COVID-19 causing critical illness and death is at the core of public anxiety. The critical care community has enormous experience in treating severe acute respiratory infections every year, often from uncertain causes. The care of severely ill patients, in particular older persons with COVID-19 must be grounded in this evidence base and, in parallel, ensure that learning from each patient could be of great importance to care all population,
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              Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

              China and the rest of the world are experiencing an outbreak of a novel betacoronavirus known as severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). 1 By Feb 12, 2020, the rapid spread of the virus had caused 42 747 cases and 1017 deaths in China and cases have been reported in 25 countries, including the USA, Japan, and Spain. WHO has declared 2019 novel coronavirus disease (COVID-19), caused by SARS-CoV-2, a public health emergency of international concern. In contrast to severe acute respiratory system coronavirus and Middle East respiratory syndrome coronavirus, more deaths from COVID-19 have been caused by multiple organ dysfunction syndrome rather than respiratory failure, 2 which might be attributable to the widespread distribution of angiotensin converting enzyme 2—the functional receptor for SARS-CoV-2—in multiple organs.3, 4 Patients with cancer are more susceptible to infection than individuals without cancer because of their systemic immunosuppressive state caused by the malignancy and anticancer treatments, such as chemotherapy or surgery.5, 6, 7, 8 Therefore, these patients might be at increased risk of COVID-19 and have a poorer prognosis. On behalf of the National Clinical Research Center for Respiratory Disease, we worked together with the National Health Commission of the People's Republic of China to establish a prospective cohort to monitor COVID-19 cases throughout China. As of the data cutoff on Jan 31, 2020, we have collected and analysed 2007 cases from 575 hospitals (appendix pp 4–9 for a full list) in 31 provincial administrative regions. All cases were diagnosed with laboratory-confirmed COVID-19 acute respiratory disease and were admitted to hospital. We excluded 417 cases because of insufficient records of previous disease history. 18 (1%; 95% CI 0·61–1·65) of 1590 COVID-19 cases had a history of cancer, which seems to be higher than the incidence of cancer in the overall Chinese population (285·83 [0·29%] per 100 000 people, according to 2015 cancer epidemiology statistics 9 ). Detailed information about the 18 patients with cancer with COVID-19 is summarised in the appendix (p 1). Lung cancer was the most frequent type (five [28%] of 18 patients). Four (25%) of 16 patients (two of the 18 patients had unknown treatment status) with cancer with COVID-19 had received chemotherapy or surgery within the past month, and the other 12 (25%) patients were cancer survivors in routine follow-up after primary resection. Compared with patients without cancer, patients with cancer were older (mean age 63·1 years [SD 12·1] vs 48·7 years [16·2]), more likely to have a history of smoking (four [22%] of 18 patients vs 107 [7%] of 1572 patients), had more polypnea (eight [47%] of 17 patients vs 323 [23%] of 1377 patients; some data were missing on polypnea), and more severe baseline CT manifestation (17 [94%] of 18 patients vs 1113 [71%] of 1572 patients), but had no significant differences in sex, other baseline symptoms, other comorbidities, or baseline severity of x-ray (appendix p 2). Most importantly, patients with cancer were observed to have a higher risk of severe events (a composite endpoint defined as the percentage of patients being admitted to the intensive care unit requiring invasive ventilation, or death) compared with patients without cancer (seven [39%] of 18 patients vs 124 [8%] of 1572 patients; Fisher's exact p=0·0003). We observed similar results when the severe events were defined both by the above objective events and physician evaluation (nine [50%] of 18 patients vs 245 [16%] of 1572 patients; Fisher's exact p=0·0008). Moreover, patients who underwent chemotherapy or surgery in the past month had a numerically higher risk (three [75%] of four patients) of clinically severe events than did those not receiving chemotherapy or surgery (six [43%] of 14 patients; figure ). These odds were further confirmed by logistic regression (odds ratio [OR] 5·34, 95% CI 1·80–16·18; p=0·0026) after adjusting for other risk factors, including age, smoking history, and other comorbidities. Cancer history represented the highest risk for severe events (appendix p 3). Among patients with cancer, older age was the only risk factor for severe events (OR 1·43, 95% CI 0·97–2·12; p=0·072). Patients with lung cancer did not have a higher probability of severe events compared with patients with other cancer types (one [20%] of five patients with lung cancer vs eight [62%] of 13 patients with other types of cancer; p=0·294). Additionally, we used a Cox regression model to evaluate the time-dependent hazards of developing severe events, and found that patients with cancer deteriorated more rapidly than those without cancer (median time to severe events 13 days [IQR 6–15] vs 43 days [20–not reached]; p<0·0001; hazard ratio 3·56, 95% CI 1·65–7·69, after adjusting for age; figure). Figure Severe events in patients without cancer, cancer survivors, and patients with cancer (A) and risks of developing severe events for patients with cancer and patients without cancer (B) ICU=intensive care unit. In this study, we analysed the risk for severe COVID-19 in patients with cancer for the first time, to our knowledge; only by nationwide analysis can we follow up patients with rare but important comorbidities, such as cancer. We found that patients with cancer might have a higher risk of COVID-19 than individuals without cancer. Additionally, we showed that patients with cancer had poorer outcomes from COVID-19, providing a timely reminder to physicians that more intensive attention should be paid to patients with cancer, in case of rapid deterioration. Therefore, we propose three major strategies for patients with cancer in this COVID-19 crisis, and in future attacks of severe infectious diseases. First, an intentional postponing of adjuvant chemotherapy or elective surgery for stable cancer should be considered in endemic areas. Second, stronger personal protection provisions should be made for patients with cancer or cancer survivors. Third, more intensive surveillance or treatment should be considered when patients with cancer are infected with SARS-CoV-2, especially in older patients or those with other comorbidities.
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                Author and article information

                Contributors
                eross.balint@pte.hu
                zsoltmolna@gmail.com
                szaki92@gmail.com
                znoeemi@gmail.com
                szaklaj@gmail.com
                vancsasz@yahoo.com
                flixjuhsz@gmail.com
                ocskay.klementina@gmail.com
                vorinocci@gmail.com
                katalin.martak@gmail.com
                szentesiai@gmail.com
                andrea.parniczky@gmail.com
                drdunajskastreda@gmail.com
                kissszabolcs1995@gmail.com
                foldimarcsi4@gmail.com
                fanni5257@freemail.hu
                kanjoanna@gmail.com
                pazmanyp11@gmail.com
                varro.andras@med.u-szeged.hu
                arpad.csatho@aok.pte.hu
                zsuzsanna.helyes@gmail.com
                peterfi.zoltan@pte.hu
                laszlo.czopf@aok.pte.hu
                istvan.kiss@aok.pte.hu
                zemplenyi.antal@pte.hu
                czapari.dora@pte.hu
                eszterhegyi98@gmail.com
                dobszai.dalma@gmail.com
                emimiklos@gmail.com
                martaattila42@gmail.com
                afg.toth.dominika@gmail.com
                farkasr00@gmail.com
                farkas.nelli@gmail.com
                bela.birkas@aok.pte.hu
                erika.pinter@aok.pte.hu
                gabor.petho@aok.pte.hu
                borbala.zsigmond@gmail.com
                sarkoziandrea@me.com
                anagydr@gmail.com
                p.hegyi@tm-centre.org , hegyi2009@gmail.com , https://www.tm-centre.org
                Journal
                Trials
                Trials
                Trials
                BioMed Central (London )
                1745-6215
                29 September 2020
                29 September 2020
                2020
                : 21
                : 809
                Affiliations
                [1 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Institute for Translational Medicine, Medical School, , University of Pécs, ; Szigeti út 12, Pécs, H-7624 Hungary
                [2 ]Translational Medicine Foundation, Szeged, Hungary
                [3 ]GRID grid.22254.33, ISNI 0000 0001 2205 0971, Department of Anaesthesiology and Intensive Therapy, , Poznan University for Medical Sciences, ; Poznan, Poland
                [4 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, János Szentágothai Research Centre, , University of Pécs, ; Pécs, Hungary
                [5 ]GRID grid.9008.1, ISNI 0000 0001 1016 9625, Centre for Translational Medicine, Department of Medicine, , University of Szeged, ; Szeged, Hungary
                [6 ]Heim Pál National Pediatric Institute, Budapest, Hungary
                [7 ]GRID grid.9008.1, ISNI 0000 0001 1016 9625, Doctoral School of Clinical Medicine, , University of Szeged, ; Szeged, Hungary
                [8 ]GRID grid.9008.1, ISNI 0000 0001 1016 9625, Department of Pharmacology and Pharmacotherapy, , University of Szeged, ; Szeged, Hungary
                [9 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Department of Behavioral Sciences, Medical School, , University of Pécs, ; Pécs, Hungary
                [10 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Department of Pharmacology and Pharmacotherapy, Medical School, , University of Pécs, ; Pécs, Hungary
                [11 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Division of Infectious Diseases, 1st Department of Medicine, Medical School, , University of Pécs, ; Pécs, Hungary
                [12 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Division of Cardiology, First Department of Medicine, Medical School, , University of Pécs, ; Pécs, Hungary
                [13 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Department of Public Health, Medical School, , University of Pécs, ; Pécs, Hungary
                [14 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Health Technology Assessment Center, , University of Pécs, ; Pécs, Hungary
                [15 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Division of Pharmacoeconomics, Department of Pharmaceutics, Faculty of Pharmacy, , University of Pécs, ; Pécs, Hungary
                [16 ]GRID grid.9008.1, ISNI 0000 0001 1016 9625, Faculty of Law, , University of Szeged, ; Szeged, Hungary
                [17 ]GRID grid.9679.1, ISNI 0000 0001 0663 9479, Institute Bioanalysis, Medical School, , University of Pécs, ; Pécs, Hungary
                Article
                4733
                10.1186/s13063-020-04733-0
                7522906
                0fc7f815-2a98-4e9f-89ff-28e72610539e
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 24 July 2020
                : 8 September 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100008530, European Regional Development Fund;
                Award ID: EFOP 3.6.2‐16‐2017‐00006 – LIVE LONGER
                Categories
                Study Protocol
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                © The Author(s) 2020

                Medicine
                covid-19,sars-cov-2,ncov-2019,public health,randomised controlled trial,prevention
                Medicine
                covid-19, sars-cov-2, ncov-2019, public health, randomised controlled trial, prevention

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