In vitro and clinical studies on the efficacy of α-cyclodextrin and hydroxytyrosol against SARS-CoV-2 infection.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of α-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans. PATIENTS AND METHODS: For in vitro experiments on Vero E6 cells, RNA for RT-qPCR analysis was extracted from Caco2 and human fibroblast cell lines. For study in humans, the treatment group consisted of 149 healthy volunteers in Northern Cyprus, considered at higher risk of SARS-CoV-2 infection than the general population. The volunteers used nasal spray containing α-cyclodextrin and hydroxytyrosol for 4 weeks. The control group consisted of 76 healthy volunteers who did not use the spray. RESULTS: RT-qPCR experiments on targeted genes involved in endocytosis showed a reduction in gene expression, whereas cytotoxicity and cytoprotective tests showed that the compounds exerted a protective effect against SARS-CoV-2 infection at non-cytotoxic concentrations. None of the volunteers became positive to SARS-CoV-2 RT-qPCR assay during the 30 days of treatment. CONCLUSIONS: Treatment with α-cyclodextrin and hydroxytyrosol nasal spray improved defenses against SARS-CoV-2 infection and reduced synthesis of viral particles.

Hydroxychloroquine and azithromycin used alone or combined are not effective against SARS-CoV-2 ex vivo and in a hamster model.

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.

Restarting Neglected Tropical Diseases Programs in West Africa during the COVID-19 Pandemic: Lessons Learned and Best Practices.

Countries across West Africa began reporting COVID-19 cases in February 2020. By March, the pandemic began disrupting activities to control and eliminate neglected tropical diseases (NTDs) as health ministries ramped up COVID-19-related policies and prevention measures. This was followed by interim guidance from the WHO in April 2020 to temporarily pause mass drug administration (MDA) and community-based surveys for NTDs. While the pandemic was quickly evolving worldwide, in most of West Africa, governments and health ministries took quick action to implement mitigation measures to slow the spread. The U.S. Agency for International Development's (USAID) Act to End NTDs | West program (Act | West) began liaising with national NTD programs in April 2020 to pave a path toward the eventual resumption of activities. This process consisted of first collecting and analyzing COVID-19 epidemiological data, policies, and standard operating procedures across the program's 11 countries. The program then developed an NTD activity restart matrix that compiled essential considerations to restart activities. By December 2020, all 11 countries in Act | West safely restarted MDA and certain surveys to monitor NTD prevalence or intervention impact. Preliminary results show satisfactory MDA program coverage, meaning that enough people are taking the medicine to keep countries on track toward achieving their NTD disease control and elimination goals, and community perceptions have remained positive. The purpose of this article is to share the lessons and best practices that have emerged from the adoption of strategies to limit the spread of the novel coronavirus during MDA and other program activities.

A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide.

Effective treatment of respiratory infections continues to be a major challenge. In high doses (≥160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent, including its efficacy in vitro for coronavirus family. However, the safety of prolonged in vivo implementation of high-dose iNO therapy has not been studied. Herein we aim to explore the feasibility and safety of delivering continuous high-dose iNO over an extended period of time using an in vivo animal model. Yorkshire pigs were randomized to one of the following two groups: group 1, standard ventilation; and group 2, standard ventilation + continuous iNO 160 ppm + methylene blue (MB) as intravenous bolus, whenever required, to maintain metHb <6%. Both groups were ventilated continuously for 6 hours, then the animals were weaned from sedation, mechanical ventilation and followed for 3 days. During treatment, and on the third post-operative day, physiologic assessments were performed to monitor lung function and other significative markers were assessed for potential pulmonary or systemic injury. No significant change in lung function, or inflammatory markers were observed during the study period. Both gas exchange function, lung tissue cytokine analysis and histology were similar between treated and control animals. During treatment, levels of metHb were maintained <6% by administration of MB, and NO2 remained <5 ppm. Additionally, considering extrapulmonary effects, no significant changes were observed in biochemistry markers. Our findings showed that high-dose iNO delivered continuously over 6 hours with adjuvant MB is clinically feasible and safe. These findings support the development of investigations of continuous high-dose iNO treatment of respiratory tract infections, including SARS-CoV-2.

Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19).

As the coronavirus disease 19 (COVID-19) global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the "off-label" repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world's population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment.

Antimicrobial Activity of Curcumin in Nanoformulations: A Comprehensive Review.

Curcumin (CUR) is a natural substance extracted from turmeric that has antimicrobial properties. Due to its ability to absorb light in the blue spectrum, CUR is also used as a photosensitizer (PS) in antimicrobial Photodynamic Therapy (aPDT). However, CUR is hydrophobic, unstable in solutions, and has low bioavailability, which hinders its clinical use. To circumvent these drawbacks, drug delivery systems (DDSs) have been used. In this review, we summarize the DDSs used to carry CUR and their antimicrobial effect against viruses, bacteria, and fungi, including drug-resistant strains and emergent pathogens such as SARS-CoV-2. The reviewed DDSs include colloidal (micelles, liposomes, nanoemulsions, cyclodextrins, chitosan, and other polymeric nanoparticles), metallic, and mesoporous particles, as well as graphene, quantum dots, and hybrid nanosystems such as films and hydrogels. Free (non-encapsulated) CUR and CUR loaded in DDSs have a broad-spectrum antimicrobial action when used alone or as a PS in aPDT. They also show low cytotoxicity, in vivo biocompatibility, and improved wound healing. Although there are several in vitro and some in vivo investigations describing the nanotechnological aspects and the potential antimicrobial application of CUR-loaded DDSs, clinical trials are not reported and further studies should translate this evidence to the clinical scenarios of infections.

The effects of orally administered lactoferrin in the prevention and management of viral infections: A systematic review.

It has been demonstrated that lactoferrin (LF) plays a role in host defence, but evidence on its potential antiviral property from clinical studies is fragmented. Our systematic review aimed at identifying the effects of orally administered LF against virus infections. The systematic search was conducted on PubMed, Scopus, Web of Science, BioRxiv.org and ClinicalTrials.gov from database inception to 7th January 2021. Eligible articles investigated any virus family and provided data on the effects of orally administered LF of any origin in the prevention and/or management of confirmed viral infections in people of any age. A narrative synthesis of the results was performed. Quality was assessed with the Cochrane Risk-Of-Bias and ROBINS-1 tools. A total of 27 records were included, nine of which were registered protocols. We found data on Flaviviridae (n = 10), Retroviridae (n = 3), Coronaviridae (n = 2), Reoviridae (n = 2) and Caliciviridae (n = 1). Most published trials were at high risk of bias. The findings were heterogeneous across and within viral families regarding virological, immunological and biological response, with no clear conclusion. Some weak but positive results were reported about decrease of symptom severity and duration, or reduction in viral loads. Despite high tolerability, the effects of LF as oral supplement are still inconsistent, both in preventing and managing viral infections. Small sample sizes, variety in recruitment and treatment protocols, and low study quality may have contributed to such heterogeneity. Better-designed studies are needed to further investigate its potential benefits against viral infections, including SARS-CoV-2.

Cardiac Corrected QT Interval Changes Among Patients Treated for COVID-19 Infection During the Early Phase of the Pandemic.

Importance: Critical illness, a marked inflammatory response, and viruses such as SARS-CoV-2 may prolong corrected QT interval (QTc). Objective: To evaluate baseline QTc interval on 12-lead electrocardiograms (ECGs) and ensuing changes among patients with and without COVID-19. Design, Setting, and Participants: This cohort study included 3050 patients aged 18 years and older who underwent SARS-CoV-2 testing and had ECGs at Columbia University Irving Medical Center from March 1 through May 1, 2020. Patients were analyzed by treatment group over 5 days, as follows: hydroxychloroquine with azithromycin, hydroxychloroquine alone, azithromycin alone, and neither hydroxychloroquine nor azithromycin. ECGs were manually analyzed by electrophysiologists masked to COVID-19 status. Multivariable modeling evaluated clinical associations with QTc prolongation from baseline. Exposures: COVID-19, hydroxychloroquine, azithromycin. Main Outcomes and Measures: Mean QTc prolongation, percentage of patients with QTc of 500 milliseconds or greater. Results: A total of 965 patients had more than 2 ECGs and were included in the study, with 561 (58.1%) men, 198 (26.2%) Black patients, and 191 (19.8%) aged 80 years and older. There were 733 patients (76.0%) with COVID-19 and 232 patients (24.0%) without COVID-19. COVID-19 infection was associated with significant mean QTc prolongation from baseline by both 5-day and 2-day multivariable models (5-day, patients with COVID-19: 20.81 [95% CI, 15.29 to 26.33] milliseconds; P < .001; patients without COVID-19: -2.01 [95% CI, -17.31 to 21.32] milliseconds; P = .93; 2-day, patients with COVID-19: 17.40 [95% CI, 12.65 to 22.16] milliseconds; P < .001; patients without COVID-19: 0.11 [95% CI, -12.60 to 12.81] milliseconds; P = .99). COVID-19 infection was independently associated with a modeled mean 27.32 (95% CI, 4.63-43.21) millisecond increase in QTc at 5 days compared with COVID-19-negative status (mean QTc, with COVID-19: 450.45 [95% CI, 441.6 to 459.3] milliseconds; without COVID-19: 423.13 [95% CI, 403.25 to 443.01] milliseconds; P = .01). More patients with COVID-19 not receiving hydroxychloroquine and azithromycin had QTc of 500 milliseconds or greater compared with patients without COVID-19 (34 of 136 [25.0%] vs 17 of 158 [10.8%], P = .002). Multivariable analysis revealed that age 80 years and older compared with those younger than 50 years (mean difference in QTc, 11.91 [SE, 4.69; 95% CI, 2.73 to 21.09]; P = .01), severe chronic kidney disease compared with no chronic kidney disease (mean difference in QTc, 12.20 [SE, 5.26; 95% CI, 1.89 to 22.51; P = .02]), elevated high-sensitivity troponin levels (mean difference in QTc, 5.05 [SE, 1.19; 95% CI, 2.72 to 7.38]; P < .001), and elevated lactate dehydrogenase levels (mean difference in QTc, 5.31 [SE, 2.68; 95% CI, 0.06 to 10.57]; P = .04) were associated with QTc prolongation. Torsades de pointes occurred in 1 patient (0.1%) with COVID-19. Conclusions and Relevance: In this cohort study, COVID-19 infection was independently associated with significant mean QTc prolongation at days 5 and 2 of hospitalization compared with day 0. More patients with COVID-19 had QTc of 500 milliseconds or greater compared with patients without COVID-19.

Antimicrobial stewardship strategies in wound care: evidence to support the use of dialkylcarbamoyl chloride (DACC)- coated wound dressings.

BACKGROUND: Traditionally, infections are treated with antimicrobials (for example, antibiotics, antiseptics, etc), but antimicrobial resistance (AMR) has become one of the most serious health threats of the 21st century (before the emergence of COVID-19). Wounds can be a source of infection by allowing unconstrained entry of microorganisms into the body, including antimicrobial-resistant bacteria. The development of new antimicrobials (particularly antibiotics) is not keeping pace with the evolution of resistant microorganisms and novel ways of addressing this problem are urgently required. One such initiative has been the development of antimicrobial stewardship (AMS) programmes, which educate healthcare workers, and control the prescribing and targeting of antimicrobials to reduce the likelihood of AMR. Of great importance has been the European Wound Management Association (EWMA) in supporting AMS by providing practical recommendations for optimising antimicrobial therapy for the treatment of wound infection. The use of wound dressings that use a physical sequestration and retention approach rather than antimicrobial agents to reduce bacterial burden offers a novel approach that supports AMS. Bacterial-binding by dressings and their physical removal, rather than active killing, minimises their damage and hence prevents the release of damaging endotoxins. AIM: Our objective is to highlight AMS for the promotion of the judicious use of antimicrobials and to investigate how dialkylcarbamoyl chloride (DACC)-coated dressings can support AMS goals. METHOD: MEDLINE, Cochrane Database of Systematic Reviews, and Google Scholar were searched to identify published articles describing data relating to AMS, and the use of a variety of wound dressings in the prevention and/or treatment of wound infections. The evidence supporting alternative wound dressings that can reduce bioburden and prevent and/or treat wound infection in a manner that does not kill or damage the microorganisms (for example, by actively binding and removing intact microorganisms from wounds) were then narratively reviewed. RESULTS: The evidence reviewed here demonstrates that using bacterial-binding wound dressings that act in a physical manner (for example, DACC-coated dressings) as an alternative approach to preventing and/or treating infection in both acute and hard-to-heal wounds does not exacerbate AMR and supports AMS. CONCLUSION: Some wound dressings work via a mechanism that promotes the binding and physical uptake, sequestration and removal of intact microorganisms from the wound bed (for example, a wound dressing that uses DACC technology to successfully prevent/reduce infection). They provide a valuable tool that aligns with the requirements of AMS (for example, reducing the use of antimicrobials in wound treatment regimens) by effectively reducing wound bioburden without inducing/selecting for resistant bacteria.

Promotion of Surgical Masks Antimicrobial Activity by Disinfection and Impregnation with Disinfectant Silver Nanoparticles.

BACKGROUND: The COVID-19 pandemic is requesting highly effective protective personnel equipment, mainly for healthcare professionals. However, the current demand has exceeded the supply chain and, consequently, shortage of essential medical materials, such as surgical masks. Due to these alarming limitations, it is crucial to develop effective means of disinfection, reusing, and thereby applying antimicrobial shielding protection to the clinical supplies. PURPOSE: Therefore, in this work, we developed a novel, economical, and straightforward approach to promote antimicrobial activity to surgical masks by impregnating silver nanoparticles (AgNPs). METHODS: Our strategy consisted of fabricating a new alcohol disinfectant formulation combining special surfactants and AgNPs, which is demonstrated to be extensively effective against a broad number of microbial surrogates of SARS-CoV-2. RESULTS: The present nano-formula reported a superior microbial reduction of 99.999% against a wide number of microorganisms. Furthermore, the enveloped H5N1 virus was wholly inactivated after 15 min of disinfection. Far more attractive, the current method for reusing surgical masks did not show outcomes of detrimental amendments, suggesting that the protocol does not alter the filtration effectiveness. CONCLUSION: The nano-disinfectant provides a valuable strategy for effective decontamination, reuse, and even antimicrobial promotion to surgical masks for frontline clinical personnel.

Effect of triple antimicrobial therapy on electrocardiography parameters in patients with mild-to-moderate coronavirus disease 2019.

OBJECTIVE: The effects of treatment of coronavirus disease 2019 (COVID-19) with a triple combination composed of hydroxychloroquine, an an-tiviral, and an antibiotic on electrocardiography (ECG) parameters in patients with mild-to-moderate symptoms are not wholly understood. We aimed to explore the changes in ECG parameters after treatment with triple combination therapy in patients with mild-to-moderate symptomatic COVID-19. METHODS: This retrospective, single-center case series analyzed 91 patients with mild-to-moderate symptomatic COVID-19 at Ankara Gazi Mus-tafa Kemal State Hospital of Ankara City, Turkey, from April 1, 2020, to April 30, 2020. Forty-three patients were treated with hydroxychloroquine+oseltamivir+azithromycin (Group 1) and 48 patients were treated with hydroxychloroquine+oseltamivir+levofloxacin (Group 2). Heart rate, P wave duration, P wave dispersion, PR interval, QRS duration, corrected QT interval (QTc), QTc dispersion (QTD), delta QTc, Tp-e, Tp-e dispersion, and Tp-e/QTc ratio were all calculated from the baseline and posttreatment 12-lead ECG recordings. RESULTS: The QTc, QRS duration, Tp-e, PR interval, and P wave duration were significantly increased after treatment (p<0.001; p<0.001; p<0.001; p=0.001; p=0.001). The posttreatment C-reactive protein level was significantly lower than at baseline in Group 1 (p=0.014). At admission, 30% of patients had QT prolongation, and 4.3% of them had a QT duration >500 ms. Both Group 1 and Group 2 showed significant prolongation of the QTc interval (Group 1; p<0.001 vs. Group 2; p<0.001), QRS duration (Group 1; p=0.006 vs. Group 2; p=0.014), Tp-e (Group 1; p=0.036 vs. Group 2; p<0.001), and PR interval (Group 1; p=0.002 vs. Group2; p=0.05). The QTD was significantly decreased in Group 1 (p<0.001). None of the patients experienced any overt ventricular arrhythmia. CONCLUSION: To the best of our knowledge, this study is the first to investigate QT prolongation in a population of COVID-19 patients treated with triple combination therapy. We found that there was a significant decrease in the QTD after the treatment in patients who were taking triple therapy including azithromycin.

COVID-19 and nutriceutical therapies, especially using zinc to supplement antimicrobials.

The nutritional status of a patient can be critical for the efficacy of other pharmaceuticals, especially organic antibiotics, to treat viral pandemics. There may be political and scientific difficulties in achieving a constructive synergy of nutritional and prescribed allopathic remedies. For adequate treatment, timelines may need to extend well beyond eliminating viral proliferation, e.g., with vaccines, to include the goals of (a) reducing post-viral fatigue, (b) promoting earliest recovery, and (c) future resistance in often poorly nourished patients, e.g., obese (!). Many trace minerals (TM) and vitamins may need to be replenished. This review focusses only upon zinc to illustrate some problems in rectifying these TM deficiencies affecting the balance between continued ill-health ('illth') or regaining optimal physical and mental wellbeing. Ultimately, this is a matter of behaviour, lifestyle, and informed choice(s). See Hetzel and McMichael 1959.

An overview of chitosan and its application in infectious diseases.

Infectious diseases, such as the coronavirus disease-19, SARS virus, Ebola virus, and AIDS, threaten the health of human beings globally. New viruses, drug-resistant bacteria, and fungi continue to challenge the human efficacious drug bank. Researchers have developed a variety of new antiviral and antibacterial drugs in response to the infectious disease crisis. Meanwhile, the development of functional materials has also improved therapeutic outcomes. As a natural material, chitosan possesses good biocompatibility, bioactivity, and biosafety. It has been proven that the cooperation between chitosan and traditional medicine greatly improves the ability of anti-infection. This review summarized the application and design considerations of chitosan-composed systems for the treatment of infectious diseases, looking forward to providing the idea of infectious disease therapy.

Economic and Behavioral Influencers of Vaccination and Antimicrobial Use.

Despite vast improvements in global vaccination coverage during the last decade, there is a growing trend in vaccine hesitancy and/or refusal globally. This has implications for the acceptance and coverage of a potential vaccine against COVID-19. In the United States, the number of children exempt from vaccination for "philosophical belief-based" non-medical reasons increased in 12 of the 18 states that allowed this policy from 2009 to 2017 (1). Meanwhile, the overuse and misuse of antibiotics, especially in young children, have led to increasing rates of drug resistance that threaten our ability to treat infectious diseases. Vaccine hesitancy and antibiotic overuse exist side-by-side in the same population of young children, and it is unclear why one modality (antibiotics) is universally seen as safe and effective, while the other (vaccines) is seen as potentially hazardous by some. In this review, we consider the drivers shaping the use of vaccines and antibiotics in the context of three factors: individual incentives, risk perceptions, and social norms and group dynamics. We illustrate how these factors contribute to the societal and individual costs of vaccine underuse and antimicrobial overuse. Ultimately, we seek to understand these factors that are at the nexus of infectious disease epidemiology and social science to inform policy-making.

Use of antimicrobial mouthwashes (gargling) and nasal sprays by healthcare workers to protect them when treating patients with suspected or confirmed COVID-19 infection.

BACKGROUND: COVID-19 infection poses a serious risk to patients and - due to its contagious nature - to those healthcare workers (HCWs) treating them. If the mouth and nose of HCWs are irrigated with antimicrobial solutions, this may help reduce the risk of active infection being passed from infected patients to HCWs through droplet transmission or direct contact. However, the use of such antimicrobial solutions may be associated with harms related to the toxicity of the solutions themselves, or alterations in the natural microbial flora of the mouth or nose. Understanding these possible side effects is particularly important when the HCWs are otherwise fit and well. OBJECTIVES: To assess the benefits and harms of antimicrobial mouthwashes and nasal sprays used by healthcare workers (HCWs) to protect themselves when treating patients with suspected or confirmed COVID-19 infection. SEARCH METHODS: Information Specialists from Cochrane ENT and Cochrane Oral Health searched the Central Register of Controlled Trials (CENTRAL 2020, Issue 6); Ovid MEDLINE; Ovid Embase and additional sources for published and unpublished trials. The date of the search was 1 June 2020.  SELECTION CRITERIA: This is a question that urgently requires evidence, however at the present time we did not anticipate finding many completed randomised controlled trials (RCTs). We therefore planned to include the following types of studies: RCTs; quasi-RCTs; non-randomised controlled trials; prospective cohort studies; retrospective cohort studies; cross-sectional studies; controlled before-and-after studies. We set no minimum duration for the studies.   We sought studies comparing any antimicrobial mouthwash and/or nasal spray (alone or in combination) at any concentration, delivered to HCWs, with or without the same intervention being given to the patients with COVID-19. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were: 1) incidence of symptomatic or test-positive COVID-19 infection in HCWs; 2) significant adverse event: anosmia (or disturbance in sense of smell). Our secondary outcomes were: 3) viral content of aerosol, when present (if intervention administered to patients); 4) other adverse events: changes in microbiome in oral cavity, nasal cavity, oro- or nasopharynx; 5) other adverse events: allergy, irritation/burning of nasal, oral or oropharyngeal mucosa (e.g. erosions, ulcers, bleeding), long-term staining of mucous membranes or teeth, accidental ingestion. We planned to use GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We found no completed studies to include in this review. We identified three ongoing studies (including two RCTs), which aim to enrol nearly 700 participants. The interventions included in these trials are povidone iodine, nitric oxide and GLS-1200 oral spray (the constituent of this spray is unclear and may not be antimicrobial in nature).   AUTHORS' CONCLUSIONS: We identified no studies for inclusion in this review. This is not surprising given the relatively recent emergence of COVID-19 infection. It is promising that the question posed in this review is being addressed by two RCTs and a non-randomised study. We are concerned that only one of the ongoing studies specifically states that it will evaluate adverse events and it is not clear if this will include changes in the sense of smell or to the oral and nasal microbiota, and any consequences thereof. Very few interventions have large and dramatic effect sizes. If a positive treatment effect is demonstrated when studies are available for inclusion in this review, it may not be large. In these circumstances in particular, where those receiving the intervention are otherwise fit and well, it may be a challenge to weigh up the benefits against the harms if the latter are of uncertain frequency and severity.

The effect of propolis supplementation on clinical symptoms in patients with coronavirus (COVID-19): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: This study aims to assess the effect of propolis supplementation on clinical symptoms in patients with coronavirus (COVID-19). TRIAL DESIGN: This is a Double-Blind, Placebo-Controlled, Parallel Arm, Randomized Phase ΙΙ Clinical Trial. PARTICIPANTS: Patients with the confirmed COVID-19 based on the PCR test are eligible to participate in the trial if they are 18 to 75 years of age and have no history of the current use of warfarin or propolis supplement and presence of sensitivity to bee products. Patients will be recruited from the Al-Zahra hospital in Isfahan city, Isfahan, Iran. INTERVENTION AND COMPARATOR: Participants (N=40) in the intervention group will receive an identical propolis tablet (containing 300 mg Iranian green propolis extract) three times a day for a period of 2 weeks. Participants (N=40) in the control group will receive an identical placebo tablet (containing 300 mg microcrystalline cellulose) three times a day for 2 weeks. All tablets are prepared by the Reyhan Naghsh Jahan Pharmaceutical Co., Isfahan, Iran. MAIN OUTCOMES: The main outcomes are changes in the coronavirus disease's clinical symptoms including duration and severity from baseline to the end of 2 weeks. RANDOMIZATION: Eligible patients will be randomly allocated in a 1:1 ratio to the intervention or control group. Randomization will be performed on the basis of permuted block sizes of 4 and will be stratified according to sex categories. Randomization sequences will be prepared by the trial's pharmacist with the use of random-number tables. BLINDING (MASKING): The trial-group assignment will be concealed from all participants, clinicians, and investigators throughout the trial. To ensure blinding, randomization sequences will be kept in identical, opaque, sealed, sequentially numbered envelopes. Only the trial's pharmacist has access to the randomization list. Also, the placebo tablet will be similar to the propolis tablet in terms of texture, taste, color, odor, and weight. Both tablets will be provided in containers that are completely identical in weight, shape, labelling, and packaging. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The calculated total sample size is 80 patients, with 40 patients in each group. TRIAL STATUS: The protocol is Version 1.0, October 10, 2020. Recruitment began August 22, 2020, and is anticipated to be completed by March 21, 2021. TRIAL REGISTRATION: The name of the trial register: The effect of propolis supplementation on clinical symptoms in patients with coronavirus (COVID-19): A randomized, double-blind, placebo-controlled clinical trial. IRCT registration number: IRCT20200802048267N1 . Date of trial registration: 20 October 2020, retrospectively registered. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.