Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0•9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0•9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.

Coronaviruses (CoVs) are enveloped, positive sense, single-stranded RNA viruses. The viruses have adapted to infect a large number of animal species, ranging from bats to camels. At present, seven CoVs infect humans, of which Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is responsible for causing the Coronavirus Disease 2019 (COVID-19) in humans. Since its emergence in late 2019, SARS-CoV-2 has spread rapidly across the globe. Healthcare systems around the globe have been stretched beyond their limits posing new challenges to emergency healthcare services and critical care. The outbreak continues to jeopardize human health, social life and economy. All known human CoVs have zoonotic origins. Recent detection of SARS-CoV-2 in pet, zoo and certain farm animals has highlighted its potential for reverse zoonosis. This scenario is particularly alarming, since these animals could be potential reservoirs for secondary zoonotic infections. In this article, we highlight interspecies SARS-CoV-2 infections and focus on the reverse zoonotic potential of this virus. We also emphasize the importance of potential secondary zoonotic events and the One-Health and One-World approach to tackle such future pandemics.

BACKGROUND: COVID-19 has caused havoc across the globe since, no specific treatment exists for this disease, thus, far. Hence, there is an urgent need to find an effective treatment to mitigate this scourge. Honey and Nigella sativa are two natural substances with anti-inflammatory, anti-viral, anti-microbial and immune modulating properties. They could be potentially beneficial in these patients. METHODS: We conducted an add-on, randomized, open label, placebo-controlled clinical trial using parallel group design. This was a multi-centered study with superiority framework conducted in RT-PCR confirmed COVID-19 patients showing moderate or severe disease. All patients receiving standard care were randomized into treatment and control groups. In the treatment arm, patients received HNS (honey plus Nigella sativa) in predefined doses for up to 13 days. The primary outcome measures (time taken for alleviation of symptoms, viral clearance and clinical status improvement on day 6) outcomes were assessed. RESULTS: Of 1046 patients testing positive for the SARS-CoV-2, 210 showing moderate and 103 showing severe disease were randomized into treatment and control groups as per inclusion criteria. In the moderate cases, 107 were assigned to the HNS group and 103 to the control group. Among 103 severe cases, 50 were assigned to the HNS group and 53 to the control group. In the moderate and severe cases, the HNS treatment was associated with a normalized median symptoms alleviation time reduction of 3 and 7 days (HR: 6.11; 95% CI: 4.23-8.84 and HR: 4.04; 95% CI, 2.46-6.64) respectively. The HNS treatment in both groups were further associated with 4 days earlier reduction in median viral clearance time (Moderate HR: 5.53; 95% CI: 3.76-8.14) and Severe HR: 4.32; 95% CI: 2.62-7.13). Moreover, in the intention-to-treat analysis, the HNS groups led to a lower (better) clinical score on day 6 with resumption of normal activity among 63.6% of the moderate (OR: 0.07; 95% CI: 0.03-0.13) and 28% of severe cases (OR: 0.03; 95% CI: 0.01-0.09). Furthermore, a significant (14.87%) reduction (OR: 0.18; 95% CI: 0.02-0.92) in mortality was observed in the HNS arm. No difference in adverse effects were seen between the HNS and control arms. CONCLUSIONS: A significant reduction in in the severity of disease, the time taken for viral clearance and mortality was observed with HNS treatment in COVID-19 patients. HNS represents a safe, effective, over the counter and affordable therapy for this pandemic essentially lowering health care burden. It can be used alone or in combination with other expensive treatments and give an additive effect. Hence, the potential of HNS against COVID-19 should be explored in future larger studies. (Funded by Smile Welfare Organization, Shaikh Zayed Medical Complex and Services Institute of Medical Sciences; NIH Clinical Trial Register number: NCT04347382.)

Until now, no specific and effective treatment exists for coronavirus disease 2019 (COVID‐19). Since honey and Nigella sativa (HNS) have established antiviral, antibacterial, antiinflammatory, antioxidant, and immunomodulatory properties, we tested their efficacy for this disease in a multicenter, placebo‐controlled, and randomized clinical trial at four medical care facilities in Pakistan. RT‐PCR confirmed COVID‐19 adults showing moderate or severe disease were enrolled in the trial. Patients were randomly assigned in a 1:1 ratio to receive either honey (1 g kg−1 day−1) and Nigella sativa seeds (80 mg kg−1 day−1) or a placebo for up to 13 days along with standard care. The outcomes included symptoms' alleviation, viral clearance, and 30‐day mortality in the intention‐to‐treat population. Three hundred and thirteen patients, 210 with moderate and 103 with severe disease, underwent randomization from April 30 to July 29, 2020. Among the moderate cases, 107 were assigned to HNS, whereas 103 were assigned to the placebo group. Among the severe cases, 50 were given HNS, and 53 were given the placebo. HNS resulted in ~50% reduction in time taken to alleviate symptoms as compared to placebo (moderate cases: 4 vs. 7 days, Hazard Ratio [HR]: 6.11; 95% Confidence Interval [CI]: 4.23–8.84, p < 0.0001 and for severe cases: 6 vs. 13 days, HR: 4.04; 95% CI: 2.46–6.64; p < 0.0001). HNS also cleared the virus earlier than placebo in both moderate cases (6 vs. 10 days, HR: 5.53; 95% CI: 3.76–8.14, p < 0.0001) and severe cases (8.5 vs. 12 days, HR: 4.32; 95% CI: 2.62–7.13, p < 0.0001). HNS further led to a better clinical score on day 6 with normal activity resumption in 63.6% vs. 10.9% among moderate cases (OR: 0.07; 95% CI: 0.03–0.13, p < 0.0001) and hospital discharge in 50% versus 2.8% in severe cases (OR: 0.03; 95% CI: 0.01–0.09, p < 0.0001). In severe cases, the mortality rate was less than 1/4th in the HNS group than in placebo (4% vs. 18.87%, OR: 0.18; 95% CI: 0.02–0.92, p = 0.029). No HNS‐related adverse effects were observed. HNS, compared with placebo, significantly improved symptoms, expedited viral load clearance, and reduced mortality in COVID‐19 patients. This trial was registered on April 15, 2020 with ClinicalTrials.gov Identifier: NCT04347382.

Objectives Considering the therapeutic potential of honey and Nigella sativa (HNS) in coronavirus disease 2019 (COVID-19) patients, the objective of the study is defined to evaluate the prophylactic role of HNS. Trial design The study is a randomized, placebo-controlled, adaptive clinical trial with parallel group design, superiority framework with an allocation ratio of 1:1 among experimental (HNS) and placebo group. An interim analysis will be done when half of the patients have been recruited to evaluate the need to adapt sample size, efficacy, and futility of the trial. Participants All asymptomatic patients with hospital or community based COVID-19 exposure will be screened if they have had 4 days exposure to a confirmed case. Non-pregnant adults with significant exposure level will be enrolled in the study High-risk exposure (<6 feet distance for >10min without face protection) Moderate exposure (<6 feet distance for >10min with face protection) Subjects with acute or chronic infection, COVID-19 vaccinated, and allergy to HNS will be excluded from the study. Recruitment will be done at Shaikh Zayed Post-Graduate Medical Institute, Ali Clinic and Doctors Lounge in Lahore (Pakistan). Intervention and comparator In this clinical study, patients will receive either raw natural honey (0.5 g) and encapsulated organic Nigella sativa seeds (40 mg) per kg body weight per day or empty capsule with and 30 ml of 5% dextrose water as a placebo for 14 days. Both the natural products will be certified for standardization by Government College University (Botany department). Furthermore, each patient will be given standard care therapy according to version 3.0 of the COVID-19 clinical management guidelines by the Ministry of National Health Services of Pakistan. Main outcomes Primary outcome will be Incidence of COVID-19 cases within 14 days of randomisation. Secondary endpoints include incidence of COVID-19-related symptoms, hospitalizations, and deaths along with the severity of COVID-19-related symptoms till 14th day of randomization. Randomisation Participants will be randomized into experimental and control groups (1:1 allocation ratio) via the lottery method. There will be stratification based on high risk and moderate risk exposure. Blinding (masking) Quadruple blinding will be ensured for the participants, care providers and outcome accessors. Data analysts will also be blinded to avoid conflict of interest. Site principal investigator will be responsible for ensuring masking. Numbers to be randomised (sample size) 1000 participants will be enrolled in the study with 1:1 allocation. Trial Status The final protocol version 1.4 was approved by institutional review board of Shaikh Zayed Post-Graduate Medical Complex on February 15, 2021. The trial recruitment was started on March 05, 2021, with a trial completion date of February 15, 2022. Trial registration Clinical trial was registered on February 23, 2021, www.clinicaltrials.gov with registration ID NCT04767087. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.