Repurposing naproxen as a potential nucleocapsid antagonist of beta-coronaviruses: targeting a conserved protein in the search for a broad-spectrum treatment option.

Ongoing mutations in the coronavirus family, especially beta-coronaviruses, raise new concerns about the possibility of new unexpected outbreaks. Therefore, it is crucial to explore new alternative treatments to reduce the impact of potential future strains until new vaccines can be developed. A promising approach to combat the virus is to target its conserved parts such as the nucleocapsid, especially via repurposing of existing drugs. The possibility of this approach is explored here to find a potential anti-nucleocapsid compound to target these viruses. 3D models of the N- and C-terminal domains (CTDs) of the nucleocapsid consensus sequence were constructed. Each domain was then screened against an FDA-approved drug database, and the most promising candidate was selected for further analysis. A 100 ns molecular dynamics (MD) simulation was conducted to analyze the final candidate in more detail. Naproxen was selected and found to interact with the N-terminal domain via conserved salt bridges and hydrogen bonds which are completely conserved among all Coronaviridae members. MD analysis also revealed that all relevant coordinates of naproxen with N terminal domain were kept during 100 ns of simulation time. This study also provides insights into the specific interaction of naproxen with conserved RNA binding pocket of the nucleocapsid that could interfere with the packaging of the viral genome into capsid and virus assembly. Additionally, the in-vitro binding assay demonstrated direct interaction between naproxen and recombinant nucleocapsid protein, further supporting the computational predictions.Communicated by Ramaswamy H. Sarma.

Relationship between smoking and tuberculosis recurrence: A systematic review and meta-analysis.

INTRODUCTION: Of the problems in tuberculosis (TB) control program is the recurrence of this disease. In some studies, smoking has been reported as the most important risk factor. Therefore, the present study aimed at examining the association between smoking and tuberculosis recurrence using meta-analysis. METHODS: To report the findings of this meta-analysis, we used PRISMA. The protocol of this study has been recorded in PROSPERO. The research question has been formulated based on PICO, and the search was performed using both MeSH and non-MeSH keywords. After screening and selecting the articles and evaluating their quality using the NOS checklist, the overall estimate of the odds ratio of tuberculosis recurrence in smokers was assessed with a 95% confidence interval. RESULTS: Fourteen studies met the inclusion criteria. The total number of samples in the group of patients with tuberculosis recurrence was 1988 with 855 (43%) smokers, and in the group of patients affected by tuberculosis without recurrence, it was 27,226 with 7503 (27.56%) smokers. In 13 studies, the odds ratio of tuberculosis recurrence was higher in smokers; this difference was statistically significant in 12 of them. Combining the results of these 14 studies, the odds ratio of tuberculosis recurrence in smokers was 2.10 times higher, using the random effects model (95% CI:1.69, 2.61). CONCLUSION: Based on the results of study present, smoking increases the risk of tuberculosis recurrence. Therefore, to eradicate tuberculosis by 2030, more serious interventions should be taken to quit smoking, which in turn reduces the incidence of tuberculosis.

Inhalation phage therapy as a new approach to preventing secondary bacterial pneumonia in patients with moderate to severe COVID-19: A double-blind clinical trial study.

Inhalation phage therapy is proposed as a replacement approach for antibiotics in the treatment of pulmonary bacterial infections. This study investigates phage therapy on bacterial pneumonia in patients with moderate to severe COVID-19 via the inhalation route. In this double-blind clinical trial, 60 patients with positive COVID-19 hospitalized in three central Mazandaran hospitals were chosen and randomly divided into two intervention and control groups. Standard country protocol drugs plus 10 mL of phage suspension every 12 h with a mesh nebulizer was prescribed for 7 days in the intervention group. The two groups were compared in terms of O2Sat, survival rate, severe secondary pulmonary bacterial infection and duration of hospitalization. Comparing the results between the intervention and control group, in terms of the trend of O2Sat change, negative sputum culture, no fever, no dyspnea, duration of hospitalization, duration of intubation and under ventilation, showed that the difference between these two groups was statistically different (P value < 0.05). In conclusion, inhalation phage therapy may have a potential effect on secondary infection and in the outcome of COVID-19 patients. However, more clinical trials with control confounding factors are needed to further support this concept.

Prevalence of hepatitis B and C virus infections and immunity among hemodialysis patients in the Mazandaran province, Northern Iran.

Background: Hemodialysis (HD) is one of the most common causes of blood-borne infections. In order to prevent viral hepatitis and confront with the virus on the next step, health providers specify infected patients by screening and vaccination. This study is designed to investigate the prevalence of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections in HD patients in Mazandaran, Iran. Methods: The medical records of 216 patients referred to the hemodialysis centers were evaluated in this cross-sectional study between 2019 and 2020. The collected data was analyzed using t-test and Chi-square. Results: Among 216 patients, 106 cases were female (49.07%) and 110 subjects were male (50.9%). The mean age was 40.1 y/o in females and 50.9 y/o in the male patients. The study recorded nine HBs-Ag positive (prevalence: 0.06%) and 15 HCV-Ab positive (prevalence: 6.94%) patients. Also, the most common co-morbidities were diabetes and hypertension. It was observed that 13 patients from 34 patients with negative HBs-Ag (who had 10-100 U HBs-Ab in the first stage) experienced sudden drop in the antibody titration to less than 10 U (P < 0.05). From 50 HBs-Ag negative patients with HBs-Ab more than 100 U in the first stage, antibody titration of five patients was decreased to less than 10 U in the second stage (P < 0.05). Conclusions: The prevalence of HCV and HBV was low in HD patients in Mazandaran province. However, due to the large number of patients with non-protective HBs-Ab levels, there is a risk of an increased prevalence of the disease.

Non-effectiveness of Ivermectin on Inpatients and Outpatients With COVID-19; Results of Two Randomized, Double-Blinded, Placebo-Controlled Clinical Trials.

Background: Ivermectin which was widely considered as a potential treatment for COVID-19, showed uncertain clinical benefit in many clinical trials. Performing large-scale clinical trials to evaluate the effectiveness of this drug in the midst of the pandemic, while difficult, has been urgently needed. Methods: We performed two large multicenter randomized, double-blind, placebo-controlled clinical trials evaluating the effectiveness of ivermectin in treating inpatients and outpatients with COVID-19 infection. The intervention group received ivermectin, 0.4mg/kg of body weight per day for 3 days. In the control group, placebo tablets were used for 3 days. Results: Data for 609 inpatients and 549 outpatients were analyzed. In hospitalized patients, complete recovery was significantly higher in the ivermectin group (37%) compared to placebo group (28%; RR, 1.32 [95% CI, 1.04-1.66]; p-value = 0.02). On the other hand, the length of hospital stay was significantly longer in the ivermectin group with a mean of 7.98 ± 4.4 days compared to the placebo receiving group with a mean of 7.16 ± 3.2 days (RR, 0.80 [95% CI, 0.15-1.45]; p-value = 0.02). In outpatients, the mean duration of fever was significantly shorter (2.02 ± 0.11 days) in the ivermectin group versus (2.41 ± 0.13 days) placebo group with p value = 0.020. On the day seventh of treatment, fever (p-value = 0.040), cough (p-value = 0.019), and weakness (p-value = 0.002) were significantly higher in the placebo group compared to the ivermectin group. Among all outpatients, 7% in ivermectin group and 5% in placebo group needed to be hospitalized (RR, 1.36 [95% CI, 0.65-2.84]; p-value = 0.41). Also, the result of RT-PCR on day five after treatment was negative for 26% of patients in the ivermectin group versus 32% in the placebo group (RR, 0.81 [95% CI, 0.60-1.09]; p-value = 0.16). Conclusion: Our data showed, ivermectin, compared with placebo, did not have a significant potential effect on clinical improvement, reduced admission in ICU, need for invasive ventilation, and death in hospitalized patients; likewise, no evidence was found to support the prescription of ivermectin on recovery, reduced hospitalization and increased negative RT-PCR assay for SARS-CoV-2 5 days after treatment in outpatients. Our findings do not support the use of ivermectin to treat mild to severe forms of COVID-19. Clinical Trial Registration: www.irct.ir IRCT20111224008507N5 and IRCT20111224008507N4.

IFI27 transcription is an early predictor for COVID-19 outcomes, a multi-cohort observational study.

Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. Methods: We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. Results: We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. Conclusion: These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.

Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial.

INTRODUCTION: Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and daclatasvir versus standard care for outpatients with mild COVID-19 infection. METHODS: This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1. RESULTS: Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/daclatasvir arm and 16 in the control arm; P < 0.001. CONCLUSIONS: In this study, sofosbuvir/daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/daclatasvir arm, this was not statistically significant. Sofosbuvir/daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.

The combination of sofosbuvir and daclatasvir is effective and safe in treating patients with hepatitis C and severe renal impairment.

BACKGROUND AND AIM: Many of the treatment regimens available for hepatitis C include sofosbuvir. Unfortunately, sofosbuvir has not been recommended for use in patients with severe renal impairment leaving these group of patients with very few options. Nevertheless, there are many reports in which these patients have been treated with sofosbuvir-containing regiments without important adverse events. This study aims at determining the safety and effectiveness of a sofosbuvir-based treatment in patients with severe renal impairment, including those on hemodialysis. METHOD: We enrolled subjects with hepatitis C and estimated glomerular filtration rate under ml/min/1.73m2 from 13 centers in Iran. Patients were treated for 12 weeks with a single daily pill containing 400-mg sofosbuvir and 60-mg daclatasvir. Patients with cirrhosis were treated for 24 weeks. Response to treatment was evaluated 12 weeks after end of treatment (sustained viral response [SVR]). ClinicalTrials.gov identifier: NCT03063879. RESULTS: A total of 103 patients were enrolled from 13 centers. Seventy-five patients were on hemodialysis. Thirty-nine had cirrhosis and eight were decompensated. Fifty-three were Genotype 1, and 27 Genotype 3. Twenty-seven patients had history of previous failed interferon-based treatment. Three patients died in which cause of death was not related to treatment. Six patients were lost to follow-up. The remaining 94 patients all achieved SVR. No adverse events leading to discontinuation of medicine was observed. CONCLUSIONS: The combination of sofosbuvir and daclatasvir is an effective and safe treatment for patients infected with all genotypes of hepatitis C who have severe renal impairment, including patients on hemodialysis.

Serum mannan-binding lectin in patients with pulmonary tuberculosis: Its lack of a relationship to the disease and response to treatment.

Background: Lectin pathway mediates complement activation, which is activated by many microorganisms. This study aimed at determining the serum levels of mannose-binding lectin (MBL) in patients with pulmonary tuberculosis, assessing its relationship to antiuberculosis treatment response, and comparing them with a control group. Methods: This cross-sectional study was conducted on patients with pulmonary tuberculosis during 2012 and 2013 in South West of Iran. PPD-ST-negative individuals were selected as controls from healthy relatives of patients. Serum MBL levels were measured using ELISA kit (Human MBL HK323, Hycultbiotech Company, Netherlands). All patients were followed- up for response to treatment. We applied Mann-Whitney and Fisher's exact tests and used SPSS Version 17 software for statistical analysis. Results: The study included 62 patients as the case group and 63 noninfected TB patients as the control group. The MBL (ng/mL) in patients with pulmonary tuberculosis (median = 1012) was significantly (p= 0.037) higher than that of the control group (median= 296.2). No significant difference was found in the MBL level (ng/mL) between patients with response to antituberculosis treatment (median= 1012) and patients with treatment failure (median= 798.9) (p= 0.84). Conclusion: MBL may be involved in the pathogenesis of tuberculosis and in the low values that are protective against tuberculosis, and it seems that it has no effect on the antituberculosis treatment response.

Antibiotics use patterns for surgical prophylaxis site infection in different surgical wards of a teaching hospital in ahvaz, iran.

BACKGROUND: Despite the effectiveness of prophylactic antimicrobials to prevent surgical site infection the use of antibiotic prophylaxis is often inappropriate. OBJECTIVES: The current study aimed to determine the pattern of prophylactic antibiotic use in a teaching hospital affiliated to Jundishapur University of Medical Sciences, Ahvaz, Iran. PATIENTS AND METHODS: The current descriptive study included 8586 patients who received prophylactic antibiotics before surgery from April 2011 to March 2012, in Razi Hospital affiliated to Jundishapur University of Medical Sciences. Indications for antibiotic use, proper or inappropriate antibiotics, an antibiotic or combination of antibiotics, dosage and length of treatment for each patient based on the infectious disease textbook (Mandel's Principle and practice of infectious diseases) definitions were administrated. RESULTS: Of the total 8586 patients who took antibiotics for preventive purposes, 4815 (56%) required antimicrobial prophylaxis, and 3771 (44%) patients did not. Of the 4815 patients who received prophylaxis, 86.9% received it appropriately, 13.1% received it inappropriately; 8.2% received inappropriate dosage, and 9.5% received antibiotic longer than 24 hours. CONCLUSIONS: The current study revealed that 44% of those who received prophylaxis did not need it. In the patients who received antibiotics, the most common mistakes were antibiotic selection followed by prolonged prophylaxis (> 24 hours) and excess dose.

Investigation of the effect of ginger on the lipid levels. A double blind controlled clinical trial.

OBJECTIVE: To study the effect of fine powder of ginger on lipid level in volunteer patients. METHODS: This is a double blind controlled clinical trial study in 2 cardiac clinics Cardiac Disease Clinic, Babol, north of Iran, between April to May 2004. We randomly divided the patients with hyperlipidemia into 2 groups, treatment group (receiving ginger capsules 3 g/day in 3 divided doses) and placebo group (lactose capsule 3 g/day in 3 divided doses) for 45 days. All subjects with diabetes mellitus, hypothyroidism, nephrotic syndrome, and alcohol drinking, pregnancy and peptic ulcer were excluded. Lipid concentrations profile before and after treatment was measured by enzymatic assay. RESULTS: Forty-five patients in the treatment group and 40 patients in placebo group participated in this study. There was a significant reduce in triglyceride, cholesterol, low density lipoprotein (LDL), very low density lipoprotein (VLDL), levels of before and after study separately in each group (p<0.05). Mean changes in triglyceride and cholesterol levels of ginger group were significantly higher than placebo group (p<0.05). Mean reduction in LDL level and increase in high density lipoprotein level of ginger group were higher than the placebo group, but in VLDL level of placebo was higher than ginger (p>0.05). CONCLUSION: The results show that ginger has a significant lipid lowering effect compared to placebo.