Comparing efficacy and safety of high-dose and standard-dose rifampicin in the treatment of brucellosis: a randomized clinical trial.

BACKGROUND: In a few studies, higher doses of rifampicin improved the outcome of patients with TB. There is no information regarding efficacy and safety of higher doses of rifampicin in patients with brucellosis. OBJECTIVES: To compare efficacy and safety of higher and standard doses of rifampicin, each with doxycycline, in the treatment of patients with brucellosis. METHODS: Within a randomized clinical trial, clinical response and adverse events of high-dose rifampicin (900-1200 mg/day) plus doxycycline 100 mg twice daily were compared with standard-dose rifampicin (600 mg/day) plus doxycycline 100 mg twice daily in 120 patients with brucellosis. RESULTS: Clinical response occurred in 57 (95%) of patients in the high-dose group and 49 (81.66%) of patients in the standard-dose group (P = 0.04). The most common adverse events of the treatment were nausea (37.5%), skin rash (13.33%), vomiting (10%) and transaminitis (7.22%). Incidence of these events was comparable between the groups. CONCLUSIONS: The rate of clinical response in patients with brucellosis who were treated with high-dose rifampicin plus standard-dose doxycycline was significantly higher than in the patients who received the standard doses of rifampicin and doxycycline, without further adverse events. The high-dose rifampicin therefore improved clinical response in patients with brucellosis with a similar safety profile to the standard dose. If these findings are confirmed in future studies, higher doses of rifampicin may be recommended for treatment of patients with brucellosis.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

DRESS Syndrome Induced by Sorafenib in a Patient With Medullary Thyroid Cancer: A Case Report.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and life-threatening hypersensitivity reaction. It is characterized by fever, skin lesions, and internal organ involvement. Sorafenib is a tyrosine kinase inhibitor that is used for the treatment of certain cancers such as hepatocellular, renal cell, and thyroid cancer. Case Presentation: The case is a 40 years old man who presented with fever, generalized skin rash, and pruritus. The patient has received sorafenib for the treatment of medullary thyroid cancer (MTC) from 3 weeks ago. Following presentation, the drug was discontinued and causality was assessed by scoring system RegiSCAR and Naranjo scale that showed a probable DRESS. There was no internal organ involvement based on the laboratory evaluations. The considerable abnormality was eosinophilia among patient's laboratory tests. Antihistamines and topical and systemic corticosteroids were utilized for the management of the symptoms. Conclusion: To the best of our knowledge, this is the first case report of DRESS syndrome by sorafenib in the patients with MTC. Clinicians should be aware of sign and symptoms suggesting DRESS syndrome of sorafenib.

A Randomized Clinical Trial of the Efficacy and Safety of Interferon ß-1a in Treatment of Severe COVID-19.

To the best of our knowledge, there is no published study on the use of interferon ß-1a (IFN ß-1a) in the treatment of severe COVID-19. In this randomized clinical trial, the efficacy and safety of IFN ß-1a were evaluated in patients with severe COVID-19. Forty-two patients in the interferon group received IFN ß-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir). Each 44-µg/ml (12 million IU/ml) dose of interferon ß-1a was subcutaneously injected three times weekly for two consecutive weeks. The control group consisted of 39 patients who received only the national protocol medications. The primary outcome of the study was time to reach clinical response. Secondary outcomes were duration of hospital stay, length of intensive care unit stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects, and complications during the hospitalization. Between 29 February and 3 April 2020, 92 patients were recruited, and a total of 42 patients in the IFN group and 39 patients in the control group completed the study. As the primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 ± 5.8 versus 8.3 ± 4.9 days, respectively, P = 0.95). On day 14, 66.7% versus 43.6% of patients in the IFN group and the control group, respectively, were discharged (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.05 to 6.37). The 28-day overall mortality was significantly lower in the IFN than the control group (19% versus 43.6%, respectively, P = 0.015). Early administration significantly reduced mortality (OR, 13.5; 95% CI, 1.5 to 118). Although IFN did not change the time to reach the clinical response, adding it to the national protocol significantly increased discharge rate on day 14 and decreased 28-day mortality. (This study is in the Iranian Registry of Clinical Trials under identifier IRCT20100228003449N28.).

Acute cerebellar toxicity induced by high dose of cytarabine (HiDAC): A case report.

Cytarabine is a pyrimidine analogue that is used for the treatment of acute myeloid leukemia at different doses. Standard doses of cytarabine are used for induction therapy, while high doses are used for post-remission (consolidation) and relapsed/refractory treatment. One of the major side effects of its high doses is acute cerebellar toxicity occurring in 10 to 25% of patients. We report a case that developed this side effect after receiving two doses of high-dose cytarabine. The patient's symptoms improved after withholding the drug. Thereafter, the patient tolerated treatment continuation with lower doses.

Effects of Different Concentrations of Reversine on Plasticity of Mesenchymal Stem Cells.

Dedifferentiation can be induced by small molecules. One of these small molecules used in this study in order to increase the plasticity of differentiation of stem cells was reversine. The objective of present study was to investigate the effect of different concentrations of reversine on the plasticity of ovine fetal bone-marrow mesenchymal stem cells (BM-MSCs). BM-MSCs were extracted from ovine fetal and cultured. Passaged-3 cells were evaluated for their differentiation potential into osteocytes and adipocytes cells. In the present study, BM-MSCs were culture plated in the presence of 0, 300, 600, 900 and 1200 nM of reversine. The number of viable cells was determined by MTT test after addition of different concentrations of reversine. Furthermore, expression of the nanog gene was evaluated. The culture without reversine was taken as the control group. Expression of nanog was analysed by immunocytochemistry. Multi-lineage differentiation showed that the BM-MSCs could be differentiated into adipose cells and osteocytes. Our results indicated that the addition of 1200 nM of reversine to medium significantly decreased overall proliferation compared to the other treatment groups (p > 0.05). Real-time PCR analysis showed that after addition of 600 nM of reversine significantly increased nanog expression compared to other treatments. All treatments received reversine were seen to be relative expression of nanog. Our findings confirm that low concentrations reversine increases the plasticity of ovine BM-MSCs.

Characterization and Classification of Mesenchymal Stem Cells in Several Species Using Surface Markers for Cell Therapy Purposes.

Mesenchymal stem cells are multipotent cells capable of replicating as undifferentiated cells, and have the potential of differentiating into mesenchymal tissue lineages such as osteocytes, adipocytes and chondrocytes. Such lineages can then be used in cell therapy. The aim of present study was to characterize bone marrow derived mesenchymal stem cells in four different species, including: sheep, goat, human and mouse. Human bone-marrow mesenchymal stem cells were purchased, those of sheep and goat were isolated from fetal bone marrow, and those of mouse were collected by washing bone cavity of femur and tibia with DMEM/F12. Using flow-cytometry, they were characterized by CD surface antigens. Furthermore, cells of third passage were examined for their osteogenic and adipogenic differentiation potential by oil red and alizarin red staining respectively. According to the results, CD markers studied in the four groups of mesenchymal stem cells showed a different expression. Goat and sheep expressed CD44 and CD166, and weakly expressed CD34, CD45, CD105 and CD90. Similarly, human and mouse mesenchymal cells expressed CD44, CD166, CD105 and CD90 whereas the expression of CD34 and CD45 was negative. In conclusion, although all mesenchymal stem cells display plastic adherence and tri-lineage differentiation, not all express the same panel of surface antigens described for human mesenchymal stem cells. Additional panel of CD markers are necessary to characterize regenerative potential and possible application of these stem cells in regenerative medicine and implantology.

Ovine fetal mesenchymal stem cell differentiation to cardiomyocytes, effects of co-culture, role of small molecules; reversine and 5-azacytidine.

The aim of the present study was to investigate the effect of small molecules: Reversine and 5-azacytidine (5-AC), in an indirect co-culture condition with the cardiac fibroblasts as well as non co-culture condition, in order to explore the effect of such molecules in the process of differentiation of the ovine bone-marrow mesenchymal stem cells (BM-MSCs) towards cardiomyocytes. Surface antigens of the isolated cells were analysed using flow-cytometry. In addition, following to three passages cells were examined for their differentiation capacity into osteocytes and adipose cells, in order to ensure the mesenchymal origin of the stem cells. Six types of treatments were carried out in the present investigation, such that, in the first treatment BM-MSCs were cultured for 28 days as control group; the second treatment was composed of culturing ovine fetal cardiac fibroblasts on inserts, aiming to use these inserts for culturing plates which were seeded with BM-MSCs (Chamber group). As the third treatment, BM-MSCs were supplemented with 10-µM 5-AC and incubated for 48 h. The fourth treatment was composed of supplementing BM-MSCs with the 600-nM reversine, incubated for 48 h, and subsequently the incubation was further extended for another 48 h in the presence of 5-AC. The fifth treatment was composed of supplementing the chamber group with 10-µM 5-AC and incubation for 48 h, and the last or the sixth treatment was such that chamber group was supplemented with 600-nM reversine and an incubation period of 48 h. Following to the incubation, medium was replaced with 10-µM 5-AC and further incubated for another round of 48 h. In all treatments, following to addition of the small molecules incubations were carried out for 28 days; same as controls. Expression of cardiac alpha-actinin was analysed by immunocytochemistry. BM-MSCs have shown to express CD44 and CD166 along with a weak expression of the CD90, CD34, in addition to CD45. Multilineage differentiation has indicated that BM-MSCs could differentiate into adipose and osteocytes cells as well. In the treatment 4 it was observed that FGF signalling involved genes and all cardiac-related genes (ANP, MYH6 and Troponin I) were significantly expressed, except connexin 43 compared to other treatments. All treatments received small molecules, either alone or as a co-culture were seen to express sarcomeric alpha-actinin. This finding was partially supported by immunocytochemistry. These results validate that reversine and 5-AC have an effect on ovine BM-MSC differentiation into cardiomyocytes. Copyright © 2016 John Wiley & Sons, Ltd.

The interfering effects of superovulation and vitrification upon some important epigenetic biomarkers in mouse blastocyst.

Appropriate epigenetic changes in preimplantation embryos are critical for embryonic development and successful pregnancy. The aim of this study was to evaluate the effects of some assisted reproductive techniques (ARTs) on a panel of epigenetic biomarkers by immunofluorescence staining at blastocyst stage. For this purpose, four treatment groups were designed: control (C), superovulation (S), superovulation+in vitro culture (SI), and superovulation+vitrification+in vitro culture (SVI). Results showed that vitrification decreased the developmental competence of embryos cultured in vitro (P<0.05). Semi-quantitative analysis revealed that vitrification decreased the fluorescence intensity of global DNA methylation in the inner cell mass (ICM), in SVI Group in comparison to C group (P<0.05). Superovulation, elevated the level of H3K9acetylation of trophectoderm (TE) in comparison to C and SI groups (P<0.05). Furthermore, ARTs manipulations influenced H3K9acetylation in the ICM (P<0.05). The fluorescence intensity of H4K12acetylation in TE for SVI group was higher than C and S (P<0.05). For H3K4tri-methylation, S group had higher fluorescence intensity in the ICM in comparison to SI and SVI (P<0.05). Finally, in vitro culture decreased Pou5f1 protein signal in comparison to in vivo-derived embryos at blastocyst stage (P<0.05). In conclusion, ART manipulations may have important influences on multiple epigenetic biomarkers.

Performance of biological methods on self-healing and mechanical properties of concrete using S. pasteurii.

Biological methods (adding bacteria to the concrete mixtures) among the most recently investigated procedures increase the durability of concrete and repair concrete cracks. In the present study, different biological methods were used to heal the cracks of concrete and the most suitable method was subsequently introduced as the main aim of the research. For this purpose, the culture medium, various sources of calcium salts as bacterial nutrients, and the effect of air-entrained agent on the healing process were studied. The results showed that the use of bacterial nutrient inside the concrete mixes has an affirmative impact on the mechanical properties and self-healing characteristics of concretes. Simultaneous use of Sporosarcina pasteurii bacteria and calcium nitrate-urea or calcium chloride-urea as a bacterial nutrient in the concrete mixture increased the 28 days compressive strength of concretes by 23.4% and 7.5%, respectively. The utilization of bacterial cells, nutrients, and culture in the concrete mixture provided the ability to heal wide cracks where the healing time was significantly reduced (about 8 days). On the other hand, separation of the bacterial culture medium slightly reduced the self-healing performance of the concretes.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Prevention of Vancomycin-Induced Nephrotoxicity; An Updated Review of Clinical and Preclinical Studies.

PURPOSE: This paper aims to review clinical and preclinical evidence regarding new strategies for the prevention of vancomycin-induced nephrotoxicity. METHODS: Evidence from 2014 to the end of 2019 was included. Twelve animal studies and one clinical trial were evaluated. RESULTS: Although the incidence of vancomycin-induced nephrotoxicity was not reduced significantly in the clinical trial, antioxidants reduced the incidence of vancomycin-induced nephrotoxicity in preclinical studies. CONCLUSION: Antioxidants including vitamin C, vitamin E, cilastatin, melatonin, zingerone, rutin, naringenin, saffron, silymarin, and dexmedetomidine were nephroprotective against vancomycininduced nephrotoxicity in preclinical studies. The nephroprotective effects of these antioxidants must be confirmed before routine use in clinical practice.

Comparing efficacy and safety of tocilizumab and methylprednisolone in the treatment of patients with severe COVID-19.

OBJECTIVES: This study was designed to compare the efficacy and safety of methylprednisolone and tocilizumab in the treatment of patients with severe COVID-19. METHODS: During a prospective cohort study, hospitalized patients with severe COVID-19 received intravenous methylprednisolone (250-500 mg daily up to three doses), weight-based tocilizumab (maximum 800 mg, one or two doses as daily interval) or dexamethasone (8 mg daily). The primary outcome was time to onset of clinical response. Secondary outcomes were improvement rate of oxygen saturation and CRP, need for ICU admission, duration of hospitalization and 28-day mortality. During study, adverse events of the treatments were recorded. RESULTS: Although the difference was not statistically significant (p = 0.090), clinical response occurred faster in the tocilizumab group than other groups (10 vs. 16 days). Clinical response was detected in 74.19%, 81.25%, and 60% of patients in the methylprednisolone, tocilizumab, and dexamethasone groups respectively (p = 0.238). Based on the Cox regression analysis and considering dexamethasone as the reference group, HR (95% CI) of clinical response was 1.08 (0.65-1.79) and 1.46 (0.89-2.39) in the methylprednisolone and tocilizumab groups respectively. Improvement rate of oxygen saturation and CRP was not significantly different between the groups (p = 0.791 and p = 0.372 respectively). Also need for ICU admission and 28-day mortality was comparable between the groups (p = 0.176 and p = 0.143 respectively). Compared with methylprednisolone, tocilizumab caused more sleep disturbances (p = 0.019). Other adverse events were comparable among patients in the groups. CONCLUSION: When or where access to tocilizumab is a problem, methylprednisolone may be considered as an alternative for the treatment of patients with severe COVID-19.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Intravenous magnesium sulfate for prevention of vancomycin plus piperacillin-tazobactam induced acute kidney injury in critically ill patients: An open-label, placebo-controlled, randomized clinical trial.

BACKGROUND: Recent studies have shown an increased risk of acute kidney injury (AKI) induced by vancomycin + piperacillin-tazobactam (VPT) combination. In this study, the efficacy of intravenous magnesium sulfate in prevention of VPT induced AKI in critically ill patients admitted to the ICU has been evaluated. METHODS: In an open-label, placebo-controlled, randomized clinical trial, 72 adults (≥ 18 years old) who had indications to receive VPT as empiric therapy were assigned to the magnesium or control group in 1:1 ratio. Concomitant with VPT, intravenous infusion of magnesium sulfate was started for patients in the magnesium group. The target serum level of magnesium was defined 3 mg/dl. Patients in the control group received normal saline as placebo. The target serum level of magnesium was defined 1.9 mg/dl in this group. The study's primary outcome was incidence of AKI during and up to 48 h after the treatment course. Escalation and de-escalation of VPT regimen, duration of hospitalization, length of ICU stay and 28-day mortality were secondary outcomes. RESULTS: Thirty patients in each group completed the examination. Five patients in the magnesium group and 11 patients in the control group experienced AKI (p = 0.072). De-escalation of VPT regimen was done approximately in 60% of patients. Duration of hospitalization and length of ICU stay were not statistically different between the groups. Finally, 28-day mortality was 23.33% in each group. Although the incidence of AKI was not statistically different between the groups in unadjusted logistic regression model, it became significant after adjusting for confounding factors [unadjusted model (OR = 0.34; 95% CI: 0.10-1.16, p = 0.084), adjusted model: (OR = 0.26; 95% CI: 0.07-0.96, p = 0.04)]. CONCLUSIONS: Administration of magnesium sulfate with the target serum levels around 3 mg/dL reduced the incidence of AKI in critically ill patients who were receiving VPT as empric therapy.

Clinical outcomes of patients with mild COVID-19 following treatment with hydroxychloroquine in an outpatient setting.

The role of hydroxychloroquine (HCQ) in early outpatient management of mild coronavirus disease 2019 (COVID-19) needs further investigation. This study was a multicenter, population-based national retrospective-cohort investigation of 28,759 adults with mild COVID-19 seen at the network of Comprehensive Healthcare Centers (CHC) between March and September 2020 throughout Iran. The baseline characteristics and outcome variables were extracted from the national integrated health system database. A total of 7295 (25.37%) patients who presented with mild COVID-19 within 3-7 days of symptoms onset received HCQ (400 mg twice daily on day 1 followed by 200 mg twice daily for the next four days and were then followed for 14 days). The main outcome measures were hospitalization or death for six months follow-up. COVID-19-related hospitalizations or deaths occurred in 523 (7.17%) and 27 (0.37%) respectively, in HCQ recipients and 2382 (11.10%) and 287 (1.34%) respectively, in non-recipients. The odds of hospitalization or death was reduced by 38% (odds ratio [OR] = 0.62; 95% confidence interval [CI]: 0.56-0.68, p = < 0.001) and 73% (OR = 0.27; 95% CI: 0.18-0.41, p = < 0.001) in HCQ recipients and non-recipients. These effects were maintained after adjusting for age, comorbidities, and diagnostic modality. No serious HCQ-related adverse drug reactions were reported. In our large outpatient national cohort of adults with mild COVID-19 disease who were given HCQ early in the course of the disease, the odds of hospitalization or death was reduced significantly regardless of age or comorbidities.

Comparing outcomes of hospitalized patients with moderate and severe COVID-19 following treatment with hydroxychloroquine plus atazanavir/ritonavir.

BACKGROUND: The role of the antiviral therapy in treatment of COVID-19 is still a matter to be investigated. Also efficacy and safety of antiviral regimens were not compared according severity of the disease. In this study the efficacy and safety of hydroxychloroquine plus atazanavir/ritonavir was compared in patients with moderate and severe COVID-19. METHODS: We prospectively evaluated the clinical outcomes of 213 patients with COVID-19 during the hospitalization course and up to 56 days after the hospital discharge. The disease was categorized to moderate and severe based on the severity of pneumonia and peripheral oxygen saturation (SpO2). The patients received the national treatment protocol containing hydroxychloroquine (400 mg BD in first day and then 200 mg BD) plus atazanavir/ritonavir (300/100 mg daily) for 7 days. Main outcomes included discharge rates at day 7, 14 and 28, 28-day mortality, rate of intensive care unit (ICU) admission and intubation, length of hospital and ICU stay and incidence of adverse events. RESULTS: The mean (SD) age of patients was 60(14) years and 53% were male. According to WHO definition, 51.64% and 48.36% of the patients had moderate (SpO2 ≥ 90%) and severe disease (SpO2 < 90%) at baseline, respectively. The discharge rate of the moderate group was significantly higher than the severe group at day 7, 14 and 28 (HR = 0.49; 95% CI: 0.35-0.69, p = < 0.001 at day 7, HR = 0.48; 95% CI: 0.35-0.66, p = < 0.001 at day 14 and HR = 0.49; 95% CI: 0.36-0.67, p = < 0.001at day 28). The 28-day mortality of the severe group was six times higher than the moderate group (HR = 6.00; 95% CI: 2.50-14.44), p = < 0.001). The need of admission in ICU for the severe group and the moderate group was 37.86% and 18.18% of the patients. Length of hospital stay was significantly shorter in the moderate group in comparison with the severe group (5 ± 4 vs. 8 ± 6 days, p < 0.001). Patients in the moderate group experienced the serious adverse events and complications less than the severe group. The discharged patients were followed up to 56 days after discharge. Some of the patients complained of symptoms such as exertional dyspnea, weakness and new-onset hair loss. CONCLUSION: Our study did not support the use of hydroxychloroquine plus atazanavir/ritonavir in patients who had SpO2 < 90% at the time of hospital admission. SpO2 was the only predictor of clinical outcomes (duration of hospital stay, discharge from the hospital and mortality) in patients treated with hydroxychloroquine plus atazanavir/ritonavir.

Interferon ß-1b in treatment of severe COVID-19: A randomized clinical trial.

In this study, efficacy and safety of interferon (IFN) ß-1b in the treatment of patients with severe COVID-19 were evaluated. Among an open-label, randomized clinical trial, adult patients (≥18 years old) with severe COVID-19 were randomly assigned (1:1) to the IFN group or the control group. Patients in the IFN group received IFN ß-1b (250 mcg subcutaneously every other day for two consecutive weeks) along with the national protocol medications while in the control group, patients received only the national protocol medications (lopinavir/ritonavir or atazanavir/ritonavir plus hydroxychloroquine for 7-10 days). The primary outcome of the study was time to clinical improvement. Secondary outcomes were in-hospital complications and 28-daymortality. Between April 20 and May 20, 2020, 80 patients were enrolled and finally 33 patients in each group completed the study. Time to clinical improvment in the IFN group was significantly shorter than the control group ([9(6-10) vs. 11(9-15) days respectively, p = 0.002, HR = 2.30; 95% CI: 1.33-3.39]). At day 14, the percentage of discharged patients was 78.79% and 54.55% in the IFN and control groups respectively (OR = 3.09; 95% CI: 1.05-9.11, p = 0.03). ICU admission rate in the control group was significantly higher than the IFN group (66.66% vs. 42.42%, p = 0.04). The duration of hospitalization and ICU stay were not significantly different between the groups All-cause 28-day mortality was 6.06% and 18.18% in the IFN and control groups respectively (p = 0.12). IFN ß-1b was effective in shortening the time to clinical improvement without serious adverse events in patients with severe COVID-19. Furthermore, admission in ICU and need for invasive mechanical ventilation decreased following administration of IFN ß-1b. Although 28-day mortality was lower in the IFN group, further randomized clinical trials with large sample size are needed for exact estimation of survival benefit of IFN ß-1b.

Preparation and Characterization of Silk Fibroin Nanoparticles as a Potential Drug Delivery System for 5-Fluorouracil.

Purpose: The aim of this study is to prepare 5-fluorouracil (5-FU) loaded silk fibroin nanoparticles (SFNPs) and to achieve a controlled release delivery system with the high loading capacity. Methods: SFNPs with 1:1, 1:3, and 1:10 ratios of 5-FU to silk fibroin were prepared. SFNPs were characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) analysis, Scanning electron microscope (SEM), and Transmission electron microscope (TEM). Loading efficiency, in vitro release, and cell viability were studied for optimal SFNPs. Results: The ratio of 1:1 was optimal formulation with the size and polydispersity index (PDI) of 221.03 nm and 0.093 before freeze drying, and 286.7 nm and 0.154 after freeze drying by lactose, respectively. The loading efficiency and loading content of this ratio were 52.32% and 34.35%, respectively. FT-IR and XRD analysis indicated the conformational change (from random coil to ß-sheet) in the structure of nanoparticles by increasing amount of the drug, which caused the smaller size, the higher loading efficiency, and the slower release pattern. The drugloaded nanoparticles reached to the half maximal inhibitory concentration (IC50) that were comparable with free drug on MCF7 (human breast cancer) cell line. Conclusion: This study was planned to achieve a promising controlled release drug delivery system for carrying 5-FU, as a potent anticancer drug. SFNPs were found proper candidates for delivery of a hydrophilic drug such as 5-FU.

Hyperviscous Semen Causes Poor Sperm Quality and Male Infertility through Induction of Oxidative Stress.

BACKGROUND/AIMS: Semen hyperviscosity (SHV) is one of the significant factors involved in poor semen quality and male infertility. It also leads major problems during assisted reproduction techniques and in vitro fertilization process. Although influence of SHV on sperm quality, fertilization rate and male infertility have been widely considered, molecular and cellular mechanisms for these abnormalities are not well understood. In this review, we aimed to discuss the proposed cellular and molecular mechanisms of SHV on male reproductive system, the importance of oxidative stress (OS) and the mechanisms by which SHV induces OS and impairment of other antioxidants. METHODS: A PubMed/Medline and EM-BASE search was performed using keywords: "hyperviscosity semen", "oxidative stress", and "male infertility". CONCLUSION: OS induced by reactive oxygen species can be considered as a major mechanism in patients with hyperviscosity semen that is associated with DNA fragmentation, lipid peroxidation and sperm membrane disintegrity, apoptosis, depletion of antioxidants, and subsequently poor sperm quality and male infertility. Therefore, antioxidant therapy may improve main pathological effects of hyperviscosity semen, especially oxidative damages and inflammation, on sperm quality and function. Further, randomized controlled studies are necessary to confirm these results and make a comparison between effects of various antioxidants such as N-acethyl-cysteine and Curcumin on fertility problem in patients with hyperviscous semen.