Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine (FAKHRAVAC®) in healthy adults aged 18-55 years: Randomized, double-blind, placebo-controlled, phase I clinical trial.

Background: The FAKHRAVAC®, an inactivated SARS-CoV-2 vaccine, was assessed for safety and immunogenicity. Methods and findings: In this double-blind, placebo-controlled, phase I trial, we randomly assigned 135 healthy adults between 18 and 55 to receive vaccine strengths of 5 or 10 µg/dose or placebo (adjuvant only) in 0-14 or 0-21 schedules. This trial was conducted in a single center in a community setting. The safety outcomes in this study were reactogenicity, local and systemic adverse reactions, abnormal laboratory findings, and Medically Attended Adverse Events (MAAE). Immunogenicity outcomes include serum neutralizing antibody activity and specific IgG antibody levels.The most frequent local adverse reaction was tenderness (28.9%), and the most frequent systemic adverse reaction was headache (9.6%). All adverse reactions were mild, occurred at a similar incidence in all six groups, and were resolved within a few days. In the 10-µg/dose vaccine group, the geometric mean ratio for neutralizing antibody titers at two weeks after the second injection compared to the placebo group was 9.03 (95% CI: 3.89-20.95) in the 0-14 schedule and 11.77 (95% CI: 2.77-49.94) in the 0-21 schedule. The corresponding figures for the 5-µg/dose group were 2.74 (1.2-6.28) and 5.2 (1.63-16.55). The highest seroconversion rate (four-fold increase) was related to the 10-µg/dose group (71% and 67% in the 0-14 and 0-21 schedules, respectively). Conclusions: FAKHRAVAC® is safe and induces a strong humoral immune response to the SARS-CoV-2 virus at 10-µg/dose vaccine strength in adults aged 18-55. This vaccine strength was used for further assessment in the phase II trial.Trial registrationThis study is registered with https://www.irct.ir; IRCT20210206050259N1.

Redox-Mediated Rewiring of Signalling Pathways: The Role of a Cellular Clock in Brain Health and Disease.

Metazoan signalling pathways can be rewired to dampen or amplify the rate of events, such as those that occur in development and aging. Given that a linear network topology restricts the capacity to rewire signalling pathways, such scalability of the pace of biological events suggests the existence of programmable non-linear elements in the underlying signalling pathways. Here, we review the network topology of key signalling pathways with a focus on redox-sensitive proteins, including PTEN and Ras GTPase, that reshape the connectivity profile of signalling pathways in response to an altered redox state. While this network-level impact of redox is achieved by the modulation of individual redox-sensitive proteins, it is the population by these proteins of critical nodes in a network topology of signal transduction pathways that amplifies the impact of redox-mediated reprogramming. We propose that redox-mediated rewiring is essential to regulate the rate of transmission of biological signals, giving rise to a programmable cellular clock that orchestrates the pace of biological phenomena such as development and aging. We further review the evidence that an aberrant redox-mediated modulation of output of the cellular clock contributes to the emergence of pathological conditions affecting the human brain.

The Frequency of Intestinal Parasitic Infections in COVID-19 Patients: A Case-Control Study in Tehran, Capital of Iran.

The present study was done to evaluate the prevalence of intestinal parasitic infections (IPIs) in patients with COVID-19 in health care centers (Imam Reza and Golestan hospitals), Tehran, capital of Iran. By designing a matched case-control study, 200 fecal samples were collected for each of the COVID-19 patients and healthy individuals. Nasopharyngeal/oropharyngeal swab samples were collected from all participants for the diagnosis of COVID-19. RNA extraction was performed, and then real time reverse-transcription polymerase chain reaction (rRT-PCR) assay was applied to detect viral RNA. Considering the lung complications, 25%> lung complications was detected in 49 patients, 25-49% in 42 patients, and 50%≤ in 109 patients. Fecal samples were examined using different parasitological techniques. After nested-PCR, sequencing was applied to identify Cryptosporidium spp. and microsporidia spp. A relatively lower prevalence of IPIs was detected among control group (7.5%), than in COVID-19 patients (13%), though not significant (P=0.13). The most prevalent parasite among patients was Blastocystis sp. (6%). Also, 13.76% of IPIs were detected in inpatients with more than 50% lung complication. As well, a remarkably significant difference in IPIs was observed among diarrheic COVID-19 patients, in comparison with nondiarrheic patients (P < 0.00001). Moreover, the isolated sequences in the present study belonged to C. parvum subtype IIa and Enterocytozoon bieneusi genotypes D and Peru 8. In conclusion, more epidemiological and clinical research studies are needed to better understand the status and interaction of IPI in COVID-19 in Iran and other countries.

Safety and efficacy of the FAKHRAVAC compared with BBIBP-Corv2 against SARS-CoV-2 in adults: a non-inferiority multi-center trial.

BACKGROUND: We compared Fakhravac and BBIBP-Corv2 vaccines in a phase III trial. METHOD: We conducted a multicenter, parallel-group, active-control, non-inferiority clinical trial with pragmatic considerations assessing the safety and efficacy of Fakhravac and BBIBP-Corv2 vaccines. We started with two randomized double-blind arms and added two non-randomized open-label arms (based on participant preference) because of slow recruitment. The adult population received 0.5 ml (10 µg per dose) intramuscular injections of Fakhravac or BBIBP-Corv-2 vaccines 21 days apart. The primary outcome was the occurrence of PCR-positive symptomatic Covid-19 disease 14 days or more after the second injection. A 10% non-inferiority margin to the reported 72.8% efficacy of BBIBP-Corv2 was assumed. Cox proportional hazard modeling was used to estimate hazard ratios and their 95% confidence intervals. RESULT: We enrolled 24,056 adults in four groups (randomized-Fakhravac: 824, randomized-BBIBP-Corv2: 832; Non-randomized-Fakhravac: 19,429, Non-randomized-BBIBP-Corv2: 2971). All observed local and systemic adverse reactions were generally self-limited and resolved completely. We observed similar Serious Adverse Event (SAE) rates in the BBIBP-Corv2 (2.57, 95% CI 1.33-4.49) and Fakhravac (2.25, 95% CI 1.72-2.89) groups; none of which were related to the vaccines received. We recorded 9815 Medically Attendant Adverse Events (MAAE), 736 of which were categorized as somehow related. The rate of related MAAE in the Fakhravac was similar to the BBIBP-Corv2 groups (0.31 and 0.26 per 1000 person-day) in the randomized and considerably higher (0.24 and 0.07 per 1000 person-day) in the non-randomized arms. We observed 129 (35% of the 365 required by target sample size) events of PCR + symptomatic Covid-19 during four months of active follow-up in the randomized arm, demonstrating that those receiving the Fakhravac vaccine were significantly less likely (HR = 0.69; 95% CI 0.49-0.98) to be diagnosed with PCR + symptomatic Covid-19 compared with those receiving BBIBP-Corv2 vaccine. After adjusting for type I error using the O'Brien Fleming method, the Fakhravac vaccine was non-inferior to the BBIBP-Corv2 (assuming a 10% non-inferiority margin to the reported 72.8% BBIBP-Corv2 vaccine efficacy; HR < 1.35) (One-way test: HR = 0.66; 99.8% CI 0.38-1.15). In the non-randomized arm, the results were inconclusive (HR = 1.23; 95% CI 0.96-1.61). We observed 5 cases of hospitalized Covid-19 in the randomized arm, none of which occurred in the Fakhravac vaccine group. Those receiving the Fakhravac vaccine were four times less likely to go to the hospital because of a Covid-19 diagnosis (HR = 0.24; 95% CI 0.10-0.60). The vaccine efficacy of the Fakhravac vaccine is estimated to be 81.5% (95% CI 81-82.4%). CONCLUSION: Fakhravac inactivated SARS-CoV-2 vaccine has comparable safety and efficacy to the BBIBP-Corv2 vaccine. Trial registration This study was registered with the Iranian Registry of Clinical Trials ( www.irct.ir : IRCT20210206050259N3).

Effect of fluvoxamine on preventing neuropsychiatric symptoms of post COVID syndrome in mild to moderate patients, a randomized placebo-controlled double-blind clinical trial.

BACKGROUND: Shortly after the Coronavirus disease 2019 (COVID-19) pandemic, a considerable number of recovered patients reported persisting symptoms, especially neuropsychological manifestations, which were later named post-COVID syndrome (PCS). Immune dysregulation was suggested as one of the main mechanisms for PCS. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessive-compulsive disorder, has been suggested as an anti-COVID drug due to its anti-inflammatory effects, mainly through the sigma-1 receptor. Therefore, we aimed to evaluate fluvoxamine's effect on PCS neuropsychiatric symptoms. METHOD: In this double-blind randomized clinical trial, we included confirmed mild to moderate COVID-19 outpatients using polymerase chain reaction (PCR) by an infectious disease specialist. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50%. Then we performed permuted block randomization and assigned patients 1:1 into two groups to either receive fluvoxamine 100 mg tablet or a placebo daily for 10 days. Eligible patients were evaluated after 12 weeks for the presence of fatigue, as the primary, and other PCS symptoms as secondary outcomes. RESULTS: We screened a total of 486 patients from March to June 2022. After 12 weeks, 42 patients receiving fluvoxamine and 43 patients receiving Placebo were evaluated for PCS. Patients had a mean age of 38.5 ± 14.1 and 48% of them were women. Fatigue was significantly lower in the fluvoxamine group (p-value 0.026). No significant differences were observed in other symptoms. CONCLUSION: We concluded that taking fluvoxamine during active COVID-19 can reduce the chance of fatigue but the advantage of fluvoxamine was not observed for other symptoms. Further studies are necessary to confirm these preliminary results.

COVID-19 and its implications on the clinico-radiological course of multiple sclerosis: A case-control study.

Background: Multiple sclerosis (MS) is an immune-mediated disease that has been related to several risk factors such as various viral infections. We carried out this study in order to establish a relationship between COVID-19 infection and MS severity. Methods: In a case-control study, we recruited patients with relapsing-remitting multiple sclerosis (RRMS). Patients were divided into two groups based on positive COVID-19 PCR at the end of the enrollment phase. Each patient was prospectively followed for 12 months. Demographical, clinical, and past medical history were collected during routine clinical practice. Assessments were performed every six months; MRI was performed at enrollment and 12 months later. Results: Three hundred and sixty-two patients participated in this study. MS patients with COVID-19 infection had significantly higher increases in the number of MRI lesions (p: 0.019, OR(CI): 6.37(1.54-26.34)) and EDSS scores (p: 0.017), but no difference was found in total annual relapses or relapse rates. COVID-19 infections were positively correlated with EDSS progression (p: 0.02) and the number of new MRI lesions (p: 0.004) and predicted the likelihood of the number of new MRI lesions by an odds of 5.92 (p: 0.018). Conclusion: COVID-19 may lead to higher disability scores in the RRMS population and is associated with developing new Gd-enhancing lesions in MRI imaging. However, no difference was observed between the groups regarding the number of relapses during follow-up.

Antecedentes: La esclerosis múltiple (EM) es una enfermedad inmunomediada que se ha relacionado con varios factores de riesgo, como diversas infecciones virales. Realizamos este estudio para establecer una relación entre la infección por COVID-19 y la gravedad de la EM. Métodos: En un estudio de casos y controles, reclutamos pacientes con esclerosis múltiple remitente-recurrente (EMRR). Los pacientes se dividieron en dos grupos según la PCR positiva para COVID-19 al final de la fase de inscripción. Cada paciente fue seguido prospectivamente durante 12 meses. Los antecedentes demográficos, clínicos y médicos anteriores se recogieron durante la práctica clínica habitual. Las evaluaciones se realizaron cada 6 meses. La resonancia magnética se realizó en el momento de la inscripción y 12 meses después. Resultados: Trescientos sesenta y dos pacientes participaron en este estudio. Los pacientes con EM con infección por COVID-19 tuvieron aumentos significativamente más altos en el número de lesiones de resonancia magnética (p = 0,019; OR = 6,37 [IC 95%: 1,54-26,34]) y puntajes EDSS (p = 0,017), pero no se encontraron diferencias en el total de recaídas anuales o en las tasas de recaída. Las infecciones por COVID-19 se correlacionaron positivamente con la progresión de EDSS (p = 0,02) y la cantidad de nuevas lesiones en la resonancia magnética (p = 0,004) y predijeron la probabilidad de la cantidad de nuevas lesiones en la resonancia magnética con una probabilidad de 5,92 (p = 0,018). Conclusión: COVID-19 puede conducir a puntajes de discapacidad más altos en la población de EMRR y está asociado con el desarrollo de nuevas lesiones realzadas con Gd en imágenes de resonancia magnética. Sin embargo, no se observó diferencia entre los grupos en cuanto al número de recaídas durante el seguimiento.

COVID-19 and its implications on the clinico-radiological course of multiple sclerosis: A case–control study / COVID-19 y sus implicaciones en el curso clínico-radiológico de la esclerosis múltiple: un estudio de casos y controles

Background: Multiple sclerosis (MS) is an immune-mediated disease that has been related to several risk factors such as various viral infections. We carried out this study in order to establish a relationship between COVID-19 infection and MS severity.MethodsIn a case–control study, we recruited patients with relapsing–remitting multiple sclerosis (RRMS). Patients were divided into two groups based on positive COVID-19 PCR at the end of the enrollment phase. Each patient was prospectively followed for 12 months. Demographical, clinical, and past medical history were collected during routine clinical practice. Assessments were performed every six months; MRI was performed at enrollment and 12 months later.ResultsThree hundred and sixty-two patients participated in this study. MS patients with COVID-19 infection had significantly higher increases in the number of MRI lesions (p: 0.019, OR(CI): 6.37(1.54–26.34)) and EDSS scores (p: 0.017), but no difference was found in total annual relapses or relapse rates. COVID-19 infections were positively correlated with EDSS progression (p: 0.02) and the number of new MRI lesions (p: 0.004) and predicted the likelihood of the number of new MRI lesions by an odds of 5.92 (p: 0.018).ConclusionCOVID-19 may lead to higher disability scores in the RRMS population and is associated with developing new Gd-enhancing lesions in MRI imaging. However, no difference was observed between the groups regarding the number of relapses during follow-up. (AU)

Antecedentes: La esclerosis múltiple (EM) es una enfermedad inmunomediada que se ha relacionado con varios factores de riesgo, como diversas infecciones virales. Realizamos este estudio para establecer una relación entre la infección por COVID-19 y la gravedad de la EM.MétodosEn un estudio de casos y controles, reclutamos pacientes con esclerosis múltiple remitente-recurrente (EMRR). Los pacientes se dividieron en dos grupos según la PCR positiva para COVID-19 al final de la fase de inscripción. Cada paciente fue seguido prospectivamente durante 12 meses. Los antecedentes demográficos, clínicos y médicos anteriores se recogieron durante la práctica clínica habitual. Las evaluaciones se realizaron cada 6 meses. La resonancia magnética se realizó en el momento de la inscripción y 12 meses después.ResultadosTrescientos sesenta y dos pacientes participaron en este estudio. Los pacientes con EM con infección por COVID-19 tuvieron aumentos significativamente más altos en el número de lesiones de resonancia magnética (p=0,019; OR=6,37 [IC 95%: 1,54-26,34]) y puntajes EDSS (p=0,017), pero no se encontraron diferencias en el total de recaídas anuales o en las tasas de recaída. Las infecciones por COVID-19 se correlacionaron positivamente con la progresión de EDSS (p=0,02) y la cantidad de nuevas lesiones en la resonancia magnética (p=0,004) y predijeron la probabilidad de la cantidad de nuevas lesiones en la resonancia magnética con una probabilidad de 5,92 (p=0,018).ConclusiónCOVID-19 puede conducir a puntajes de discapacidad más altos en la población de EMRR y está asociado con el desarrollo de nuevas lesiones realzadas con Gd en imágenes de resonancia magnética. Sin embargo, no se observó diferencia entre los grupos en cuanto al número de recaídas durante el seguimiento. (AU)

Phase II randomized, double blind, placebo controlled, clinical trial of safety and immunogenicity of an inactivated SARS-CoV-2 vaccine FAKHRAVAC in adults aged 18-70 years.

BACKGROUND: The FAKHRAVAC®, an inactivated SARS-CoV-2 vaccine, was assessed for safety and immunogenicity in a phase II trial. METHODS: We did a phase II, single-centered, randomized, double-blind, placebo-controlled clinical trial of the FAKHRAVAC inactivated SARS-CoV-2 vaccine on adults aged 18 to 70. The two parallel groups received two intramuscular injections of either a 10-µg vaccine or a placebo at 2-week intervals. The participants' immunogenicity responses and the occurrence of solicited and unsolicited adverse events were compared over the study period of up to 6 months. Immunogenicity outcomes include serum neutralizing antibody activity and specific IgG antibody levels. RESULTS: Five hundred eligible participants were randomly (1:1) assigned to vaccine or placebo groups. The median age of the participants was 36 years, and 75% were male. The most frequent local adverse reaction was tenderness (21.29% after the first dose and 8.52% after the second dose), and the most frequent systemic adverse reaction was headache (11.24% after the first dose and 8.94% after the second dose). Neutralizing antibody titers two and four weeks after the second injection in the vaccine group showed about 3 and 6 times increase compared to the placebo group (GMR = 2.69, 95% CI 2.32-3.12, N:309) and (GMR = 5.51, 95% CI 3.94-8.35, N:285). A four-fold increase in the neutralizing antibody titer was seen in 69.6% and 73.4% of the participants in the vaccine group two and four weeks after the second dose, respectively. Specific ELIZA antibody response against a combination of S1 and RBD antigens 4 weeks after the second injection increased more than three times in the vaccine compared to the placebo group (GMR = 3.34, 95% CI 2.5-4.47, N:142). CONCLUSIONS: FAKHRAVAC® is safe and induces a significant humoral immune response to the SARS-CoV-2 virus at 10-µg antigen dose in adults aged 18-70. A phase III trial is needed to assess the clinical efficacy. TRIAL REGISTRATION: Trial Registry Number: Ref., IRCT20210206050259N2 ( http://irct.ir ; registered on 08/06/2021).

Frequency, subtypes distribution, and risk factors of Blastocystis spp. in COVID-19 patients in Tehran, capital of Iran: A case-control study.

Background: Recent theories on the possible interactions between the intestinal parasites and COVID-19 have stated that these co-infections may cause immune imbalance and further complications in the affected patients. Until now, there is no data about Blastocystis subtypes as an intestinal parasite in COVID-19 patients. Therefore, the present work was done to evaluate the molecular prevalence of Blastocystis spp. and related risk factors in Iranian patients with COVID-19. Method: Stool samples were gathered from 200 COVID-19 patients and 200 control, being matched regarding age, gender and residence. Then, stool samples were surveyed by parasitological methods, including direct slide smear and formalin-ether concentration. In the following, PCR and sequencing were used to detect Blastocystis spp. and their subtypes. Results: The frequency of Blastocystis spp. in patients with COVID-19 (7.5%; 15/200 by molecular method vs. 6%; 12/200 by microscopy method) was slightly higher than in individuals without COVID-19 (4.5%; 9/200 by molecular method vs. 4%; 8/200 by microscopy method), this difference was not statistically significant (P value = 0.57 for molecular method vs. P value = 0.81 for microscopy method). Regarding associated factors for Blastocystis spp., we found significant differences regarding the residence (rural), loose and watery stool with diarrhea, and duration of treatment (6 weeks <) in the COVID-19 group. Blastocystis ST3 was the most common subtype in the patients with COVID-19 and control group. Conclusions: Based on this results, health education, improved sanitation and good personal hygiene are highly recommended to prevent Blastocystis in COVID-19 patients.

COVID-19 and its implications on the clinico-radiological course of multiple sclerosis: A case-control study.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease that has been related to several risk factors such as various viral infections. We carried out this study in order to establish a relationship between COVID-19 infection and MS severity. METHODS: In a case-control study, we recruited patients with relapsing-remitting multiple sclerosis (RRMS). Patients were divided into two groups based on positive COVID-19 PCR at the end of the enrollment phase. Each patient was prospectively followed for 12 months. Demographical, clinical, and past medical history were collected during routine clinical practice. Assessments were performed every six months; MRI was performed at enrollment and 12 months later. RESULTS: Three hundred and sixty-two patients participated in this study. MS patients with COVID-19 infection had significantly higher increases in the number of MRI lesions (p: 0.019, OR(CI): 6.37(1.54-26.34)) and EDSS scores (p: 0.017), but no difference was found in total annual relapses or relapse rates. COVID-19 infections were positively correlated with EDSS progression (p: 0.02) and the number of new MRI lesions (p: 0.004) and predicted the likelihood of the number of new MRI lesions by an odds of 5.92 (p: 0.018). CONCLUSION: COVID-19 may lead to higher disability scores in the RRMS population and is associated with developing new Gd-enhancing lesions in MRI imaging. However, no difference was observed between the groups regarding the number of relapses during follow-up.

Cardio-Pulmonary Histopathology with Clinical Correlations of Deceased Patients with COVID-19: A Case Series in Tehran, Iran.

BACKGROUND: SARS-CoV-2 may affect vital organs. The present study investigated the histopathology of pulmonary and cardiac tissues with clinical correlation in deceased patients with COVID-19. METHODS: We obtained pulmonary and cardiac tissues from 30 deceased patients with COVID-19 in Tehran, Iran, from January to May 2021. Sampling was performed through a percutaneous needle biopsy. After slide preparation, two expert pathologists studied them. We assessed the correlation between clinical and pathological data by Fisher's exact test. RESULTS: The mean age of the patients was 73.8±13.4 years, and the male-to-female ratio was 23/7. The most common underlying disease was hypertension (HTN) in 25 patients (83%). Fifty-five tissue samples were achieved, including 28 pulmonary and 27 cardiac samples. Our results showed that all patients (100%) developed diffuse alveolar damage (DAD), and 26 (93%) developed hyaline membrane formation. The most common phase of DAD was the exudative-proliferative phase in 16 (57.1%). Three cardiac samples (11%) revealed myocarditis, and seven (26%) showed cardiomyocyte hypertrophy. In univariate analysis using Fischer's exact test, myocarditis had significant relationships with C-reactive protein (CRP) levels higher than 80 mg/dL (P=0.008) and elevated cardiac troponin levels higher than two-fold (P=0.01). CONCLUSION: COVID-19 can affect the major vital organs. However, only myocarditis had a significant relationship with the circulating levels of inflammatory factors.

Efficacy of a standardized herbal formulation from Glycyrrhiza glabra L. as an adjuvant treatment in hospitalized patients with COVID-19: A Randomized Controlled trial.

Introduction: As no specific pharmacological intervention has been known for COVID-19, medicinal plants may be a suitable candidate for management of this disease. The aim of this study was to investigate the efficacy of a herbal syrup from licorice as an adjuvant treatment in hospitalized patients with COVID-19. Materials and methods: 213 hospitalized patients diagnosed with COVID-19 were assigned to receive either standardized licorice syrup as an adjuvant treatment plus standard care [Syrup Group (SYRUP), N = 91], or standard care alone [Standard Group (STANDARD), N = 104], for 7 days. The primary endpoint was duration of hospitalization in survivors. The secondary endpoints included 25% increase in oxygen saturation, C-reactive protein (CRP) difference and lymphocyte difference from baseline, number of death and number of patients transferred to ICU. Results: Mean duration of admission was 5.24 days in SYRUP and 7.14 days in STANDARD (p < 0.001). Oxygen saturation increased in 86 of 91 patients (94.5%) in the licorice group, compared to 83 of 104 patients (79.8%) in the control group (p = 0.002). There was no significant difference between the two groups in the number of patients died during hospitalization (p = 0.837). Five patients in SYRUP and 16 patients in STANDARD were transferred to ICU (p < 0.026). Mean reduction in CRP (p < 0.001) and mean increase in the number of lymphocytes (p = 0.008) in SYRUP were significantly higher than STANDARD. Discussion: Licorice syrup as an adjuvant treatment demonstrated promising results on duration of hospital admission, O2 saturation as well as inflammatory markers in COVID-19 patients; however, further clinical studies with larger sample size are suggested to achieve more conclusive results.

Comparison of the Safety and Immunogenicity of FAKHRAVAC and BBIBP-CorV Vaccines when Administrated as Booster Dose: A Parallel Two Arms, Randomized, Double Blind Clinical Trial.

Purpose: This study was completed to assess the immunogenicity and safety of the FAKHRAVAC and BBIBP-CorV vaccines as a booster dose in the population with a history of receiving two doses of BBIBP-CorV vaccine. Methods: In this double-blind, parallel clinical trial, we randomly assigned healthy adults with a history of receiving two doses of the BBIBP-CorV vaccine, who then received either the FAKHRAVAC or BBIBP-CorV vaccine as a booster dose. The trial is registered in the Iranian Registry of Clinical Trial document depository (Code: IRCT20210206050259N4). Results: The outcomes that were monitored in this study were serum neutralizing antibody (Nab) activity, immunoglobulin G (IgG) level, local and systemic adverse reactions, serious adverse events, suspected unexpected serious adverse reactions, and medically attended adverse events. After administering vaccines to 435 participants, the most frequent local and systemic adverse reactions were tenderness and nausea in 23.7% and 1.4% of cases, respectively. All adverse events were mild, occurred at a similar incidence in the two groups, and were resolved within a few days. Conclusions: On the 14th day after the booster dose injection, the seroconversion rate (i.e., four-fold increase) of Nabs for seronegative participants were 87% and 84.6% in the FAKHRAVAC® and BBIBP-CorV groups, respectively. This study shows that the FAKHRAVAC® vaccine, as a booster dose, has a similar function to the BBIBP-CorV vaccine in terms of increasing the titer of virus-neutralizing antibodies, the amount of specific antibodies, and safety.

Efficacy and safety of acetylcysteine for the prevention of liver injury in COVID-19 intensive care unit patients under treatment with remdesivir.

Aim: The present double-blinded placebo-controlled randomized clinical trial evaluated prophylactic use of acetylcysteine for the prevention of liver injury in patients with severe COVID-19 pneumonia under treatment with remdesivir. Background: Liver injury is reportedly common in patients with severe COVID-19 pneumonia and can occur not only as a result of disease progression, but as an iatrogenic reaction to remdesivir. Methods: A total of 83 adult patients with severe COVID-19 pneumonia were randomly assigned in parallel groups to receive either acetylcysteine or placebo. All the patients received standard care according to institutional protocols, including remdesivir for a total of five days. One gram acetylcysteine was administered intravenously every 12 hours for 42 patients, and 41 patients received the same volume of 0.9% sodium chloride as placebo (Trial Registration: www.irct.ir identifier, IRCT20210726051995N1). Results: After 5 days, median aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in the acetylcysteine than in the placebo group. Of those who received the placebo, 30 (73.2%), 4 (9.7%), and 3 (7.3%) patients had serum AST levels elevated between 1-2.5, 2.5-5, and over 5 times the upper limit of normal (ULN), respectively; while in the acetylcysteine group, 33 (78.6%) and 0 patients had AST levels between 1-2.5 and over 2.5 times ULN, respectively (p-value=0.037). In the acetylcysteine group, 23 (54.8%), 1 (2.4%), and 1 (2.4%) patient had serum ALT levels elevated between 1-2.5, 2.5-5, and over 5 times ULN, respectively; in the placebo group, however, 24 (58.5%), 7 (17.1%), and 1 (2.4%) patient had serum ALT levels between 1-2.5, 2.5-5, and over 5 times ULN, respectively (p-value=0.073). Conclusion: Intravenous administration of acetylcysteine significantly prevents liver transaminases elevation and liver injury in seriously ill COVID-19 patients treated with remdesivir.

Cellular self-organization: An overdrive in Cambrian diversity?

During the early Cambrian period metazoan life forms diverged at an accelerated rate to occupy multiple ecological niches on earth. A variety of explanations have been proposed to address this major evolutionary phenomenon termed the "Cambrian explosion." While most hypotheses address environmental, developmental, and ecological factors that facilitated evolutionary innovations, the biological basis for accelerated emergence of species diversity in the Cambrian period remains largely conjectural. Herein, we posit that morphogenesis by self-organization enables the uncoupling of genomic mutational landscape from phenotypic diversification. Evidence is provided for a two-tiered interpretation of genomic changes in metazoan animals wherein mutations not only impact upon function of individual cells, but also alter the self-organization outcome during developmental morphogenesis. We provide evidence that the morphological impacts of mutations on self-organization could remain repressed if associated with an unmet negative energetic cost. We posit that accelerated morphological diversification in transition to the Cambrian period has occurred by emergence of dormant (i.e., reserved) morphological novelties whose molecular underpinnings were seeded in the Precambrian period.

Efficacy of Red Blood Cell Exchange as Adjunctive Treatment for Hypoxemia and Survival Rate of Patients With Severe Coronavirus-2 Disease: An Open-Labeled Phase 2 Randomized Clinical Trial.

Background: Severe acute respiratory syndrome (SARS) coronavirus-2 may infect red blood cells (RBCs) and impact oxygenation. We aimed to evaluate the efficacy of RBC exchange as an adjunctive treatment for hypoxemia and the survival rate of patients with severe coronavirus disease 2019 (COVID-19). Methods: In a randomized clinical trial, we divided sixty patients with severe COVID-19 into two groups. The intervention group received the standard treatment of severe COVID-19 with RBC exchange three to four times in 2 days. The control group only received the standard treatment. Our primary outcomes were improving hypoxemia in 7 days, recovery or discharge, and death in 28 days. We conducted Chi-square test, independent samples t-test, and Fisher's exact test to analyze the results. The ethical committee of Aja University of Medical Sciences approved the study (IR.AJAUMS.REC.1399.054), and the Iranian clinical trial registration organization registered it (IRCT20160316027081N2). Results: Twenty-nine men and thirty-one women with a mean age of 67.5 years entered the study. The frequency of hypertension and diabetes mellitus was 86.7 and 68.3%, respectively. The most common symptoms of severe COVID-19 were dyspnea (91.6%), cough (75%), and fever (66.6%). Our results showed that hypoxemia improved in 21 of the 30 patients (70%) in the intervention group and 10 of the 30 patients (33.3%) in the control group (P < 0.004). The recovery and discharge rates were 19 of 30 patients (63.3%) in the intervention group and 2 of 30 patients (6.7%) in the control group (P < 0.001). Conclusion: The RBC exchange improved the oxygenation and survival rate in patients with severe COVID-19.

Thalamic hemi-chorea: a rare complication after receiving the adenoviral vector-based COVID-19 vaccine: a case report.

Lacunar strokes occur when a branch of a large cerebral artery is blocked. The thalamus is often affected, causing uncontrollable motions. A 72-year-old previously healthy man presented with involuntary motions in the right limbs, which were present at rest, and exacerbated during voluntary actions. He had received the first dose of the adenoviral vector-based coronavirus disease 2019 vaccine (ChAdOx1 nCoV-19) 9 days ago. Severe thrombocytopenia and elevated levels of lactate dehydrogenase, ferritin, C-reactive protein, and D-dimer were found, without any evidence of connective tissue disease. Electromyography demonstrated typical choreiform movements, and the brain magnetic resonance imaging indicated a small high signal lesion on the left side of the thalamus. Detection of the immunoglobulin G antibodies against platelet factor 4 in the blood, negative heparin-induced platelet activation (HIPA) test, and positive modified HIPA test confirmed the thalamic stroke due to the vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). He was admitted to the intensive care unit and received nadroparin, sodium ozagrel, edaravone, methylprednisolone, and haloperidol. His hemi-chorea improved gradually over 2 weeks, and he was discharged after 21 days with rehabilitation advice. VIPIT due to the ChAdOx1 nCoV-19 is a novel immune-mediated response that needs clinicians' awareness and further investigations.

Acute vestibular neuritis: A rare complication after the adenoviral vector-based COVID-19 vaccine.

Vestibular neuritis was first reported in 1952 by Dix and Hallpike, and 30% of patients reporting a flu-like symptom before acquiring the disorder. The most common causes are viral infections, often resulting from systemic viral infections or bacterial labyrinthitis. Here we presented a rare case of acute vestibular neuritis after the adenoviral vector-based COVID-19 vaccination. A 51-year-old male pilot awoke early in the morning with severe vertigo, nausea, and vomiting after receiving the first dose of the ChAdOx1 nCoV-19 vaccine 11 days ago. Nasopharyngeal SARS-CoV-2 RT-PCR test and chest CT scan were inconclusive for COVID-19 pneumonia. Significant findings were a severe spontaneous and constant true-whirling vertigo which worsened with head movement, horizontal-torsional spontaneous nystagmus, abnormal caloric test, positive bedside head impulse tests, and inability to tolerate head-thrust test. PTA, MRI of the brain and internal auditory canal, and cerebral CT arteriography were normal. According to the clinical, imaging, and laboratory findings, he was admitted to the neurology ward and received treatment for vestibular neuritis. His vertigo increased gradually over 6-8 h, peaking on the first day, and gradually subsided over 7 days. Ten days later, the symptoms became tolerable; the patient was discharged with advice for home-based vestibular rehabilitation exercises. Despite the proper treatment and rehabilitation, signs of dynamic vestibular imbalances persisted after 1 year. Based on the Federal Aviation Administration (FAA) regulations, the Air Medical Council (AMC) suspended him from flight duties until receiving full recovery. Several cases of vestibular neuritis have been reported in the COVID-19 patients and after the COVID-19 vaccination. This is the first case report of acute vestibular neuritis after the ChAdOx1 nCoV-19 vaccination in a healthy pilot without past medical history. However, the authors believe that this is a primary clinical suspicion that must be considered and confirmed after complete investigations.

Evaluation of the efficacy of oral nano-silymarin formulation in hospitalized patients with COVID-19: A double-blind placebo-controlled clinical trial.

Considering the outbreak pandemic of Coronavirus Disease 2019 (COVID-19), the lack of effective therapeutic strategies for the management of this viral disease, and the increasing evidence on the antiviral potential of silymarin, this study aimed to investigate the effectiveness of silymarin nanomicelles on the symptom's resolution time, laboratory parameters, and liver enzymes in patients with COVID-19. The participants were assigned to the nano-silymarin (n = 25) (receiving SinaLive soft gel, containing 70 mg silymarin as nanomicelles) or placebo groups (n = 25) three times daily for two weeks. Patients' symptoms and laboratory findings were assessed at baseline and during the follow-up period (one week and one month after the beginning of the treatment). No significant differences were observed between the two groups in terms of symptoms resolution time, laboratory parameters, and hospitalization duration (p > 0.05). However, the alanine aminotransferase level decreased significantly in the treatment group, compared to the placebo group (p < 0.001). Concomitant use of dexamethasone and remdesivir with silymarin might make the effects of silymarin on the improvement of patients' condition unclear. Further clinical trials are recommended with diverse dosages and larger sample sizes.

Notch ankyrin domain: evolutionary rise of a thermodynamic sensor.

Notch signalling pathway plays a key role in metazoan biology by contributing to resolution of binary decisions in the life cycle of cells during development. Outcomes such as proliferation/differentiation dichotomy are resolved by transcriptional remodelling that follows a switch from Notchon to Notchoff state, characterised by dissociation of Notch intracellular domain (NICD) from DNA-bound RBPJ. Here we provide evidence that transitioning to the Notchoff state is regulated by heat flux, a phenomenon that aligns resolution of fate dichotomies to mitochondrial activity. A combination of phylogenetic analysis and computational biochemistry was utilised to disclose structural adaptations of Notch1 ankyrin domain that enabled function as a sensor of heat flux. We then employed DNA-based micro-thermography to measure heat flux during brain development, followed by analysis in vitro of the temperature-dependent behaviour of Notch1 in mouse neural progenitor cells. The structural capacity of NICD to operate as a thermodynamic sensor in metazoans stems from characteristic enrichment of charged acidic amino acids in ß-hairpins of the ankyrin domain that amplify destabilising inter-residue electrostatic interactions and render the domain thermolabile. The instability emerges upon mitochondrial activity which raises the perinuclear and nuclear temperatures to 50 °C and 39 °C, respectively, leading to destabilization of Notch1 transcriptional complex and transitioning to the Notchoff state. Notch1 functions a metazoan thermodynamic sensor that is switched on by intercellular contacts, inputs heat flux as a proxy for mitochondrial activity in the Notchon state via the ankyrin domain and is eventually switched off in a temperature-dependent manner. Video abstract.