A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.

A pre-existing case of HBV infection with elevated HBV DNA after COVID-19 pneumonia treatment.

The patient presented with fever and appetite loss. Computed tomography (CT) revealed a moderate grade 2 pneumonia. Besides, further blood examination showed his HB antigen as negative, anti-HBs/c anti-body as positive, and HBV DNA level as 1.0 LIU/mL. Therefore, he was diagnosed with COVID-19. Administered treatments comprised oxygen inhalation and steroid therapy, including pulses, remdesivir, and baricitinib, which improved pneumonia. Interestingly, one month posttreatment, his HBV DNA level in-creased to 1.4 LIU/mL, followed by a further increase to 1.7 LIU/Ml, showing an improvement. Tenofovir alafenamide fumarate was thus administered. In clinical practice, immunosuppressive therapy is used for patients with moderate-to-severe COVID-19 pneumo-nia. However, close attention should also be paid to the elevation of blood HBV DNA levels during and after treatment.Copyright © 2022 The Japan Society of Hepatology.

Investigation on the binding behavior of human α1-acid glycoprotein with Janus Kinase inhibitor baricitinib: Multi-spectroscopic and molecular simulation methodologies.

Baricitinib is a Janus Kinase (JAK) inhibitor that is primarily used to treat moderately to severely active rheumatoid arthritis in adults and has recently been reported for the treatment of patients with severe COVID-19. This paper describes the investigation of the binding behavior of baricitinib to human α1-acid glycoprotein (HAG) employing a variety of spectroscopic techniques, molecular docking and dynamics simulations. Baricitinib can quench the fluorescence from amino acids in HAG through a mix of dynamic and static quenching, according to steady-state fluorescence and UV spectra observations, but it is mainly static quenching at low concentration. The binding constant (Kb) of baricitinib to HAG at 298 K was at the level of 104 M-1, indicating a moderate affinity of baricitinib to HAG. Hydrogen bonding and hydrophobic interactions conducted the main effect, according to thermodynamic characteristics, competition studies between ANS and sucrose, and molecular dynamics simulations. For the change in HAG conformation, the results of multiple spectra showed that baricitinib was able to alter the secondary structure of HAG as well as increase the polarity of the microenvironment around the Trp amino acid. Furthermore, the binding behavior of baricitinib to HAG was investigated by molecular docking and molecular dynamics simulations, which validated experimental results. Also explored is the influence of K+, Co2+, Ni2+, Ca2+, Fe3+, Zn2+, Mg2+ and Cu2+plasma on binding affinity.

Real-World Single-Centre Experience of Jak Inhibitor Use in Ra

Background/Aims The use of Janus Kinase Inhibitors (JAKi) has been gradually increasing overtime in the management of rheumatoid arthritis (RA) and other inflammatory arthritis and these appeal to patients. being oral agents. Nevertheless, rheumatologists have become cautious about their use since recent trials have shown safety concerns about VTEs, MACE and malignancies. Methods We decided to study use of JAKi at our centre in Princess of Wales Hospital Bridgend. The aim was to assess whether appropriate patients were selected (considering cautions about MACE, VTEs and malignancies). We also wanted to see whether all patients had required pretreatment safety testing and post-treatment monitoring performed. Results These were 70 patients;59 were females and 11 were males. All of them were diagnosed as RA. Average age was 61.1 years (20-85), average duration of disease 129.9 months (16-340) and average duration of treatment was 58.1 weeks. The most common JAKi being used was baricitinib (84%) followed by tofacitinib (12%) and upadacitinib (4%). 50% patient were on concomitant csDMARDs among whom two-thirds were on methotrexate. Looking at previous biologic use, 9 patients were biologic naive, 22 had one biologic, 15 had two biologics used in the past. All patients were appropriately selected (severe RA and no significant risk factors for MACE, VTEs and malignancies). All patients had pre-treatment Hepatitis B, Hepatitis C, latent TB, FBC and LFTs checked. All patients had FBC and LFTs monitored post treatment. No patient developed VTE, MACE or cancer on treatment. 84.2% patients had lipids tested before starting JAKi. 22.8% patients had abnormal lipids before Rx initiation and 62.5% of these were on lipid lowering Rx. All patients had lipids tested post treatment, but the timing was quite variable and only 62.5% of patients had lipids tested on the recommended time. There were 2 deaths recorded in this cohort. One of those was an 80-year-old RA patient on baricitinib 2mg OD, who died due to chest infection on the background of ILD. He was not on steroids or csDMARDs. The second patient was 63 years' old (on baricitinib 4mg OD), and died due to respiratory sepsis, and was also on azathioprine. She had RA with advanced ILD. The reasons for discontinuing JAKi were inefficacy (46%), side effects (39%) and both inefficacy and side effects (15%). 41.4%of patient experienced side effects due to JAKi. These included infection 28%, deranged lipids 17%, cytopenia 14%, deranged LFTs 14%, GI side effects 10%, skin rash 7% and varicella zoster 3%. Conclusion There has been steady increase in the use of tsDMARDs for RA and other rheumatic conditions. Due to short half-life, these drugs became a popular choice during COVID-19 pandemic but on the other hand safety monitoring became extremely challenging during this time.

A Retrospective Case Control Study to Assess the Effectiveness of Baricitinib among Moderate to Severe Covid-19 Cases, Experience from a South Indian Tertiary Care Centre

Intro: Dysregulated inflammation plays a key role in the development of severe SARS-CoV-2 infection. One of the key cellular signaling pathway involved in the inflammatory response is JAK/STAT signaling. Among the hospitalized Covid patients with hypoxia to reduce the progression to ARDS, immunomodulators have a definite role. Baricitinib is an oral selective Janus kinase 1/2 inhibitor with anti-inflammatory properties. This study evaluates the efficacy and all-cause mortality among moderate to severe Covid patients who received Baricitinib. Method(s): A retrospective case-control study was carried out among moderate to severe Covid patients who had received Baricitinib. COVID severity matched group from the same time period was selected as the control. We evaluated the efficacy (based on WHO-ordinal scale) and difference in all-cause mortality among case and control groups. Baseline characteristics and outcome variables were retrospectively captured from the hospital health information system. Finding(s): During our study period, 2547 active Covid patients have admitted, out of which 105 patients received Baricitinib. Based on the retrospective analysis 75 patients were selected as the case group and 75 covidpositive patients of similar age and sex were identified by a simple random selection technique to serve as a control group. The age group of the baricitinib group 60.82 (+/- 13) and the Control group 62.34 (+/-13). Among the participants, 62.66% were severe (58% Baricitinib group & 66% control), 36% were with moderate severity (40% Baricitinib group & 33.33% control). The all-cause mortality of cohort was 43% (n=64), 36% (n=27) of cases as compared to 49.3% (n=37) of control group, (P Value= 0.06). Improvement in WOS score by at least 1-point cases 47% and 37.3 % in controls, (P Value= 0.09). Conclusion(s): Baricitinib when combined with standard of care, among hospitalized patients with moderate to severe Covid infection, showed a trend towards clinical improvement and decreased all-cause mortality.Copyright © 2023

Personalized approach to the management of a patient with COVID-19 with a complicated comorbid background

The aim of the work is to form the principles of a personalized approach to the management of patients with COVID-19 with a complicated comorbid background. Material and methods. The article describes a clinical case of successful recovery of an 87-year-old patient from a new coronavirus infection COVID-19, complicated by pneumonia involving 36% of the lung parenchyma area. Along with age, the situation was aggravated by the comorbid status of the patient: the presence of chronic lymphocytic leukemia, hypertension, mechanical prostheses of the mitral and aortic valves, postinfarction cardiosclerosis, paroxysmal atrial fibrillation, type 2 diabetes mellitus, stage 4 CKD, anemic syndrome, and subclinical hypothyroidism. Results. The C-reactive protein level at admission was 114.46 mg/L. The patient refused hospitalization. Baricitinib 4 mg, favipiravir according to the scheme, vitamin D 2000 units were prescribed for the previously taken therapy. Already after 3 days, C-reactive protein decreased by 4.6 times, and by the 8th day by 15.5 times and amounted to 7.38 mg/ml. The temperature returned to normal on day 2 from the start of baricitinib. In dynamics, a decrease in creatinine level to 177.0 mumol/l was noted, the glomerular filtration rate increased to 30 ml/min/1.73 m2, which corresponded to stage 3b of CKD (a pronounced decrease in glomerular filtration rate). Conclusion. Despite the age of the patient, many comorbidities, each of which could be fatal, the timely use of baricitinib on an outpatient basis made it possible to stop the progressive course of the disease.Copyright © Eco-Vector, 2023. All rights reserved.

Experience of Baricitinib in a Real-World Population with Efficacy and Side Effects: A South London Regional Analysis

Background/Aims Baricitinib is the most common Janus Kinase inhibitor (JAKi) used in the treatment of rheumatological conditions. Whilst randomised controlled trials have demonstrated the efficacy and safety profile of baricitinib, real-world data on the experience of JAKi use in clinical practice is lacking. The aim of this analysis was to evaluate baricitinib use in a real-world patient population in South London. Methods We looked at two rheumatology departments in South London (St George's Hospital;a tertiary teaching centre and Kingston Hospital;a district general hospital). All patients prescribed baricitinib between January 2017 to June 2022 were included. A retrospective assessment of electronic patient notes was performed to evaluate disease activity (determined by DAS-28 scores at baseline, 3-6 months and presently);adverse effects including side effects, rates of and reasons for discontinuation;and prescribing practice, including previous use of other biological disease modifying anti-rheumatic drugs (bDMARDs). Baseline data including age, gender, co-morbidities and rheumatological diagnoses were also included. Results 233 patients were included in this evaluation, with seropositive rheumatoid arthritis being the most common diagnosis (58%) and with a significant female population (87%). Baricitinib improved average DAS-28 scores from 5.75 (range 3.57-8.3) at baseline to 3.23 (range 0.28-7.49) at 3-6 months post-baricitinib, with the most recent DAS-28 score of 2.90 (range 0.56-6.77). Rates of adverse effects were low as shown in Table 1. Baricitinib was discontinued in 60/233 patients, with average duration to discontinuation of 9.5 months. The most common reasons for discontinuation were: ineffective disease control (28/60), recurrent bacterial infection (5/60), deranged liver function (3/60) and venous thromboembolism (2/60). Eight patients died whilst taking baricitinib. Where documented, the causes of death were Covid-19 (4/8) and malignancy (1/8). 110 out of 233 patients had received other bDMARDs before starting baricitinib. Documented reasons for baricitinib choice over tumour necrosis factor inhibitors (TNFi) included: previous lack of response to TNFi (89/233), contra-indication to TNFi (11/233) and preference of oral route (10/ 233). Conclusion Our real-world study of JAKi use shows that baricitinib is efficacious in the treatment of rheumatological conditions. Moreover, baricitinib is well tolerated, with low rates of adverse effects and subsequent discontinuation. (Table Presented).

Janus Kinase Inhibitors in Rheumatoid Arthritis Patients: Real-World Experience from a Regional Centre in Uk

Background/Aims Tofacitinib and baricitinib were the first orally available, targeted synthetic Janus kinase (JAK) inhibitors approved for the treatment of rheumatoid arthritis (RA) in the UK. Evidence suggests that JAK inhibitors are as efficacious as biological DMARDs in the treatment of RA. Their safety profile has been demonstrated in long term extension studies and RCTs. However, real-world, long-term data remains as important in bridging the gap between controlled studies and routine practice. We report our initial real-world experience of a cohort of RA patients commenced on JAKi before the SARS-CoV-2 pandemic within a regional centre in the UK. Methods All patients commenced on JAKi for the treatment of RA between February 2018 and March 2020 were identified from our in-house database. Data was retrospectively collected from clinical notes and electronic health records from February 2018 up until April 2022. This included patient demographics, disease duration, serological status, concurrent csDMARD usage, history of bDMARD exposure, duration of use and reason for discontinuation of the drug if appropriate. DAS- 28 scores were recorded at baseline and quarterly. SPSS (version 22.0) was used for data analysis. Results One hundred thirty patients were treated with JAK inhibitors (Tofacitinib 22%, Baricitinib 78%);80% female, mean (S.D.) age 61.5 (12.3) years. 92 (70.8%) patients were seropositive. 70 (53.8%) patients were on concurrent csDMARDs and 23 (17.7%) on concurrent steroids. The mean number of previous bDMARDs was 1.8 +/- 1.7;41 (31.5%) were bDMARD naive. The mean baseline DAS-28 ESR (S.D.) score was 5.96 (0.96). There were significant differences in mean DAS- 28 ESR scores (compared with baseline) of 1.54, 1.96, 2.41, 2.33 and 1.80 at 3, 6, 12, 18 and 24 months respectively (p<0.0001). Mean DAS-28 ESR scores were not statistically significant between bDMARD naive patients and those that had previously received bDMARDs. Overall JAKi retention rate was 66.9% with a mean follow up duration of 27.4+/-13.1 months. Persistence was 88.5%, 76.9%, 73.2% and 68.5% at 6, 12, 18, and 24 months, respectively. Of the 38 patients who stopped JAK inhibitors, 11 stopped due to inefficacy (6, primary inefficacy). 3 patients were lost to follow-up and 6 deceased. Cause of death was sepsis (2), venous thromboembolism (1) and unknown (3). 18 patients stopped because of adverse events (AEs). The most common AEs were recurrent infections (11), gastrointestinal side effects (9), lymphopenia (7), thromboembolic events (6) and herpes zoster (5). In total 6 (4.1%) patients had thromboembolic events which included pulmonary embolism (4) and deep vein thrombosis (1) and central retinal artery thrombosis (1). Conclusion JAK inhibitors in this real-world population of RA patients were effective in reducing disease activity and patients had high persistence rates. Recurrent infections, herpes zoster and thrombo-embolism remain adverse events of concern.

Baricitinib Treatment of Coronavirus Disease 2019 Is Associated With a Reduction in Secondary Infections.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

SARS-CoV-2 ANTIVIRAL ACTIVITY OF ZOTATIFIN, A HOST-TARGETING eIF4A INHIBITOR

Background: Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic initiation factor 4A (eIF4A), a host RNA helicase required for SARS-CoV-2 replication. Zotatifin selectively inhibits translation of ribonucleic acids (RNAs) containing specific short polypurine motifs in their 5-prime (5') regions. Two such highly conserved motifs are found in the SARS-CoV-2 genome. Zotatifin is currently being evaluated in a Phase 1b dose escalation study in 36 patients with mild to moderate COVID disease. In this in vitro study, we evaluated the selectivity of zotatifin's inhibition of SARS-CoV-2 translation, the antiviral activity of zotatifin alone against different human coronaviruses and the antiviral activity of zotatifin in combination with other antivirals against SARSCoV-2. Method(s): The selectivity of zotatifin for viral translation was evaluated in a cell-based reporter assay wherein luciferase translation was driven by 5'-sequences from SARS-CoV-2 or tubulin, a housekeeping gene. The antiviral activity of zotatifin was evaluated against SARS-CoV-1, SARS-CoV-2 variants (Wash/1/2020 (ancestral), delta, omicron BA.2), MERS-CoV and HCoV-299E in primary or established cell lines using cytopathic effect or infectious virus as endpoints. The antiviral activity of zotatifin in combination with remdesivir, N-hydroxycytidine (NHC;active nucleoside analogue metabolite of molnupiravir), nirmatrelvir, baricitinib or sotrovimab was evaluated against SARS-CoV-2 and analyzed by the method of Pritchard and Shipman. Result(s): Zotatifin inhibited the translation of the SARS-CoV-2 luciferase reporter construct with a mean IC50 of 3 nM and was ~14-fold less potent in inhibiting the tubulin reporter construct. Zotatifin potently inhibited the replication of all human coronaviruses tested with 50% effective concentrations (EC50s) ranging from 0.016 to 37.3 nM. The 50% cytotoxic concentration (CC50) value for zotatifin was 250 to >100,000 nM, yielding selectivity indices of 7 to >6250. Zotatifin was ~20 to >100-fold more potent than remdesivir, nirmatrelvir or NHC (figure) and demonstrated additive interactions when combined with remdesivir, NHC, nirmatrelvir, baricitinib or sotrovimab in vitro. Conclusion(s): The potent broad-spectrum activity of zotatifin against a variety of human coronaviruses and additive activity when combined with different anti-SARS-CoV-2 antivirals highlight the advantages of eIF4A as a target and warrant further evaluation in human clinical trials.

Personalized approach to the management of a patient with COVID-19 with a complicated comorbid background.

The aim of the work is to form the principles of a personalized approach to the management of patients with COVID-19 with a complicated comorbid background. Material and methods. The article describes a clinical case of successful recovery of an 87-year-old patient from a new coronavirus infection COVID-19, complicated by pneumonia involving 36% of the lung parenchyma area. Along with age, the situation was aggravated by the comorbid status of the patient: the presence of chronic lymphocytic leukemia, hypertension, mechanical prostheses of the mitral and aortic valves, postinfarction cardiosclerosis, paroxysmal atrial fibrillation, type 2 diabetes mellitus, stage 4 CKD, anemic syndrome, and subclinical hypothyroidism. Results. The C-reactive protein level at admission was 114.46 mg/L. The patient refused hospitalization. Baricitinib 4 mg, favipiravir according to the scheme, vitamin D 2000 units were prescribed for the previously taken therapy. Already after 3 days, C-reactive protein decreased by 4.6 times, and by the 8th day by 15.5 times and amounted to 7.38 mg/ml. The temperature returned to normal on day 2 from the start of baricitinib. In dynamics, a decrease in creatinine level to 177.0 mumol/l was noted, the glomerular filtration rate increased to 30 ml/min/1.73 m2, which corresponded to stage 3b of CKD (a pronounced decrease in glomerular filtration rate). Conclusion. Despite the age of the patient, many comorbidities, each of which could be fatal, the timely use of baricitinib on an outpatient basis made it possible to stop the progressive course of the disease.Copyright © Eco-Vector, 2023. All rights reserved.

Effects of some biological factors on Coronavirus

This research was been adopted to study the relationship between Covid and some necessary biological factors in human body and how these factors affected, This studying included three stages (Sever - Moderate - Mild) it was studied 20 patient for every stage and monitor the biological factors during infection and after infection.Copyright © 2023, Codon Publications. All rights reserved.

Development of Diphenyl carbonate-Crosslinked Cyclodextrin Based Nanosponges for Oral Delivery of Baricitinib: Formulation, Characterization and Pharmacokinetic Studies.

Background: The aim of the present investigation is to prepare baricitinib (BAR)-loaded diphenyl carbonate (DPC) ß-cyclodextrin (ßCD) based nanosponges (NSs) to improve the oral bioavailability. Methods: BAR-loaded DPC-crosslinked ßCD NSs (B-DCNs) were prepared prepared by varying the molar ratio of ßCD: DPC (1:1.5 to 1:6). The developed B-DCNs loaded with BAR were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), % yield and percent entrapment efficiency (%EE). Results: Based on the above evaluations, BAR-loaded DPC ßCD NSs (B-CDN3) was optimized with mean size (345.8±4.7 nm), PDI (0.335±0.005), Yield (91.46±7.4%) and EE (79.1±1.6%). The optimized NSs (B-CDN3) was further confirmed by SEM, spectral analysis, BET analysis, in vitro release and pharmacokinetic studies. The optimized NSs (B-CDN3) showed 2.13 times enhancement in bioavailability in comparison to pure BAR suspension. Conclusion: It could be anticipated that NSs loaded with BAR as a promising tool for release and bioavailability for the treatment of rheumatic arthritis and Covid-19.

Triple immune modulator therapy for aberrant hyperinflammatory responses in severe COVID-19.

A dysregulated hyperinflammatory response is a key pathogenesis of severe COVID-19, but optimal immune modulator treatment has not been established. To evaluate the clinical effectiveness of double (glucocorticoids and tocilizumab) and triple (plus baricitinib) immune modulator therapy for severe COVID-19, a retrospective cohort study was conducted. For the immunologic investigation, a single-cell RNA sequencing analysis was performed in serially collected PBMCs and neutrophil specimens. Triple immune modulator therapy was a significant factor in a multivariable analysis for 30-day recovery. In the scRNA-seq analysis, type I and II IFN response-related pathways were suppressed by GC, and the IL-6-associated signature was additionally downregulated by TOC. Adding BAR to GC and TOC distinctly downregulated the ISGF3 cluster. Adding BAR also regulated the pathologically activated monocyte and neutrophil subpopulation induced by aberrant IFN signals. Triple immune modulator therapy in severe COVID-19 improved 30-day recovery through additional regulation of the aberrant hyperinflammatory immune response.

Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)-study protocol for a phase 2, randomized, placebo controlled trial.

BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.

Improving properties of baricitinib due to interaction with Pluronic micelles

Baricitinib is a new generation medicinal compound that has been recommended for the treatment of rheumatoid arthritis in 2017 as well as alopecia areata and COVID-19 in 2022. The use of baricitinib is complicated by its poor aqueous solubility and unwanted side effects. Therefore, the aim of this work is an improvement of the baricitinib solubility using Pluronic micelles. The effect of the micelles on the solubility and membrane permeability of baricitinib is revealed using the isothermal saturation method and the Franz diffusion cell, respectively. It was observed that degree of baricitinib solubilization depends on the Pluronics structure and pH. The regularities of the interaction of the drug with the micelles were established by means of light scattering and 1D and DOSY 1H NMR. It was demonstrated that the ionization state of baricitinib, depending on pH, affects the drug ability to be included in the micelles. The most effective solubilizer of baricitinib among the Pluronics under study was proposed. The data obtained may be useful for the development of water-soluble formulations of baricitinib.

Safety profile assessment of drug products used for the pathogenetic treatment of COVID-19.

Objective. To review and summarize literature data in studies of safety of the drug products used for the pathogenetic treatment of COVID-19. Materials and methods. As the first stage of monitoring the drug's safety, which are used in the treatment of COVID-19 in Russia, a systematic review of studies of the drug's safety profiles was carried out: Mefloquine, hydroxychloroquine, azithromycin, lopinavir/ritonavir, favipiravir, tocilizumab, olokizumab, baricitinib in the international databases Medline, PubMed, ClinicalTrials.gov and Cochrane Library for the period 2019-2021. Results. The review included 51 articles that met the selection criteria. Based on the results of the review, it can be concluded that the safety profile (frequency, severity and severity) of most drugs repurposed for COVID-19 corresponds to those for the registered indications. At the same time, according to world experience, there is an increase in the number of reports of adverse drug reactions of hydroxychloroquine and azithromycin, which is provoked by the active use of these drugs for combination therapy. Conclusions. According to the literature, a high incidence of adverse events was noted in hydroxychloroquine, chloroquine and azithromycin. Subsequent analysis and comparison of the safety profiles of hydroxychloroquine, chloroquine and azithromycin with data from the national automated information system (AIS) database of Roszdravnadzor is a necessary component of effective and safe pharmacotherapy for COVID-19.Copyright © 2021, Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy. All rights reserved.

Predictive factors for centralized rehabilitation in hospitalized COVID-19 patients

Introduction: The Post-Covid-19 Functional Status (PCFS) is a simple and validated tool to assess the functional status of Covid-19 recovered patients. The aim of the study is to identify the predictive factors for referring severe and critical Covid-19 patients for rehabilitation to a specialized and centralized center. Method(s): Functional status of the Covid-19 patients admitted to Hotel-Dieu de France hospital was assessed at their hospital discharge using the PCFS. Dependency was categorized as low if PCFS <= 2 (A) and high if PCFS >= 3 (B). The patients' demographic and clinical data were obtained. After identifying univariate related variables, a multivariate analysis using the binominal logistic regression was performed. Result(s): Over 540 hospitalized patients, death rate was 13.0%. Survivors were classified as 74% in A and 26% in B. Risk factors identified on admission were: age, female sex, arterial hypertension, diabetes mellitus, higher need of oxygen, high News-2, high neutrophil count, high LDH, high D-dimers and high procalcitonin. Risk factors during follow-up period were: longer hospital stay, ICU admission, high scan severity score, thromboembolic or hemorrhagic event, treatment with steroids, baricitinib and tocilizumab. Multivariate analysis showed that age (OR=1.029;p=0.04), female sex (OR=3.537;p<10-3), procalcitonin (OR=1.186;p<10-2), a lobar condensation (OR=0.063;p<10-2) and an admission to ICU (OR=3.758;p=0.015) were independent risk factors. Conclusion(s): Multiple confounding risk factors determined functional outcome of severe Covid-19 using PCFS. This can be of a great benefit to early identify the candidates for a centralized rehabilitation with customized program.

COVID-19: From the Molecular Mechanisms to Treatment

The 2019 novel coronavirus (SARS-CoV-2) causes severe pneumonia called COVID-19 and leads to severe acute respiratory syndrome with a high mortality rate. The SARS-CoV-2 virus in the human body leads to jumpstarting immune reactions and multi-organ inflammation, which has poorer outcomes in the presence of predisposing conditions, including hypertension, dyslipidemia, dysglycemia, abnormal adiposity, and even endothelial dysfunction via biomolecular mechanisms. In addition, leucopenia, hypoxemia, and high levels of both cytokines and chemokines in the acute phase of this disease, as well as some abnormalities in chest CT images, were reported in most patients. The spike protein in SARS-CoV-2, the primary cell surface protein, helps the virus anchor and enter the human host cells. Additionally, new mutations have mainly happened for spike protein, which has promoted the infection's transmissibility and severity, which may influence manufactured vaccines' efficacy. The exact mechanisms of the pathogenesis, besides molecular aspects of COVID-19 related to the disease stages, are not well known. The altered molecular functions in the case of immune responses, including T CD4+, CD8+, and NK cells, besides the overactivity in other components and outstanding factors in cytokines like interleukin-2, were involved in severe cases of SARS-CoV-2. Accordingly, it is highly needed to identify the SARS-CoV-2 bio-molecular characteristics to help identify the pathogenesis of COVID-19. This study aimed to investigate the bio-molecular aspects of SARS-CoV-2 infection, focusing on novel SARS-CoV-2 variants and their effects on vaccine efficacy.Copyright © 2022 NRITLD, National Research Institute of Tuberculosis and Lung Disease, Iran.