The antibiotic knowledge, attitudes and behaviours of patients purchasing antibiotics with prescription in Russia: a qualitative, comparative analysis.

Objectives: The study aimed to investigate behaviour, knowledge and practices towards antibiotic (AB) use among patients who purchased ABs with a prescription across Russia. Methods: Semi-structured interviews conducted in all eight Federal Districts, Moscow and Saint Petersburg in 2022 by 21 researchers trained specifically for this study. Data were analysed using a directed content analysis approach. Results: In total, 151 respondents were interviewed. Respiratory symptoms were the most common reason for AB prescription. The majority of patients discussed their complaints with family members or friends before consulting the physician and occasionally looked for information on antimicrobial treatment on the internet. The decision to use an AB was usually made by the physician, although patients often anticipated its prescription. Respondents typically chose to go to the nearest drug store to pick up the medicines, not seeking any recommendation from the local pharmacists. The level of knowledge about the effects of ABs was generally low. In most cases, patients were not aware of antimicrobial resistance and rarely recalled any information campaigns targeting prudent AB use. Respondents admitted COVID-19 had an impact on their behaviour: they have become more caring towards their health, but less likely to seek medical care because of the risk of infection. Conclusions: Our findings, in particular low awareness of the population about the effects of ABs and antimicrobial resistance, peculiarities of attitudes and behaviour (significant influence of the environment, tendency to self-diagnose, fairly high level of trust in doctors etc.) can be useful for the development of effective initiatives aiming for prudent AB use.

Rapidly Progressive Portal Cavernoma Cholangiopathy in a Patient With Infeasible Decompressive Shunt Surgery.

We present a 27-year-old man with a 2-year history of extrahepatic portal vein obstruction and selective immunoglobulin A deficiency, referred for acute cholangitis from portal cavernoma cholangiopathy (PCC). Because recurrent cholangitis rapidly led to liver failure, orthotopic liver transplantation (OLT) was successfully performed. To date, this is one of the few cases of patients with symptomatic PCC who required OLT and the first case who had a successful 6-year follow-up. Thus, OLT can be used for symptomatic PCC associated with nonshuntable anatomy, ineffective biliary drainage, and progressive liver damage. Selective immunoglobulin A deficiency may play a role in recurrent cholangitis.

Factor XII Silencing Using siRNA Prevents Thrombus Formation in a Rat Model of Extracorporeal Life Support.

Heparin anticoagulation increases the bleeding risk during extracorporeal life support (ECLS). This study determined whether factor XII (FXII) silencing using short interfering RNA (siRNA) can provide ECLS circuit anticoagulation without bleeding. Adult male, Sprague-Dawley rats were randomized to four groups (n = 3 each) based on anticoagulant: (1) no anticoagulant, (2) heparin, (3) FXII siRNA, or (4) nontargeting siRNA. Heparin was administered intravenously before and during ECLS. FXII or nontargeting siRNA were administered intravenously 3 days before the initiation of ECLS via lipidoid nanoparticles. The rats were placed on pumped, arteriovenous ECLS for 8 hours or until the blood flow resistance reached three times its baseline resistance. Without anticoagulant, mock-oxygenator resistance tripled within 7 ± 2 minutes. The resistance in the FXII siRNA group did not increase for 8 hours. There were no significant differences in resistance or mock-oxygenator thrombus volume between the FXII siRNA and the heparin groups. However, the bleeding time in the FXII siRNA group (3.4 ± 0.6 minutes) was significantly shorter than that in the heparin group (5.5 ± 0.5 minutes, p < 0.05). FXII silencing using siRNA provided simpler anticoagulation of ECLS circuits with reduced bleeding time as compared to heparin. http://links.lww.com/ASAIO/A937.

Lipid nanoparticle chemistry determines how nucleoside base modifications alter mRNA delivery.

Therapeutic mRNA has the potential to revolutionize the treatment of myriad diseases and, in 2020, facilitated the most rapid vaccine development in history. Among the substantial advances in mRNA technology made in recent years, the incorporation of base modifications into therapeutic mRNA sequences can reduce immunogenicity and increase translation. However, experiments from our lab and others have shown that the incorporation of base modifications does not always yield superior protein expression. We hypothesized that the variable benefit of base modifications may relate to lipid nanoparticle chemistry, formulation, and accumulation within specific organs. To test this theory, we compared IV-injected lipid nanoparticles formulated with reporter mRNA incorporating five base modifications (ψ, m1ψ, m5U, m5C/ψ, and m5C/s2U) and four ionizable lipids (C12-200, cKK-E12, ZA3-Ep10, and 200Oi10) with tropism for different organs. In general, the m1ψ base modification best enhanced translation, producing up to 15-fold improvements in total protein expression compared to unmodified mRNA. Expression improved most dramatically in the spleen (up to 50-fold) and was attributed to enhanced protein expression in monocytic lineage splenocytes. The extent to which these effects were observed varied with delivery vehicle and correlated with differences in innate immunogenicity. Through comparison of firefly luciferase and erythropoietin mRNA constructs, we also found that mRNA modification-induced enhancements in protein expression are limited outside of the spleen, irrespective of delivery vehicle. These results highlight the complexity of mRNA-loaded lipid nanoparticle drug design and show that the effectiveness of mRNA base modifications depend on the delivery vehicle, the target cells, and the site of endogenous protein expression.

A Clinical Case of Nosocomial Pneumonia as a Complication of COVID-19: How to Balance Benefits and Risks of Immunosuppressive Therapy?

We report a Russian case of a 61-year-old male patient with confirmed COVID-19 infection who developed nosocomial pneumonia complicated by lung abscess associated with multi-drug-resistant isolates of Klebsiella pneumoniae and Acinetobacter baumannii, which could have been provoked due to the immunosuppressive therapy. We discuss the existing literature highlighting the issue of the prudent balance between benefits and risks when prescribing immunomodulators to hospitalized patients with COVID-19 due to the risk of difficult-to-treat nosocomial infections caused by MDR Gram-negative bacterial pathogens. Currently, there is evidence of a substantial positive effect of dexamethasone on the course of COVID-19 in patients requiring supplemental oxygen or anti-interleukin-6 drugs in individuals with prominent systemic inflammation. However, it seems that in real clinical practice, the proposed criteria for initiating treatment with immunomodulators are interpreted arbitrarily, and the doses of dexamethasone can significantly exceed those recommended.

Co-Infection in COVID-19 Pneumonia: Discussion Continues.

Sixty-six patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 and pneumonia on chest computer tomography were prospectively recruited. A combined respiratory swab for polymerase chain reaction (PCR), urine sample for pneumococcal and Legionella antigen, and sputum or endotracheal aspirate were collected. Urinary antigen and blood culture tests were negative in all cases as well as the PCR tests for other respiratory viruses and atypical bacterial pathogens. In total, 5 patients (7.5%) had co-infection. By PCR a high prevalence of colonization with bacterial pathogens was found. In conclusion, co-infection is rare in coronavirus disease 2019 patients, and additional examination to identify other pathogens should be performed only in selected cases.

Branched-Tail Lipid Nanoparticles Potently Deliver mRNA In Vivo due to Enhanced Ionization at Endosomal pH.

The potential of mRNA therapeutics will be realized only once safe and effective delivery systems are established. Unfortunately, delivery vehicle development is stymied by an inadequate understanding of how the molecular properties of a vehicle confer efficacy. Here, a small library of lipidoid materials is used to elucidate structure-function relationships and identify a previously unappreciated parameter-lipid nanoparticle surface ionization-that correlates with mRNA delivery efficacy. The two most potent materials of the library, 306O10 and 306Oi10 , induce substantial luciferase expression in mice following a single 0.75 mg kg-1 mRNA dose. These lipidoids, which have ten-carbon tails and identical molecular weights, vary only in that the 306O10 tail is straight and the 306Oi10 tail has a one-carbon branch. Remarkably, this small difference in structure conferred a tenfold improvement in 306Oi10 efficacy. The enhanced potency of this branched-tail lipidoid is attributed to its strong surface ionization at the late endosomal pH of 5.0. A secondary lipidoid library confirms that Oi10 materials ionize more strongly and deliver mRNA more potently than lipidoids containing linear tails. Together, these data highlight the exquisite control that lipid chemistry exerts on the mRNA delivery process and show that branched-tail lipids facilitate protein expression in animals.