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IntroductionThere is a significant need for new antimicrobial compounds that are effective against drug-resistant microbes. Thioredoxin reductase (TrxR) is critical in redox homeostasis and was identified as a potential drug target and confirmed through inhibition by compounds auranofin and Bay11-7085.MethodsAdditional TrxR inhibitors were designed and found to exhibit antimicrobial activity against Gram-positive (Enterococcus faecium and Staphylococcus aureus) and glutathione-deficient bacteria (Helicobacter pylori). Investigational compounds were tested for antimicrobial activity, anti-biofilm efficacy, target impact, and cytotoxicity.ResultsThe first-generation molecules AU1 and AU5 inhibited TrxR activity and inhibited methicillin-resistant S. aureus strain MW2 with minimal inhibitory concentrations (MIC) of 0.125 and 0.5 μg/mL, respectively. In an S. aureus enzymatic assay, AU1 inhibited TrxR enzymatic activity in a dose-dependent manner causing a decrease in intracellular free thiols. In addition, biofilm studies demonstrated that AU1 and AU5 reduced biofilm formation at 1X MIC and disrupted mature biofilms at 4X MIC. Cytotoxicity profiles were created using human cell lines and primary cells with LD50 exceeding MICs by at least 12X.DiscussionThus, AU1 and AU5 were TrxR inhibitors that yielded low-concentration antimicrobial activity impacting S. aureus in planktonic and biofilm forms with limited toxic liability.

Microbe entry through catheter ports can lead to biofilm accumulation and complications from catheter-related bloodstream infection and ultimately require antimicrobial treatment and catheter replacement. Although strides have been made with microbial prevention by applying standardized antiseptic techniques during catheter implantation, both bacterial and fungal microbes can present health risks to already sick individuals. To reduce microbial adhesion, murine and human catheters were coated with polyurethane and auranofin using a dip coating method and compared to non-coated materials. Upon passage of fluid through the coated material in vitro, flow dynamics were not impacted. The unique antimicrobial properties of the coating material auranofin has shown inhibitory activity against bacteria such as Staphylococcus aureus and fungi such as Candida albicans. Auranofin coating on catheters at 10mg/mL reduced C. albicans accumulation in vitro from 2.0 x 108 to 7.8 x 105 CFU for mouse catheters and from 1.6 x 107 to 2.8 x 106 for human catheters, showing an impact to mature biofilms. Assessment of a dual microbe biofilm on auranofin-coated catheters resulted in a 2-log reduction in S. aureus and a 3-log reduction in C. albicans compared to uncoated catheters. In vivo assessment in a murine subcutaneous model demonstrated that catheters coated with 10 mg/mL auranofin reduced independent S. aureus and C. albicans accumulation by 4-log and 1-log, respectively, compared to non-coated catheters. In conclusion, the auranofin-coated catheters demonstrate proficiency at inhibiting multiple pathogens by decreasing S. aureus and C. albicans biofilm accumulation.

IntroductionRituximab and azathioprine are used to induce or maintain remission in patients with ANCA-associated vasculitis (AAV). We evaluated the incidence of serious infections and infection-related deaths in patients with AAV treated with rituximab and azathioprine, during the maintenance of remission period.MethodsWe searched PubMed and EMBASE for randomized clinical trials (RCTs) and observational studies evaluating immunosuppressive agents in patients with AAV. We defined serious or severe infections according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The study was registered on PROSPERO (CRD42022366269).ResultsFrom 1,265 abstracts, we identified 21 studies (7 RCTs and 14 observational), with relevant data. We included data from 1,284 and 2,938 individuals for assessment in our primary and secondary outcomes, respectively. The overall cumulative incidence of serious infections was 15.99% (CI 95%: 6.95–27.53%) during the total follow-up period (induction and maintenance) and 7.62% (CI 95%: 4.43–11.43%) during the maintenance period. Additionally, we found a 0.49% overall case fatality rate (CI 95%: 0.02–1.37%) and a 0.09% infection-related mortality rate (CI 95%: 0.00–0.51%) during maintenance treatment. Notably, we found a 14.61% (CI 95%: 10.19–19.61%) cumulative incidence of serious infections among patients who received rituximab and a 5.93% (CI 95%: 1.19–13.26%) cumulative incidence of serious infections among patients who received azathioprine during maintenance. Moreover, the cumulative incidence of serious infections during the total follow-up period (induction and maintenance) was 20.81% (CI 95%:4.56–43.70%) for the combination of cyclophosphamide and azathioprine and 14.12% (CI 95%: 5.20–26.00%) for rituximab.DiscussionThe cumulative incidence of serious infections during total follow-up and maintenance was within expected limits, while fatal infections during maintenance treatment were uncommon. Additionally, treatment with rituximab for both induction and maintenance did not exceed the anticipated by previous studies incidence of serious infections. Clinical practice and long-term follow up data are needed to corroborate these findings.Systematic review registrationIdentifier: PROSPERO (CRD42022366269).

Background: Remdesivir is widely used for the management of COVID-19 and several studies have reported bradycardia as a potential side effect associated with this agent. The aim of the present study was to evaluate the incidence rate, severity, and potential risk factors of remdesivir-associated bradycardia.Methods: We performed a retrospective cohort study among hospitalized adult patients with COVID-19 who were treated with remdesivir from March 2020 to October 2021. Our primary outcome of interest was the incidence rate and severity of bradycardia after remdesivir administration. We defined mild bradycardia as a heart rate of 51–59 beats per minute, moderate bradycardia as a heart rate of 41–50 beats per minute, and severe bradycardia as a heart rate of ≤40 beats per minute. We also performed univariable and multivariable regression analyses to determine potential bradycardia risk factors. Baseline characteristics were reported as means with standard deviations or medians with interquartile ranges (IQRs). All the statistical tests are shown as odds ratios (ORs) with 95% confidence intervals (CIs).Results: In total, 1,635 patients were included in this study. The median age with IQR was 68 (57–79) years and 51.7% of the patients were male. In total, 606 (37.1%) patients developed bradycardia. Among them, 437 patients (26.7%) developed mild bradycardia, 158 patients (9.7%) moderate bradycardia, while 11 patients (0.7%) experienced severe bradycardia. In our adjusted multivariate logistic regression, the odds of bradycardia development after remdesivir administration were higher among patients with age ≥65 years (OR 1.76, 95% CI: 1.04–2.99, p = 0.04), those with hypertension (OR 1.37, 95% CI: 1.07–1.75, p = 0.01), and obesity (OR 1.32, 95% CI: 1.02–1.68, p = 0.03).Conclusion: More than 1 out of 3 patients (37%) who received remdesivir for COVID-19 developed bradycardia with the majority of these patients developing mild or moderate bradycardia that is usually a benign manifestation not needing treatment in most cases. Age ≥65 years, hypertension, and obesity were potential risk factors for remdesivir-associated bradycardia among hospitalized COVID-19 patients. Clinicians should be aware of this adverse event and consider close clinical monitoring for patients at high risk for this adverse event.

Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19–1.52) and opportunistic (RR 2.69; 95% CI: 1.22–5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05–1.39), peficitinib (RR 1.40; 95% CI: 1.05–1.86) and upadacitinib (RR 1.30; 95% CI: 1.09–1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Stress during hospitalization can significantly impact cats, prompting the exploration of various strategies, including non-pharmacological approaches, to alleviate stress. However, certain situations may necessitate the use of anxiolytic medications like gabapentin and alprazolam to reduce stress levels. This study aimed to assess the effectiveness of gabapentin or alprazolam in cats undergoing short-term hospitalization on stress reduction, food consumption, and pain scores. Sixty cats undergoing elective ovariohysterectomy were divided into three groups, gabapentin-, alprazolam- or placebo-treated, and received treatment twice daily for two days. The study found that both gabapentin and alprazolam significantly reduced stress levels. Cats treated with alprazolam exhibited increased food intake, while those receiving gabapentin showed lower pain scores on the first postoperative day. However, both treatments led to increased levels of sedation. The study suggests that incorporating anxiolytics may be an effective adjunctive strategy for improving the experience of short-term hospitalization in cats. This prospective, randomized study aimed to assess the anxiolytic efficacy of gabapentin or alprazolam in cats during short-term postoperative hospitalization. Sixty cats were randomly assigned to three groups (gabapentin-treated [100 mg per cat], alprazolam-treated [0.125 mg per cat], or placebo-treated), with treatments administered twice daily for two days. Stress levels were evaluated using Cat Stress Scores, serum cortisol, and glucose concentrations. Pain scores, food consumption, and adverse effects such as sedation were also monitored. Fifty-five cats completed the study. Both medications demonstrated similar reductions in stress levels. Cats receiving gabapentin had lower pain scores, while those receiving alprazolam exhibited significantly increased food intake on the first postoperative day. However, both medications resulted in comparable levels of sedation. In the context of postoperative hospitalization, pharmacological intervention with anxiolytics could be effective in reducing stress levels. Despite potential side effects, gabapentin and alprazolam may contribute to an improved quality of short-term hospitalization for cats. [ABSTRACT FROM AUTHOR]

Pipelines in the offshore sector make common use of polypropylene (and other polymer) coating systems to protect the infrastructure and provide thermal insulation. High pressure high temperature pipelines are subject to large axial loads due to restraint by seafloor soils of thermal strains in the pipe wall. Friction between pipe coating material and seafloor soil plays a defining role in the build-up of axial stress and the formation of lateral buckling. Accurate quantification of pipe-soil interface friction is key to robust pipeline stability design and possibilities to enhance or manipulate the friction coefficient may be attractive to designers. An extensive campaign of soil and interface tests using a range of granular materials and polypropylene surface specimens engineered to achieve varying surface textures was carried out. The results show that interface friction primarily depends on stress level and the magnitude of the surface texture in relation to the particle size. Herein, a new relative texture parameter, [T.sub.a], is developed that, unlike alternative relative roughness parameters, can be obtained using conventional profilometry measurement techniques. An expression for estimating the friction coefficient in relation to texture and stress level is proposed that can serve as a useful predictor of pipe-soil interface friction. Key words: interface friction, laboratory tests, pipes and pipelines, direct shear, polymer, sand. Les pipelines du secteur offshore utilisent couramment des systemes de revetement en polypropylene (et autres polymeres) pour proteger l'infrastructure et assurer l'isolation thermique. Les pipelines a haute pression et haute temperature sont soumis a des charges axiales importantes en raison de la retenue par les sols du fond marin des contraintes thermiques dans la paroi du tuyau. Le frottement entre le materiau de revetement des tuyaux et le sol du fond marin joue un role determinant dans l'accumulation des contraintes axiales et la formation du flambage lateral. La quantification precise du frottement de l'interface tuyau-sol est la cle d'une conception robuste de la stabilite des pipelines et les possibilites d'ameliorer ou de manipuler le coefficient de frottement peuvent etre interessantes pour les concepteurs. Une vaste campagne d'essais de sol et d'interface utilisant une gamme de materiaux granulaires et des specimens de surface en polypropylene concus pour obtenir differentes textures de surface a ete menee. Les resultats montrent que le frottement d'interface depend principalement du niveau de contrainte et de l'importance de la texture de surface par rapport a la taille des particules. Un nouveau parametre de texture relative, [T.sub.a], est developpe qui, contrairement aux autres parametres de rugosite relative, peut etre obtenu en utilisant les techniques de mesure de profilometrie conventionnelles. Une expression permettant d'estimer le coefficient de frottement en fonction de la texture et du niveau de contrainte est proposee, qui peut servir de predicteur utile du frottement de l'interface tuyau-sol. [Traduit par la Redaction] Mots-cles : friction d'interface, essais en laboratoire, tuyaux et canalisations, cisaillement direct, polymere, sable., 1. Introduction Offshore pipelines undergo significant changes in effective axial stress between their as-laid condition and their operational state caused by variations in pipe temperature and internal pressure, typically in [...]

A simplified analytical solution is derived for the dynamic response of a flexible vertical retaining wall supported on a rotationally compliant footing, subjected to vertically-propagating harmonic S-waves under plane-strain conditions. The wall retains a semi-infinite, homogeneous viscoelastic soil layer of constant thickness and material properties. The proposed solution is based on the Veletsos-Younan simplifying assumption of zero vertical normal stresses in the soil, and negligible variation of vertical displacements with horizontal distance from the wall. A modified integration technique is employed, inspired by the seminal work of Vlasov and Leontiev, which simplifies the analysis by suppressing the vertical coordinate and transforming the governing partial differentialequation into an ordinary one that admits an elementary solution. Both cantilever and top-hinged walls are studied. Closed-form solutions are derived for lateral soil displacements, dynamic soil pressures, and equivalent Winkler springs connecting the wall to the far-field soil. It is shown that for cantilever conditions even a small amount of wall flexibility leads to a strong reduction in soil thrust, while the rotation at the wall base causes an additional decrease in thrust. The predictions of the method are in good agreement with available solutions, while new resultsfor combined wall flexibility and rotational compliance are presented. The proposed approach offers a simpler alternative to the complex elastodynamic solutions of Veletsos and Younan.

ABSTRACT We conducted a post hoc analysis in seropositive patients who were negative or borderline for functional neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline from a phase 1, 2, and 3 trial of casirivimab and imdevimab (CAS+IMD) treatment in hospitalized coronavirus disease 2019 (COVID-19) patients on low-flow or no supplemental oxygen prior to the emergence of Omicron-lineage variants. Patients were randomized to a single dose of 2.4 g CAS+IMD, 8.0 g CAS+IMD, or placebo. Patients seropositive for anti-SARS-CoV-2 antibodies at baseline were analyzed by their baseline neutralizing antibody status. At baseline, 20.6% (178/864) of seropositive patients were negative or borderline for neutralizing antibodies, indicating negative or very low functionally neutralizing anti-SARS-CoV-2 antibodies. CAS+IMD reduced viral load in patients who were negative or borderline for neutralizing antibodies versus placebo, but not in patients who were positive for neutralizing antibodies. In patients who were negative or borderline for neutralizing antibodies, we observed a trend in reduction of the proportion of patients who died or required mechanical ventilation, as well as in all-cause mortality, by day 29 with CAS+IMD versus placebo. The proportions of patients who died or required mechanical ventilation from days 1 to 29 were 19.1% in the placebo group and 10.9% in the CAS+IMD combined-dose group, and the proportions of patients who died (all-cause mortality) from days 1 to 29 were 16.2% in the placebo group and 9.1% in the CAS+IMD combined-dose group. In patients who were positive for neutralizing antibodies, no measurable harm or benefit was observed in either the proportion of patients who died or required mechanical ventilation or the proportion of patients who died (all-cause mortality). In hospitalized COVID-19 patients on low-flow or no supplemental oxygen, CAS+IMD reduced viral load, the risk of death or mechanical ventilation, and all-cause mortality in seropositive patients who were negative or borderline for neutralizing antibodies. IMPORTANCE The clinical benefit of CAS+IMD in hospitalized seronegative patients with COVID-19 has previously been demonstrated, although these studies observed no clinical benefit in seropositive patients. As the prevalence of SARS-CoV-2-seropositive individuals rises due to both vaccination and previous infection, it is important to understand whether there is a subset of hospitalized patients with COVID-19 with antibodies against SARS-CoV-2 who could benefit from anti-SARS-CoV-2 monoclonal antibody treatment. This post hoc analysis demonstrates that there is a subset of hospitalized seropositive patients with inadequate SARS-CoV-2-neutralizing antibodies (i.e., those who were negative or borderline for neutralizing antibodies) who may still benefit from CAS+IMD treatment if infected with a susceptible SARS-CoV-2 variant. Therefore, utilizing serostatus alone to guide treatment decisions for patients with COVID-19 may fail to identify those seropositive patients who could benefit from anti-SARS-CoV-2 monoclonal antibody therapies known to be effective against circulating strains, dependent upon how effectively their endogenous antibodies neutralize SARS-CoV-2.

Background: Biologic (bDMARD) and targeted synthetic (tsDMARD) disease-modifying anti-rheumatic drugs have broadened the treatment options and are increasingly used for patients with psoriatic arthritis (PsA). These agents block different pro-inflammatory cytokines or specific intracellular signaling pathways that promote inflammation and can place patients at risk of serious infections. We aimed to review the incidence of opportunistic infections (OIs) in patients with PsA who were treated with these agents.Methods: We searched PubMed and EMBASE through 14 April 2022 for randomized clinical trials evaluating bDMARD or tsDMARD in the treatment of PsA. Trials were eligible if they compared the effect of a bDMARD or tsDMARD with placebo and provided safety data. We used the Revised Cochrane risk-of-bias tool to assess the risk of bias among trials, and stratified the studies by mechanism of action (MOA) of the agents studied.Results: We included 47 studies in this analysis. A total of 17,197 patients received at least one dose of an agent of interest. The cumulative incidence of OIs by MOA was as follows: 1) JAK inhibitors: 2.72% (95% CI: 1.05%–5.04%), 2) anti-IL-17: 1.18% (95% CI: 0.60%–1.9%), 3) anti-IL-23: 0.24% (95% CI: 0.04%–0.54%), and 4) anti-TNFs: 0.01% (95% CI: 0.00%–0.21%). Based on their MOA, these agents are known to increase the risk of certain serious infections. The cumulative incidence of herpes zoster infection following treatment with JAK inhibitors (JAKi) was 2.53% (95% CI: 1.03%–4.57%) and the cumulative incidence of opportunistic Candida spp. infections following treatment with anti-IL-17, was 0.97% (95% CI: 0.51%–1.56%).Conclusion: The overall incidence of OIs among patients with PsA who were treated with biologic and targeted synthetic agents is low. However, careful monitoring is warranted for specific OIs such as herpes zoster infection following JAKi treatment, mucocutaneous candidiasis following anti-IL-17 treatment, and Mycobacterium tuberculosis infection following anti-TNF treatment.