β-Lactam Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus Infective Endocarditis.

Importance: Infective endocarditis (IE) caused by Staphylococcus aureus is associated with high mortality, approximately 20% to 30%, mostly in the first month, with no improvement in recent decades. Current opinion is that antistaphylococcal penicillin and cefazolin are equally effective in treating methicillin-susceptible S aureus (MSSA) IE, and both are recommended as possible first-line treatments. Most MSSA strains carry the β-lactamase blaZ gene, and some blaZ-positive strains exhibit an inoculum effect, meaning increased minimum inhibitory concentrations at high inoculum.

Voriconazole as an alternative oral treatment in fluconazole-resistant urinary candidiasis.

Objectives: This study aims to assess the urinary diffusion and clinical effectiveness of voriconazole in patients with fluconazole-resistant urinary candidiasis.

Patients And Methods: In this prospective pilot study, we utilized a validated chromatography method to measure voriconazole in urine over a 12-hour period between two administrations of the drug and in plasma at trough.

Results: Thirty-five patients, including five with fluconazole-resistant urinary candidiasis, were included.

Phase Separation in Complex Mixtures with Many Components: Analytical Expressions for Spinodal Manifolds.

The phase behavior is investigated for systems composed of a large number of macromolecular components , with ≥ 2. Liquid-liquid phase separation is modeled using a virial expansion up to the second order of the concentrations of the components. Formal analytical expressions for the spinodal manifolds in dimensions are derived, which simplify their calculation (by transforming the original problem into inequalities that can be evaluated numerically using linear programming techniques).

Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling.

Chimeric antigen receptor (CAR) T cells used for the treatment of B cell malignancies can identify T cell subsets with superior clinical activity. Here, using infusion products of individuals with large B cell lymphoma, we integrated functional profiling using timelapse imaging microscopy in nanowell grids with subcellular profiling and single-cell RNA sequencing to identify a signature of multifunctional CD8 T cells (CD8-fit T cells). CD8-fit T cells are capable of migration and serial killing and harbor balanced mitochondrial and lysosomal volumes.

IL7 increases targeted lipid nanoparticle-mediated mRNA expression in T cells in vitro and in vivo by enhancing T cell protein translation.

The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition to vaccines, LNP-mRNA can be used in many other applications. For example, targeting the LNP with anti-CD5 antibodies (CD5/tLNP) can allow for efficient delivery of mRNA payloads to T cells to express protein.

Liquid biopsy approach to monitor the efficacy and response to CAR-T cell therapy.

Background: Chimeric antigen receptor (CAR)-T cells are approved for use in the treatment of hematological malignancies. Axicabtagene ciloleucel (YESCARTA) and brexucabtagene autoleucel (TECARTUS) genetically modified autologous T cells expressing an anti-CD19 scFv based on the FMC63 clone have shown impressive response rates for the treatment of CD19+B cell malignancies, but there remain challenges in monitoring long-term persistence as well as the functional characterization of low-level persisting CAR-T cells in patients. Furthermore, due to CD19-negative driven relapse, having the capability to monitor patients with simultaneous detection of the B cell malignancy and persisting CAR-T cells in patient peripheral blood is important for ensuring timely treatment optionality and understanding relapse.

Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.

Circulating microRNAs from plasma as preclinical biomarkers of epileptogenesis and epilepsy.

Epilepsy frequently develops as a result of brain insult; however, there are no tools allowing to predict which patients suffering from trauma will eventually develop epilepsy. microRNAs are interesting candidates for biomarkers, as several of them have been described to change their levels in the brains, and in the plasma of epileptic subjects. This study was conducted to evaluate the usefulness of plasma miRNAs as epileptogenesis/epilepsy biomarkers.

Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7).

Unlabelled: Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability.

Can we predict the influence of inflammation on voriconazole exposure? An overview.

Voriconazole is a triazole antifungal indicated for invasive fungal infections that exhibits a high degree of inter-individual and intra-individual pharmacokinetic variability. Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. Therapeutic drug monitoring is recommended by measurement of minimum plasma concentrations.

Phase Behavior of Ternary Polymer Mixtures in a Common Solvent.

The Edmond-Ogston model for phase separation is extended to ternary polymer mixtures in a common solvent (de facto a quaternary mixture). The model assumes a truncated virial expansion of the Helmholtz free energy up to the second-order terms in the concentration of the polymers, and the second virial coefficients (, , , , , ) are the six parameters of the model. New results from this model are presented in relation to earlier work on binary mixtures: a necessary condition for the virial coefficients for the occurrence of phase separation in two or three phases, an analysis of the different regions of (local) thermodynamic instability using the Descartes sign rule, an expression for the critical curves, a relation between the tangents in points along the critical curve, a relation between the concentration of components in the different phases according to the so-called Lambert-W function, and a consistency check for the composition of coexisting phases in ternary mixtures.

Power exchanged between subsystems with non-diffuse fields in statistical energy analysis.

This article is a discussion on the necessity of the assumption of diffuse field in statistical energy analysis and the validity of the coupling power proportionality which states that the vibrational power exchanged between coupled subsystems is proportional to the difference of their modal energies. It is proposed to re-formulate the coupling power proportionality in terms of local energy density instead of modal energy. We show that this generalized form remains valid even if the vibrational field is not diffuse.

Amoxicillin therapeutic drug monitoring for endocarditis: A comparative study (EI-STAB).

Introduction: International guidelines recommend high doses of β-lactams for most cases of infective endocarditis (IE). Therapeutic drug monitoring (TDM) is increasingly used to adjust β-lactam dose based on plasma concentrations, although there are no comparative studies to support this practice. The benefit of amoxicillin TDM during IE was evaluated.

Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma.

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg).

Exploring how changes to the steroidal core alter oleogelation capability in sterol: γ-oryzanol blends.

Oleogels based on sterols such as β-sitosterol blended with the sterol ester γ-oryzanol are a very interesting class of systems, but there are aspects of their formation and structure that remain elusive. It has previously been shown that a methyl group on the C30 position of the sterol-ester plays an important role in gelation. This work explored the effect that having C30 methyl groups on both the sterol and the sterol-ester had on the gelation process and subsequent gel structure.

An acoustic signature of extreme failure on model granular materials.

Unexpectedly, granular materials can fail, the structure even destroyed, spontaneously in simple isotropic compression with stick-slip-like frictional behaviour. This extreme behaviour is conceptually impossible for saturated two-phase assembly in classical granular physics. Furthermore, the triggering mechanisms of these laboratory events remain mysterious, as in natural earthquakes.

Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma.

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial.

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses.

The in vivo persistence of adoptively transferred T cells is predictive of antitumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific chimeric antigen receptor (CAR) T cells as the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on time-lapse imaging microscopy in nanowell grids (TIMING), which integrates killing, cytokine secretion, and transcriptional profiling.

B-cell lymphoma-associated hemophagocytic lymphohistiocytosis: A case report.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by an exaggerated but dysregulated immune response resulting in hyperinflammation, with a potential for progression to multiple organ dysfunction and failure. Infectious diseases, inflammatory disorders, malignancies and immunodeficiency syndromes are known triggers of HLH in adults. The present study reported the case of a middle-aged man with HLH triggered by B-cell lymphoma who was successfully treated with dexamethasone; etoposide, prednisone, vincristine, cyclophosphamide, hydroxy-doxorubicin and rituximab chemotherapy; and multiple intrathecal methotrexate with a good outcome.

The Regulatory RNA Confers a Potential Selective Advantage to for Intestinal Colonization.

The aim of this study was to evaluate the role of the regulatory small RNA (sRNA) Ern0160 in gastrointestinal tract (GIT) colonization by . For this purpose, four strains of were used, Aus0004 (WT), an -deleted Aus0004 mutant (Δ0160), a -complemented Δ0160 strain overexpressing (Δ0160_0160), and a strain Δ0160 with an empty pAT29 vector (Δ0160_pAT29). Strains were studied both and , alone and in competitive assays.