Integrase strand transfer inhibitor resistance mediated by R263K plus E157Q in a patient with HIV infection treated with bictegravir/tenofovir alafenamide/emtricitabine: case report and review of the literature.

OBJECTIVES: The in vivo selection of E157Q plus R263K has not been reported in patients treated with coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). To the best of our knowledge, we hereby report the first case of high-grade INSTI resistance associated with the presence of these aminoacidic substitutions in a treatment-experienced HIV patient treated with BIC/FTC/TAF. METHODS: Clinical case report and review of the literature. RESULTS: A heavily treatment-experienced patient was switched to BIC/FTC/TAF due to drug-drug interactions after being diagnosed with disseminated Mycobacterium avium-intracellulare disease. He had been treated before with raltegravir with poor adherence. No mutations in the integrase gene were detected 1 year after finishing treatment with raltegravir. Months after being switched to BIC/FTC/TAF, and again with poor adherence documented, virological failure (VF) was detected. The polymorphic substitution E157Q and the resistance mutation R263K in the integrase gene were detected, as well as M184V, among other mutations in the reverse transcriptase gene. The patient is currently being treated with dolutegravir q12h plus boosted darunavir along with directly observed treatment, and for the first time in 20 years, plasmatic viral load values are below 100 copies/mL. CONCLUSIONS: This case illustrates that the combination of E157Q and R263K plus M184V can be selected in vivo in a clinical scenario of poor adherence with BIC/FTC/TAF, although it is a very rare phenomenon. Previous VF with first-generation integrase strand transfer inhibitors (INSTIs) should be kept in mind when switching patients to second-generation INSTIs.

Novel insight into the lipid network of plasma extracellular vesicles reveal sex-based differences in the lipidomic profile of alcohol use disorder patients.

BACKGROUND: Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. METHODS: We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX2, which evaluates enzymatic dysregulation using an enrichment algorithm. RESULTS: Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with "negative intrinsic curvature" and "positive intrinsic curvature", respectively. CONCLUSIONS: Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD.

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX², which evaluates enzymatic dysregulation using an enrichment algorithm. Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with "negative intrinsic curvature" and "positive intrinsic curvature", respectively. Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD.

Predominantly Pro-Inflammatory Phenotype with Mixed M1/M2 Polarization of Peripheral Blood Classical Monocytes and Monocyte-Derived Macrophages among Patients with Excessive Ethanol Intake.

Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD). We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers (EADs). PB samples from 20 EADs and 22 healthy controls were collected for isolation of CD14+ monocytes and short-term culture with LPS/IFNγ, IL4/IL13, or without stimulation. These conditions were also used to polarize MDMs into M1, M2, or M0 phenotypes. Cytokine production was assessed in the blood and culture supernatants. M1/M2-related markers were analyzed using mRNA expression and surface marker detection. Additionally, the miRNA profile of CD14+ monocytes was analyzed. PB samples from EADs exhibited increased levels of pro-inflammatory cytokines. Following short-term culture, unstimulated blood samples from EADs showed higher levels of soluble TNF-α and IL-8, whereas monocytes expressed increased levels of surface TNF-α and elevated mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase. MDMs from EADs showed higher levels of TNF-α and CD206 surface markers and increased IL-10 production. LPS/IFNγ induced higher mRNA expression of Nrf2 only in the controls. miRNA analysis revealed a distinctive miRNA profile that is potentially associated with liver carcinogenesis and ALD through inflammation and oxidative stress. This study confirms the predominantly pro-inflammatory profile of PB monocytes among EADs and suggests immune exhaustion features in MDMs.

Dalbavancin for treating prosthetic joint infections caused by Gram-positive bacteria: A proposal for a low dose strategy. A retrospective cohort study / Dalbavancina para el tratamiento de infección periprotésica causada por microorganismos grampositivos. Propuesta para una estrategia con dosis bajas. Un estudio retrospectivo de cohortes

BACKGROUND: Gram-positive bacteria are the leading cause of prosthetic joint infection (PJI). Dalbavancin is a lipoglycopeptide with remarkable pharmacokinetic properties and high bactericidal activity against most Gram-positive bacteria. Although clear evidence regarding its effectiveness in bone and joint infections lacks, recent studies suggest a promising role of dalbavancin in PJI. METHODS: From June 1st 2016 to May 1st 2018, all patients diagnosed of PJI and treated with DAL alone or in combination with other drugs were retrospectively evaluated. Dalbavancin susceptibility of every isolate was studied following CLSI criteria. The primary objective was to assess the clinical efficacy and tolerability of the drug in patients with PJI. A cost-analysis was performed following the DALBUSE study methodology. RESULTS: Sixteen patients were treated with dalbavancin, eight with total hip arthroplasty infection (THAi) and eight with total knee arthroplasty infection (TKAi). Staphylococcus spp. and Enterococcus spp. were the microorganisms involved. No major side effects were detected. Infection resolved in 12 patients. In 2 patients the treatment failed, and another patient died due to unrelated causes. One patient is currently being treated for hematogenous-spread knee infection secondary to prosthetic aortic arch endocarditis. After discontinuation of dalbavancin, and excluding patients who died or with clinical failure, the median follow up of the cohort was 503 days (interquartile range IQR, 434.5 to 567 days). We calculate that US$ 264,769 were saved. CONCLUSION: This study suggests that dalbavancin treatment for PJI caused by Gram-positive bacteria is a safe and effective option that reduces hospital stay and costs. Future reports are needed to confirm these findings

INTRODUCCIÓN: Las bacterias grampositivas son la principal causa de infección periprotésica (IPP). Dalbavancina es un lipoglicopéptido con interesantes propiedades farmacocinéticas y una importante actividad bactericida frente a la mayoría de grampositivos. Aunque aún necesitamos mayor evidencia en relación con su uso en infección osteoarticular, estudios recientes sugieren un papel importante de dalbavancina en la IPP. MÉTODOS: Desde el 1 de Junio de 2016 al 1 de Mayo de 2018, todos los pacientes diagnosticados con IPP y tratados con dalbavancina sola o en combinación con otros fármacos fueron evaluados de forma retrospectiva. La sensibilidad a dalbavancina de los aislamientos fue evaluada según las recomendaciones de CLSI. El objetivo primario fue determinar la eficacia y tolerabilidad del fármaco en pacientes con IPP. Se realizó un análisis de coste siguiendo la metodología descrita en el estudio DALBUSE. RESULTADOS: Dieciséis pacientes fueron tratados con dalbavancina, ocho con infección de prótesis total de cadera y ocho con infección de prótesis total de rodilla. Staphylococcus spp. y Enterococcus spp. fueron los microorganismos implicados. No hubo efectos adversos relevantes. La infección se resolvió en 12 pacientes. En dos pacientes el tratamiento falló, y otro paciente falleció por causas no relacionadas. Un paciente es actualmente en tratamiento supresor por infección por diseminación hematógena de prótesis total de rodilla a partir de endocarditis protésica aórtica. Tras la discontinuación de dalbavancina, y exceptuando los pacientes fallecidos y/o con fallo terapéutico, el seguimiento medio fue de 503 días (rango intercuartílico 434.5-567 dias). Se estimó un ahorro de 264.769 dólares USA. CONCLUSIONES: Este estudio sugiere que dalbavancina para el tratamiento de IPP causada por microorganismos grampositivos es segura y una opción eficaz que reduce la estancia hospitalaria y los costes. Se precisan más comunicaciones para confirmar estos datos