Vibrating-mesh nebulisers have a reputation for having a gentle and successful aerosolization process while preserving the integrity of biologic formulations. The main component of a vibrating-mesh ...nebuliser is the oscilLating membrane. This is formed by thousands of micron-sized pores that oscillate to generate a fine mist. These pores have the potential to be blocked depending on the formulation, especially if it is not a homogeneous solution. In this experiment, poly-lactic-co- glycolic acid nanoparticles (PLGA-NPs) of three varied sizes (100, 200 and 500 nm) were nebulised. The aim was to understand the impact of particle size and concentration on nebulisation using the FOX vibrating-mesh nebuliser. PLGA-NPs of 100 and 200 nm size were successfully nebulised over a wide concentration range (from 0.1 to 10 mg/ml) in terms of percentage aerosolised and nebulisation time. Particles of larger size (500 nm) showed a long nebulisation time which might correlate with membrane blockages. A substantial proportion of the nanomedicines in the market and under development have a particle size around 100-200 nm. The result of this study showed that the FOX vibrating-mesh nebuliser can be a suitable platform to successfully deliver these types of nanomedicines to the lungs.
The genomes of HIV-2 and some SIV strains contain the accessory gene vpx, which carries out several functions during infection, including the downregulation of SAMHD1. Vpx is also commonly used in ...experiments to increase HIV-1 infection efficiency in myeloid cells, particularly in studies that investigate the activation of antiviral pathways. However, the potential effects of Vpx on cellular innate immune signaling is not completely understood. We investigated whether and how Vpx affects ISG responses in monocytic cell lines and MDMs during HIV-1 infection.
HIV-1 infection at excessively high virus doses can induce ISG activation, although at the expense of high levels of cell death. At equal infection levels, the ISG response is potentiated by the presence of Vpx and requires the initiation of reverse transcription. The interaction of Vpx with the DCAF1 adaptor protein is important for the enhanced response, implicating Vpx-mediated degradation of a host factor. Cells lacking SAMHD1 show similarly augmented responses, suggesting an effect that is independent of SAMHD1 degradation. Overcoming SAMHD1 restriction in MDMs to reach equal infection levels with viruses containing and lacking Vpx reveals a novel function of Vpx in elevating innate immune responses.
Vpx likely has as yet undefined roles in infected cells. Our results demonstrate that Vpx enhances ISG responses in myeloid cell lines and primary cells independently of its ability to degrade SAMHD1. These findings have implications for innate immunity studies in myeloid cells that use Vpx delivery with HIV-1 infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Protein synthesis is a highly energy-consuming process that is downregulated in response to many environmental stresses or adverse conditions. Studies in the yeast Saccharomyces cerevisiae have shown ...that bulk translation is inhibited during adaptation to iron deficiency, which is consistent with its requirement for ribosome biogenesis and recycling. Although iron deficiency anemia is the most common human nutritional disorder, how iron modulates translation in mammals is poorly understood. Studies during erythropoiesis have shown that iron bioavailability is coordinated with globin synthesis via bulk translation regulation. However, little is known about the control of translation during iron limitation in other tissues. Here, we investigated how iron depletion affects protein synthesis in human osteosarcoma U-2 OS cells. By adding an extracellular iron chelator, we observed that iron deficiency limits cell proliferation, induces autophagy, and decreases the global rate of protein synthesis. Analysis of specific molecular markers indicates that the inhibition of bulk translation upon iron limitation occurs through the eukaryotic initiation factor eIF2α and mechanistic target of rapamycin (mTOR) pathways. In contrast to other environmental and nutritional stresses, iron depletion does not trigger the assembly of messenger ribonucleoprotein stress granules, which typically form upon polysome disassembly.
Arboviruses pose a significant threat to public health globally, demanding innovative approaches for their control. For this, a better understanding of the complex web of interactions established in ...arbovirus-infected mosquitoes is fundamental. High-throughput analyses allow a genome-wide view of arbovirus-induced alterations at different gene expression levels. This review provides a comprehensive perspective into the current literature in transcriptome and proteome landscapes in mosquitoes infected with arboviruses. It also proposes a coordinated research effort to define the critical nodes that determine arbovirus infection and transmission.
In the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs), vancomycin stands as the prevalent therapeutic agent. Daptomycin remains an alternative ...antibiotic to treat MRSA BSIs in cases where vancomycin proves ineffective. However, studies have conflicted on whether daptomycin is more effective than vancomycin among patients with MRSA BSI.
To compare the effectiveness of daptomycin and vancomycin for the prevention of mortality among adult patients with MRSA BSI.
Systematic searches of databases were performed, including Embase, PubMed, Web of Science, and Cochrane Library. The Newcastle Ottawa Scale (NOS) and Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) were used to assess the quality of individual observational and randomized control studies, respectively. Pooled odd ratios were calculated using random effects models.
Twenty studies were included based on a priori set inclusion and exclusion criteria. Daptomycin treatment was associated with non-significant lower mortality odds, compared to vancomycin treatment (OR = 0.81; 95% CI, 0.62, 1.06). Sub-analyses based on the time patients were switched from another anti-MRSA treatment to daptomycin demonstrated that switching to daptomycin within 3 or 5 days was significantly associated with 55% and 45% decreased odds of all-cause mortality, respectively. However, switching to daptomycin any time after five days of treatment was not significantly associated with lower odds of mortality. Stratified analysis based on vancomycin minimum inhibitory concentration (MIC) revealed that daptomycin treatment among patients infected with MRSA strains with MIC≥1 mg/L was significantly associated with 40% lower odds of mortality compared to vancomycin treatment.
Compared with vancomycin, an early switch from vancomycin to daptomycin was significantly associated with lower odds of mortality. In contrast, switching to daptomycin at any time only showed a trend towards reduced mortality, with a non-significant association. Therefore, the efficacy of early daptomycin use over vancomycin against mortality among MRSA BSIs patients may add evidence to the existing literature in support of switching to daptomycin early over remaining on vancomycin. More randomized and prospective studies are needed to assess this association.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVES:To determine the epidemiology of Candida bloodstream infections, variables influencing mortality, and antifungal resistance rates in ICUs in Spain.
DESIGN:Prospective, observational, ...multicenter population-based study.
SETTING:Medical and surgical ICUs in 29 hospitals distributed throughout five metropolitan areas of Spain.
PATIENTS:Adult patients (≥ 18 yr) with an episode of Candida bloodstream infection during admission to any surveillance area ICU from May 2010 to April 2011.
INTERVENTIONS:Candida isolates were sent to a reference laboratory for species identification by DNA sequencing and susceptibility testing using the methods and breakpoint criteria promulgated by the European Committee on Antimicrobial Susceptibility Testing. Prognostic factors associated with early (0–7 d) and late (8–30 d) mortality were analyzed using logistic regression modeling.
MEASUREMENTS AND MAIN RESULTS:We detected 773 cases of candidemia, 752 of which were included in the overall cohort. Among these, 168 (22.3%) occurred in adult ICU patients. The rank order of Candida isolates was as followsCandida albicans (52%), Candida parapsilosis (23.7%), Candida glabrata (12.7%), Candida tropicalis (5.8%), Candida krusei (4%), and others (1.8%). Overall susceptibility to fluconazole was 79.2%. Cumulative mortality at 7 and 30 days after the first episode of candidemia was 16.5% and 47%, respectively. Multivariate analysis showed that early appropriate antifungal treatment and catheter removal (odds ratio, 0.27; 95% CI, 0.08–0.91), Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.11; 95% CI, 1.04–1.19), and abdominal source (odds ratio, 8.15; 95% CI, 1.75–37.93) were independently associated with early mortality. Determinants of late mortality were age (odds ratio, 1.04; 95% CI, 1.01–1.07), intubation (odds ratio, 7.24; 95% CI, 2.24–23.40), renal replacement therapy (odds ratio, 6.12; 95% CI, 2.24–16.73), and primary source (odds ratio, 2.51; 95% CI, 1.06–5.95).
CONCLUSIONS:Candidemia in ICU patients is caused by non-albicans species in 48% of cases, C. parapsilosis being the most common among these. Overall mortality remains high and mainly related with host factors. Prompt adequate antifungal treatment and catheter removal could be critical to decrease early mortality.
Objective
This study aimed to assess the probability of reaching an adequate pharmacokinetic/pharmacodynamic (pK/pD) index for different cefepime dosages in frail patients with bacteremia treated in ...the emergency room.
Methods
Simulation study based on Gram-negative bacterial strains that cause bacteremia. The probability of reaching a time above the minimum inhibitory concentration (MIC) at 50% and 100% dosing intervals (fT > 50 and fT > 80% MIC) was assessed for two different renal clearance intervals.
Results
One hundred twenty nine strains were collected, the predominant species being Escherichia coli (n = 83 64.3%). In patients with a ClCr of 30 mL/min, an fT > 50% MIC was reached in more than 90% of the simulations. However, a dose of at least 1 g every 12 h must be administered to reach an fT > 80% MIC. In patients with a ClCr of 30–60 mL/min, the probability of reaching an fT > 50% MIC was higher than 90% with doses of 1 g every 8 h or more, but this value was not reached in > 90% simulations for any of the doses tested in this study.
Conclusions
Standard cefepime dosing can reach an adequate PK/PD index in frail patients. Nevertheless, a high dose or extended infusion is necessary to reach an fT > 80% MIC in patients with a ClCr > 60 mL/min.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to determine among patients with candidemia the real rate of ophthalmoscopy and the impact of performing ocular assessment on the outcome of the disease. We performed a ...post hoc analysis of a prospective, multicenter, population-based candidemia surveillance program implemented in Spain during 2010-2011 (CANDIPOP). Ophthalmoscopy was performed in only 168 of the 365 patients with candidemia (46%). Ocular lesions related to candidemia were found in only 13/168 patients (7.7%), of whom 1 reported ocular symptoms (incidence of symptomatic disease in the whole population, 0.27% 1/365). Ophthalmological findings led to a change in antifungal therapy in only 5.9% of cases (10/168), and performance of the test was not related to a better outcome. Ocular candidiasis was not associated with a worse outcome and progressed favorably in all but 1 evaluable patient, who did not experience vision loss. The low frequency of ophthalmoscopy and ocular involvement and the asymptomatic nature of ocular candidiasis, with a favorable outcome in almost all cases, lead us to reconsider the need for systematic ophthalmoscopy in all candidemic patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The objectives of our study were to describe the characteristics of patients with
candidemia and to perform an in-depth microbiological characterization of isolates and compare them with those of ...patients with
candidemia. We described the risk factors and outcomes of 22 patients with candidemia caused by the
complex. Incident isolates were identified using molecular techniques, and susceptibility to fluconazole, anidulafungin, and micafungin was studied. Biofilm formation was measured using the crystal violet assay (biomass production) and the XTT reduction assay (metabolic activity), and virulence was studied using the
model. Biofilm formation was compared with that observed for
The main conditions predisposing to infection were malignancy (68%), immunosuppressive therapy (59%), and neutropenia (18%). Clinical presentation of candidemia was less severe in patients infected by the
complex than in patients infected by
, and 30-day mortality was lower in
patients (13.6% versus 33.9%, respectively;
= 0.049). Isolates were identified as
(
= 17) and
(
= 5). The isolates produced biofilms with low metabolic activity and moderate biomass. The
model showed that
was less virulent than
(mean of 6 days versus 1 day of survival, respectively;
< 0.001). Patients with candidemia caused by the
complex had severe and debilitating underlying conditions. Overall, the isolates showed diminished susceptibility to fluconazole and echinocandins, although poor biofilm formation and the low virulence were associated with a favorable outcome.
Different scales have been validated to assess the medication regimen complexity. However, the effect of this complexity on the risk of health care center consultations in patients with drug-related ...problems is unknown. This study’s objective is to evaluate the association between the Medication Regimen Complexity Index (MCRI) and the number of drugs prescribed and new consultations to the health care system in patients who visit an emergency service due to drug-related problems. This is a retrospective observational study. We included patients >65 years who attended in an emergency service for drug-related problems. To identify variables associated with health care center reconsultation, a multivariate analysis was performed, including demographic and comorbidity variables, number of drugs prescribed, and MCRI value. Two hundred and one patients were included. A significant association was found between the prescription of more than five drugs (odds ratio OR = 2.50, 95% confidence interval CI = 1.08, 5.79), an MCRI > 20 (2.98 1.46–6.09), and an increase in the number of drugs prescribed (2.87 1.57–5.21) and its MCRI (2.06 1.13–3.77) at discharge and a new visit to the emergency department. An association was found between the prescription of more than five drugs, an MCRI > 20, an increase in the number of drugs, and in MCRI value at discharge and a new visit to any other health care center. The number of prescribed drugs and the medication complexity of patients who visit the emergency department for drug-related problems was associated with an increase in the number of revisits to the emergency department and to other health care centers.
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