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Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA., Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model., Results: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3-5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (-1.39 [-2.21, -0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [-1.17, 1.53], 0.50 [-1.11, 2.13] and 0.32 [-0.19, 0.84], respectively) or overall response (-0.99 [-2.21, 0.29], -0.89 [-2.41, 0.65] and 0.06 [-0.43, 0.57], respectively)., Conclusions: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole.

Background: Stress-related hyperglycaemia (SHG) is commonly seen in acutely ill patients and has been associated with poor outcomes in many studies performed in different acute care settings. We aimed to review the available evidence describing the associations between SHG and different outcomes in acutely ill patients admitted to an ICU. Study designs, populations, and outcome measures used in observational studies were analysed., Methods: We conducted a systematic scoping review of observational studies following the Joanna Briggs methodology. Medline, Embase, and the Cochrane Library were searched for publications between January 2000 and December 2015 that reported on SHG and mortality, infection rate, length of stay, time on ventilation, blood transfusions, renal replacement therapy, or acquired weakness., Results: The search yielded 3,063 articles, of which 43 articles were included (totalling 536,476 patients). Overall, the identified studies were heterogeneous in study conduct, SHG definition, blood glucose measurements and monitoring, treatment protocol, and outcome reporting. The most frequently reported outcomes were mortality (38 studies), ICU and hospital length of stay (23 and 18 studies, respectively), and duration of mechanical ventilation (13 studies). The majority of these studies (40 studies) compared the reported outcomes in patients who experienced SHG with those who did not. Fourteen studies (35.9%) identified an association between hyperglycaemia and increased mortality (odds ratios ranging from 1.13 to 2.76). Five studies identified hyperglycaemia as an independent risk factor for increased infection rates, and one identified it as an independent predictor of increased ICU length of stay., Discussion: SHG was consistently associated with poor outcomes. However, the wide divergences in the literature mandate standardisation of measuring and monitoring SHG and the creation of a consensus on SHG definition. A better comparability between practices will improve our knowledge on SHG consequences and management.

Ferritin is a highly-conserved iron-storage protein that has also been identified as an acute phase protein within the innate immune system. The iron-storage function is mediated through complementary roles played by heavy (H)-chain subunit as well as the light (L) in mammals or middle (M)-chain in teleosts, respectively. In this study, we report the identification of five ferritin subunits (H1, H2, M1, M2, M3) in the Atlantic salmon that were supported by the presence of iron-regulatory regions, gene structure, conserved domains and phylogenetic analysis. Tissue distribution analysis across eight different tissues showed that each of these isoforms is differentially expressed. We also examined the expression of the ferritin isoforms in the liver and kidney of juvenile Atlantic salmon that was challenged with Aeromonas salmonicida as well as in muscle cell culture stimulated with interleukin-1β. We found that each isoform displayed unique expression profiles, and in certain conditions the expressions between the isoforms were completely diametrical to each other. Our study is the first report of multiple ferritin isoforms from both the H- and M-chains in a vertebrate species, as well as ferritin isoforms that showed decreased expression in response to infection. Taken together, the results of our study suggest the possibility of functional differences between the H- and M-chain isoforms in terms of tissue localisation, transcriptional response to bacterial exposure and stimulation by specific immune factors.

Background: The relationship between fish health and muscle growth is critical for continued expansion of the aquaculture industry. The effect of immune stimulation on the expression of genes related to the energy balance of fish is poorly understood. In mammals immune stimulation results in major transcriptional changes in muscle, potentially to allow a reallocation of amino acids for use in the immune response and energy homeostasis. The aim of this study was to investigate the effects of immune stimulation on fish muscle gene expression., Results: Atlantic salmon (Salmo salar) primary muscle cell cultures were stimulated with recombinant (r)IL-1β, a major proinflammatory cytokine, for 24 h in order to simulate an acute immune response. The transcriptomic response was determined by RNA hybridization to a 4 × 44 K Agilent Atlantic salmon microarray platform. The rIL-1β stimulation induced the expression of genes related to both the innate and adaptive immune systems. In addition there were highly significant changes in the expression of genes related to regulation of the cell cycle, growth/structural proteins, proteolysis and lipid metabolism. Of interest were a number of IGF binding proteins that were differentially expressed, which may demonstrate cross talk between the growth and immune systems., Conclusion: We show rIL-1β modulates the expression of not only immune related genes, but also that of genes involved in processes related to growth and metabolism. Co-stimulation of muscle cells with both rIGF-I and rIL-1β demonstrates cross talk between these pathways providing potential avenues for further research. This study highlights the potential negative effects of inflammation on muscle protein deposition and growth in fish and extends our understanding of energy allocation in ectothermic animals.

E3 ubiquitin ligases are central for the selection of proteins targeted for degradation by the ubiquitin proteasome pathway. In this study atrogin-1 (Fbox-32), a major E3 ligase in muscle, has been characterized in Atlantic salmon (Salmo salar). The protein sequence is highly conserved between teleosts and mammals and is characterized by the presence of five conserved motifs related to the identification of protein targets. The genomic structure is conserved between teleosts and mammals and contains 9 exon and 8 introns. The phylogenetic relationship between atrogin-1 and two other closely related ubiquitin E3 ligases FBXO25 and MuRF1 showed atrogin-1 and FBXO25 grouped together with MuRF1 being more distant. The mRNAs were expressed in multiple tissues, atrogin-1 and MuRF1 were most abundant in white muscle and heart whereas FBXO25 had greatest expression in brain, white muscle and heart. The transcriptional modulation of these E3 ligases was examined in starved fish and fish following different immune stimulations. Expression of atrogin-1 and MuRF1 was increased following food deprivation, implementing these two genes in degradation of muscle protein during starvation. During viral infection atrogin-1 expression was not altered, whereas it was increased following stimulation with LPS, indicating an onset of catabolic processes during inflammatory responses., (Copyright © 2010 Elsevier Inc. All rights reserved.)