Higher Daptomycin Dose Associated with Improved Survival in Methicillin-Resistant Staphylococcus aureus Bacteremia

Study Objective: Current guidelines recommend higher daptomycin doses than the daptomycin label dose of 6 mg/kg for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia; however, the evidence supporting this recommendation is from in vitro and case series studies. This study evaluated the comparative effectiveness of the daptomycin label dose versus higher daptomycin doses in patients with MRSA bacteremia. Design: Retrospective national cohort study. Setting: Veterans Affairs medical centers. Patients: A total of 371 adults with MRSA bacteremia who were admitted between 2002 and 2015 and treated initially with vancomycin within 24 hours of initial culture collection and then switched to daptomycin therapy within 7 days; 138 patients (37.2%) received daptomycin doses higher than the daptomycin label dose (7 mg/kg or greater), and 233 (62.8%) received the daptomycin label dose (6 mg/kg). Measurements and Main Results: Clinical outcomes were compared among those who received the daptomycin label dose and those who received the higher dose using propensity score–matched Cox proportional hazards regression models. To identify dose partitioning associated with optimal survival, classification and regression tree (CART) analysis was used among patients, controlling for confounding with a 30-day mortality disease risk score. Propensity score–matched 30-day mortality was 8.6% (6/70 patients) among the higher dose group versus 18.6% (13/70 patients) among the label dose group (hazard ratio 0.31, 95% confidence interval 0.10–0.94). No significant differences were observed in inpatient mortality, length of stay, 30-day readmission, or 30-day S. aureus reinfection between groups. CART analysis resulted in doses of 7 mg/kg or greater providing benefit only among patients with higher (more than 51%) predicted probabilities of 30-day mortality (p\u3c0.001). Conclusion: To our knowledge, this is the first comparative effectiveness study of daptomycin doses in patients with MRSA bacteremia. Survival benefits were observed with doses higher than the daptomycin label dose (7 mg/kg or greater) for the treatment of MRSA bacteremia. These data suggest that higher doses than the daptomycin label dose may be preferred over the label dose for improving clinical outcomes in patients with MRSA bacteremia

Aspergillus fumigatus Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity

Trehalose biosynthesis is found in fungi but not humans. Proteins involved in trehalose biosynthesis are essential for fungal pathogen virulence in humans and plants through multiple mechanisms. Loss of canonical trehalose biosynthesis genes in the human pathogen Aspergillus fumigatus significantly alters cell wall structure and integrity, though the mechanistic link between these virulence-associated pathways remains enigmatic. Here we characterize genes, called tslAand tslB, which encode proteins that contain domains similar to those corresponding to trehalose-6-phosphate phosphatase but lack critical catalytic residues for phosphatase activity. Loss of tslA reduces trehalose content in both conidia and mycelia, impairs cell wall integrity, and significantly alters cell wall structure. To gain mechanistic insights into the role that TslA plays in cell wall homeostasis, immunoprecipitation assays coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to reveal a direct interaction between TslA and CsmA, a type V chitin synthase enzyme. TslA regulates not only chitin synthase activity but also CsmA sub-cellular localization. Loss of TslA impacts the immunopathogenesis of murine invasive pulmonary aspergillosis through altering cytokine production and immune cell recruitment. In conclusion, our data provide a novel model whereby proteins in the trehalose pathway play a direct role in fungal cell wall homeostasis and consequently impact fungus-host interactions

Weak biofilm formation among carbapenem-resistant Klebsiella pneumoniae

Biofilm formation of multidrug and extensively drug resistant Klebsiella pneumoniaeisolates is poorly understood. We investigated 139 diverse clinical K. pneumoniaeisolates that possess various resistance patterns to evaluate the relationship between biofilm formation and resistance. Antimicrobial resistance was compared among a diverse collection of weak versus strong biofilm-forming K. pneumoniae, and predictors of strong biofilm formation were identified. Multi-drug resistant isolates were more common among weak (97.9%) versus strong biofilm formers (76%; P = 0.002). Carbapenem-resistant K. pneumoniae were 91% less likely to form strong biofilm (odds ratio 0.09; 95% confidence interval 0.02–0.33). The statistically significant inverse relationship between biofilm formation and antibiotic resistance suggests that virulence may be a trade-off for survival

Crystallographic characterisation of ultra-thin, or amorphous transparent conducting oxides:the case for raman spectroscopy.

The electronic and optical properties of transparent conducting oxides (TCOs) are closely linked to their crystallographic structure on a macroscopic (grain sizes) and microscopic (bond structure) level. With the increasing drive towards using reduced film thicknesses in devices and growing interest in amorphous TCOs such as n-type InGaZnO 4 (IGZO), ZnSnO 3 (ZTO), p-type Cu x CrO 2 , or ZnRh 2 O 4 , the task of gaining in-depth knowledge on their crystal structure by conventional X-ray diffraction-based measurements are becoming increasingly difficult. We demonstrate the use of a focal shift based background subtraction technique for Raman spectroscopy specifically developed for the case of transparent thin films on amorphous substrates. Using this technique we demonstrate, for a variety of TCOs CuO, a-ZTO, ZnO:Al), how changes in local vibrational modes reflect changes in the composition of the TCO and consequently their electronic properties

Attitudes Towards and Limitations to ICT Use in Assisted and Independent Living Communities: Findings from a Specially-Designed Technological Intervention

Much literature has been devoted to theoretical explanations of the learning processes of older adults and to the methods of teaching best utilized in older populations. However, there has been less focus on the education of older adults who reside in assisted and independent living communities (AICs), especially with regards to information and communication technology (ICT) education. The purpose of this study is to determine whether participants\u27 attitudes and views towards computers and the Internet are affected as a result of participating in an eight-week training program designed to enhance computer and Internet use among older adults in such communities. Specifically, we examine if ICT education specially designed for AIC residents results in more positive attitudes towards ICTs and a perceived decrease in factors that may limit or prevent computer and Internet use. We discuss the implications of these results for enhancing the quality of life for older adults in AICs and make recommendations for those seeking to decrease digital inequality among older adults in these communities through their own ICT classes

Combined histomorphometric and gene-expression profiling applied to toxicology

We have developed a unique methodology for the combined analysis of histomorphometric and gene-expression profiles amenable to intensive data mining and multisample comparison for a comprehensive approach to toxicology. This hybrid technology, termed extensible morphometric relational gene-expression analysis (EMeRGE), is applied in a toxicological study of time-varied vehicle- and carbon-tetrachloride (CCl(4))-treated rats, and demonstrates correlations between specific genes and tissue structures that can augment interpretation of biological observations and diagnosis

MUC1 Regulates Cyclin D1 Gene Expression Through p120 Catenin and β-catenin

MUC1 interacts with β-catenin and p120 catenin to modulate WNT signaling. We investigated the effect of overexpressing MUC1 on the regulation of cyclin D1, a downstream target for the WNT/β-catenin signaling pathway, in two human pancreatic cancer cell lines, Panc-1 and S2-013. We observed a significant enhancement in the activation of cyclin D1 promoter-reporter activity in poorly differentiated Panc1.MUC1F cells that overexpress recombinant MUC1 relative to Panc-1.NEO cells, which express very low levels of endogenous MUC1. In stark contrast, cyclin D1 promoter activity was not affected in moderately differentiated S2-013.MUC1F cells that overexpressed recombinant MUC1 relative to S2-013.NEO cells that expressed low levels of endogenous MUC1. The S2-013 cell line was recently shown to be deficient in p120 catenin. MUC1 is known to interact with P120 catenin. We show here that re-expression of different isoforms of p120 catenin restored cyclin D1 promoter activity. Further, MUC1 affected subcellular localization of p120 catenin in association with one of the main effectors of P120 catenin, the transcriptional repressor Kaiso, supporting the hypothesis that p120 catenin relieved transcriptional repression by Kaiso. Thus, full activation of cyclin D1 promoter activity requires β-catenin activation of TCF-lef and stabilization of specific p120 catenin isoforms to relieve the repression of KAISO. Our data show MUC1 enhances the activities of both β-catenin and p120 catenin

Identification of inhibitors of the Schistosoma mansoni VKR2 kinase domain

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivoS. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target

Spatial and environmental drivers of macrophyte diversity and community composition in temperate and tropical calcareous rivers

The hypothesis was examined that sources of variation in macrophyte species richness (alpha-diversity: S) and community composition (“species-set”), attributable to spatial and environmental, variables, may differ in importance between tropical and temperate calcareous rivers (>10 mg CaCO3 L−1). To test this hypothesis geographic, environmental, and aquatic vegetation data was acquired for 1151 sites on calcareous rivers within the British Isles, supporting 106 macrophyte species (mean S: 3.1 species per sample), and 203 sites from Zambian calcareous rivers, supporting 255 macrophyte species (mean S: 8.3 species per sample). The data were analysed using an eigenfunction spatial analysis procedure, Moran’s Eigenvector Maps (MEM), to assess spatial variation of species richness and community composition at large regional scale (>105 km2: British Isles and Zambia); and at medium catchment scale (104–105 km2: British Isles only). Variation-partitioning was undertaken using multiple regression for species richness data, and partial redundancy analysis (pRDA) for community data. For the British Isles, spatial and environmental variables both significantly contributed to explaining variation in both species richness and community composition. In addition, a substantial amount of the variation in community composition, for the British Isles as a whole and for some RBUs, was accounted for by spatially-structured environmental variables. In Zambia, species richness was explained only by pure spatial variables, but environmental and spatially-structured environmental variables also explained a significant part of the variation for community composition. At medium-scale, in the British Isles, species richness was explained by spatial variables, and only for four of the six RBUs

Paediatric asthma and non-allergic comorbidities : a review of current risk and proposed mechanisms

It is increasingly recognized that children with asthma are at a higher risk of other non-allergic concurrent diseases than the non-asthma population. A plethora of recent research has reported on these comorbidities and progress has been made in understanding the mechanisms for comorbidity. The goal of this review was to assess the most recent evidence (2016-2021) on the extent of common comorbidities (obesity, depression and anxiety, neurodevelopmental disorders, sleep disorders and autoimmune diseases) and the latest mechanistic research, highlighting knowledge gaps requiring further investigation. We found that the majority of recent studies from around the world demonstrate that children with asthma are at an increased risk of having at least one of the studied comorbidities. A range of potential mechanisms were identified including common early life risk factors, common genetic factors, causal relationships, asthma medication and embryologic origins. Studies varied in their selection of population, asthma definition and outcome definitions. Next, steps in future studies should include using objective measures of asthma, such as lung function and immunological data, as well as investigating asthma phenotypes and endotypes. Larger complex genetic analyses are needed, including genome-wide association studies, gene expression-functional as well as pathway analyses or Mendelian randomization techniques; and identification of gene-environment interactions, such as epi-genetic studies or twin analyses, including omics and early life exposure data. Importantly, research should have relevance to clinical and public health translation including clinical practice, asthma management guidelines and intervention studies aimed at reducing comorbidities.Swedish Research Council (grant no 2018-02640)Swedish Heart-Lung Foundation (grant no 20210416)Publishe