Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with ...Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin–tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35–1.94 and adjusted OR 0.92; 95% CI 0.50–1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors.
Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our ...previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader–antagonist profile and demonstrated activity in a xenograft model of breast cancer.
Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment ...responses and a need for better understanding of the underlying mechanisms.
We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification.
Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms.
Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms.
This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.
Understanding the movement patterns of fishes in the wild requires an awareness of the intrinsic and extrinsic factors underlying their behaviour. Using field observations, we explored whether eight ...species of coral reef fish display modality in their swimming behaviour, which is a convergence in fin use patterns among and within species when they conduct daily activities (e.g. feeding, travelling, chasing). While a range of different fins were used during steady swimming by each species, most fishes converged towards median-paired fin use (e.g. pelvics, pectorals) when undertaking searching and feeding. Conversely, all species adopted caudal fin use during high-speed activities such as chasing. Such modality in fin use was relatively conserved across juvenile and adult conspecifics and transcended differences in phylogenetic history and trophic preferences, suggesting that overarching constraints underpin patterns of fish swimming behaviour in complex habitats.
Finkel, Rusbult, Kumashiro, and Hannon (2002, Study 1) demonstrated a causal link between subjective commitment to a relationship and how people responded to hypothetical betrayals of that ...relationship. Participants primed to think about their commitment to their partner (high commitment) reacted to the betrayals with reduced exit and neglect responses relative to those primed to think about their independence from their partner (low commitment). The priming manipulation did not affect constructive voice and loyalty responses. Although other studies have demonstrated a correlation between subjective commitment and responses to betrayal, this study provides the only experimental evidence that inducing changes to subjective commitment can causally affect forgiveness responses. This Registered Replication Report (RRR) meta-analytically combines the results of 16 new direct replications of the original study, all of which followed a standardized, vetted, and preregistered protocol. The results showed little effect of the priming manipulation on the forgiveness outcome measures, but it also did not observe an effect of priming on subjective commitment, so the manipulation did not work as it had in the original study. We discuss possible explanations for the discrepancy between the findings from this RRR and the original study.
The effects of blending, chemical and enzymatic esterification on the viscosity, melting and crystallization behaviour of blends of high oleic algal oil (HOAO), tricaproin (trihexanoin) and ...tricaprylin (trioctanoin) were determined. Blending HOAO with lower molecular weight tricaproin and tricaprylin reduced viscosity in a predictable fashion related to the average molecular weight of the molecular mixtures. For example, the HOAO kinematic viscosity at 40 °C decreased from 39.6 cSt to 33.3 cSt upon addition of 30% (mol mol
−1
) tricaprylin. However, molecular randomization by interesterification did not affect the kinematic and dynamic viscosities of the blends; the viscosity of the 30 : 70 HOAO : tricaprylin blend decreased non-significantly to 31.4 cSt. On the other hand, addition of tricaprylin and tricaproin combined with chemical and enzymatic interesterification did significantly reduce the crystallization and melting temperatures of the mixtures. The melting temperatures of HOAO decreased from −3.7 °C to −4.5 °C upon addition of 30% (mol mol
−1
) tricaprylin, while the crystallization temperature decreased from −34.8 °C to −37.8 °C. Surprisingly, enzymatic interesterification of this mixture drastically decreased the crystallization and melting temperatures of the blends, to −58.3 °C and −21.4 °C, respectively. A statistical thermodynamic model was developed to explain the decrease in melting temperature as a function of molecular randomization of the mixtures, which predicted the observed decrease quantitatively. This decrease in melting temperature was governed by an enthalpic effect. Thus, viscosity reduction in triacylglycerol mixtures is solely affected by the average molecular weight of the constituent triacylglycerol molecules, but their melting points can be significantly reduced by randomizing chemical structure. Blending and interesterification are both required to reduce viscosity and decrease the melting point of triacylglycerol biolubricants.
Blending and interesterification of high oleic algal oil with medium chain triglycerides decreased viscosity and inhibited crystallization of triacylglycerol oils used as sustainable lubricant feedstocks.
Local, tacit and normally unspoken OHS (occupational health and safety) knowledge and practices can too easily be excluded from or remain below the industry horizon of notice, meaning that they ...remain unaccounted for in formal OHS policy and practice. In this article we stress the need to more systematically and routinely tap into these otherwise 'hidden' communication channels, which are central to how everyday safe working practices are achieved. To demonstrate this approach this paper will draw on our ethnographic research with a gang of migrant curtain wall installers on a large office development project in the north of England. In doing so we reflect on the practice-based nature of learning and sharing OHS knowledge through examples of how workers' own patterns of successful communication help avoid health and safety problems. These understandings, we argue, can be advanced as a basis for the development of improved OHS measures, and of organizational knowing and learning.
The UK construction industry labour market is characterized by high levels of self-employment, subcontracting, informality and flexibility. A corollary of this, and a sign of the increasing ...globalization of construction, has been an increasing reliance on migrant labour, particularly that from the Eastern European Accession states. Yet, little is known about how migrant workers' experiences within and outside work shape their work in the construction sector. In this context better qualitative understandings of the social and communication networks through which migrant workers gain employment, create routes through the sector and develop their role/career are needed. We draw on two examples from a short-term ethnographic study of migrant construction worker employment experiences and practices in the town of Crewe in Cheshire, UK, to demonstrate how informal networks intersect with formal elements of the sector to facilitate both recruitment and up-skilling. Such research knowledge, we argue, offers new evidence of the importance of attending to migrant workers' own experiences in the development of more transparent recruitment processes.
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