A Bayesian Model Based on Local Phenotypic Resistance Data to Inform Empiric Antibiotic Escalation Decisions.

Introduction: Clinicians commonly escalate empiric antibiotic therapy due to poor clinical progress without microbiology guidance. When escalating, they should take account of how resistance to an initial antibiotic affects the probability of resistance to subsequent options. The term "escalation antibiogram" (EA) has been coined to describe this concept.

Epidemiology of Escherichia coli bloodstream infection antimicrobial resistance trends across South West England during the first 2 years of the coronavirus disease 2019 pandemic response.

Objectives: Between 2016 and 2019, the proportion of Escherichia coli bloodstream infection (BSI) with resistance to at least one antibiotic increased nationally. Public health interventions implemented in response to the COVID-19 pandemic changed population contact patterns and healthcare systems, with consequent effects on epidemiological trends of numerous pathogens. We investigated the impact of COVID-19 restrictions on epidemiological trends of E.

Five inhibitory receptors display distinct vesicular distributions in T cells.

T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3 and TIGIT, as investigated here.

Uncertainty-Aware Protein-Level Quantification and Differential Expression Analysis of Proteomics Data with seaMass.

seaMass is an R package for protein-level quantification, normalization, and differential expression analysis of proteomics mass spectrometry data after peptide identification, protein grouping, and feature-level quantification. Using the concept of a blocked experimental design, seaMass can analyze all common discovery proteomics paradigms, including label-free (e.g.

Diagnostic MALDI-TOF MS can differentiate between high and low toxic bacteraemia isolates as a predictor of patient outcome.

bacteraemia (SAB) is a major cause of blood-stream infection (BSI) in both healthcare and community settings. While the underlying comorbidities of a patient significantly contributes to their susceptibility to and outcome following SAB, recent studies show the importance of the level of cytolytic toxin production by the infecting bacterium. In this study we demonstrate that this cytotoxicity can be determined directly from the diagnostic MALDI-TOF mass spectrum generated in a routine diagnostic laboratory.

Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer's Disease Consistent With Cerebral Pantothenate Deficiency.

Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβ/tau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology.

Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26.

Age-related macular degeneration (AMD) is a leading cause of visual loss. It has a strong genetic basis, and common haplotypes on chromosome (Chr) 1 (CFH Y402H variant) and on Chr10 (near HTRA1/ARMS2) contribute the most risk. Little is known about the early molecular and cellular processes in AMD, and we hypothesized that analyzing submacular tissue from older donors with genetic risk but without clinical features of AMD would provide biological insights.

Widespread severe cerebral elevations of haptoglobin and haemopexin in sporadic Alzheimer's disease: Evidence for a pervasive microvasculopathy.

Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration but there are no available treatments with demonstrated disease-modifying actions. It is therefore relevant to study hitherto-unknown aspects of brain structure and function to seek new disease-related mechanisms that might be targeted by novel disease-modifying interventions. During hypothesis-generating proteomic investigations in a case-control study of sAD, we observed widespread elevations of haptoglobin and haemopexin in all six brain-regions studied, which together represent much of the brain.

mzMLb: A Future-Proof Raw Mass Spectrometry Data Format Based on Standards-Compliant mzML and Optimized for Speed and Storage Requirements.

With ever-increasing amounts of data produced by mass spectrometry (MS) proteomics and metabolomics, and the sheer volume of samples now analyzed, the need for a common open format possessing both file size efficiency and faster read/write speeds has become paramount to drive the next generation of data analysis pipelines. The Proteomics Standards Initiative (PSI) has established a clear and precise extensible markup language (XML) representation for data interchange, mzML, receiving substantial uptake; nevertheless, storage and file access efficiency has not been the main focus. We propose an HDF5 file format "mzMLb" that is optimized for both read/write speed and storage of the raw mass spectrometry data.

Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation.

Objective: The impact of diabetes mellitus on the central nervous system is less widely studied than in the peripheral nervous system, but there is increasing evidence that it elevates the risk of developing cognitive deficits. The aim of this study was to characterize the impact of experimental diabetes on the proteome and metabolome of the hippocampus. We tested the hypothesis that the vitamin B6 isoform pyridoxamine is protective against functional and molecular changes in diabetes.

Regional protein expression in human Alzheimer's brain correlates with disease severity.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen the spatial scope of the study of AD and prioritise the study of human brains.

Expanding the Use of Spectral Libraries in Proteomics.

The 2017 Dagstuhl Seminar on Computational Proteomics provided an opportunity for a broad discussion on the current state and future directions of the generation and use of peptide tandem mass spectrometry spectral libraries. Their use in proteomics is growing slowly, but there are multiple challenges in the field that must be addressed to further increase the adoption of spectral libraries and related techniques. The primary bottlenecks are the paucity of high quality and comprehensive libraries and the general difficulty of adopting spectral library searching into existing workflows.

Ceasing the use of the highest priority critically important antimicrobials does not adversely affect production, health or welfare parameters in dairy cows.

Due to scientific, public and political concern regarding antimicrobial resistance (AMR), several EU countries have already taken steps to reduce antimicrobial (AM) usage in production animal medicine, particularly that of the highest priority critically important AMs (HP-CIAs). While veterinarians are aware of issues surrounding AMR, potential barriers to change such as concerns of reduced animal health, welfare or production may inhibit progress towards more responsible AM prescribing. Farmers from seven dairy farms in South West England engaged in changing AM use through an active process of education and herd health planning meetings.

Evaluation of metrics for benchmarking antimicrobial use in the UK dairy industry.

The issue of antimicrobial resistance is of global concern across human and animal health. In 2016, the UK government committed to new targets for reducing antimicrobial use (AMU) in livestock. Although a number of metrics for quantifying AMU are defined in the literature, all give slightly different interpretations.

Quantitative data describing the impact of the flavonol rutin on in-vivo blood-glucose and fluid-intake profiles, and survival of human-amylin transgenic mice.

Here we provide data describing the time-course of blood-glucose and fluid-intake profiles of diabetic hemizygous human-amylin (hA) transgenic mice orally treated with rutin, and matched control mice treated with water. We employed "parametric change-point regression analysis" for investigation of differences in time-course profiles between the control and rutin-treatment groups to extract, for each animal, baseline levels of blood glucose and fluid-intake, the change-point time at which blood glucose (diabetes-onset) and fluid-intake (polydipsia-onset) accelerated away from baseline, and the rate of this acceleration. The parametric change-point regression approach applied here allowed a much more accurate determination of the exact time of onset of diabetes than do the standard diagnostic criteria.

Rutin suppresses human-amylin/hIAPP misfolding and oligomer formation in-vitro, and ameliorates diabetes and its impacts in human-amylin/hIAPP transgenic mice.

Pancreatic islet β-cells secrete the hormones insulin and amylin, and defective β-cell function plays a central role in the pathogenesis of type-2 diabetes (T2D). Human amylin (hA, also termed hIAPP) misfolds and forms amyloid aggregates whereas orthologous mouse amylin does neither. Furthermore, hA elicits apoptosis in cultured β-cells and β-cell death in ex-vivo islets.

Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer's disease: metabolic basis for dementia.

Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer's disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and metals in seven post-mortem brain regions of nine AD patients and nine controls, and plasma-glucose and plasma-copper levels in an ante-mortem case-control study.

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy.

High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However, our understanding of the molecular mechanisms that cause the marked distal pathology is incomplete. We performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN.

Boosting drug named entity recognition using an aggregate classifier.

Objective: Drug named entity recognition (NER) is a critical step for complex biomedical NLP tasks such as the extraction of pharmacogenomic, pharmacodynamic and pharmacokinetic parameters. Large quantities of high quality training data are almost always a prerequisite for employing supervised machine-learning techniques to achieve high classification performance. However, the human labour needed to produce and maintain such resources is a significant limitation.

Streaming visualisation of quantitative mass spectrometry data based on a novel raw signal decomposition method.

As data rates rise, there is a danger that informatics for high-throughput LC-MS becomes more opaque and inaccessible to practitioners. It is therefore critical that efficient visualisation tools are available to facilitate quality control, verification, validation, interpretation, and sharing of raw MS data and the results of MS analyses. Currently, MS data is stored as contiguous spectra.

Age-dependent changes in heparan sulfate in human Bruch's membrane: implications for age-related macular degeneration.

Purpose: Heparan sulfate (HS) has been implicated in age-related macular degeneration (AMD), since it is the major binding partner for complement factor H (CFH) in human Bruch's membrane (BrM), and CFH has a central role in inhibiting complement activation on extracellular matrices. The aim was to investigate potential aging changes in HS quantity and composition in human BrM.

Methods: Postmortem human ocular tissue was obtained from donors without known retinal disease.