Augmented renal clearance: a retrospective, cohort study of urinary creatinine clearance in critically ill patients in the United Kingdom

Objective: Augmented renal clearance (ARC) is associated with sub-therapeutic antibiotic, anti-epileptic, and anticoagulant serum concentrations leading to adverse patient outcomes. We aimed to describe the prevalence and associated risk factors for ARC development in a large, single-centre cohort in the United Kingdom. Methods: We conducted a retrospective observational study of critically unwell patients admitted to intensive care between 2014 and 2016. Urinary creatinine clearance was used to determine the ARC prevalence during the first 7 days of admission. Repeated measures logistic regression was used to determine risk factors for ARC development. Results: The ARC prevalence was 47.0% (95% confidence interval [95%CI]: 44.3%–49.7%). Age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and sepsis diagnosis were significantly associated with ARC. ARC was more prevalent in younger vs. older (odds ratio [OR] 0.95 [95%CI: 0.94–0.96]), male vs. female (OR 0.32 [95%CI: 0.26–0.40]) patients with lower vs. higher APACHE II scores (OR 0.94 [95%CI: 0.92–0.96]). Conclusions: This patient group probably remains unknown to many clinicians because measuring urinary creatinine clearance is not usually indicated in this group. Clinicians should be aware of the ARC risk in this group and consider measurement of urinary creatinine clearance

The aminopeptidase inhibitor CHR-2863 is an orally bioavailable inhibitor of murine malaria

Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an everincreasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria

The relationship among oceanography, prey fields, and beaked whale foraging habitat in the Tongue of the Ocean

This article is distributed under the terms of the Creative Commons CC0 public domain dedication. The definitive version was published in PLoS One 6 (2011): e19269, doi:10.1371/journal.pone.0019269.Beaked whales, specifically Blainville's (Mesoplodon densirostris) and Cuvier's (Ziphius cavirostris), are known to feed in the Tongue of the Ocean, Bahamas. These whales can be reliably detected and often localized within the Atlantic Undersea Test and Evaluation Center (AUTEC) acoustic sensor system. The AUTEC range is a regularly spaced bottom mounted hydrophone array covering >350 nm2 providing a valuable network to record anthropogenic noise and marine mammal vocalizations. Assessments of the potential risks of noise exposure to beaked whales have historically occurred in the absence of information about the physical and biological environments in which these animals are distributed. In the fall of 2008, we used a downward looking 38 kHz SIMRAD EK60 echosounder to measure prey scattering layers concurrent with fine scale turbulence measurements from an autonomous turbulence profiler. Using an 8 km, 4-leaf clover sampling pattern, we completed a total of 7.5 repeat surveys with concurrently measured physical and biological oceanographic parameters, so as to examine the spatiotemporal scales and relationships among turbulence levels, biological scattering layers, and beaked whale foraging activity. We found a strong correlation among increased prey density and ocean vertical structure relative to increased click densities. Understanding the habitats of these whales and their utilization patterns will improve future models of beaked whale habitat as well as allowing more comprehensive assessments of exposure risk to anthropogenic sound.The data collection and analysis was funded by the Office of Naval Research as N00014-08-1-1162

The role of war in deep transitions: exploring mechanisms, imprints and rules in sociotechnical systems

This paper explores in what ways the two world wars influenced the development of sociotechnical systems underpinning the culmination of the first deep transition. The role of war is an underexplored aspect in both the Techno-Economic Paradigms (TEP) approach and the Multi-level perspective (MLP) which form the two key conceptual building blocks of the Deep Transitions (DT) framework. Thus, we develop a conceptual approach tailored to this particular topic which integrates accounts of total war and mechanisms of war from historical studies and imprinting from organisational studies with the DT framework’s attention towards rules and meta-rules. We explore in what ways the three sociotechnical systems of energy, food, and transport were affected by the emergence of new demand pressures and logistical challenges during conditions of total war; how war impacted the directionality of sociotechnical systems; the extent to which new national and international policy capacities emerged during wartime in the energy, food, and transport systems; and the extent to which these systems were influenced by cooperation and shared sacrifice under wartime conditions. We then explore what lasting changes were influenced by the two wars in the energy, food, and transport systems across the transatlantic zone. This paper seeks to open up a hitherto neglected area in analysis on sociotechnical transitions and we discuss the importance of further research that is attentive towards entanglements of warfare and the military particularly in the field of sustainability transitions

Mitochondria and Energetic Depression in Cell Pathophysiology

Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell’s ability to do work and control the intracellular Ca2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.peer-reviewe

Simulation-based online scheduling of a make-to-order job shop

Thesis (MScEng (Industrial Engineering))--University of Stellenbosch, 2009.Scheduling is a core activity in the manufacturing business. It assists with efficient and effective utilization of capital-intensive resources and increased throughput, thus increasing profitability. The focus in this thesis is on scheduling of manufacturing orders in a make-to-order job-shop enterprise. It is widely accepted that manufacturing of large volumes and production with as few as possible product variants is the most cost-effective business approach, but the need for low volume, once-off engineering parts will always exist. Many approaches to scheduling exist, including translation of a scheduling problem to a Travelling Salesman analogue, while Discrete-event computer simulation is well established as a means to assist with scheduling. Simulation is appealing in the manufacturing environment, as it can realistically imitate dynamic, stochastic processes while being descriptive in forecasting the future. In this thesis, the development and testing of a simulation-based scheduler is described. The scheduler was developed for, and in collaboration with a South African make-to-order job-shop enterprise. A supporting information system was also developed and it is required that the enterprise changes some of its business processes if this scheduler is implemented. The scheduler considers the status of the enterprise each time a new order is received, and the current schedule is reviewed and may be revised at such a point in time, making it a real-time scheduler. Several classic scheduling dispatching rules and –measures were incorporated in the scheduler. These include First-in First-out, Earliest Due Date, Longest Processing Time, Shortest Processing Time, Smallest Slack and Critical Ratio (dispatching rules), while the performance measures are Makespan, Earliness, Lateness, Average Flow Time and Machine Usage. The proposed scheduler has been verified and validated using test data and designed confidence building tests, and its performance was also compared to an actual, historical schedule. The functioning of the scheduler is finally demonstrated using a stochastic test environment. The scheduler has generally performed satisfactorily and should be implemented as the final phase of this project

Mitochondrial abnormalities in Parkinson's disease

The cause of neurodegeneration in the substantia nigra of the brains of Parkinson's disease (PD) patients remains unknown. The presence of a defect of NADH CoQ1 reductase (complex I of the mitochondrial respiratory chain) in the disease is now well established, although its relevance to disease pathogenesis is unknown. The tissue specificity of the defect is contentious, and was therefore investigated in PD platelets. Complex I activity measured in PD whole platelet homogenates was normal. However when a platelet mitochondrially- enriched fraction (MEF) was prepared, and the complex I assay was modified to maximise activity in platelet MEFs, a slight (16%), but statistically significant decrease in mean complex I activity in PD samples was detected. The molecular basis of the complex I enzymatic defect in PD is unknown. To determine the presence of any defect in the complex I protein, the structure and subunit composition of the complex in the PD substantia nigra was investigated by two methods; immunoprecipitation of the complex using antibodies raised to the holoenzyme, followed by denaturing electrophoresis and silver staining of the polypeptides; and quantitation of the concentration of the complex by ELISA (enzyme-linked immunosorbent assay), using affinity-purified antibodies to the complex I holoenzyme and to specific complex I subunits. By immunoprecipitation, no major differences were detected between complex I from PD and control substantia nigra. However, by ELISA it was shown that PD substantia nigra samples with low complex I enzymatic activity (40% less than controls) contained low concentrations of complex I protein (40% less than controls). To explore the possibility that the complex I defect in PD is caused by a defect in the detoxification process of a putative complex I inhibitor, experiments were initiated to correlate complex I activity in the PD substantia nigra with the presence of mutations in the cytochrome P450 debrisoquine hydroxylase gene (CYP2D6). Due to the limited sample number, no samples contained homozygous recessive mutations which would affect the debrisoquine metaboliser phenotype

Die landbouskuldvraagstuk in Suid-Afrika

Verhandeling (M. Com.) -- Universiteit van Stellenbosch, 1939.Full text to be digitised and attached to bibliographic record