Wavelet Signatures and Diagnostics for the Assessment of ICU Agitation-Sedation Protocols

The use of quantitative modelling to enhance understanding of the agitation-sedation (A-S) system and the provision of an A-S simulation platform are key tools in this area of patient critical care. A suite of wavelet techniques and metrics based on the discrete wavelet transform (DWT) are developed in this chapter which are shown to successfully establish the validity of deterministic agitation-sedation (A-S) models against empirical (recorded) dynamic A-S infusion profiles. The DWT approach is shown to provide robust performance metrics of A-S control and also yield excellent visual assessment tools. This approach is generalisable to any study which investigates the similarity or closeness of bivariate time series of, say, a large number of units (patients, households etc) and of disparate lengths and of possibly extremely long length. This work demonstrates the value of the DWT for assessing ICU agitation-sedation deterministic models, and suggests new wavelet based diagnostics by which to assess the A-S models

Density Estimation and Wavelet Thresholding via Bayesian Methods: A Wavelet Probability Band and Related Metrics Approach to Assess Agitation and Sedation in ICU Patients

A wave is usually defined as an oscillating function that is localized in both time and frequency. A wavelet is a “small wave”, which has its energy concentrated in time providing a tool for the analysis of transient, non-stationary, or time-varying phenomena. Wavelets have the ability to allow simultaneous time and frequency analysis via a flexible mathematical foundation. Wavelets are well suited to the analysis of transient signals in particular. The localizing property of wavelets allows a wavelet expansion of a transient component on an orthogonal basis to be modelled using a small number of wavelet coefficients using a low pass filter. This wavelet paradigm has been applied in a wide range of fields, such as signal processing, data compression and image analysis

Assembly and function of AP-3 complexes in cells expressing mutant subunits

The mouse mutants mocha and pearl are deficient in the AP-3 δ and β3A subunits, respectively. We have used cells from these mice to investigate both the assembly of AP-3 complexes and AP-3 function. In mocha cells, the β3 and μ3 subunits coassemble into a heterodimer, whereas the σ3 subunit remains monomeric. In pearl cells, the δ and σ3 subunits coassemble into a heterodimer, whereas μ3 gets destroyed. The yeast two hybrid system was used to confirm these interactions, and also to demonstrate that the A (ubiquitous) and B (neuronal-specific) isoforms of β3 and μ3 can interact with each other. Pearl cell lines were generated that express β3A, β3B, a β3Aβ2 chimera, two β3A deletion mutants, and a β3A point mutant lacking a functional clathrin binding site. All six constructs assembled into complexes and were recruited onto membranes. However, only β3A, β3B, and the point mutant gave full functional rescue, as assayed by LAMP-1 sorting. The β3Aβ2 chimera and the β3A short deletion mutant gave partial functional rescue, whereas the β3A truncation mutant gave no functional rescue. These results indicate that the hinge and/or ear domains of β3 are important for function, but the clathrin binding site is not needed

Dual role for phosphoinositides in regulation of yeast and mammalian phospholipase D enzymes

Phospholipase D (PLD) generates lipid signals that coordinate membrane trafficking with cellular signaling. PLD activity in vitro and in vivo is dependent on phosphoinositides with a vicinal 4,5-phosphate pair. Yeast and mammalian PLDs contain an NH2-terminal pleckstrin homology (PH) domain that has been speculated to specify both subcellular localization and regulation of PLD activity through interaction with phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2). We report that mutation of the PH domains of yeast and mammalian PLD enzymes generates catalytically active PI(4,5)P2-regulated enzymes with impaired biological functions. Disruption of the PH domain of mammalian PLD2 results in relocalization of the protein from the PI(4,5)P2-containing plasma membrane to endosomes. As a result of this mislocalization, mutations within the PH domain render the protein unresponsive to activation in vivo. Furthermore, the integrity of the PH domain is vital for yeast PLD function in both meiosis and secretion. Binding of PLD2 to model membranes is enhanced by acidic phospholipids. Studies with PLD2-derived peptides suggest that this binding involves a previously identified polybasic motif that mediates activation of the enzyme by PI(4,5)P2. By comparison, the PLD2 PH domain binds PI(4,5)P2 with lower affinity but sufficient selectivity to function in concert with the polybasic motif to target the protein to PI(4,5)P2-rich membranes. Phosphoinositides therefore have a dual role in PLD regulation: membrane targeting mediated by the PH domain and stimulation of catalysis mediated by the polybasic motif

Characterization of Intrinsic Properties of Promoters.

Accurate characterization of promoter behavior is essential for the rational design of functional synthetic transcription networks such as logic gates and oscillators. However, transcription rates observed from promoters can vary significantly depending on the growth rate of host cells and the experimental and genetic contexts of the measurement. Furthermore, in vivo measurement methods must accommodate variation in translation, protein folding, and maturation rates of reporter proteins, as well as metabolic load. The external factors affecting transcription activity may be considered to be extrinsic, and the goal of characterization should be to obtain quantitative measures of the intrinsic characteristics of promoters. We have developed a promoter characterization method that is based on a mathematical model for cell growth and reporter gene expression and exploits multiple in vivo measurements to compensate for variation due to extrinsic factors. First, we used optical density and fluorescent reporter gene measurements to account for the effect of differing cell growth rates. Second, we compared the output of reporter genes to that of a control promoter using concurrent dual-channel fluorescence measurements. This allowed us to derive a quantitative promoter characteristic (ρ) that provides a robust measure of the intrinsic properties of a promoter, relative to the control. We imposed different extrinsic factors on growing cells, altering carbon source and adding bacteriostatic agents, and demonstrated that the use of ρ values reduced the fraction of variance due to extrinsic factors from 78% to less than 4%. This is a simple and reliable method to quantitatively describe promoter properties.TJR was supported by a Microsoft Research studentship and EC FP7 Project No. 612146 (PLASWIRES) awarded to JH, JRB by a Microsoft Research studentship and internship, and FF by CONICYT-PAI/Concurso Nacional de Apoyo al Retorno de Investigadores/as desde el Extranjero Folio 8213002 7, and EPSRC grant EP/H019162/1 awarded to JH. JWA acknowledges the EPSRC and the Wellcome Trust for support.This is the author accepted manuscript. The final version is available from ACS via http://dx.doi.org/10.1021/acssynbio.5b0011

Evidence of methodological bias in hospital standardised mortality ratios: retrospective database study of English hospitals

Objective To assess the validity of case mix adjustment methods used to derive standardised mortality ratios for hospitals, by examining the consistency of relations between risk factors and mortality across hospitals

Fuel channel bore estimation for onload pressurised fuel grab load trace data

Accurate fuel channel bore estimation enables information about the health of the graphite core of an advanced gas-cooled reactor to be inferred. This was extensively explored previously for offload depressurised fuel grab load trace (FGLT) data: by isolating the frictional component of the FGLT and using inspection data as a ground truth, a linear regression model was trained to estimate the fuel channel bore. However, when data gathered during onload refuelling has the added complication of the interaction between the fuel assembly and coolant gas, the same process cannot be used. This paper describes the process for removing the aerodynamic effects of the coolant gas in the core from onload pressurised FGLT data. This effect cannot be directly measured, so initially, an empirical model was created by comparing the response from both offload depressurised and onload pressurised events. This model is then used to estimate the offload equivalent FGLT response, and by using a bore estimation model, trained on offload data, it is possible to produce bore estimations for onload FGLT data

Changes in admission thresholds in English Emergency Departments

YesBackground: The most common route to a hospital bed in an emergency is via an emergency department (ED). Many recent initiatives and interventions have the objective of reducing the number of unnecessary emergency admissions. We aimed to assess whether ED admission thresholds had changed over time taking account of the casemix of patients arriving at ED. Methods: We conducted a retrospective cross-sectional analysis of more than 20 million attendances at 47 consultant-led emergency departments in England between April 2010 and March 2015. We used mixed- effects logistic regression to estimate the odds of a patient being admitted to hospital and the impact of a range of potential explanatory variables. Models were developed and validated for four attendance subgroups : ambulance-conveyed children; walk-in children; ambulance-conveyed adults; and walk-in adults. Results: 23.8% of attendances were for children aged under 18 years, 49.7% were female and 30.0% were conveyed by ambulance. The number of ED attendances increased by 1.8% per annum between April 2010 – March 2011 (year 1) and April 2014 –March 2015 (year 5). The proportion of these attendances that were admitted to hospital changed little between year 1 (27.0%) and year 5 (27.5%). However, after adjusting for patient and attendance characteristics the odds of admission over the five year period had reduced by: 15.2% (95% CI 13.4% - 17.0%) for ambulance-conveyed children; 22.6% (95% CI 21.7%-23.5%) for walk-in children; 20.9% (95% CI 4%-21.5%) for ambulance conveyed adults; and 22.9% (95% CI 22.4%-23.5%) for walk-in adults. Conclusions: The casemix-adjusted odds of admission via ED to NHS hospitals in England have decreased since April 2010. EDs are admitting a similar proportion of patients to hospital despite increases in the complexity and acuity of presenting patients. Without these threshold changes, the number of emergency admissions would have been 11.9% higher than was the case in year 5

CHANS : the characteristics of cost-effective policy responses for harmful algal blooms [poster]

Presented at CERF 2015: Grand Challenges in Coastal & Estuarine Science, Portland, Oregon, November 8 - 12, 2015 and at the Eighth Symposium on Harmful Algae in the U.S., Long Beach, California, November 15 – 19, 2015A growing concern for coastal management is the choice of appropriate public or private responses to HABs as a natural hazard. Considerable efforts have been devoted to understanding the scientific aspects of HABs, including their distributions in space and time, their ecological roles, and the nature of their toxic effects, among others. Much energy also has been directed at exploring socio-economic impacts and identifying potential management actions, including actions to prevent, control, or mitigate blooms. Using blooms of Florida red tide (Karenia brevis) as a case study, we develop an approach to the choice of policy responses to K. brevis blooms. Importantly, several new types of public health, environmental, and socio-economic impacts now are beginning to be revealed, including human gastrointestinal and potential neurological illnesses; morbidities and mortalities of protected species, including manatees, cetaceans, and sea turtles; increased numbers of hospital emergency room visits for the elderly; increased respiratory morbidities in workers, such as beach lifeguards; and potential reduced K- 12 school attendance. Optimal policy responses to this hazard are likely to depend critically upon why and where a bloom occurs, its spatial and temporal scales and toxicity, and the nature of its impacts. In the face of significant ongoing scientific uncertainties, and given estimates of impacts, we find that policies to expand and stabilize scientific research programs and environmental monitoring efforts, to develop and implement education programs for both residents and tourists, and to communicate the physical aspects of blooms to the public in a timely fashion are likely optimal.This research was sponsored by the National Science Foundation under NSF/CNH Grant No. 1009106