Is there more to glycaemic control than meets the eye?

Tight glycaemic control has emerged as a major focus in critical care. However, the struggle to repeat, improve and standardize the results of the initial landmark studies is ongoing. The prospective computerized glycaemic control study by Shulman et al. highlights two emerging and often overlooked aspects of intensive insulin therapy protocols beyond simple glycaemic performance. First, the clinical ergonomics and ability to integrate into the critical care unit workflow must be considered as they may impact results and definitely affect uptake. Second, the real lessons of any protocol's performance are likely to be best realized by comparison with other results, a task that is very difficult without a consensus method of reporting that allows such comparisons across studies. Embracing these issues will take the field closer to accepted, repeatable approaches to tight glycaemic control

H.L.A. Hart’s Lost Essay: Discretion and the Legal Process School

This Essay analyzes an essay by H. L. A. Hart about discretion that has never before been published, and has often been considered lost. Hart, one of the most significant legal philosophers of the twentieth century, wrote the essay at Harvard Law School in November 1956, shortly after he arrived as a visiting professor. In the essay, Hart argued that discretion is a special mode of reasoned, constrained decisionmaking that occupies a middle ground between arbitrary choice and determinate rule application. Hart believed that discretion, soundly exercised, provides a principled way of coping with legal indeterminacy that is fully consistent with the rule of law. This Essay situates Hart’s paper – Discretion – in historical and intellectual context, interprets its main arguments, and assesses its significance in jurisprudential history. In the context of Hart’s work, Discretion is notable because it sketches a theory of legal reasoning in depth, with vivid examples. In the context of jurisprudential history, Discretion is significant because it sheds new light on long-overlooked historical and theoretical connections between Hart’s work and the Legal Process School, the American jurisprudential movement dominant at Harvard during Hart’s year as a visiting professor. Hart’s Discretion is part of our jurisprudential heritage, advancing our understanding of legal philosophy and its history

Cardiac output estimation using pulmonary mechanics in mechanically ventilated patients

The application of positive end expiratory pressure (PEEP) in mechanically ventilated (MV) patients with acute respiratory distress syndrome (ARDS) decreases cardiac output (CO). Accurate measurement of CO is highly invasive and is not ideal for all MV critically ill patients. However, the link between the PEEP used in MV, and CO provides an opportunity to assess CO via MV therapy and other existing measurements, creating a CO measure without further invasiveness

Postnatal epigenetic reprogramming in the germline of a marsupial, the tammar wallaby

Background: Epigenetic reprogramming is essential to restore totipotency and to reset genomic imprints during mammalian germ cell development and gamete formation. The dynamic DNA methylation change at DMRs (differentially methylated regions) within imprinted domains and of retrotransposons is characteristic of this process. Both marsupials and eutherian mammals have genomic imprinting but these two subgroups have been evolving separately for up to 160 million years. Marsupials have a unique reproductive strategy and deliver tiny, altricial young that complete their development within their mother's pouch. Germ cell proliferation in the genital ridge continues after birth in the tammar wallaby (Macropus eugenii), and it is only after 25 days postpartum that female germ cells begin to enter meiosis and male germ cells begin to enter mitotic arrest. At least two marsupial imprinted loci (PEG10 and H19) also have DMRs. To investigate the evolution of epigenetic reprogramming in the marsupial germline, here we collected germ cells from male pouch young of the tammar wallaby and analysed the methylation status of PEG10 and H19 DMR, an LTR (long terminal repeat) and a non-LTR retrotransposons. Results: Demethylation of the H19 DMR was almost completed by 14 days postpartum and de-novo methylation started from 34 days postpartum. These stages correspond to 14 days after the completion of primordial germ cell migration into genital ridge (demethylation) and 9 days after the first detection of mitotic arrest (re-methylation) in the male germ cells. Interestingly, the PEG10 DMR was already unmethylated at 7 days postpartum, suggesting that the timing of epigenetic reprogramming is not the same at all genomic loci. Retrotransposon methylation was not completely removed after the demethylation event in the germ cells, similar to the situation in the mouse. Conclusions: Thus, despite the postnatal occurrence of epigenetic reprogramming and the persistence of genome-wide undermethylation for 20 days in the postnatal tammar, the relative timing and mechanism of germ cell reprogramming are conserved between marsupials and eutherians. We suggest that the basic mechanism of epigenetic reprogramming had already been established before the marsupial-eutherian split and has been faithfully maintained for at least 160 million years and may reflect the timing of the onset of mitotic arrest in the male germline.ArticleEPIGENETICS & CHROMATIN. 6:14 (2013)journal articl

A novel mechanical lung model of pulmonary diseases to assist with teaching and training

BACKGROUND: A design concept of low-cost, simple, fully mechanical model of a mechanically ventilated, passively breathing lung is developed. An example model is built to simulate a patient under mechanical ventilation with accurate volumes and compliances, while connected directly to a ventilator. METHODS: The lung is modelled with multiple units, represented by rubber bellows, with adjustable weights placed on bellows to simulate compartments of different superimposed pressure and compliance, as well as different levels of lung disease, such as Acute Respiratory Distress Syndrome (ARDS). The model was directly connected to a ventilator and the resulting pressure volume curves recorded. RESULTS: The model effectively captures the fundamental lung dynamics for a variety of conditions, and showed the effects of different ventilator settings. It was particularly effective at showing the impact of Positive End Expiratory Pressure (PEEP) therapy on lung recruitment to improve oxygenation, a particulary difficult dynamic to capture. CONCLUSION: Application of PEEP therapy is difficult to teach and demonstrate clearly. Therefore, the model provide opportunity to train, teach, and aid further understanding of lung mechanics and the treatment of lung diseases in critical care, such as ARDS and asthma. Finally, the model's pure mechanical nature and accurate lung volumes mean that all results are both clearly visible and thus intuitively simple to grasp

Model-based optimal PEEP in mechanically ventilated ARDS patients in the Intensive Care Unit

Background: The optimal level of positive end-expiratory pressure (PEEP) is still widely debated in treating acute respiratory distress syndrome (ARDS) patients. Current methods of selecting PEEP only provide a range of values and do not provide unique patient-specific solutions. Model-based methods offer a novel way of using non-invasive pressure-volume (PV) measurements to estimate patient recruitability. This paper examines the clinical viability of such models in pilot clinical trials to assist therapy, optimise patient-specific PEEP, assess the disease state and response over time. Methods: Ten patients with acute lung injury or ARDS underwent incremental PEEP recruitment manoeuvres. PV data was measured at increments of 5 cmH(2)O and fitted to the recruitment model. Inspiratory and expiratory breath holds were performed to measure airway resistance and auto-PEEP. Three model-based metrics are used to optimise PEEP based on opening pressures, closing pressures and net recruitment. ARDS status was assessed by model parameters capturing recruitment and compliance. Results: Median model fitting error across all patients for inflation and deflation was 2.8% and 1.02% respectively with all patients experiencing auto-PEEP. In all three metrics' cases, model-based optimal PEEP was higher than clinically selected PEEP. Two patients underwent multiple recruitment manoeuvres over time and model metrics reflected and tracked the state or their ARDS. Conclusions: For ARDS patients, the model-based method presented in this paper provides a unique, non-invasive method to select optimal patient-specific PEEP. In addition, the model has the capability to assess disease state over time using these same models and methods

A systemic approach to the database marketing process

The role of database marketing (DBM) has become increasingly important for organisations that have large databases of information on customers with whom they deal directly. At the same time, DBM models used in practice have increased in sophistication. This paper examines a systemic view of DBM and the role of analytical techniques within DBM. It extends existing process models to develop a systemic model that encompasses the increased complexity of DBM in practice. The systemic model provides a framework to integrate data mining, experimental design and prioritisation decisions. This paper goes on to identify opportunities for research in DBM, including DBM process models used in practice, the use of evolutionary operations techniques in DBM, prioritisation decisions, and the factors that surround the uptake of DBM.<br /

Comparative analysis of the mammalian WNT4 promoter

BACKGROUND: WNT4 is a critical signalling molecule in embryogenesis and homeostasis, but the elements that control its transcriptional regulation are largely unknown. This study uses comparative cross species sequence and functional analyses between humans and a marsupial (the tammar wallaby,Macropus eugenii) to refine the mammalian Wnt4 promoter. RESULTS: We have defined a highly conserved 89 bp minimal promoter region in human WNT4 by comparative analysis with the tammar wallaby. There are many conserved transcription factor binding sites in the proximal promoter region, including SP1, MyoD, NFkappaB and AP2, as well as highly conserved CpG islands within the human, mouse and marsupial promoters, suggesting that DNA methylation may play an important role in WNT4 transcriptional regulation. CONCLUSION: Using a marsupial model, we have been able to provide new information on the transcriptional regulators in the promoter of this essential mammalian developmental gene, WNT4. These transcription factor binding sites and CpG islands are highly conserved in two disparate mammals, and are likely key controlling elements in the regulation of this essential developmental gene