Automatic covariate selection in logistic models for chest pain diagnosis: A new approach

A newly established method for optimizing logistic models via a minorization-majorization procedure is applied to the problem of diagnosing acute coronary syndromes (ACS). The method provides a principled approach to the selection of covariates which would otherwise require the use of a suboptimal method owing to the size of the covariate set. A strategy for building models is proposed and two models optimized for performance and for simplicity are derived via ten-fold cross-validation. These models confirm that a relatively small set of covariates including clinical and electrocardiographic features can be used successfully in this task. The performance of the models is comparable with previously published models using less principled selection methods. The models prove to be portable when tested on data gathered from three other sites. Whilst diagnostic accuracy and calibration diminishes slightly for these new settings, it remains satisfactory overall. The prospect of building predictive models that are as simple as possible for a required level of performance is valuable if data-driven decision aids are to gain wide acceptance in the clinical situation owing to the need to minimize the time taken to gather and enter data at the bedside

Host and Bacterial Proteins That Repress Recruitment of LC3 to Shigella Early during Infection

Shigella spp. are intracytosolic gram-negative pathogens that cause disease by invasion and spread through the colonic mucosa, utilizing host cytoskeletal components to form propulsive actin tails. We have previously identified the host factor Toca-1 as being recruited to intracellular S. flexneri and being required for efficient bacterial actin tail formation. We show that at early times during infection (40 min.), the type three-secreted effector protein IcsB recruits Toca-1 to intracellular bacteria and that recruitment of Toca-1 is associated with repression of recruitment of LC3, as well as with repression of recruitment of the autophagy marker NDP52, around these intracellular bacteria. LC3 is best characterized as a marker of autophagosomes, but also marks phagosomal membranes in the process LC3-associated phagocytosis. IcsB has previously been demonstrated to be required for S. flexneri evasion of autophagy at late times during infection (4–6 hr) by inhibiting binding of the autophagy protein Atg5 to the Shigella surface protein IcsA (VirG). Our results suggest that IcsB and Toca-1 modulation of LC3 recruitment restricts LC3-associated phagocytosis and/or LC3 recruitment to vacuolar membrane remnants. Together with published results, our findings suggest that IcsB inhibits innate immune responses in two distinct ways, first, by inhibiting LC3-associated phagocytosis and/or LC3 recruitment to vacuolar membrane remnants early during infection, and second, by inhibiting autophagy late during infection

An effector of the Irish potato famine pathogen antagonizes a host autophagy cargo receptor

Plants use autophagy to safeguard against infectious diseases. However, how plant pathogens interfere with autophagy-related processes is unknown. Here, we show that PexRD54, an effector from the Irish potato famine pathogen Phytophthora infestans, binds host autophagy protein ATG8CL to stimulate autophagosome formation. PexRD54 depletes the autophagy cargo receptor Joka2 out of ATG8CL complexes and interferes with Joka2's positive effect on pathogen defense. Thus, a plant pathogen effector has evolved to antagonize a host autophagy cargo receptor to counteract host defenses

Cost-effectiveness and quality-of-life analysis of physician-staffed helicopter emergency medical services

Background: The long-term health outcomes and costs of helicopter emergency medical services (HEMS) assistance remain uncertain. The aim of this study was to investigate the cost-effectiveness of HEMS assistance compared with emergency medical services (EMS). Methods: A prospective cohort study was performed at a level I trauma centre. Quality-of-life measurements were obtained at 2 years after trauma, using the EuroQol - Five Dimensions (EQ-5D) as generic measure to determine health status. Health outcomes and costs were combined into costs per quality-adjusted life year (QALY). Results: The study population receiving HEMS assistance was more severely injured than that receiving EMS assistance only. Over the 4-year study interval, HEMS assistance saved a total of 29 additional lives. No statistically significant differences in quality of life were found between assistance with HEMS or with EMS. Two years after trauma the mean EQ-5D utility score was 0.70 versus 0.71 respectively. The incremental cost-effectiveness ratio for HEMS versus EMS was €28 327 per QALY. The sensitivity analysis showed a cost-effectiveness ratio between €16 000 and €62 000. Conclusion: In the Netherlands, the costs of HEMS assistance per QALY remain below the acceptance threshold. HEMS should therefore be considered as cost effective. Copyrigh

The civilian validation of the Modified Physiological Triage Tool (MPTT): an evidence-based approach to primary major incident triage

INTRODUCTION: Triage is a key principle in the effective management of a major incident. Existing triage tools have demonstrated limited performance at predicting need for life-saving intervention (LSI). Derived on a military cohort, the Modified Physiological Triage Tool (MPTT) has demonstrated improved performance. Using a civilian trauma registry, this study aimed to validate the MPTT in a civilian environment. METHODS: Retrospective database review of the Trauma Audit and Research Network (TARN) database for all adult patients (>18 years) between 2006 and 2014. Patients were defined as Priority One if they received one or more LSIs from a previously defined list. Only patients with complete physiological data were included. Patients were categorised by the MPTT and existing triage tools using first recorded hospital physiology. Performance characteristics were evaluated using sensitivity, specificity and area under receiver operating characteristic (AUROC). RESULTS: During the study period, 218 985 adult patients were included in the TARN database. 127 233 (58.1%) had complete data: 55.6% male, aged 61.4 (IQR 43.1-80.0) years, Injury Severity Score 9 (IQR 9-16), 96.5% suffered blunt trauma and 24 791 (19.5%) were Priority One. The MPTT (sensitivity 57.6%, specificity 71.5%) outperformed all existing triage methods with a 44.7% absolute reduction in undertriage compared with existing UK civilian methods. AUROC comparison supported the use of the MPTT over other tools (p<0.001.) CONCLUSION: Within a civilian trauma registry population, the MPTT demonstrates improved performance at predicting need for LSI, with the lowest rates of undertriage and an appropriate level of overtriage. We suggest the MPTT be considered as an alternative to existing triage tools

Sequence-based prediction for vaccine strain selection and identification of antigenic variability in foot-and-mouth disease virus

Identifying when past exposure to an infectious disease will protect against newly emerging strains is central to understanding the spread and the severity of epidemics, but the prediction of viral cross-protection remains an important unsolved problem. For foot-and-mouth disease virus (FMDV) research in particular, improved methods for predicting this cross-protection are critical for predicting the severity of outbreaks within endemic settings where multiple serotypes and subtypes commonly co-circulate, as well as for deciding whether appropriate vaccine(s) exist and how much they could mitigate the effects of any outbreak. To identify antigenic relationships and their predictors, we used linear mixed effects models to account for variation in pairwise cross-neutralization titres using only viral sequences and structural data. We identified those substitutions in surface-exposed structural proteins that are correlates of loss of cross-reactivity. These allowed prediction of both the best vaccine match for any single virus and the breadth of coverage of new vaccine candidates from their capsid sequences as effectively as or better than serology. Sub-sequences chosen by the model-building process all contained sites that are known epitopes on other serotypes. Furthermore, for the SAT1 serotype, for which epitopes have never previously been identified, we provide strong evidence - by controlling for phylogenetic structure - for the presence of three epitopes across a panel of viruses and quantify the relative significance of some individual residues in determining cross-neutralization. Identifying and quantifying the importance of sites that predict viral strain cross-reactivity not just for single viruses but across entire serotypes can help in the design of vaccines with better targeting and broader coverage. These techniques can be generalized to any infectious agents where cross-reactivity assays have been carried out. As the parameterization uses pre-existing datasets, this approach quickly and cheaply increases both our understanding of antigenic relationships and our power to control disease

Host-pathogen interactions and subversion of autophagy

Macroautophagy (“autophagy”), is the process by which cells can form a double membraned vesicle that encapsulates material to be degraded by the lysosome. This can include complex structures such as damaged mitochondria, peroxisomes, protein aggregates and large swathes of cytoplasm that could not be processed efficiently by other means of degradation. Recycling of amino acids and lipids through autophagy, allows the cell to form intracellular pools that aids survival during periods of stress, including growth factor deprivation, amino acid starvation or a depleted oxygen supply. One of the major functions of autophagy that has emerged over the last decade is its importance as a safeguard against infection. The ability of autophagy to selectively target intracellular pathogens for destruction is now regarded as a key aspect of the innate immune response. However, pathogens have evolved mechanisms to either evade or reconfigure the autophagy pathway for their own survival. Understanding how pathogens interact with and manipulate the host autophagy pathway will hopefully provide a basis for combating infection and increase our understanding of the role and regulation of autophagy. Herein, we will discuss how the host cell can identify and target invading pathogens and how pathogens have adapted in order to evade destruction by the host cell. In particular, we will focus on interactions between the mammalian ATG8 proteins and the host and pathogen effector proteins