Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus.

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus

Comparing apples with apples: hierarchical task analysis as a simple systems framework to improve patient safety.

Changing healthcare culture to improve patient safety is the goal of healthcare systems across the world. However the proliferation of Human Factors/Ergonomics (HFE) systems methods may be limiting the embedding of improvements as well-established methods from other safety critical industries are modified. This paper explores how the basic HFE method of Hierarchical Task Analysis (HTA) could be used to compare ‘apples with apples’ by looking at national guidance and local hospital guidance for the care of women and their babies during labour and child birth. It is concluded that HTA could offer a simple framework to visualize operational systems as shared mental models which are accessible within and between multi-disciplinary teams, as part of process improvement projects (including Plan-Do-Study-Act; PDSA) and as the foundation for HFE in healthcare education to ensure the consistency of messages throughout the patient journey

More holes than cheese. What prevents the delivery of effective, high quality, and safe healthcare in England?

What prevents the delivery of effective, high quality, and safe healthcare in the National Health Service (NHS) in England? This paper presents 760 challenges which 330 NHS staff reported as preventing the delivery of effective, high quality and safe care. Some problems have been known for over 25 years (staff shortages, finance and patient complexity) but other challenges raise questions about the commitment of the NHS to patient and staff safety. For example Organisational Culture leading to ‘stifling bureaucracy’, ‘odds stacked against smooth […] working’ and Workload resulting in ‘firefighting daily’ and ‘perpetual crisis mode’. The role of Human Factors/Ergonomics professional input (engagement with safety scientists) is discussed in the context of success stories and examples of Human Factors Integration from other safety critical industries (Defence, Nuclear and Rail)

The dichotomy of the application of a systems approach in UK healthcare: the challenges and priorities for implementation

There is increasing demand for a systems approach within national healthcare guidelines to provide a systematic and sustainable framework for improvements in patient safety. Supported by this is the growing body of evidence within Human Factors/Ergonomics (HFE) healthcare literature for the inclusion of this approach in health service design, provision and evaluation. This paper considers the current interpretation of this within UK healthcare systems and the dichotomy which exists in the challenge to implement a systems approach. Three case studies, from primary and secondary care, present a systems approach, offering a novel perspective of primary care and blood sampling. These provide practical illustrations of how HFE methods have been used in collaboration with healthcare staff to understand the system for the purpose of professional education, design and safety of clinical activities. The paper concludes with the challenge for implementation and proposes five roles for systems HFE to support patient safety

Development of a Clinical Interface for a Novel Newborn Resuscitation Device: Human Factors Approach to Understanding Cognitive User Requirements

Background: A novel medical device has been developed to address an unmet need of standardizing and facilitating heart rate recording during neonatal resuscitation. In a time-critical emergency resuscitation, where failure can mean death of an infant, it is vital that clinicians are provided with information in a timely, precise, and clear manner to capacitate appropriate decision making. This new technology provides a hands-free, wireless heart rate monitoring solution that easily fits the clinical pathway and procedure for neonatal resuscitation.Objective: This study aimed to understand the requirements of the interface design for a new device by using a human factors approach. This approach combined a traditional user-centered design approach with an applied cognitive task analysis to understand the tasks involved, the cognitive requirements, and the potential for error during a neonatal resuscitation scenario.Methods: Fourteen clinical staff were involved in producing the final design requirements. Two pediatric doctors supported the development of a visual representation of the activities associated with neonatal resuscitation. This design was used to develop a scenario-based workshop. Two workshops were carried out in parallel and involved three pediatric doctors, three neonatal nurses, two advance neonatal practitioners, and four midwives. Both groups came together at the end to reflect on the findings from the separate sessions.Results: The outputs of this study have provided a comprehensive description of information requirements during neonatal resuscitation and enabled product developers to understand the preferred requirements of the user interface design for the device. The study raised three key areas for the designers to consider, which had not previously been highlighted: (1) interface layout and information priority, as heart rate should be central and occupy two-thirds of the screen; (2) size and portability, to enable positioning of the product local to the baby’s head and allow visibility from all angles; and (3) auditory feedback, to support visual information on heart rate rhythm and reliability of the trace with an early alert for intervention while avoiding parental distress.Conclusions: This study demonstrates the application of human factors and the applied cognitive task analysis method, which identified previously unidentified user requirements. This methodology provides a useful approach to aid development of the clinical interface for medical devices

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype

Blood sampling: two sides to the story

This study aimed to investigate why there is variability in taking blood. A multi method Pilot study was completed in four National Health Service Scotland hospitals. Human Factors/Ergonomics principles were applied to analyse data from 50 observations, 15 interviews and 12-months of incident data from all Scottish hospitals. The Functional Resonance Analysis Method (FRAM) was used to understand why variability may influence blood sampling functions. The analysis of the 61 pre blood transfusion sampling incidents highlighted limitations in the data collected to understand factors influencing performance. FRAM highlighted how variability in the sequence of blood sampling functions and the number of practitioners involved in a single blood sampling activity was influenced by the working environment, equipment, clinical context, work demands and staff resources. This pilot study proposes a realistic view of why blood sampling activities vary and proposes the need to consider the system’s resilience in future safety management strategies

A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells

Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1\ua0(IDO1) are immunoregulatory enzymes catalyzing the degradation of L-arginine and L-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines. Polyamines, either produced by DCs or released by bystander Arg1+ myeloid-derived suppressor cells, conditioned DCs toward an IDO1-dependent, immunosuppressive phenotype via activation of the Src kinase, which has IDO1-phosphorylating activity. Thus our data indicate that Arg1 and IDO1 are linked by an entwined pathway in immunometabolism and that their joint modulation could represent an important target for effective immunotherapy in several disease settings