The introduction of an holistic design approach through a teaching company scheme

Traditional design approaches separate the various functions of design such as material selection, performance modelling and tolerance specification into discrete entities. Whilst this allows more focused methods to be used at each stage, areas of conflict or benefit may be overlooked, and the designer is left to bring the loose ends together. This paper looks at a synthesis approach that draws upon a number of current design themes. The design process is considered along with various aspects such as product development, design-for-`X' methodologies and material selection. The need for the preservation of design knowledge and reasoning, the so called wh-? questions, within the process are considered along with various models of the design process. The paper draws these various aspects together to form a more holistic approach to design. The application of this technique within the Teaching Company Scheme is briefly discussed

The effects of wrist motion and hand orientation on muscle forces: a physiologic wrist simulator study

Although the orientations of the hand and forearm vary for different wrist rehabilitation protocols, their effect on muscle forces has not been quantified. Physiologic simulators enable a biomechanical evaluation of the joint by recreating functional motions in cadaveric specimens. Control strategies used to actuate joints in 5 physiologic simulators usually employ position or force feedback alone to achieve optimum load distribution across the muscles. After successful tests on a phantom limb, unique combinations of position and force feedback – hybrid control and cascade control – were used to simulate multiple cyclic wrist motions of flexion-extension, radioulnar deviation, dart thrower’s motion, and 10 circumduction using six muscles in ten cadaveric specimens. Low kinematic errors and coefficients of variation of muscle forces were observed for planar and complex wrist motions using both novel control strategies. The effect of gravity was most pronounced when the hand was in the horizontal orientation, resulting in higher extensor forces (p<0.017) and higher out-of-plane kinematic errors (p<0.007), as compared to the vertically 15 upward or downward orientations. Muscle forces were also affected by the direction of rotation during circumduction. The peak force of flexor carpi radialis was higher in clockwise circumduction (p=0.017), while that of flexor carpi ulnaris was higher in anticlockwise circumduction (p=0.013). Thus, the physiologic wrist simulator accurately replicated cyclic planar and complex motions in cadaveric specimens. Moreover, the dependence of muscle 20 forces on the hand orientation and the direction of circumduction could be vital in the specification of such parameters during wrist rehabilitation

Increasing Follow-up in College Students with Latent Tuberculosis Infection

Around 13 million people in the United States have latent tuberculosis infection (LTBI) with a 5-10% chance of developing active tuberculosis (TB) in their lifetime if not treated (Center for Disease Control, 2015). At a University Student Health Center (SHC), there is a matriculation requirement for TB testing for students that screen as high risk. Many students have these testing requirements performed at outside clinics, including foreign clinics, and follow-up regarding education about LTBI and treatment recommendations was often missing. The purpose of this evidence-based practice (EBP) project was to increase follow-up, education, and treatment options after diagnosis of LTBI. Students presenting with LTBI to the SHC received a standardized message through the secure patient-portal regarding their diagnosis, treatment options and education about LTBI. It asked them to follow-up with a message, telephone call or in-person appointment. Prior to the intervention, most students with LTBI received no follow-up, and after the intervention 100% of new cases received follow-up. A total of 42 students were sent a secure message, 31 read the secure message and 13 of those students contacted the health center or an outside provider for further follow-up. Out of those 13 students, 7 started treatment for LTBI. The goals of this study were to increase follow-up and education around LTBI, and increase the number of students choosing treatment, all of these outcomes were met. The secure message system was a reliable way to contact students regarding their diagnosis and education around LTBI. Keywords: Latent tuberculosis, interferon-gamma release assay, tuberculin skin test, mycobacterium tuberculosi

Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

BACKGROUND: Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound. METHODS: We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment. FINDINGS: Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3-4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred. INTERPRETATION: The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy. FUNDING: Oxford Biomedical Research Centre, National Institute for Health Research

Recent advances on information transmission and storage assisted by noise

The interplay between nonlinear dynamic systems and noise has proved to be of great relevance in several application areas. In this presentation, we focus on the areas of information transmission and storage. We review some recent results on information transmission through nonlinear channels assisted by noise. We also present recent proposals of memory devices in which noise plays an essential role. Finally, we discuss new results on the influence of noise in memristors.Comment: To be published in "Theory and Applications of Nonlinear Dynamics: Model and Design of Complex Systems", Proceedings of ICAND 2012 (Springer, 2014

Resting-State Functional MRI Metrics in Patients With Chronic Mild Traumatic Brain Injury and Their Association With Clinical Cognitive Performance.

Mild traumatic brain injury (mTBI) accounts for more than 80% of people experiencing brain injuries. Symptoms of mTBI include short-term and long-term adverse clinical outcomes. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was conducted to measure voxel-based indices including fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) in patients suffering from chronic mTBI; 64 patients with chronic mTBI at least 3 months post injury and 40 healthy controls underwent rs-fMRI scanning. Partial correlation analysis controlling for age and gender was performed within mTBI cohort to explore the association between rs-fMRI metrics and neuropsychological scores. Compared with controls, chronic mTBI patients showed increased fALFF in the left middle occipital cortex (MOC), right middle temporal cortex (MTC), and right angular gyrus (AG), and increased ReHo in the left MOC and left posterior cingulate cortex (PCC). Enhanced FC was observed from left MOC to right precuneus; from right MTC to right superior temporal cortex (STC), right supramarginal, and left inferior parietal cortex (IPC); and from the seed located at right AG to left precuneus, left superior medial frontal cortex (SMFC), left MTC, left superior temporal cortex (STC), and left MOC. Furthermore, the correlation analysis revealed a significant correlation between neuropsychological scores and fALFF, ReHo, and seed-based FC measured from the regions with significant group differences. Our results demonstrated that alterations of low-frequency oscillations in chronic mTBI could be representative of disruption in emotional circuits, cognitive performance, and recovery in this cohort

In vivo imaging and quantitative analysis of leukocyte directional migration and polarization in inflamed tissue

Directional migration of transmigrated leukocytes to the site of injury is a central event in the inflammatory response. Here, we present an in vivo chemotaxis assay enabling the visualization and quantitative analysis of subtype-specific directional motility and polarization of leukocytes in their natural 3D microenvironment. Our technique comprises the combination of i) semi-automated in situ microinjection of chemoattractants or bacteria as local chemotactic stimulus, ii) in vivo near-infrared reflected-light oblique transillumination (RLOT) microscopy for the visualization of leukocyte motility and morphology, and iii) in vivo fluorescence microscopy for the visualization of different leukocyte subpopulations or fluorescence-labeled bacteria. Leukocyte motility parameters are quantified off-line in digitized video sequences using computer-assisted single cell tracking. Here, we show that perivenular microinjection of chemoattractants [macrophage inflammatory protein-1alpha (MIP-1alpha/Ccl3), platelet-activating factor (PAF)] or E. coli into the murine cremaster muscle induces target-oriented intravascular adhesion and transmigration as well as polarization and directional interstitial migration of leukocytes towards the locally administered stimuli. Moreover, we describe a crucial role of Rho kinase for the regulation of directional motility and polarization of transmigrated leukocytes in vivo. Finally, combining in vivo RLOT and fluorescence microscopy in Cx3CR1(gfp/gfp) mice (mice exhibiting green fluorescent protein-labeled monocytes), we are able to demonstrate differences in the migratory behavior of monocytes and neutrophils.Taken together, we propose a novel approach for investigating the mechanisms and spatiotemporal dynamics of subtype-specific motility and polarization of leukocytes during their directional interstitial migration in vivo

Troponin release following endurance exercise: is inflammation the cause? a cardiovascular magnetic resonance study

Background: The aetiology and clinical significance of troponin release following endurance exercise is unclear but may be due to transient myocardial inflammation. Cardiovascular magnetic resonance (CMR) affords us the opportunity to evaluate the presence of myocardial inflammation and focal fibrosis and is the ideal imaging modality to study this hypothesis. We sought to correlate the relationship between acute bouts of ultra endurance exercise leading to cardiac biomarkers elevation and the presence of myocardial inflammation and fibrosis using CMR.Methods: 17 recreation athletes (33.5 +/- 6.5 years) were studied before and after a marathon run with troponin, NTproBNP, and CMR. Specific imaging parameters to look for inflammation included T2 weighted images, and T1 weighted spin-echo images before and after an intravenous gadolinium-DTPA to detect myocardial hyperemia secondary to inflammation. Late gadolinium imaging was performed (LGE) to detect any focal regions of replacement fibrosis.Results: Eleven of the 17 participant had elevations of TnI above levels of cut off for myocardial infarction 6 hrs after the marathon (0.075 +/- 0.02, p = 0.007). Left ventricular volumes were reduced post marathon and a small increase in ejection fraction was noted (64 +/- 1% pre, 67 +/- 1.2% post, P = 0.014). Right ventricular volumes, stroke volume, and ejection fraction were unchanged post marathon. No athlete fulfilled criteria for myocardial inflammation based on current criteria. No regions of focal fibrosis were seen in any of the participants.Conclusion: Exercise induced cardiac biomarker release is not associated with any functional changes by CMR or any detectable myocardial inflammation or fibrosis

Epidemiologic evidence for asthma and exposure to air toxics: linkages between occupational, indoor, and community air pollution research.

Outdoor ambient air pollutant exposures in communities are relevant to the acute exacerbation and possibly the onset of asthma. However, the complexity of pollutant mixtures and etiologic heterogeneity of asthma has made it difficult to identify causal components in those mixtures. Occupational exposures associated with asthma may yield clues to causal components in ambient air pollution because such exposures are often identifiable as single-chemical agents (e.g., metal compounds). However, translating occupational to community exposure-response relationships is limited. Of the air toxics found to cause occupational asthma, only formaldehyde has been frequently investigated in epidemiologic studies of allergic respiratory responses to indoor air, where general consistency can be shown despite lower ambient exposures. The specific volatile organic compounds (VOCs) identified in association with occupational asthma are generally not the same as those in studies showing respiratory effects of VOC mixtures on nonoccupational adult and pediatric asthma. In addition, experimental evidence indicates that airborne polycyclic aromatic hydrocarbon (PAH) exposures linked to diesel exhaust particles (DEPs) have proinflammatory effects on airways, but there is insufficient supporting evidence from the occupational literature of effects of DEPs on asthma or lung function. In contrast, nonoccupational epidemiologic studies have frequently shown associations between allergic responses or asthma with exposures to ambient air pollutant mixtures with PAH components, including black smoke, high home or school traffic density (particularly truck traffic), and environmental tobacco smoke. Other particle-phase and gaseous co-pollutants are likely causal in these associations as well. Epidemiologic research on the relationship of both asthma onset and exacerbation to air pollution is needed to disentangle effects of air toxics from monitored criteria air pollutants such as particle mass. Community studies should focus on air toxics expected to have adverse respiratory effects based on biological mechanisms, particularly irritant and immunological pathways to asthma onset and exacerbation