Non-Celiac Gluten Sensitivity and Autoimmunity. A Case Report

Introduction, objective: To present a case report in which the finding of non-coeliac gluten sensitivity was decisive for the treatment of a complex autoimmune disease. Materials and methods: A 43-year-old woman with polyarthritis, psoriatic features, anti-SSA/Ro and anti-cyclic citrullinated peptide antibodies, with refractory course, was evaluated for gluten sensitivity despite negative serology for coeliac disease. Results: The patient carried the HLA DQ2 haplotype and duodenal biopsy showed lymphocytic enteritis. A gluten-free diet resolved the clinical picture and permitted tapering of immunosuppressive therapy. Conclusion: Non-coeliac gluten sensitivity can be associated with autoimmunity despite the absence of the specific autoantibodies of coeliac disease.

Non-contact test set-up for aeroelasticity in a rotating turbomachine combining a novel acoustic excitation system with tip-timing

Due to trends in aero-design, aeroelasticity becomes increasingly important in modern turbomachines. Design requirements of turbomachines lead to the development of high aspect ratio blades and blade integral disc designs (blisks), which are especially prone to complex modes of vibration. Therefore, experimental investigations yielding high quality data are required for improving the understanding of aeroelastic effects in turbomachines. One possibility to achieve high quality data is to excite and measure blade vibrations in turbomachines. The major requirement for blade excitation and blade vibration measurements is to minimize interference with the aeroelastic effects to be investigated. Thus in this paper, a non-contact-and thus low interference-experimental set-up for exciting and measuring blade vibrations is proposed and shown to work. A novel acoustic system excites rotor blade vibrations, which are measured with an optical tip-timing system. By performing measurements in an axial compressor, the potential of the acoustic excitation method for investigating aeroelastic effects is explored. The basic principle of this method is described and proven through the analysis of blade responses at different acoustic excitation frequencies and at different rotational speeds. To verify the accuracy of the tip-timing system, amplitudes measured by tip-timing are compared with strain gage measurements. They are found to agree well. Two approaches to vary the nodal diameter (ND) of the excited vibration mode by controlling the acoustic excitation are presented. By combining the different excitable acoustic modes with a phase-lag control, each ND of the investigated 30 blade rotor can be excited individually. This feature of the present acoustic excitation system is of great benefit to aeroelastic investigations and represents one of the main advantages over other excitation methods proposed in the past. In future studies, the acoustic excitation method will be used to investigate aeroelastic effects in high-speed turbomachines in detail. The results of these investigations are to be used to improve the aeroelastic design of modern turbomachines.

Second worldwide proficiency study on variable number of tandem repeats typing of Mycobacterium tuberculosis complex

Global Network for the Molecular Surveillance of Tuberculosis 2010: A. Miranda (Tuberculosis Laboratory of the National Institute of Health, Porto, Portugal)

In situ characterization of sediment oxygen demand across the spectrum of non-resuspension to full resuspension with varying bed shear stress

Sediment oxygen demand (SOD) can be a significant oxygen sink in various types of water bodies, particularly slow-moving waters with substantial organic sediment accumulation. In most settings where SOD is a concern, the prevailing hydraulic conditions are such that the impact of sediment resuspension on SOD is not considered. However, in the case of Bubbly Creek in Chicago, Illinois, the prevailing slack water conditions are interrupted by infrequent intervals of very high flow rates associated with pumped combined sewer overflow (CSO) during intense hydrologic events. These events can cause resuspension of the highly organic, nutrient-rich bottom sediments, resulting in precipitous drawdown of dissolved oxygen (DO) in the water column. While many past studies have addressed the dependence of SOD on near-bed velocity and bed shear stress prior to the point of sediment resuspension, there has been limited research that has attempted to characterize the complex and dynamic phenomenon of resuspended-sediment oxygen demand. To address this issue, a new in situ experimental apparatus referred to as the U of I Hydrodynamic SOD Sampler was designed to achieve a broad range of velocities and associated bed shear stresses. This allowed SOD to be analyzed across the spectrum of no sediment resuspension associated with low velocity/ bed shear stress through full sediment resuspension associated with high velocity / bed shear stress. The current study split SOD into two separate components: (1) SODNR is the sediment oxygen demand associated with non-resuspension conditions and is a surface sink calculated using traditional methods to yield a value with units (g/m2/day); and (2) SODR is the oxygen demand associated with resuspension conditions, which is a volumetric sink most accurately characterized using non-traditional methods and units that reflect suspension in the water column (mg/L/day). In the case of resuspension, the suspended sediment concentration was analyzed as a function of bed shear stress, and a formulation was developed to characterize SODR as a function of suspended sediment concentration in a form similar to first-order biochemical oxygen demand (BOD) kinetics with Monod DO term. The results obtained are intended to be implemented into a numerical model containing hydrodynamic, sediment transport, and water quality components to yield oxygen demand varying in both space and time for specific flow events. Such implementation will allow evaluation of proposed Bubbly Creek water quality improvement alternatives which take into account the impact of SOD under various flow conditions. Although the findings were based on experiments specific to the conditions in Bubbly Creek, the techniques and formulations developed in this study should be applicable to similar sites.

Adaptability, Transformation and Complex Changes in Namibia and Tanzania: Resilience and Innovation System Development in Local Communities

This thesis is a research about the recent complex spatial changes in Namibia and Tanzania and local communities’ capacity to cope with, adapt to and transform the unpredictability engaged to these processes. I scrutinise the concept of resilience and its potential application to explaining the development of local communities in Southern Africa when facing various social, economic and environmental changes. My research is based on three distinct but overlapping research questions: what are the main spatial changes and their impact on the study areas in Namibia and Tanzania? What are the adaptation, transformation and resilience processes of the studied local communities in Namibia and Tanzania? How are innovation systems developed, and what is their impact on the resilience of the studied local communities in Namibia and Tanzania? I use four ethnographic case studies concerning environmental change, global tourism and innovation system development in Namibia and Tanzania, as well as mixed-methodological approaches, to study these issues. The results of my empirical investigation demonstrate that the spatial changes in the localities within Namibia and Tanzania are unique, loose assemblages, a result of the complex, multisided, relational and evolutional development of human and non-human elements that do not necessarily have linear causalities. Several changes co-exist and are interconnected though uncertain and unstructured and, together with the multiple stressors related to poverty, have made communities more vulnerable to different changes. The communities’ adaptation and transformation measures have been mostly reactive, based on contingency and post hoc learning. Despite various anticipation techniques, coping measures, adaptive learning and self-organisation processes occurring in the localities, the local communities are constrained by their uneven power relationships within the larger assemblages. Thus, communities’ own opportunities to increase their resilience are limited without changing the relations in these multiform entities. Therefore, larger cooperation models are needed, like an innovation system, based on the interactions of different actors to foster cooperation, which require collaboration among and input from a diverse set of stakeholders to combine different sources of knowledge, innovation and learning. Accordingly, both Namibia and Tanzania are developing an innovation system as their key policy to foster transformation towards knowledge-based societies. Finally, the development of an innovation system needs novel bottom-up approaches to increase the resilience of local communities and embed it into local communities. Therefore, innovation policies in Namibia have emphasised the role of indigenous knowledge, and Tanzania has established the Living Lab network.

Engineering the transition from non-living to living matter

Re-creating and understanding the origin of life represents one of the major challenges facing the scientific community. We will never know exactly how life started on planet Earth, however, we can reconstruct the most likely chemical pathways that could have contributed to the formation of the first living systems. Traditionally, prebiotic chemistry has investigated the formation of modern life’s precursors and their self-organisation under very specific conditions thought to be ‘plausible’. So far, this approach has failed to produce a living system from the bottom-up. In the work presented herein, two different approaches are employed to explore the transition from inanimate to living matter. The development of microfluidic technology during the last decades has changed the way traditional chemical and biological experiments are performed. Microfluidics allows the handling of low volumes of reagents with very precise control. The use of micro-droplets generated within microfluidic devices is of particular interest to the field of Origins of Life and Artificial Life. Whilst many efforts have been made aiming to construct cell-like compartments from modern biological constituents, these are usually very difficult to handle. However, microdroplets can be easily generated and manipulated at kHz rates, making it suitable for high-throughput experimentation and analysis of compartmentalised chemical reactions. Therefore, we decided to develop a microfluidic device capable of manipulating microdroplets in such a way that they could be efficiently mixed, split and sorted within iterative cycles. Since no microfluidic technology had been developed before in the Cronin Group, the first chapter of this thesis describes the soft lithographic methods and techniques developed to fabricate microfluidic devices. Also, special attention is placed on the generation of water-in-oil microdroplets, and the subsequent modules required for the manipulation of the droplets such as: droplet fusers, splitters, sorters and single/multi-layer micromechanical valves. Whilst the first part of this thesis describes the development of a microfluidic platform to assist chemical evolution, finding a compatible set of chemical building blocks capable of reacting to form complex molecules with endowed replicating or catalytic activity was challenging. Abstract 10 Hence, the second part of this thesis focuses on potential chemistry that will ultimately possess the properties mentioned above. A special focus is placed on the formation of peptide bonds from unactivated amino acids, despite being one of the greatest challenges in prebiotic chemistry. As opposed to classic prebiotic experiments, in which a specific set of conditions is studied to fit a particular hypothesis, we took a different approach: we explored the effects of several parameters at once on a model polymerisation reaction, without constraints on hypotheses on the nature of optimum conditions or plausibility. This was facilitated by development of a new high-throughput automated platform, allowing the exploration of a much larger number of parameters. This led us to discover that peptide bond formation is less challenging than previously imagined. Having established the right set of conditions under which peptide bond formation was enhanced, we then explored the co-oligomerisation between different amino acids, aiming for the formation of heteropeptides with different structure or function. Finally, we studied the effect of various environmental conditions (rate of evaporation, presence of salts or minerals) in the final product distribution of our oligomeric products.

‘Failure to maintain’: care rationing and the clinical and financial burden of nurse sensitive hospital-acquired complications in complex older patients

Background: The ageing population, with concomitant increase in chronic conditions, is increasing the presence of older people with complex needs in hospital. People with dementia are one of these complex populations and are particularly vulnerable to complications in hospital. Registered nurses can offer simultaneous assessment and intervention to prevent or mitigate hospital-acquired complications through their skilled brokerage between patient needs and hospital functions. A range of patient outcome measures that are sensitive to nursing care has been tested in nursing work environments across the world. However, none of these measures have focused on hospitalised older patients. Method: This thesis explores nursing-sensitive complications for older patients with and without dementia using an internationally recognised, risk-adjusted patient outcome approach. Specifically explored are: the differences between rates of complications; the costs of complications; and cost comparisons of patient complexity. A retrospective cohort study of an Australian state’s 2006–07 public hospital discharge data was utilised to identify patient episodes for people over age 50 (N=222,440) where dementia was identified as a primary or secondary diagnosis (N=44,422). Extra costs for patient episodes were estimated based on length of stay (LOS) above the average for each patient’s Diagnosis Related Group (DRG) (N=157,178) and were modelled using linear regression analysis to establish the strongest patient complexity predictors of cost. Results: Hospitalised patients with a primary or secondary diagnosis of dementia had higher rates of complications than did their same-age peers. The highest rates and relative risk for people with dementia were found in four key complications: urinary tract infections; pressure injuries; pneumonia, and delirium. While 21.9% of dementia patients (9,751/44,488, p<0.0001) suffered a complication, only 8.8% of non-dementia patients did so (33,501/381,788, p<0.0001), giving dementia patients a 2.5 relative risk of acquiring a complication (p<0.0001). These four key complications in patients over 50 both with and without dementia were associated with an eightfold increase in length of stay (813%, or 3.6 days/0.4 days) and double the increased estimated mean episode cost (199%, or A$16,403/ A$8,240). These four complications were associated with 24.7% of the estimated cost of additional days spent in hospital in 2006–07 in NSW (A$226million/A$914million). Dementia patients accounted for 22.0% of these costs (A$49million/A$226million) even though they were only 10.4% of the population (44,488/426,276 episodes). Hospital-acquired complications, particularly for people with a comorbidity of dementia, cost more than other kinds of inpatient complexity but admission severity was a better predictor of excess cost. Discussion: Four key complications occur more often in older patients with dementia and the high rate of these complications makes them expensive. These complications are potentially preventable. However, the care that can prevent them (such as mobility, hydration, nutrition and communication) is known to be rationed or left unfinished by nurses. Older hospitalised people who have complex needs, such as those with dementia, are more likely to experience care rationing as their care tends to take longer, be less predictable and less curative in nature. This thesis offers the theoretical proposition that evidence-based nursing practices are rationed for complex older patients and that this rationed care contributes to functional and cognitive decline during hospitalisation. This, in turn, contributes to the high rates of complications observed. Thus four key complications can be seen as a ‘Failure to Maintain’ complex older people in hospital. ‘Failure to Maintain’ is the inadequate delivery of essential functional and cognitive care for a complex older person in hospital resulting in a complication, and is recommended as a useful indicator for hospital quality. Conclusions: When examining extra length of stay in hospital, complications and comorbid dementia are costly. Complications are potentially preventable, and dementia care in hospitals can be improved. Hospitals and governments looking to decrease costs can engage in risk-reduction strategies for common nurse sensitive complications such as healthy nursing work environments that minimise nurses’ rationing of functional and cognitive care. The conceptualisation of complex older patients as ‘business as usual’ rather than a ‘burden’ is likely necessary for sustainable health care services of the future. The use of the ‘Failure to Maintain’ indicators at institution and state levels may aid in embedding this approach for complex older patients into health organisations. Ongoing investigation is warranted into the relationships between the largest health services expense (hospitals), the largest hospital population (complex older patients), and the largest hospital expense (nurses). The ‘Failure to Maintain’ quality indicator makes a useful and substantive contribution to further clinical, administrative and research developments.

Assessment of non-standard HIV antiretroviral therapy regimens at Lighthouse Trust in Lilongwe, Malawi

Aim: Lighthouse Trust in Lilongwe, Malawi serves approximately 25,000 patients with HIV antiretroviral therapy (ART) regimens standardized according to national treatment guidelines. However, as a referral centre for complex cases, Lighthouse Trust occasionally treats patients with non-standard ART regimens (NS-ART) that deviate from the treatment guidelines. We evaluated factors contributing to the use of NS-ART and whether patients could transition to standard regimens. Methods: This was a cross-sectional study of all adult patients at Lighthouse Trust being treated with NS-ART as of February 2012. Patients were identified using the electronic data system. Medical charts were reviewed and descriptive statistics were obtained. Results: One hundred six patients were initially found being treated with NS-ART, and 92 adult patients were confirmed to be on NS-ART after review. Mean patient age was 42.4 ± 10.3 years, and 52 (57%) were female. Mean duration of treatment with the NS-ART being used at the time of data collection was 2.1 ± 1.5 years. Eight patients (9%) were on modified first-line NS-ART and 84 (91%) were on modified second-line NS-ART, with 90 patients (98%) having multiple factors contributing to NS-ART use. Severe toxicity from one medication contributed in 28 cases (30%) and toxicity from multiple medications contributed in 46 cases (50%), while 22 patients (24%) were transitioned to NS-ART following a stockout of their original medication. Following clinical review, 84 patients (91%) were transitioned to standard regimens, and eight (9%) were maintained on NS-ART because of incompatibility of their clinical features with the latest national guidelines. Conclusions: Primary factors contributing to NS-ART use were medication toxicities and medication stockouts. Most patients were transitioned to standard regimens, although the need for NS-ART remains.

Large-scale neural dynamics: simple and complex

We review the use of neural field models for modelling the brain at the large scales necessary for interpreting EEG, fMRI, MEG and optical imaging data. Albeit a framework that is limited to coarse-grained or mean-field activity, neural field models provide a framework for unifying data from different imaging modalities. Starting with a description of neural mass models we build to spatially extended cortical models of layered two-dimensional sheets with long range axonal connections mediating synaptic interactions. Reformulations of the fundamental non-local mathematical model in terms of more familiar local differential (brain wave) equations are described. Techniques for the analysis of such models, including how to determine the onset of spatio-temporal pattern forming instabilities, are reviewed. Extensions of the basic formalism to treat refractoriness, adaptive feedback and inhomogeneous connectivity are described along with open challenges for the development of multi-scale models that can integrate macroscopic models at large spatial scales with models at the microscopic scale.

Enhancement of non-viral transfection efficiency with nuclear localization signal peptides

Dissertação de Mestrado, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016

Complex demonstratives and referential descriptions as descriptive designators

Na literatura filosófica, o debate em torno da semântica dos demonstrativos complexos e descrições referenciais tornou-se, em grande medida, polarizado. Isto porque estas expressões são vistas muito comumente ou como (i) `diretamente referenciais’, no sentido em que contribuem para o conteúdo literal somente suas extensões atuais ou como (ii) quantificacionais, no sentido em que contribuem para o conteúdo literal uma condição para determinação de possíveis extensões, uma condição que contenha o conteúdo descritivo de seus nominais. Neste artigo, apresento argumentos em favor de uma concepção alternativa, segundo a qual demonstrativos complexos e descrições referenciais são termos que se referem e descrevem sem quantificar. Em poucas palavras, eles são designadores descritivos. ______________________________________________________________________________________________ ABSTRACT

Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex

Breast cancer is a leading killer of women worldwide. Cyclodextrin-based estrogen receptor-targeting drug-delivery systems represent a promising direction in cancer therapy but have rarely been investigated. To seek new targeting therapies for membrane estrogen receptor-positive breast cancer, an estrogen-anchored cyclodextrin encapsulating a doxorubicin derivative Ada-DOX (CDE1-Ada-DOX) has been synthesized and evaluated in human breast cancer MCF-7 cells. First, we synthesized estrone-conjugated cyclodextrin (CDE1), which formed the complex CDE1-Ada-DOX via molecular recognition with the derivative adamantane-doxorubicin (Ada-DOX) (Kd =1,617 M(-1)). The structure of the targeting vector CDE1 was fully characterized using (1)H- and (13)C-nuclear magnetic resonance, mass spectrometry, and electron microscopy. CDE1-Ada-DOX showed two-phase drug-release kinetics with much slower release than Ada-DOX. The fluorescence polarization analysis reveals that CDE1-Ada-DOX binds to recombinant human estrogen receptor α fragments with a Kd of 0.027 µM. Competition assay of the drug complex with estrogen ligands demonstrated that estrone and tamoxifen competed with CDE1-Ada-DOX for membrane estrogen receptor binding in MCF-7 cells. Intermolecular self-assembly of CDE1 molecules were observed, showing tail-in-bucket and wire-like structures confirmed by transmission electronic microscopy. CDE1-Ada-DOX had an unexpected lower drug uptake (when the host-guest ratio was >1) than non-targeting drugs in MCF-7 cells due to ensconced ligands in cyclodextrins cavities resulting from the intermolecular self-assembly. The uptake of CDE1-Ada-DOX was significantly increased when the host-guest ratio was adjusted to be less than half at the concentration of CDE1 over 5 µM due to the release of the estrone residues. CDE1 elicited rapid activation of mitogen-activated protein kinases (p44/42 MAPK, Erk1/2) in minutes through phosphorylation of Thr202/Tyr204 in MCF-7 cells. These results demonstrate a targeted therapeutics delivery of CDE1-Ada-DOX to breast cancer cells in a controlled manner and that the drug vector CDE1 can potentially be employed as a molecular tool to differentiate nongenomic from genomic mechanism.

Dynamic virtual workspace for teleoperation of heterogeneous robots in non-deterministic environments

Robots are ever increasing in a variety of different workplaces providing an array of benefits such alternative solutions to traditional human labor. While developing fully autonomous robots is the ultimate goal in many robotic applications the reality is that there still exist many situationswere robots require some level of teleoperation in order to achieve assigned goals especially when deployed in non-deterministic environments. For instance teleoperation is commonly used in areas such as search and rescue, bomb disposal and exploration of inaccessible or harsh terrain. This is due to a range of factors such as the lack of ability for robots to quickly and reliably navigate unknown environments or provide high-level decision making especially intime critical tasks. To provide an adequate solution for such situations human-in-the-loop control is required. When developing human-in-the-loop control it is important to take advantage of the complimentary skill-sets that both humans and robots share. For example robots can performrapid calculations, provide accurate measurements through hardware such as sensors and store large amounts of data while humans provide experience, intuition, risk management and complex decision making capabilities. Shared autonomy is the concept of building robotic systems that take advantage of these complementary skills-sets to provide a robust an efficient robotic solution. While the requirement of human-in-the-loop control exists Human Machine Interaction (HMI) remains an important research topic especially the area of User Interface (UI) design.In order to provide operators with an effective teleoperation system it is important that the interface is intuitive and dynamic while also achieving a high level of immersion. Recent advancements in virtual and augmented reality hardware is giving rise to innovative HMI systems. Interactive hardware such as Microsoft Kinect, leap motion, Oculus Rift, Samsung Gear VR and even CAVE Automatic Virtual Environments [1] are providing vast improvements over traditional user interface designs such as the experimental web browser JanusVR [2]. This combined with the introduction of standardized robot frameworks such as ROS and Webots [3] that now support a large number of different robots provides an opportunity to develop a universal UI for teleoperation control to improve operator efficiency while reducing teleoperation training.This research introduces the concept of a dynamic virtual workspace for teleoperation of heterogeneous robots in non-deterministic environments that require human-in-the-loop control. The system first identifies the connected robots through the use kinematic information then determines its network capabilities such as latency and bandwidth. Given the robot type and network capabilities the system can then provide the operator with available teleoperation modes such as pick and place control or waypoint navigation while also allowing them to manipulate the virtual workspace layout to provide information from onboard camera’s or sensors.

A damage accumulation model for complex strain paths: prediction of ductile failure in metals

The characterisation of strain path with respect to the directionality of defect formation is discussed. The criterion of non-monotonic strain path is used in the scalar and tensor models for damage accumulation and recovery. Comparable analysis of models and their verification has been obtained by simulation of crack initiation in a two-stage metal forming operation consisting of wire drawing followed by constrained upsetting.

Investigating combination HIV prevention: isolated interventions or complex system

Treatment as prevention has mobilized new opportunities in preventing HIV transmission and has led to bold new UNAIDS targets in testing, treatment coverage and transmission reduction. These will require not only an increase in investment but also a deeper understanding of the dynamics of combining behavioural, biomedical and structural HIV prevention interventions. High-income countries are making substantial investments in combination HIV prevention, but is this investment leading to a deeper understanding of how to combine interventions? The combining of interventions involves complexity, with many strategies interacting with non-linear and multiplying rather than additive effects. Discussion: Drawing on a recent scoping study of the published research evidence in HIV prevention in high-income countries, this paper argues that there is a gap between the evidence currently available and the evidence needed to guide the achieving of these bold targets. The emphasis of HIV prevention intervention research continues to look at one intervention at a time in isolation from its interactions with other interventions, the community and the socio-political context of their implementation. To understand and evaluate the role of a combination of interventions, we need to understand not only what works, but in what circumstances, what role the parts need to play in their relationship with each other, when the combination needs to adapt and identify emergent effects of any resulting synergies. There is little development of evidence-based indicators on how interventions in combination should achieve that strategic advantage and synergy. This commentary discusses the implications of this ongoing situation for future research and the required investment in partnership. We suggest that systems science approaches, which are being increasingly applied in other areas of public health, could provide an expanded vocabulary and analytic tools for understanding these complex interactions, relationships and emergent effects. Conclusions: Relying on the current linear but disconnected approaches to intervention research and evidence we will miss the potential to achieve and understand system-level synergies. Given the challenges in sustaining public health and HIV prevention investment, meeting the bold UNAIDS targets that have been set is likely to be dependent on achieving systems level synergies.