Towards a foundation for holistic power system validation and testing

Renewable energy sources and further electrificationof energy consumption are key enablers for decreasing green-house gas emissions, but also introduce increased complexitywithin the electric power system. The increased availability ofautomation, information and communication technology, andintelligent solutions for system operation have transformed thepower system into a smart grid. In order to support thedevelopment process of smart grid solutions on the system level,testing has to be done in a holistic manner, covering the multi-domain aspect of such complex systems. This paper introducesthe concept of holistic power system testing and discuss first stepstowards a corresponding methodology that is being developed inthe European ERIGrid research infrastructure project.Comment: 2016 IEEE 21st International Conference on Emerging Technologies and Factory Automation (ETFA

Investigating The Dynamics of Hepatic Inflammation Through Simulation

Inflammation is a fundamental mechanism for the body to induce repair and healing in tissues, and exacerbated inflammatory responses are associated with a wide variety of diseases and disorders. Categorising the various cells, proteins, and precise mechanisms involved in initiating and driving inflammation poses significant challenges, due to the complex interplay that occurs between them. In this thesis, I will introduce a deadly parasitic disease called Visceral Leishmaniasis (VL) as a case study in using computational modelling techniques to elucidate the mechanisms underpinning inflammation. During VL infection, inflammatory aggregations of immune system cells form, these are called granulomas. Granulomas function to contain and subsequently remove infection. Whilst immunological studies have provided insights into the structure and function of granulomas, there remains a breadth of questions which laboratory techniques are currently incapable of answering. As such, the challenges facing biologists from a scientific perspective will be addressed, I will then argue after a thorough review of the relevant literature, that agent-based computational modelling is a logical choice for research into granuloma formation, and that such models can help answer some outstanding questions in the field. The thesis presents the process of designing and developing the first spatially resolved model of liver localised granuloma formation during VL. The development and use of modelling and simulation to study granulomas has involved close collaboration with immunologists at all stages through conceptualisation, modelling, implementation, and also results interpretation. I describe the use of established statistical techniques to instill confidence in both the model, and the results it can produce through simulation. Through iterative hypothesis generation and testing, the research undertaken has allowed for several predictions to be made, some of which have biological significance and which were later validated experimentally. Specifically, transcriptomic data analysis revealed that both infected and uninfected Kupffer cells are equally capable of responding to infection in a similar manner, something which wasn't previously evident in the literature. Using this transcriptomic data, I investigated through simulation, several experimental scenarios and elucidated a novel mechanism of immune system regulation in the liver microenvironment. Using an experimental model of Leishmania donovani infection, I demonstrated that such an immune regulatory mechanism can be overcome with the expansion of early promoter cells called Natural Killer T cells

Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling

Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation

Large-scale land acquisitions exacerbate local farmland inequalities in Tanzania

This research article was published by PNAS Vol. 120 | No. 32Land inequality stalls economic development, entrenches poverty, and is associated with environmental degradation. Yet, rigorous assessments of land-use interventions attend to inequality only rarely. A land inequality lens is especially important to understand how recent large-scale land acquisitions (LSLAs) affect smallholder and indigenous communities across as much as 100 million hectares around the world. This paper studies inequalities in land assets, specifically landholdings and farm size, to derive insights into the distributional outcomes of LSLAs. Using a household survey covering four pairs of land acquisition and control sites in Tanzania, we use a quasi-experimental design to characterize changes in land inequality and subsequent impacts on well-being. We find convincing evidence that LSLAs in Tanzania lead to both reduced landholdings and greater farmland inequality among smallholders. Households in proximity to LSLAs are associated with 21.1% (P = 0.02) smaller landholdings while evidence, although insignificant, is suggestive that farm sizes are also declining. Aggregate estimates, however, hide that households in the bottom quartiles of farm size suffer the brunt of landlessness and land loss induced by LSLAs that combine to generate greater farmland inequality. Additional analyses find that land inequality is not offset by improvements in other livelihood dimensions, rather farm size decreases among households near LSLAs are associated with no income improvements, lower wealth, increased poverty, and higher food insecurity. The results demonstrate that without explicit consideration of distributional outcomes, land-use policies can systematically reinforce existing inequalities

Typology and Dynamics of Heavier Drinking Styles in Great Britain: 1978-2010.

AIMS: To identify a typology of heavier drinking styles in Great Britain and to identify socio-demographic trends in the typology over the period 1978-2010. METHODS: We applied multiple correspondence analysis and agglomerative hierarchical clustering to beverage-specific quantity-frequency measures of alcohol consumption in the repeated cross-sectional General Lifestyle Survey of Great Britain, 1978-2010. The cluster analysis focuses on the 60,043 adult respondents over this period reporting average drinking levels above the UK Government guidelines. We projected sex, age, income, education, socio-economic status and tobacco consumption variables onto the clusters to inspect socio-demographic trends in heavier drinking. RESULTS: We identified four stable clusters of heavier drinking: (a) high volume beer; (b) beer and spirit combination; (c) all beverage and (d) wine and spirit only. The socio-demographic characteristics of the clusters were distinct from both each other and the general population. However, all clusters had higher median incomes and higher smoking rates than the population. Increases in the prevalence of heavier drinking were driven by a 5-fold increase in the contribution of the female-dominated, wine and spirit only cluster. CONCLUSIONS: Recent changes in per capita alcohol consumption in Great Britain occurred within the context of a stable typology of heavier drinking styles and shifting socio-demographics. Identifying these trends is essential to better understand how drinking cultures develop over time and where potentially problematic drinking styles may emerge. Our findings suggest that careful attention to patterns and cultures of consumption is more important than relying on headline consumption data, for both understanding drinking behaviours and targeting interventions. SHORT SUMMARY: This analysis of alcohol consumption survey data identifies four styles of heavier drinking in Great Britain, which remain unchanged over the period 1978-2010. The socio-demographic characteristics of the drinking styles are distinct from both each other and the general population, with increased participation of female and older drinkers over time

Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.

BACKGROUND Current diagnostics for HIV-associated tuberculosis are suboptimal, with missed diagnoses contributing to high hospital mortality and approximately 374 000 annual HIV-positive deaths globally. Urine-based assays have a good diagnostic yield; therefore, we aimed to assess whether urine-based screening in HIV-positive inpatients for tuberculosis improved outcomes. METHODS We did a pragmatic, multicentre, double-blind, randomised controlled trial in two hospitals in Malawi and South Africa. We included HIV-positive medical inpatients aged 18 years or more who were not taking tuberculosis treatment. We randomly assigned patients (1:1), using a computer-generated list of random block size stratified by site, to either the standard-of-care or the intervention screening group, irrespective of symptoms or clinical presentation. Attending clinicians made decisions about care; and patients, clinicians, and the study team were masked to the group allocation. In both groups, sputum was tested using the Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA). In the standard-of-care group, urine samples were not tested for tuberculosis. In the intervention group, urine was tested with the Alere Determine TB-LAM Ag (TB-LAM; Alere, Waltham, MA, USA), and Xpert assays. The primary outcome was all-cause 56-day mortality. Subgroup analyses for the primary outcome were prespecified based on baseline CD4 count, haemoglobin, clinical suspicion for tuberculosis; and by study site and calendar time. We used an intention-to-treat principle for our analyses. This trial is registered with the ISRCTN registry, number ISRCTN71603869. FINDINGS Between Oct 26, 2015, and Sept 19, 2017, we screened 4788 HIV-positive adults, of which 2600 (54%) were randomly assigned to the study groups (n=1300 for each group). 13 patients were excluded after randomisation from analysis in each group, leaving 2574 in the final intention-to-treat analysis (n=1287 in each group). At admission, 1861 patients were taking antiretroviral therapy and median CD4 count was 227 cells per μL (IQR 79-436). Mortality at 56 days was reported for 272 (21%) of 1287 patients in the standard-of-care group and 235 (18%) of 1287 in the intervention group (adjusted risk reduction [aRD] -2·8%, 95% CI -5·8 to 0·3; p=0·074). In three of the 12 prespecified, but underpowered subgroups, mortality was lower in the intervention group than in the standard-of-care group for CD4 counts less than 100 cells per μL (aRD -7·1%, 95% CI -13·7 to -0·4; p=0.036), severe anaemia (-9·0%, -16·6 to -1·3; p=0·021), and patients with clinically suspected tuberculosis (-5·7%, -10·9 to -0·5; p=0·033); with no difference by site or calendar period. Adverse events were similar in both groups. INTERPRETATION Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality. FUNDING Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, and the Wellcome Trust

The Transformative Impact of Community-Led Monitoring in the South African Health System: A Comprehensive Analysis

Objectives: Community-led monitoring (CLM) is an emerging approach that empowers local communities to actively participate in data collection and decision-making processes within the health system. The research aimed to explore stakeholder perceptions of CLM data and establish a CLM Data Value Chain, covering data collection and its impact.Methods: Qualitative data were collected from stakeholders engaged in health programs in South Africa. Data analysis involved a collaborative workshop that integrated elements of affinity diagramming, thematic analysis, and the systematic coding process outlined in Giorgi’s method. The workshop fostered joint identification, co-creation of knowledge, and collaborative analysis in developing the data value chain.Results: The findings showed that CLM data enabled community-level analysis, fostering program advocacy and local collaboration. It enhanced program redesign, operational efficiency, and rapid response capabilities. Context-specific solutions emerged through the CLM Data Value Chain, promoting sustainable and efficient program implementation.Conclusion: CLM is a powerful tool for improving program implementation, quality, and advocacy in South African healthcare. It strengthens accountability, trust, and transparency by involving local communities in data-driven decision-making. CLM addresses context-specific challenges and tailors interventions to local needs

Validating Intelligent Power and Energy Systems { A Discussion of Educational Needs

Traditional power systems education and training is flanked by the demand for coping with the rising complexity of energy systems, like the integration of renewable and distributed generation, communication, control and information technology. A broad understanding of these topics by the current/future researchers and engineers is becoming more and more necessary. This paper identifies educational and training needs addressing the higher complexity of intelligent energy systems. Education needs and requirements are discussed, such as the development of systems-oriented skills and cross-disciplinary learning. Education and training possibilities and necessary tools are described focusing on classroom but also on laboratory-based learning methods. In this context, experiences of using notebooks, co-simulation approaches, hardware-in-the-loop methods and remote labs experiments are discussed.Comment: 8th International Conference on Industrial Applications of Holonic and Multi-Agent Systems (HoloMAS 2017

64Cu-MM-302 Positron Emission Tomography Quantifies Variability of Enhanced Permeability and Retention of Nanoparticles in Relation to Treatment Response in Patients with Metastatic Breast Cancer

Purpose: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. Experimental Design: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by PET/CT. Nineteen patients with HER2-positive metastatic breast cancer underwent 2 to 3 PET/CT scans postadministration of 64Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Results: Significant background uptake of 64Cu-MM-302 was observed in liver and spleen. Tumor accumulation of 64Cu-MM-302 at 24 to 48 hours varied 35-fold (0.52–18.5 %ID/kg), including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24 to 48 hours. Patients were classified on the basis of 64Cu-MM-302 lesion deposition using a cut-off point that is comparable with a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high 64Cu-MM-302 deposition was associated with more favorable treatment outcomes (HR = 0.42). Conclusions: These findings provide important evidence and quantification of the EPR effect in human metastatic tumors and support imaging nanoparticle deposition in tumors as a potential means to identify patients well suited for treatment with therapeutic nanoparticles