Mapping urban infrastructure interdependencies and fuzzy risks

This is the final version of the article. Available from Elsevier via the DOI in this record.In this study, we considered the relationships between different types of CI and services to simulate possible cascading effects during extreme hazard conditions brought on by climate change and how to analyse impacts with limited data resources. An area in central Bristol, UK, was used as the case study to investigate the interdependencies among select assets and services. A wide range of plausible scenarios caused by pipe bursts in the area were simulated using the CADDIES 2D modelling framework, to identify the hotspots with high risk. The impact on CI, including water supply, electricity, wastewater, solid waste, transportation, telecommunication, and emergency services were assessed by the HAZUR tool. The analysis demonstrated that with limited data resources the dynamics of the interdependencies between CI networks can be highlighted and a basis of risk quantification can be established. The same procedure can be repeated to evaluate the impact of other types of hazards, or the compound hazard scenarios to provide a holistic assessment. Therefore, urban planners and managers can further explore options of interventions for setting up strategies to strengthen city resilience.This study is supported by the RESCCUE (RESilience to cope with Climate Change in Urban arEas) project, funded by the European Union Horizon 2020 research and innovation programme (Grant Agreement No. 700174)

Updating dimedone - The humble hero of the organic laboratory

In this paper, we present a concise and technique-heavy route to the synthesis of dimedone for a second-year organic chemistry curriculum. Our preparation of dimedone guides students through a Michael addition followed by a Dieckmann cyclization, basic ester hydrolysis, and thermal decarboxylation, while allowing time for mechanistic discussion and analysis of the product. The wide variety of techniques covered led this to be a pedagogically diverse experiment. This task is thoroughly tested and suitable for a 6 hour laboratory class (with a 1 hour lunch break) or two 3 hour stand-alone sessions

Penetrance and expressivity of mitochondrial variants in a large clinically unselected population

\ua9 The Author(s) 2023. Published by Oxford University Press. Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting

Improved genetic testing for monogenic diabetes using targeted next-generation sequencing

addresses: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK. [email protected]: PMCID: PMC3737433types: Journal Article; Research Support, Non-U.S. Gov'tOpen Access ArticleCurrent genetic tests for diagnosing monogenic diabetes rely on selection of the appropriate gene for analysis according to the patient's phenotype. Next-generation sequencing enables the simultaneous analysis of multiple genes in a single test. Our aim was to develop a targeted next-generation sequencing assay to detect mutations in all known MODY and neonatal diabetes genes

Penetrance and expressivity of mitochondrial variants in a large clinically unselected population

This is the final version. Available on open access from Oxford University Press via the DOI in this recordData availability: The data supporting the findings of this study are available within the article and its Supplementary Data files. Additional information for reproducing the results described in the article is available upon reasonable request and subject to a data use agreement. The UK Biobank dataset is available from https://biobank.ctsu.ox.ac.ukBACKGROUND: Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. METHOD: Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. RESULTS: We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5 respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. CONCLUSION: Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.Diabetes UKMedical Research Council (MRC)Wellcome TrustNational Institute for Health and Care Research (NIHR

Key features of palliative care service delivery to Indigenous peoples in Australia, New Zealand, Canada and the United States: A comprehensive review

Background: Indigenous peoples in developed countries have reduced life expectancies, particularly from chronic diseases. The lack of access to and take up of palliative care services of Indigenous peoples is an ongoing concern. Objectives: To examine and learn from published studies on provision of culturally safe palliative care service delivery to Indigenous people in Australia, New Zealand (NZ), Canada and the United States of America (USA); and to compare Indigenous peoples’ preferences, needs, opportunities and barriers to palliative care. Methods: A comprehensive search of multiple databases was undertaken. Articles were included if they were published in English from 2000 onwards and related to palliative care service delivery for Indigenous populations; papers could use quantitative or qualitative approaches. Common themes were identified using thematic synthesis. Studies were evaluated using Daly’s hierarchy of evidence-for-practice in qualitative research. Results: Of 522 articles screened, 39 were eligible for inclusion. Despite diversity in Indigenous peoples’ experiences across countries, some commonalities were noted in the preferences for palliative care of Indigenous people: to die close to or at home; involvement of family; and the integration of cultural practices. Barriers identified included inaccessibility, affordability, lack of awareness of services, perceptions of palliative care, and inappropriate services. Identified models attempted to address these gaps by adopting the following strategies: community engagement and ownership; flexibility in approach; continuing education and training; a whole-of-service approach; and local partnerships among multiple agencies. Better engagement with Indigenous clients, an increase in number of palliative care patients, improved outcomes, and understanding about palliative care by patients and their families were identified as positive achievements. Conclusions: The results provide a comprehensive overview of identified effective practices with regards to palliative care delivered to Indigenous populations to guide future program developments in this field. Further research is required to explore the palliative care needs and experiences of Indigenous people living in urban areas

Measurement of dynamic task related functional networks using MEG

The characterisation of dynamic electrophysiological brain networks, which form and dissolve in order to support ongoing cognitive function, is one of the most important goals in neuroscience. Here, we introduce a method for measuring such networks in the human brain using magnetoencephalography (MEG). Previous network analyses look for brain regions that share a common temporal profile of activity. Here distinctly, we exploit the high spatio-temporal resolution of MEG to measure the temporal evolution of connectivity between pairs of parcellated brain regions. We then use an ICA based procedure to identify networks of connections whose temporal dynamics covary. We validate our method using MEG data recorded during a finger movement task, identifying a transient network of connections linking somatosensory and primary motor regions, which modulates during the task. Next, we use our method to image the networks which support cognition during a Sternberg working memory task. We generate a novel neuroscientific picture of cognitive processing, showing the formation and dissolution of multiple networks which relate to semantic processing, pattern recognition and language as well as vision and movement. Our method tracks the dynamics of functional connectivity in the brain on a timescale commensurate to the task they are undertaking

Modelling the impact of women’s education on fertility in Malawi

Many studies have suggested that there is an inverse relationship between education and number of children among women from sub-Saharan Africa countries, including Malawi. However, a crucial limitation of these analyses is that they do not control for the potential endogeneity of education. The aim of our study is to estimate the role of women’s education on their number of children in Malawi, accounting for the possible presence of endogeneity and for nonlinear effects of continuous observed confounders. Our analysis is based on micro data from the 2010 Malawi Demographic Health Survey, and uses a flexible instrumental variable regression approach. The results suggest that the relationship of interest is affected by endogeneity and exhibits an inverted U-shape among women living in rural areas of Malawi, whereas it exhibits an inverse (nonlinear) relationship for women living in urban areas

Development of a clinical calculator to aid the identification of MODY in pediatric patients at the time of diabetes diagnosis

This is the final version. Available from Nature Research via the DOI in this record.Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing “MODY calculator” cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish ‘Better Diabetes Diagnosis’ (BDD) population study (n= 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were signifcant independent predictors of MODY. The model showed excellent discrimination (c-statistic= 0.963) and calibrated well (Brier score= 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV)= 10% v 11% respectively i.e. ~ 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV= 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to beneft, to get the right diagnosis.Diabetes UKWellcome TrustNational Institute for Health Researc