Strengthening Urban Resilience: Understanding the Interdependencies of Outer Space and Strategic Planning for Sustainable Smart Environments

The conventional approach to urban planning has predominantly focused on horizontal dimensions, disregarding the potential risks originating from outer space. This paper aims to initiate a discourse on the vertical dimension of cities, which is influenced by outer space, as an essential element of strategic urban planning. Through an examination of a highly disruptive incident in outer space involving a collision between the Iridium 33 and Cosmos 2251 satellites, this article elucidates the intricate interdependencies between urban areas and outer space infrastructure and services. Leveraging the principles of critical infrastructure protection, which bridge the urban and outer space domains, and employing simulation methods and software, this study articulates the intricate governance complexities of urban security and presents viable solutions for its enhancement. Consequently, the study contributes to the ongoing deliberations regarding the spatial integration of security practices by providing scholarly discourse on urban governance with potential strategies for cultivating sustainable smart cities. In essence, the intrinsic resilience of urban areas heavily relies on the interconnections between cities and outer space, necessitating urban strategists to acknowledge and comprehend these intricate interdependencies. To ensure sustainable urban development, it is imperative to fortify smart cities’ resilience against space debris through the implementation of more stringent regulations

Virtual patients design and its effect on clinical reasoning and student experience : a protocol for a randomised factorial multi-centre study

Background Virtual Patients (VPs) are web-based representations of realistic clinical cases. They are proposed as being an optimal method for teaching clinical reasoning skills. International standards exist which define precisely what constitutes a VP. There are multiple design possibilities for VPs, however there is little formal evidence to support individual design features. The purpose of this trial is to explore the effect of two different potentially important design features on clinical reasoning skills and the student experience. These are the branching case pathways (present or absent) and structured clinical reasoning feedback (present or absent). Methods/Design This is a multi-centre randomised 2x2 factorial design study evaluating two independent variables of VP design, branching (present or absent), and structured clinical reasoning feedback (present or absent).The study will be carried out in medical student volunteers in one year group from three university medical schools in the United Kingdom, Warwick, Keele and Birmingham. There are four core musculoskeletal topics. Each case can be designed in four different ways, equating to 16 VPs required for the research. Students will be randomised to four groups, completing the four VP topics in the same order, but with each group exposed to a different VP design sequentially. All students will be exposed to the four designs. Primary outcomes are performance for each case design in a standardized fifteen item clinical reasoning assessment, integrated into each VP, which is identical for each topic. Additionally a 15-item self-reported evaluation is completed for each VP, based on a widely used EViP tool. Student patterns of use of the VPs will be recorded. In one centre, formative clinical and examination performance will be recorded, along with a self reported pre and post-intervention reasoning score, the DTI. Our power calculations indicate a sample size of 112 is required for both primary outcomes

Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders

Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient's age, severity of the disease, clinical and laboratory findings

Идентификация нового сайта метилирования в промоторном районе гена Sept9 для диагностики гепатоцеллюлярной карциномы

Background. Over 600,000 people die from hepatocellular carcinoma (HCC) each year worldwide. The disease is often detected at advanced stages and in many cases is not curable. Early diagnostic and monitoring of HCC recurrences remains a substantial problem in clinical oncology. That determines the need for a search for highly sensitive and specific biomarkers for the non-invasive of HCC diagnostics. The objective of the study. Identification of the hypermethylated locus in the promoter region of the septin 9 (Sept9) gene based on the annotated methylomes from the public databases. Experimental validation of methylation on a pilot panel of paired clinical samples of patients with HCC, as well as tissue samples from patients with benign liver tumors and lymphocytes from healthy donors. Materials and methods. To analyze the methyl data, samples of HCC from TCGA, hepatocellular adenoma from GEO (Gene Expression Omnibus) depository, peripheral blood cells and tissues of healthy donors from Methbank were used. Experimental validation of methylation levels of the identified site was carried out on a pilot panel of clinical samples by bisulphite pyrosequencing using PyroMark Q24.Results. Based on the analysis of methylome data, we selected cg20275528 site, which is characterized by high level of methylation in HCC tissues and minimal levels of methylation in non-tumor liver tissue, hepatocellular adenoma and peripheral blood of healthy donors. Experimental testing on a pilot panel of clinical specimens showed that the level of marker site methylation in HCC (42 % median) is significantly higher than in non-tumor liver tissues (3 % median) and benign neoplasms (1.5 % median) and exceeds the threshold value in HCC compared to paired samples of adjacent non-tumor liver tissue in 20 out of 30 studied cases (66.6 %). The general possibility for cg20275528 methylation detection in circulating DNA of plasma in HCC patients was shown.Conclusion. The obtained results indicate that the approach to the detection and experimental verification of diagnostically significant markers developed and tested in this study can be used to identify new differentially methylated sites and to establish new approaches for non-invasive HCC diagnosis.Введение. Ежегодно во всем мире от гепатоцеллюлярной карциномы (ГЦК) умирают более 600 тыс. человек. Заболевание часто выявляется на поздних стадиях и во многих случаях является некурабельным. Ранняя диагностика и мониторинг развития рецидивов ГЦК продолжают оставаться существенной проблемой клинической онкологии. Это определяет актуальность поиска высокочувствительных и специфичных биомаркеров для неинвазивной диагностики ГЦК. Цель исследования – идентификация гиперметилированного при ГЦК локуса в промоторном районе гена септин 9 (Sept9) на основании анализа общедоступных данных метиломных исследований; экспериментальная валидация метилирования на пилотной панели парных клинических образцов пациентов с ГЦК, а также образцов ткани пациентов с доброкачественными опухолями печени и лимфоцитов здоровых доноров.Материалы и методы. Для анализа метиломных данных были использованы выборки ГЦК TCGA, гепатоцеллюлярной аденомы из депозитария GEO (Gene Expression Omnibus), а также клеток периферической крови и тканей здоровых доноров Methbank. Экспериментальную валидацию уровней метилирования идентифицированного сайта проводили на пилотной выборке клинических образцов с использованием метода бисульфитного пиросеквенирования на приборе PyroMark Q24.Результаты. На основании анализа метиломных данных нами был выбран сайт cg20275528, который характеризуется высоким уровнем метилирования в тканях ГЦК и минимальными уровнями метилирования в клетках неопухолевой ткани печени, гепатоцеллюлярной аденомы и периферической крови здоровых доноров. Экспериментальная проверка на пилотной выборке клинических образцов показала, что уровень метилирования маркерного сайта в ГЦК (медиана 42 %) значительно выше, чем в неопухолевых тканях печени (медиана 3 %) и доброкачественных новообразованиях (медиана 1,5 %) и превышает пороговое значение в ГЦК по сравнению с парными образцами прилежащей неопухолевой ткани печени в 20 (66,6 %) из 30 исследованных случаев. Показана принципиальная возможность детекции метилирования cg20275528 в циркулирующей ДНК плазмы больных ГЦК.Заключение. Полученные результаты позволяют предположить, что разработанный и апробированный в этой работе подход к поиску и экспериментальной верификации диагностически значимых маркеров может быть использован для выявления новых дифференциально метилированных сайтов и разработки новых подходов к неинвазивной диагностике ГЦК

Liquid biopsies come of age: towards implementation of circulating tumour DNA

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a ‘liquid biopsy’ for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.We would like to acknowledge the support of The University of Cambridge, Cancer Research UK (grant numbers A11906, A20240, A15601) (to N.R., J.D.B.), the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 337905 (to N.R.), the Cambridge Experimental Cancer Medicine Centre, and Hutchison Whampoa Limited (to N.R.), AstraZeneca (to R.B., S.P.), the Cambridge Experimental Cancer Medicine Centre (ECMC) (to R.B., S.P.), and NIHR Biomedical Research Centre (BRC) (to R.B., S.P.). J.G.C. acknowledges clinical fellowship support from SEOM