Investigating the effect of tunnelling on existing tunnels

A major research project investigating the effect of tunnelling on existing tunnels has been completed at Imperial College London. This subject is always of great concern during the planning and execution of underground tunnelling works in the urban environment. Many cities already have extensive existing tunnel networks and so it is necessary to construct new tunnels at a level beneath them. The associated deformations that take place during tunnelling have to be carefully assessed and their impact on the existing tunnels estimated. Of particular concern is the serviceability of tunnels used for underground trains where the kinematic envelope must not be impinged upon. The new Crossrail transport line under construction in London passes beneath numerous tunnels including a number of those forming part of the London Underground networ

A PDEM-COM framework for uncertainty quantification of backward issues involving both aleatory and epistemic uncertainties

Abstract Uncertainties that exist in nature or due to lack of knowledge have been widely recognized by researchers and engineering practitioners throughout engineering design and analysis for decades. Though great efforts have been devoted to the issues of uncertainty quantification (UQ) in various aspects, the methodologies on the quantification of aleatory uncertainty and epistemic uncertainty are usually logically inconsistent. For instance, the aleatory uncertainty is usually quantified in the framework of probability theory, whereas the epistemic uncertainty is quantified mostly by non-probabilistic methods. In the present paper, a probabilistically consistent framework for the quantification of both aleatory and epistemic uncertainty by synthesizing the probability density evolution method (PDEM) and the change of probability measure (COM) is outlined. The framework is then applied to the backward issues of uncertainty quantification. In particular, the uncertainty model updating issue is discussed in this paper. A numerical example is presented, and the results indicate the flexibility and efficiency of the proposed PDEM-COM framework.</jats:p

Radiomics-Based Texture Analysis of Ga-68-DOTATATE Positron Emission Tomography and Computed Tomography Images as a Prognostic Biomarker in Adults With Neuroendocrine Cancers Treated With Lu-177-DOTATATE

Purpose: Neuroendocrine tumors (NET) are rare cancers with variable behavior. A better understanding of prognosis would aid individualized management. The aim of this hypothesis-generating pilot study was to investigate the prognostic potential of tumor heterogeneity and tracer avidity in NET using texture analysis (TA) of 68Ga-DOTATATE positron emission tomography (PET) and non-enhanced computed tomography (CT) performed at baseline in patients treated with 177Lu-DOTATATE. It aims to justify a larger-scale study to evaluate its clinical value. Methods: The pretherapy 68Ga-DOTATATE PET-CT scans of 44 patients with metastatic NET (carcinoid, pancreatic, thyroid, head and neck, catecholamine-secreting, and unknown primary NET) treated with 177Lu-DOTATATE were analyzed retrospectively using commercially available texture analysis research software. Image filtration extracted and enhanced objects of different sizes (fine, medium, coarse), then quantified heterogeneity by statistical and histogram-based parameters (mean intensity, standard deviation, entropy, mean of positive pixels, skewness, and kurtosis). Regions of interest were manually drawn around up to five of the most 68Ga-DOTATATE avid lesions for each patient. 68Gallium uptake on PET was quantified as SUVmax and SUVmean. Associations between imaging and clinical markers with progression-free (PFS) and overall survival (OS) were assessed using univariate Kaplan-Meier analysis. Independence of the significant univariate markers of survival was tested using multivariate Cox regression analysis. Results: Measures of heterogeneity (higher kurtosis, higher entropy, and lower skewness) on coarse-texture scale CT and unfiltered PET images predicted shorter PFS (CT coarse kurtosis: p=0.05, PET entropy: p=0.01, PET skewness: p=0.03) and shorter OS (CT coarse kurtosis: p=0.05, PET entropy: p=0.01, PET skewness p=0.02). Conventional PET parameters such as SUVmax and SUVmean showed trends towards predicting outcome but were not statistically significant. Multivariate analysis identified that CT-TA (coarse kurtosis: HR=2.57, 95% CI=1.22–5.38, p=0.013) independently predicted PFS, and PET-TA (unfiltered skewness: HR=9.05, 95% CI=1.19–68.91, p=0.033) independently predicted OS. Conclusion: These preliminary data generate a hypothesis that radiomic analysis of neuroendocrine cancer on 68Ga-DOTATATE PET-CT may be of prognostic value and a valuable addition to the assessment of patients

Central Diabetes Insipidus: An Unusual Complication in a Child With Juvenile Myelomonocytic Leukemia and Monosomy 7

Central diabetes insipidus (DI) is well-documented as a presenting feature of myelodysplastic syndrome and acute myeloid leukemia in adults. However, DI is unusual in pediatric patients with myeloid malignancies. We report here this rare complication in a child with neurofibromatosis type 1 who developed juvenile myelomonocytic leukemia and monosomy 7. Our case and previously reported cases of DI arising as a complication in myeloid malignancies demonstrate a close association with deletion of chromosome 7. The clinical characteristics and outcomes of these uncommon cases in children are reviewed and discussed.postprin

Evolution of 18F-FDG-PET/CT findings in patients following COVID-19 pneumonia: An Initial Investigation

Background: The evolution of pulmonary 18F-FDG uptake is unknown in patients with pneumonia due to SARS-CoV-2 (COVID-19 pneumonia) and in those with persistent respiratory symptoms post-COVID-19 termed Post-COVID-19 Lung-Disease (PCLD). The aim of this study was to assess the temporal evolution of pulmonary 18F-FDG uptake and identify a potential role for the use of 18F-FDG-PET/CT imaging in the management of these patients. Methods: Clinical data and CT imaging of all patients that underwent 18F-FDG-PET/CT imaging at UCLH, Lon-don during the UK pandemic were reviewed to find evidence of active or recovered SARS-CoV-2 infection. Results of PCR tests were used where available. Patients were divided in to acute (early and late) COVID-19 pneumonia, PCLD and asymptomatic recovery. 18F-FDG uptake in the lungs was measured as a target-to-background ratio (SUVmax/SUVmin) TBRlung which was compared to temporal-stage and plasma CRP. Results: There were 50 patients in total (median 61y, range 18-87y, 32-male): 23 incidental acute COVID-19 pneumonia cases identified retrospectively (8 Early, 15 Late), 9 asymptomatic recovered patients, and 18 cases performed for PCLD. In acute COVID-19 patients <3 weeks since disease onset TBRlung was strongly correlated with time since disease onset (rs=0.81, p<0.001)

Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesity

There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th) and 95(th) percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th) percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50) = 0.0103). This finding was not confirmed in the trios (p(GSEA,50) = 0.5991), but in KORA (p(GSEA,50) = 0.0398). The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50) = 0.1052, p(MAGENTA,75) = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle

The creation of new rotation arc to the rat latissimus dorsi musculo-cutaneous flap with delay procedures

BACKGROUND: Latissimus dorsi musculocutaneous flap is one of the most frequently performed reconstructive techniques in surgery. Latissimus dorsi muscle has two arcs of rotation. It is classified as type V muscle. This muscle can be elevated on the thoracodorsal artery to cover large defects in the anterior chest and also, the muscle can be elevated on the segmental vessels to cover midline defects posteriorly. The aim of this study was to create a new arc of rotation on a vertical axis for the muscle and investigate effectiveness of vascular and chemical delays on the latissimus dorsi muscle flap with an inferior pedicle in an experimental rat model. We hypothesized that the latissimus dorsi muscle would be based on inferior pedicle by delay procedures. METHODS: We tested two different types of delay: vascular and combination of vascular and chemical. We also tried to determine how many days of "delay" can elicit beneficial effects of vascular and combination delays in an inferior pedicled latissimus dorsi musculocutaneous flap. To accomplish this, 48 male Sprague-Dawley rats were randomly subjected to vascular or combination delay (vascular and chemical). In addition, one ear of each rat was assigned into a delay procedure and the other ear was used as a control. Results were evaluated macroscopically, and micro-angiography and histological examinations were also performed. As a result, there was a significant difference in viable flap areas between vascular delay alone and control groups (p < 0.05). RESULTS: The higher rate of flap viability was obtained in seven-day vascular delay alone. However, there was no significant difference in the viability between seven-day vascular delay and five-day vascular delay (p < 0.05), so the earliest time when the flap viability could be obtained was at five days. The rate of flap viability was significantly higher in the vascular delay combined with chemical delay than the control group (p < 0.05). CONCLUSION: The combination of vascular and chemical delays increased the rate of viability. Nevertheless, there was no significant difference between vascular delay alone and combination of vascular and chemical delays. Chemical delay did not significantly decrease the delay period. Better histological and microangiographical results were achieved in delay groups compared to control groups. We concluded that the arch of the latissimus dorsi musculocutaneous flap can be changed and the flap can be used for various purposes with the delay procedures

Gaps in COPD guidelines of low- and middle-income countries: a systematic scoping review

BACKGROUND: Guidelines are critical for facilitating cost-effective COPD care. Development and implementation in low-and middle-income countries (LMICs) is challenging. To guide future strategy, an overview of current global COPD guidelines is required. RESEARCH QUESTION: We systematically reviewed national COPD guidelines, focusing on worldwide availability and identification of potential development, content, context and quality gaps that may hamper effective implementation. STUDY DESIGN: & Methods: Scoping review of national COPD management guidelines. We assessed: (1) global guideline coverage, (2) guideline information (authors, target audience, dissemination plans), (3) content (prevention, diagnosis, treatments), (4) ethical, legal, socio-economic aspects and (5) compliance with the eight Institute of Medicine (IOM) guideline standards. LMICs guidelines were compared to those from high-income countries (HICs). MAIN RESULTS: Of the 61 national COPD guidelines identified, 30 were from LMICs. Guidelines did not cover 1.93 billion (30.2%) people living in LMICs, whereas only 0.02 billion (1.9%) in HICs were without national guidelines. Compared with HICs, LMIC guidelines targeted fewer healthcare professional groups and less often addressed case finding and co-morbidities. Over 90% of all guidelines included smoking cessation advice. Air pollution reduction strategies were less frequently mentioned in both LMICs (47%) and HICs (42%). LMIC guidelines fulfilled on average 3.37 (42%) of IOM standards compared to 5.29 (66%) in HICs (p<0.05). LMICs scored significantly lower compared with HICs regarding conflicts of interest management, updates, articulation of recommendations and funding transparency (all, p<0.05). INTERPRETATION: Several development, content, context and quality gaps exist in COPD guidelines from LMICs that may hamper effective implementation. Overall, COPD guidelines in LMICs should be more widely available and should be transparently developed and updated. Guidelines may be further enhanced by better inclusion of local risk-factors, case finding and co-morbidity management, preferably tailored to available financial and staff resources

Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation