Using multi-event hydrologic and hydraulic signatures from water level sensors to diagnose locations of uncertainty in integrated urban drainage models used in living digital twins.

Digital twins of urban drainage systems require simulation models that can adequately replicate the physical system. All models have their limitations, and it is important to investigate when and where simulation results are acceptable and to communicate the level of performance transparently to end users. This paper first defines a classification of four possible 'locations of uncertainty' in integrated urban drainage models. It then develops a structured framework for identifying and diagnosing various types of errors. This framework compares model outputs with in-sewer water level observations based on hydrologic and hydraulic signatures. The approach is applied on a real case study in Odense, Denmark, with examples from three different system sites: a typical manhole, a small flushing chamber, and an internal overflow structure. This allows diagnosing different model errors ranging from issues in the underlying asset database and missing hydrologic processes to limitations in the model software implementation. Structured use of signatures is promising for continuous, iterative improvements of integrated urban drainage models. It also provides a transparent way to communicate the level of model adequacy to end users.

Clopidogrel-Paclitaxel Drug-Drug Interaction: A Pharmacoepidemiologic Study.

Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-ß-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age- and sex-matched controls treated with paclitaxel and low-dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9-3.0). Among those receiving a high-dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high-dose paclitaxel.

Autoantibodies to MUC1 glycopeptides cannot be used as a screening assay for early detection of breast, ovarian, lung or pancreatic cancer.

BACKGROUND: Autoantibodies have been detected in sera before diagnosis of cancer leading to interest in their potential as screening/early detection biomarkers. As we have found autoantibodies to MUC1 glycopeptides to be elevated in early-stage breast cancer patients, in this study we analysed these autoantibodies in large population cohorts of sera taken before cancer diagnosis. METHODS: Serum samples from women who subsequently developed breast cancer, and aged-matched controls, were identified from UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and Guernsey serum banks to formed discovery and validation sets. These were screened on a microarray platform of 60mer MUC1 glycopeptides and recombinant MUC1 containing 16 tandem repeats. Additional case-control sets comprised of women who subsequently developed ovarian, pancreatic and lung cancer were also screened on the arrays. RESULTS: In the discovery (273 cases, 273 controls) and the two validation sets (UKCTOCS 426 cases, 426 controls; Guernsey 303 cases and 606 controls), no differences were found in autoantibody reactivity to MUC1 tandem repeat peptide or glycoforms between cases and controls. Furthermore, no differences were observed between ovarian, pancreatic and lung cancer cases and controls. CONCLUSION: This robust, validated study shows autoantibodies to MUC1 peptide or glycopeptides cannot be used for breast, ovarian, lung or pancreatic cancer screening. This has significant implications for research on the use of MUC1 in cancer detection.

Early detection of cancer in the general population: a blinded case-control study of p53 autoantibodies in colorectal cancer.

BACKGROUND: Recent reports from cancer screening trials in high-risk populations suggest that autoantibodies can be detected before clinical diagnosis. However, there is minimal data on the role of autoantibody signatures in cancer screening in the general population. METHODS: Informative p53 peptides were identified in sera from patients with colorectal cancer using an autoantibody microarray with 15-mer overlapping peptides covering the complete p53 sequence. The selected peptides were evaluated in a blinded case-control study using stored serum from the multimodal arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening where women gave annual blood samples. Cases were postmenopausal women who developed colorectal cancer following recruitment, with 2 or more serum samples preceding diagnosis. Controls were age-matched women with no history of cancer. RESULTS: The 50 640 women randomised to the multimodal group were followed up for a median of 6.8 (inter-quartile range 5.9-8.4) years. Colorectal cancer notification was received in 101 women with serial samples of whom 97 (297 samples) had given consent for secondary studies. They were matched 1 : 1 with 97 controls (296 serial samples). The four most informative peptides identified 25.8% of colorectal cancer patients with a specificity of 95%. The median lead time was 1.4 (range 0.12-3.8) years before clinical diagnosis. CONCLUSION: Our findings suggest that in the general population, autoantibody signatures are detectable during preclinical disease and may be of value in cancer screening. In colorectal cancer screening in particular, where the current need is to improve compliance, it suggests that p53 autoantibodies may contribute towards risk stratification.