Reliability-based design procedure for fatigue cracking in asphalt pavements

The need to account for the effect of design input variabilities on predicted performance has led to many design procedures that address reliability for pavement applications. The Florida cracking model uses empirically derived reliability for fatigue cracking design of asphalt pavements. A reliability approach, which is based on probabilistic uncertainty quantification, is necessary to account properly and effectively for the contribution of the variability in each parameter to the overall variance. This paper presents a load and resistance factor design (LRFD) procedure for the Florida cracking model. By delivering designs of uniform reliability, LRFD provides the basis for developing quality control and quality assurance standards. A first-order reliability method that incorporates a surrogate model based on central composite design was used to compute the reliability and formulate the partial safety factors. The reliability calibration was based on field pavement sections that had a wide range of design inputs and target reliability. Illustrative designs based on the developed LRFD procedure show the effectiveness of the partial safety factors and further confirm the credibility of the reliability analysis methodology

Cracking in asphalt materials

This chapter provides a comprehensive review of both laboratory characterization and modelling of bulk material fracture in asphalt mixtures. For the purpose of organization, this chapter is divided into a section on laboratory tests and a section on models. The laboratory characterization section is further subdivided on the basis of predominant loading conditions (monotonic vs. cyclic). The section on constitutive models is subdivided into two sections, the first one containing fracture mechanics based models for crack initiation and propagation that do not include material degradation due to cyclic loading conditions. The second section discusses phenomenological models that have been developed for crack growth through the use of dissipated energy and damage accumulation concepts. These latter models have the capability to simulate degradation of material capacity upon exceeding a threshold number of loading cycles.Peer ReviewedPostprint (author's final draft

Effects of truck traffic on top-down fatigue cracking performance of flexible pavements using a new mechanics-based analysis framework

The mechanics-based analysis framework predicts top-down fatigue cracking initiation time in asphalt concrete pavements by utilising fracture mechanics and mixture morphology-based property. To reduce the level of complexity involved, traffic data were characterised and incorporated into the framework using the equivalent single axle load (ESAL) approach. There is a concern that this kind of simplistic traffic characterisation might result in erroneous performance predictions and pavement structural designs. This paper integrates axle load spectra and other traffic characterisation parameters into the mechanics-based analysis framework and studies the impact these traffic characterisation parameters have on predicted fatigue cracking performance. The traffic characterisation inputs studied are traffic growth rate, axle load spectra, lateral wheel wander and volume adjustment factors. For this purpose, a traffic integration approach which incorporates Monte Carlo simulation and representative traffic characterisation inputs was developed. The significance of these traffic characterisation parameters was established by evaluating a number of field pavement sections. It is evident from the results that all the traffic characterisation parameters except truck wheel wander have been observed to have significant influence on predicted top-down fatigue cracking performance

A retrospective observational study of the relationship between single nucleotide polymorphisms associated with the risk of developing Colorectal cancer and survival

Background: There is variability in clinical outcome for patients with apparently the same stage colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) mapping to chromosomes 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and Xp22 have robustly been shown to be associated with the risk of developing CRC. Since germline variation can also influence patient outcome the relationship between these SNPs and patient survivorship from CRC was examined. Methods: All enrolled into the National Study of Colorectal Cancer Genetics (NSCCG) were genotyped for 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and xp22 SNPs. Linking this information to the National Cancer Data Repository allowed patient genotype to be related to survival. Results: The linked dataset consisted of 4,327 individuals. 14q22.22 genotype defined by the SNP rs4444235 showed a significant association with overall survival. Specifically, the C allele was associated with poorer observed survival (per allele hazard ratio 1.13, 95% confidence interval 1.05-1.22, P = 0.0015). Conclusion: The CRC susceptibility SNP rs4444235 also appears to exert an influence in modulating patient survival and warrants further evaluation as a potential prognostic marker

Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer

Background: Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and adverse outcome in several cancer types. We recently demonstrated that overexpression of PODXL is an independent factor of poor prognosis in colorectal cancer (CRC). The aim of this study was to validate these results in two additional independent patient cohorts and to examine the correlation between PODXL mRNA and protein levels in a subset of tumours. Method: PODXL protein expression was analyzed by immunohistochemistry in tissue microarrays with tumour samples from a consecutive, retrospective cohort of 270 CRC patients (cohort 1) and a prospective cohort of 337 CRC patients (cohort 2). The expression of PODXL mRNA was measured by real-time quantitative PCR in a subgroup of 62 patients from cohort 2. Spearman's Rho and Chi-Square tests were used for analysis of correlations between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between PODXL expression and time to recurrence (TTR), disease free survival (DFS) and overall survival (OS). Results: High PODXL protein expression was significantly associated with unfavourable clinicopathological characteristics in both cohorts. In cohort 1, high PODXL expression was associated with a significantly shorter 5-year OS in both univariable (HR = 2.28; 95% CI 1.43-3.63, p = 0.001) and multivariable analysis (HR = 2.07; 95% CI 1.25-3.43, p = 0.005). In cohort 2, high PODXL expression was associated with a shorter TTR (HR = 2.93; 95% CI 1.26-6.82, p = 0.013) and DFS (HR = 2.44; 95% CI 1.32-4.54, p = 0.005), remaining significant in multivariable analysis, HR = 2.50; 95% CI 1.05-5.96, p = 0.038 for TTR and HR = 2.11; 95% CI 1.13-3.94, p = 0.019 for DFS. No significant correlation could be found between mRNA levels and protein expression of PODXL and there was no association between mRNA levels and clinicopathological parameters or survival. Conclusions: Here, we have validated the previously demonstrated association between immunohistochemical expression of PODXL and poor prognosis in CRC in two additional independent patient cohorts. The results further underline the potential utility of PODXL as a biomarker for more precise prognostication and treatment stratification of CRC patients

Highly sensitive and specific protein detection via combined capillary isoelectric focusing and proximity ligation

Detection and quantification of proteins and their post-translational modifications are crucial to decipher functions of complex protein networks in cell biology and medicine. Capillary isoelectric focusing together with antibody-based detection can resolve and identify proteins and their isoforms with modest sample input. However, insufficient sensitivity prevents detection of proteins present at low concentrations and antibody cross-reactivity results in unspecific detection that cannot be distinguished from bona fide protein isoforms. By using DNA-conjugated antibodies enhanced signals can be obtained via rolling circle amplification (RCA). Both sensitivity and specificity can be greatly improved in assays dependent on target recognition by pairs of antibodies using in situ proximity ligation assays (PLA). Here we applied these DNA-assisted RCA techniques in capillary isoelectric focusing to resolve endogenous signaling transducers and isoforms along vascular endothelial growth factor (VEGF) signaling pathways at concentrations too low to be detected in standard assays. We also demonstrate background rejection and enhanced specificity when protein detection depended on binding by pairs of antibodies using in situ PLA, compared to assays where each antibody preparation was used on its own.</p

Highly sensitive and specific protein detection via combined capillary isoelectric focusing and proximity ligation

Detection and quantification of proteins and their post-translational modifications are crucial to decipher functions of complex protein networks in cell biology and medicine. Capillary isoelectric focusing together with antibody-based detection can resolve and identify proteins and their isoforms with modest sample input. However, insufficient sensitivity prevents detection of proteins present at low concentrations and antibody cross-reactivity results in unspecific detection that cannot be distinguished from bona fide protein isoforms. By using DNA-conjugated antibodies enhanced signals can be obtained via rolling circle amplification (RCA). Both sensitivity and specificity can be greatly improved in assays dependent on target recognition by pairs of antibodies using in situ proximity ligation assays (PLA). Here we applied these DNA-assisted RCA techniques in capillary isoelectric focusing to resolve endogenous signaling transducers and isoforms along vascular endothelial growth factor (VEGF) signaling pathways at concentrations too low to be detected in standard assays. We also demonstrate background rejection and enhanced specificity when protein detection depended on binding by pairs of antibodies using in situ PLA, compared to assays where each antibody preparation was used on its own.</p

Cohort profile : Nordic Helicobacter Pylori eradication project (NordHePEP)

AbstractPurpose: This cohort description presents the Nordic Helicobacter Pylori Eradication Project (NordHePEP), a population-based cohort of patients having received eradication treatment for Helicobacter pylori (HP). The cohort is created with the main purpose of examining whether and to what extent HP eradication treatment influences the risk of gastrointestinal cancer.Participants: NordHePEP includes all adults (aged ≥18 years) having been prescribed and dispensed HP eradication treatment according to the nationwide complete drug registries in any of the five Nordic countries (Denmark, Finland, Iceland, Norway, or Sweden) between 1994 and 2020 (start and end year varies between countries). We have retrieved and merged individual-level data from multiple national registries, including drug, patient, cancer, population, and death registries.Findings: The cohort includes 674,771 patients having received HP eradication treatment. During up to 23 years of follow-up, 59,292 (8.8%) participants were diagnosed with cancer (non-melanoma skin cancer excluded), whereof 15,496 (2.3%) in the gastrointestinal tract.Future plans: We will analyse HP eradication treatment in relation to gastrointestinal cancer risk. Standardised incidence ratios will be calculated as the observed cancer incidence in the cohort divided by the expected cancer incidence, derived from the background population of the corresponding age, sex, and calendar year.Abstract Purpose: This cohort description presents the Nordic Helicobacter Pylori Eradication Project (NordHePEP), a population-based cohort of patients having received eradication treatment for Helicobacter pylori (HP). The cohort is created with the main purpose of examining whether and to what extent HP eradication treatment influences the risk of gastrointestinal cancer. Participants: NordHePEP includes all adults (aged ≥18 years) having been prescribed and dispensed HP eradication treatment according to the nationwide complete drug registries in any of the five Nordic countries (Denmark, Finland, Iceland, Norway, or Sweden) between 1994 and 2020 (start and end year varies between countries). We have retrieved and merged individual-level data from multiple national registries, including drug, patient, cancer, population, and death registries. Findings: The cohort includes 674,771 patients having received HP eradication treatment. During up to 23 years of follow-up, 59,292 (8.8%) participants were diagnosed with cancer (non-melanoma skin cancer excluded), whereof 15,496 (2.3%) in the gastrointestinal tract. Future plans: We will analyse HP eradication treatment in relation to gastrointestinal cancer risk. Standardised incidence ratios will be calculated as the observed cancer incidence in the cohort divided by the expected cancer incidence, derived from the background population of the corresponding age, sex, and calendar year

A Validation of the Swedish Colorectal Cancer Register &ndash; With Focus on Histopathology, Complications and Recurrences

Örvar Arnarson,1,&ast; Peter Moberger,2,3,&ast; Filip Sköldberg,4,5 Kenneth Smedh,2,3 Helgi Birgisson,4,5 Ingvar Syk1 1Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden; 2Centre for Clinical research Västerås, Uppsala University, Uppsala, Sweden; 3Department of Surgery Västmanlands Hospital Västerås, Västerås, Sweden; 4Gastrointestinal Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; 5Department of Surgery, Uppsala University Hospital, Uppsala, Sweden&ast;These authors contributed equally to this workCorrespondence: Ingvar Syk, Department of Surgery, Skåne University Hospital, Malmö, SE-214 28, Email [email protected]: There is an urgent need to evaluate the quality of healthcare systems to improve and deliver high-quality care. Clinical registries have become important platforms for performance measurements, improvements, and clinical research. Hence, the quality of data in registries is crucial. This study aimed to assess the validity of data in the Swedish Colorectal Cancer Register (SCRCR).Methods: Seven hundred patients from 12 hospitals were randomly selected and proportionally distributed among three different hospital categories in Sweden using two-stage cluster sampling. Validity was assessed by re-abstracting data from the medical files of patients reported to the SCRCR in 2015. Data on histopathology, postoperative complications, and a 3-year follow-up were selected for validation. Re-abstracted data were defined as source data, and validity was defined as the proportion of cases in the SRCRC dataset that agreed with the source data. Validity was expressed as the percentage of exact agreement of non-missing data in both data sets, and Cohen´s kappa coefficient (κ) was used to measure the strength of the agreement.Results: The median agreement of the categorical histopathology variables was 93.4% (κ = 0.83). The general postoperative complication variable showed substantial agreement (84.3%, κ = 0.61). Likewise, the variable for overall cancer recurrence showed an almost perfect agreement (95.7%, κ = 0.86), whereas specific variables for local recurrence and distant recurrence displayed only moderate and fair agreement (85.9% and 89.1%, κ = 0.58 and 0.34, respectively).Conclusion: Validation of the SCRCR data showed high validity of pathology data and recurrence rates, whereas detailed data on recurrence were not as good. Data on postoperative complications were less reliable, although the incidence and Clavien–Dindo grading of severe complications (grade 3b or higher) were reliable.Keywords: quality registry, national registry, validation, colorectal cancer, Swedish registr

Risk of gastric adenocarcinoma after eradication of Helicobacter pylori

Abstract Background and Aims: Helicobacter pylori infection of the stomach is the main risk factor for gastric noncardia adenocarcinoma; however, less is known on how eradication of H pylori influences the risk of this tumor over time, particularly in Western populations. The aim of this study was to delineate how the risk of gastric noncardia adenocarcinoma develops over time after H pylori eradication treatment in a Western population compared with the background population. Methods: This population-based cohort study included all adults having received H pylori eradication treatment between 1995 and 2019 in any of the Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country. Time trends in SIR were assessed using Poisson regression. Results: Among 659,592 participants having received H pylori eradication treatment, contributing 5,480,873 person-years at risk, 1311 developed gastric noncardia adenocarcinoma. During up to 24 years of follow-up, the SIR was initially higher than the background population (SIR, 2.27; 95% CI 2.10–2.44, 1–5 years after treatment), and then gradually decreased over time and approached the level of the background population from 11 years after treatment (SIR, 1.11; 95% CI 0.98–1.27, 11–24 years after treatment). Conclusion: This study revealed a decreasing incidence of gastric noncardia adenocarcinoma after H pylori eradication treatment in 5 Western populations. The risk became virtually similar to the background population from 11 years after treatment.Abstract Background and Aims: Helicobacter pylori infection of the stomach is the main risk factor for gastric noncardia adenocarcinoma; however, less is known on how eradication of H pylori influences the risk of this tumor over time, particularly in Western populations. The aim of this study was to delineate how the risk of gastric noncardia adenocarcinoma develops over time after H pylori eradication treatment in a Western population compared with the background population. Methods: This population-based cohort study included all adults having received H pylori eradication treatment between 1995 and 2019 in any of the Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country. Time trends in SIR were assessed using Poisson regression. Results: Among 659,592 participants having received H pylori eradication treatment, contributing 5,480,873 person-years at risk, 1311 developed gastric noncardia adenocarcinoma. During up to 24 years of follow-up, the SIR was initially higher than the background population (SIR, 2.27; 95% CI 2.10–2.44, 1–5 years after treatment), and then gradually decreased over time and approached the level of the background population from 11 years after treatment (SIR, 1.11; 95% CI 0.98–1.27, 11–24 years after treatment). Conclusion: This study revealed a decreasing incidence of gastric noncardia adenocarcinoma after H pylori eradication treatment in 5 Western populations. The risk became virtually similar to the background population from 11 years after treatment