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ABSTRACTThe colorectal cancer (CRC) screening program B-PREDICT is an invited two-stage screening project using a fecal immunochemical test (FIT) for initial screening followed by a colonoscopy for those with a positive FIT. Since the gut microbiome likely plays a role in the etiology of CRC, microbiome-based biomarkers in combination with FIT could be a promising tool for optimizing CRC screening. Therefore, we evaluated the usability of FIT cartridges for microbiome analysis and compared it to Stool Collection and Preservation Tubes. Corresponding FIT cartridges as well as Stool Collection and Preservation Tubes were collected from participants of the B-PREDICT screening program to perform 16S rRNA gene sequencing. We calculated intraclass correlation coefficients (ICCs) based on center log ratio transformed abundances and used ALDEx2 to test for significantly differential abundant taxa between the two sample types. Additionally, FIT and Stool Collection and Preservation Tube triplicate samples were obtained from volunteers to estimate variance components of microbial abundances. FIT and Preservation Tube samples produce highly similar microbiome profiles which cluster according to subject. Significant differences between the two sample types can be found for abundances of some bacterial taxa (e.g. 33 genera) but are minor compared to the differences between the subjects. Analysis of triplicate samples revealed slightly worse repeatability of results for FIT than for Preservation Tube samples. Our findings indicate that FIT cartridges are appropriate for gut microbiome analysis nested within CRC screening programs.

Context:Established bone turnover markers do not reflect fracture risk in idiopathic male and premenopausal osteoporosis and the role of microRNAs (miRNAs) in these patients is currently unclear. miRNAs are a class of small non-coding RNAs that regulate gene expression and bone tissue homeostasis. They are considered a new class of endocrine regulators with promising potential as biomarkers.Objective:Evaluation of circulating miRNA signatures in male and female subjects with idiopathic and postmenopausal osteoporotic low-traumatic fractures.Design, Setting, and Patients:This was a case-control study of cross-sectional design of 36 patients with prevalent low-traumatic fractures and 39 control subjectsMain Outcome Measures:One hundred eighty-seven miRNAs were quantified in serum by qPCR, compared between groups and correlated with established bone turnover markers.Results:Significant differences in serum levels of circulating miRNAs were identified in all three subgroups (46 in premenopausal, 52 in postmenopausal, 55 in male). A set of 19 miRNAs was consistently regulated in all three subgroups. Eight miRNAs [miR-152-3p, miR-30e-5p, miR-140-5p, miR-324-3p, miR-19b-3p, miR-335-5p, miR-19a-3p, miR-550a-3p] were excellent discriminators of patients with low-traumatic fractures, regardless of age and sex, with area under the curve values > 0.9. The 11 remaining miRNAs showed area under the curve values between 0.81 and 0.89. Correlation analysis identified significant correlations between miR-29b-3p and P1NP, and miR-365-5p and iPTH, TRAP5b, P1NP and Osteocalcin, as well as BMDL1–L4and miR-19b-3p, miR-324-3p, miR-532-5p, and miR-93-5p.Conclusions:Specific serum miRNA profiles are strongly related to bone pathologies. Therefore miRNAs might be directly linked to bone tissue homeostasis. In particular, miR-29b-3p has previously been reported as regulator of osteogenic differentiation and could serve as a novel marker of bone turnover in osteoporotic patients as a member of a miRNA signature.

Context:Severe burn injury causes a massive stress response, consecutively heightened serum levels of acute phase proteins, cortisol, and catecholamines with accompanying disturbance in calcium metabolism.Objective:Evaluation of early and prolonged changes of serum bone turnover markers (BTMs) and regulators of bone metabolism.Design:Longitudinal observational design.Setting:University clinic.Patients:A total of 32 male patients with a median age of 40.5 years and a median burned total body surface area of 40% (83% patients with full thickness burn injury).Interventions:None.Main Outcome Measures:Comparison of changes of BTM/regulators of bone metabolism in the early (d 2–7) and prolonged (d 7–56) phases after trauma.Results:All investigated BTM/regulators significantly changed. During the early phase, pronounced increases were observed for serum type 1 collagen cross-linked C-telopeptide, intact N-terminal propeptide of type I procollagen, sclerostin, Dickkopf-1, bone-specific alkaline phosphatase, fibroblast growth factor 23, and intact parathyroid hormone levels, whereas 25-hydroxyvitamin D, albumin, serum, and ionized calcium levels decreased. Changes of osteoprotegerin, osteocalcin, and phosphate were less pronounced but remained significant. In the prolonged phase, changes of intact N-terminal propeptide of type I procollagen were most pronounced, followed by elevated sclerostin, osteocalcin, bone-specific alkaline phosphatase, and lesser changes for albumin levels. Calcium and ionized calcium levels tardily increased and remained within the limit of normal. In contrast, levels of intact parathyroid hormone, fibroblast growth factor 23, C-reactive protein, and to a lesser extent serum type 1 collagen cross-linked C-telopeptide and phosphate levels declined significantly during this phase of investigation.Conclusions:Ongoing changes of BTM and regulators of bone metabolism suggest alterations in bone metabolism with a likely adverse influence on bone quality and structure in male patients with severe burn injuries.

Glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD) identifies patients at risk for death or end-stage renal disease (ESRD). CKD staging by GFR should incorporate proteinuria to augment risk stratification. We therefore tested the predictive power of the combination of GFR with proteinuria in patients with different histologically-diagnosed types of glomerulonephritis (GN). In a retrospective analysis, 2,687 patients with different forms of GN from 123 Austrian centres were investigated. Full data sets were available from 1,892 subjects. Classes of CKD on the basis of estimated GFR (eGFR) and of proteinuria grouped as <1, 1–3.5, and >3.5 g/24 h were tested for their association with all-cause mortality and ESRD. During a median follow-up of 130 months [interquartile range (IQR) 90; 178] 478 patients (25.3 %) died. Median eGFR was 49 ml/min/1.73 m2(IQR 24; 81) and proteinuria 3.8 g/24 h (IQR 1.7; 8.0). Adjusted multivariate Cox regression indicated that renal survival but not overall survival is related to proteinuria >3.5 g/24 h [as opposed to <1 g/24 h; hazard ratio (HR) 1.91] and shows progression to ESRD. However, subgroup analyses revealed that this risk with proteinuria >3.5 g/24 h exists only in patients with immunoglobulin (Ig)A GN (HR 4.93), miscellaneous GN (HR 1.74), and CKD stage 5 (HR 2.50). Additionally, proteinuria is a risk factor for renal survival in males more than in females with GN and proteinuria >3.5 g/24 h (HR 1.91). Proteinuria is a strong risk factor for renal survival particularly in patients with proteinuria >3.5 g/24 h but not for all types of GN, nor for all CKD stages. Proteinuria is not a risk factor for overall survival in patients with GN.

Abstract: Weather data generated for different parts of the UK under five climate change scenarios (baseline, 2020s low CO2 emissions, 2020s high emissions, 2050s low emissions, 2050s high emissions) were inputted into weather-based models for predicting oilseed rape yields and yield losses from the two most important diseases, phoma stem canker and light leaf spot. An economic analysis of the predictions made by the models was done to provide a basis to guide government and industry planning for adaptation to effects of climate change on crops to ensure future food security. Modelling predicted that yields of fungicide-treated oilseed rape would increase by the 2020s and continue to increase by the 2050s, particularly in Scotland and northern England. If stem canker and light leaf spot were effectively controlled, the value of the crop was predicted to increase above the baseline 1980s value by £13 M in England and £28 M in Scotland by the 2050s under a high CO2 emissions scenario. However, in contrast to predictions that phoma stem canker will increase in severity and range with climate change, modelling indicated that losses due to light leaf spot will decrease in both Scotland and England. Combined losses from both phoma stem canker and light leaf spot are predicted to increase, with yield losses of up to 40% in southern England and some regions of Scotland by the 2050s under the high emission scenarios. For this scenario, UK disease losses are predicted to increase by £50 M (by comparison with the baseline losses). However, the predicted increases in fungicide-treated (potential) yield and phoma stem canker/light leaf spot yield losses compensate for each other so that the net UK losses from climate change for untreated oilseed rape are small.

Climate change affects plants in natural and agricultural ecosystems throughout the world but little work has been done on the effects of climate change on plant disease epidemics. To illustrate such effects, a weather-based disease forecasting model was combined with a climate change model predicting UK temperature and rainfall under high- and low-carbon emissions for the 2020s and 2050s. Multi-site data collected over a 15-year period were used to develop and validate a weather-based model forecasting severity of phoma stem canker epidemics on oilseed rape across the UK. This was combined with climate change scenarios to predict that epidemics will not only increase in severity but also spread northwards by the 2020s. These results provide a stimulus to develop models to predict the effects of climate change on other plant diseases, especially in delicately balanced agricultural or natural ecosystems. Such predictions can be used to guide policy and practice in adapting to effects of climate change on food security and wildlife.

Abstract: One of the most popular criteria for model selection is the Bayesian Information Criterion (BIC). It is based on an asymptotic approximation using Bayes rule when the sample size tends to infinity and the dimension of the model is fixed. Although it works well in classical applications, it performs less satisfactorily for high dimensional problems, i.e. when the number of regressors is very large compared to the sample size. For this reason, an alternative version of the BIC has been proposed for the problem of mapping quantitative trait loci (QTLs) considered in genetics. One approach is to locate QTLs by using model selection in the context of a regression model with an extremely large number of potential regressors. Since the assumption of normally distributed errors is often unrealistic in such settings, we extend the idea underlying the modified BIC to the context of robust regression. [Copyright &y& Elsevier]

ABSTRACTBackground. The outcome of patients with adenocarcinoma of the esophagogastric junction (AEG) remains poor. The programmed cell-death-protein-1 (PD-1), a co-inhibitory receptor primarily expressed by T-cells, represents a potential new therapeutic target. PD-1, PD-1 ligand 1 (PD-L1), and PD-L2 expression have all been described as prognostic factors in a variety of cancers. Their expression patterns in AEG, however, are poorly understood. We analyzed PD-L1, PD-L2 and PD-1 expression by tumor-infiltrating lymphocytes (TILs) and cancer-cells in tumor-biospecimens in AEG-patients.Methods. 168 patients who underwent esophagectomy because of AEG between 1992–2011 were included in this study. PD-L1, PD-L2 and PD-1 expression were evaluated by immunohistochemistry and correlated with various clinicopathological parameters, disease-free survival (DFS) and long-term overall survival (OS).Results. PD-L1 expression by cancer-cells (cancer-cell-PD-L1+) was found in 43.5% of patients whereas PD-L1 expression by TILs (TILs-PD-L1+) was observed in 69%. PD-L2 expression by cancer-cells and TILs was only found in 3.5% and 1.8%, respectively. Additionally, 77.4% of tumors contained PD-1+-cancer-cells and 81% PD-1+-TILs. Patients with increased expression of PD-1 by cancer-cells and TILs showed significantly reduced OS and DFS, as determined by univariate, but not multivariate analysis. Expression of PD-L1 by cancer-cells was found to be an independent predictor for improved DFS (p = 0.038) and OS (p = 0.042) in multivariate analysis.Conclusions. Cancer cells and TILs displayed PD-L1 expression in around 50% and PD-1 expression in around 80% of tumor-biospecimens obtained from AEG patients. Expression of PD-L1 is an independent predictor of favorable outcome in AEG, whereas PD-1 expression is associated with worse outcome and advanced tumor stage.