Intestinal Oxalate Absorption, Enteric Hyperoxaluria, and Risk of Urinary Stone Formation in Patients with Crohn's Disease.

Nephrolithiasis is a common urologic manifestation of Crohn's disease. The purpose of this study was to investigate the clinical characteristics, intestinal oxalate absorption, and risk factors for urinary stone formation in these patients. In total, 27 patients with Crohn's disease and 27 healthy subjects were included in the present study. Anthropometric, clinical, and 24 h urinary parameters were determined, and the [13C2]oxalate absorption test was performed. Among all patients, 18 had undergone ileal resection, 9 of whom had a history of urinary stones. Compared to healthy controls, the urinary excretion values of calcium, magnesium, potassium, sulfate, creatinine, and citrate were significantly lower in patients with Crohn's disease. Intestinal oxalate absorption, the fractional and 24 h urinary oxalate excretion, and the risk of calcium oxalate stone formation were significantly higher in patients with urolithiasis than in patients without urolithiasis or in healthy controls. Regardless of the group, between 83% and 96% of the [13C2]oxalate was detected in the urine within the first 12 h after ingestion. The length of ileum resection correlated significantly with the intestinal absorption and urinary excretion of oxalate. These findings suggest that enteric hyperoxaluria can be attributed to the hyperabsorption of oxalate following extensive ileal resection. Oral supplementation of calcium and magnesium, as well as alkali citrate therapy, should be considered as treatment options for urolithiasis.

Risk Profile of Patients with Brushite Stone Disease and the Impact of Diet.

This study examined the profile of patients and the impact of diet on the risk of brushite stone formation under controlled, standardized conditions. Sixty-five patients with brushite nephrolithiasis were enrolled in the study. Metabolic, dietary, and 24 h urinary parameters were collected under the habitual, self-selected diet of the patients and the balanced mixed, standardized diet. The [13C2]oxalate absorption, ammonium chloride, and calcium loading tests were conducted. All patients had at least one abnormality on the usual diet, with hypercalciuria (84.6%), increased urine pH (61.5%), and hyperphosphaturia (43.1%) being the most common. Absorptive hypercalciuria was present in 32.1% and hyperabsorption of oxalate in 41.2%, while distal renal tubular acidosis (dRTA) was noted in 50% of brushite stone formers. The relative supersaturation of brushite did not differ between patients with and without dRTA. Among all recent brushite-containing calculi, 61.5% were mixed with calcium oxalate and/or carbonate apatite. The relative supersaturation of brushite, apatite, and calcium oxalate decreased significantly under the balanced diet, mainly due to the significant decline in urinary calcium, phosphate, and oxalate excretion. Dietary intervention was shown to be effective and should be an integral part of the treatment of brushite stone disease. Further research on the role of dRTA in brushite stone formation is needed.

Dissecting the genetic heterogeneity of gastric cancer.

BACKGROUND: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. METHODS: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. FINDINGS: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. INTERPRETATION: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. FUNDING: German Research Foundation (DFG).

Robust statistical boosting with quantile-based adaptive loss functions.

We combine robust loss functions with statistical boosting algorithms in an adaptive way to perform variable selection and predictive modelling for potentially high-dimensional biomedical data. To achieve robustness against outliers in the outcome variable (vertical outliers), we consider different composite robust loss functions together with base-learners for linear regression. For composite loss functions, such as the Huber loss and the Bisquare loss, a threshold parameter has to be specified that controls the robustness. In the context of boosting algorithms, we propose an approach that adapts the threshold parameter of composite robust losses in each iteration to the current sizes of residuals, based on a fixed quantile level. We compared the performance of our approach to classical M-regression, boosting with standard loss functions or the lasso regarding prediction accuracy and variable selection in different simulated settings: the adaptive Huber and Bisquare losses led to a better performance when the outcome contained outliers or was affected by specific types of corruption. For non-corrupted data, our approach yielded a similar performance to boosting with the efficient L 2 loss or the lasso. Also in the analysis of skewed KRT19 protein expression data based on gene expression measurements from human cancer cell lines (NCI-60 cell line panel), boosting with the new adaptive loss functions performed favourably compared to standard loss functions or competing robust approaches regarding prediction accuracy and resulted in very sparse models.

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.