BackgroundPolycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a... Show moreBackgroundPolycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a post-hoc exploratory analysis of bile acids in ADPKD patients, who had participated in a trial on the effect of a somatostatin analogue. Our hypothesis was that serum bile acid levels increase in PLD, and that lanreotide, which reduces liver growth, may also reduce bile acid levels. Furthermore, in PLD, urinary excretion of bile acids might contribute to renal disease.MethodsWith liquid chromatography-mass spectrometry, 11 bile acids in serum and 6 in urine were quantified in 105 PLD ADPKD patients and 52 age-, sex-, mutation- and eGFR-matched non-PLD ADPKD patients. Sampling was done at baseline and after 120 weeks of either lanreotide or standard care.ResultsBaseline serum levels of taurine- and glycine-conjugated bile acids were higher in patients with larger livers. In PLD patients, multiple bile acids decreased upon treatment with lanreotide but remained stable in untreated subjects. Changes over time did not correlate with changes in liver volume. Urine bile acid levels did not change and did not correlate with renal disease progression.ConclusionIn ADPKD patients with PLD, baseline serum bile acids were associated with liver volume. Lanreotide reduced bile acid levels and has previously been shown to reduce liver volume. However, in this study, the decrease in bile acids was not associated with the change in liver volume. Show less
Background: Dialysis is associated with frequent hospitalisations. Studies comparing hospitalisations between peritoneal dialysis (PD) and haemodialysis (HD) report conflicting results and mostly... Show moreBackground: Dialysis is associated with frequent hospitalisations. Studies comparing hospitalisations between peritoneal dialysis (PD) and haemodialysis (HD) report conflicting results and mostly analyse data of patients that remain on their initial dialysis modality. This cohort study compares hospitalisations between PD and HD patients taking into account transitions between modalities. Methods: The Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes collected hospitalisation data of patients who started dialysis between 2012 and 2017. Primary outcome was hospitalisation rate, analysed with a multi-state model that attributed each hospitalisation to the current dialysis modality. Results: In total, 695 patients (252 PD, 443 HD) treated in 31 Dutch hospitals were included. The crude hospitalisation rate for PD was 2.3 ( +/- 5.0) and for HD 1.4 ( +/- 3.2) hospitalisations per patient-year. The adjusted hazard ratio for hospitalisation rate was 1.1 (95%CI 1.02-1.3) for PD compared with HD. The risk for first hospitalisation was 1.3 times (95%CI 1.1-1.6) higher for PD compared with HD during the first year after dialysis initiation. The number of hospitalisations and number of hospital days per patient-year were significantly higher for PD. The most common causes of PD and HD hospitalisations were peritonitis (23%) and vascular access-related problems (33%). Conclusion: PD was associated with higher hospitalisation rate, higher risk for first hospitalisation and higher number of hospitalisations compared with HD. Since the PD hospitalisations were mainly caused by peritonitis, more attention to infection prevention is necessary for reducing the number of hospitalisations in the future. Show less
The role of P-values for null hypothesis testing is under debate. We aim to explore the impact of the significance threshold on estimates for the strengths of associations ("effects") and the... Show moreThe role of P-values for null hypothesis testing is under debate. We aim to explore the impact of the significance threshold on estimates for the strengths of associations ("effects") and the implications for different types of epidemiological research. We consider situations with normal distribution of a true effect, while varying the effect size. We confirm the occurrence of "testimation bias": estimating effect size only if the test was statistically significant leads to exaggerated results. The absolute bias is largest for true effects around 0.7 times the size of the standard error: +220% bias if effects are selected after testing with P < .05, and +335% if tested with P P < .20 (+130%) and larger true effect sizes. We conclude that a lower P-value threshold for declaring statistical significance implies more exaggeration in an estimated effect. This implies that if a low threshold is used, effect size estimation should not be attempted, for example in the context of selecting promising discoveries that need further validation. Confirmatory studies, such as randomized controlled trials, might stick to the 0.05 threshold if adequately powered, while prediction modelling studies should use an even higher threshold, such as 0.2, to avoid strongly biased effect estimates. Show less
Background Poorly described placebo/sham controls make it difficult to appraise active intervention benefits and harms. The 12-item Template for Intervention Description and Replication (TIDieR)... Show moreBackground Poorly described placebo/sham controls make it difficult to appraise active intervention benefits and harms. The 12-item Template for Intervention Description and Replication (TIDieR) checklist was developed to improve the reporting of active interventions. The extent to which TIDieR has been used to improve description of placebo or sham control is not known. Materials and methods We systematically identified and examined all placebo/sham-controlled randomised trials published in 2018 in the top six general medical journals. We reported how many of the TIDieR checklist items were used to describe the placebo/sham control(s). We supplemented this with a sample of 100 placebo/sham-controlled trials from any journal and searched Google Scholar to identify placebo/sham-controlled trials citing TIDieR. Results We identified 94 placebo/sham-controlled trials published in the top journals in 2018. None reported using TIDieR, and none reported placebo or sham components completely. On average eight TIDieR items were addressed, with placebo/sham control name (100%) and when and how much was administered (97.9%) most commonly reported. Some items (rationale, 8.5%, whether there were modifications, 25.5%) were less often reported. In our sample of less well-cited journals, reporting was poorer (average of six items) and followed a similar pattern. Since TIDieR's first publication, six placebo-controlled trials have cited it according to Google Scholar. Two of these used the checklist to describe placebo controls; neither one completely desribed the placebo intervention. Conclusions Placebo and sham controls are poorly described within randomised trials, and TIDieR is rarely used to guide these descriptions. We recommend developing guidelines to promote better descriptions of placebo/sham control components within clinical trials. Show less
P>Background Hyaluronic acid is expressed in atherosclerotic lesions, but its exact role in atherosclerotic disease remains unknown. As degradation of hyaluronic acid by hyaluronidase into low... Show moreP>Background Hyaluronic acid is expressed in atherosclerotic lesions, but its exact role in atherosclerotic disease remains unknown. As degradation of hyaluronic acid by hyaluronidase into low molecular weight hyaluronic acid (LMW-HA) is associated with inflammation and Matrix Metalloproteinase (MMP)-9 activity, we hypothesized that hyaluronic acid metabolism is increased in plaques with unstable characteristics like large lipid core, high number of macrophages, MMP-9 activity, low collagen and smooth muscle cell content. Materials and methods Protein was isolated from 68 carotid artery specimens. The adjacent plaque segment was characterized for the histological parameters: lipid core, macrophage, collagen, smooth muscle cell (SMC) content and the amount of intra-plaque thrombus. Hyaluronidase activity, total hyaluronic acid and LMW-HA expression, the standard hayaluronic acid receptor CD44s and the VEGF-A binding isoform CD44v3, MMP-9 activity and the plaque instability associated growth factor Vascular Endothial Growth Factor (VEGF)-A were analysed and correlated with histological characteristics. Results Hyaluronidase activity, LMW-HA and CD44 expression (CD44s, CD44v3) levels were increased in atheromatous plaques compared with fibrous plaques. Total hyaluronic acid did not correlate with plaque instability. MMP-9 activity correlated with CD44s, hyaluronidase and LMW-HA expression. CD44v3 correlated with the angiogenic factor VEGF-A. In vitro stimulation of macrophages with LMW-HA increased MMP-9 activity. Conclusions We show for the first time that increased hyaluronic acid metabolism and elevated CD44 levels are associated with plaque destabilization potentially by increased MMP-9 activity and stimulation of angiogenesis. Show less
