•We tested the effect of relevance on auditory action-effect prediction, using EEG.•A prediction effect in ERPs was only evident at P2-latency with relevance.•Relevance decreased P2-timed ERP for ...prediction-incongruent sounds.•Prediction-incongruent effects led to larger pupil size, especially when relevant.•Sensory attenuation for prediction-congruent ERPs was neither evident in N1 nor P2.
Self-initiated sensory action effects are widely assumed to lead to less intense perception and reduced neural responses compared to externally triggered stimuli (sensory attenuation). However, it is unclear if sensory attenuation occurs in all cases of action-effect prediction. Specifically, when predicted action-effects are relevant to determine follow-up actions attenuation could be detrimental. We quantified auditory event-related potentials (ERP) in electroencephalography (EEG) when human participants created two-sound sequences by pressing two keys on a keyboard associated with different pitch, giving rise to identity-specific action-effect prediction after the first keypress. The first sound corresponded to (congruent) or violated (incongruent) the predicted pitch and was either relevant for the selection of the second keypress to correctly complete the sequence (Relevance) or irrelevant (Control Movement), or there was only one keypress and sound (Baseline). We found a diminished P2-timed ERP component in incongruent compared to congruent trials when the sound was relevant for the subsequent action. This effect of action-effect prediction was due to an ERP reduction for incongruent relevant sounds compared to incongruent irrelevant sounds at P2 latencies and correlated negatively with modulations of pupil dilation. Contrary to our expectation, we did not observe an N1 modulation by congruency in any condition. Attenuation of the N1 component seems absent for predicted identity-specific auditory action effects, while P2-timed ERPs as well as pupil size are sensitive to predictability, at least when action effects are relevant for the selection of the next action. Incongruent relevant stimuli thereby take a special place and seem to be subject to attentional modulations and error processing.
Abstract
Background
In primary hyperoxaluria Type 1 (PH1), endogenous oxalate overproduction significantly elevates urinary oxalate excretion, resulting in recurrent urolithiasis and/or progressive ...nephrocalcinosis and often early end-stage renal disease (ESRD). In ESRD, dialysis cannot sufficiently remove oxalate; plasma oxalate (Pox) increases markedly, inducing systemic oxalate deposition (oxalosis) and often death. Interventions to reduce Pox in PH1 subjects with ESRD could have significant clinical impact. This ongoing Phase II, open-label trial aimed to evaluate whether long-term Oxabact™ (Oxalobacter formigenes, OC5, OxThera Intellectual Property AB, Sweden) lowers Pox in PH1 ESRD subjects, ameliorating clinical outcome.
Methods
PH1 ESRD subjects on stable dialysis regimens were examined. Subjects were administered one OC5 capsule twice daily for up to 36 months or until transplantation. Total Pox values, cardiac function and safety were evaluated. Free Pox was evaluated in a comparative non-treated PH1 dialysis group using retrospective chart reviews and analyses.
Results
Twelve subjects enrolled in an initial 6-week treatment phase. Following a washout of up to 4 weeks, eight subjects entered a continuation study; outcomes after 24 months of treatment are presented. After 24 months, all subjects had reduced or non-elevated Pox compared with baseline. Cardiac function improved, then stabilized. No treatment-related serious adverse events were reported.
Conclusions
Compared with an untreated natural control cohort, 24 months OC5 administration was beneficial to PH1 ESRD subjects by substantially decreasing Pox concentrations, and improving or stabilizing cardiac function and clinical status, without increasing dialysis frequency. OC5 was safe and well-tolerated.
Graphical Abstract
Background
In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly ...elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01).
Methods
Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m
2
were analyzed for a correlation between eGFR and Pox using Spearman’s rank and Pearson’s correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used.
Results
A total of 106 patients were analyzed. A statistically significant inverse Spearman’s correlation between eGFR and Pox was observed across all analyses; correlation coefficients were − 0.44 in study OC3-DB-01, − 0.55 in study OC3-DB-02, − 0.51 in study OC5-DB-01, and − 0.49 in the pooled studies (
p
< 0.0064).
Conclusions
Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1–3b), demonstrating that a correlation is present before substantial loss in kidney function occurs.
Graphical abstract
Background
Primary hyperoxaluria (PH) is a rare, genetic disorder which involves the overproduction of endogenous oxalate, leading to hyperoxaluria, recurrent urolithiasis and/or progressive ...nephrocalcinosis and eventually resulting in kidney failure and systemic oxalosis. The aim of this trial was to investigate whether treatment involving an oxalate-metabolising bacterium (
Oxalobacter formigenes
) could reduce urinary oxalate excretion in PH patients.
Methods
The efficacy and safety of
O. formigenes
(Oxabact® OC5; OxThera AB, Stockholm, Sweden) was evaluated in a randomised, placebo-controlled, double-blind study for 8 weeks. The primary objective was reduction in urinary oxalate excretion (Uox). Secondary objectives included faecal
O. formigenes
count and decrease in plasma oxalate concentration (Pox).
Results
Twenty-eight patients randomised 1:1 to the treatment group (OC5) or the placebo group completed the study. After 8 weeks of treatment, there was no significant difference in the change in Uox (mmol/24 h/1.73 m
2
) between the groups (OC5: +0.042, placebo: −0.140). Post-hoc analysis showed a statistically significant increase in Uox per urinary creatinine excretion in the OC5 group (OC5: +5.41, placebo: −15.96;
p
= 0.030). Change in Pox from baseline was not significantly different between groups (
p
= 0.438). The
O. formigenes
cell count was significantly increased in OC5-treated patients (
p
< 0.001) versus placebo. The treatment response to
O. formigenes
was related to individual stage of kidney deterioration, and Pox was directly correlated to kidney function, even for early-stage patients (chronic kidney disease stage 1). No safety issues were observed.
Conclusions
Treatment with OC5 did not significantly reduce Uox or Pox over 8 weeks of treatment. The treatment was well tolerated and successfully delivered to the gastrointestinal tract.
Background
Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments ...aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration.
Oxalobacter formigenes
is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized
O. formigenes
formulation
,
at reducing plasma oxalate levels in patients suffering from PH.
Methods
Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m
2
) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint.
Results
Forty-three subjects were screened, 25 were recruited and one was discontinued. At Week 52,
O. formigenes
was established in the gut of subjects receiving Oxabact. Despite decreasing plasma oxalate level in subjects treated with Oxabact, and stable/increased levels with placebo, there was no significant difference between groups in the primary outcome (Least Squares mean estimate of treatment difference was − 3.80 μmol/L; 95% CI: − 7.83, 0.23;
p
-value = 0.064). Kidney function remained stable in both treatments.
Conclusions
Oxabact treatment may have stabilized/reduced plasma oxalate versus a rise with placebo, but the difference over 12 months was not statistically significant (
p
= 0.06). A subtle effect observed with Oxabact suggests that
O. formigenes
may aid in preventing kidney stones.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
.
Hyperoxaluria is a well-recognised risk factor for urolithiasis and patients with primary hyperoxaluria (PH) gradually build up calcium oxalate deposits leading to chronic kidney disease. Efforts to ...improve treatment for PH have focused on reducing urine oxalate excretion and thus decreasing lithogenesis. To determine the efficacy of treatments designed to alter a biochemical parameter it is necessary to know the biological and analytical variation of that parameter. In this study, we estimated the intra-individual biological variation of urine oxalate excretion in patients with PH, and from this determined what would constitute a significant change in the form of a reference change value (RCV). Each patient collected four 24-h urines on consecutive weeks. The intra-individual biological variation of oxalate excretion calculated from these samples ranged from 0 to 36 % with a mean of 14 %. The corresponding RCVs were 4–84 % with a mean of 32 %. This result implies that, on average, a reduction of almost one-third in urine oxalate excretion is required to prove an effect from treatment. The wide range of biological variation between individuals may reflect other, as yet unknown, determinants of oxaluria in PH, as well as inaccuracies in urine collection. The data suggest that it is more appropriate to use individual RCVs established prior to treatment to determine its efficacy: a relatively small fall in urine oxalate excretion may be outside the biological variation of some patients but not of others.
Measurement of oxalate in the blood is essential for monitoring primary hyperoxaluria patients with progressive renal impairment and on dialysis prior to transplantation. As no external quality ...assurance scheme is available for this analyte, we conducted a sample exchange scheme between six laboratories specifically involved with the investigation of primary hyperoxaluria to compare results. The methodologies compared were gas chromatography/mass spectrometry (GCMS), ion chromatography with mass spectrometry (ICMS), and enzymatic methods using oxalate oxidase and spectrophotometry. Although individual laboratories performed well in terms of reproducibility and linearity, there was poor agreement (absolute values) between centres as illustrated by a longer-term comparison of patient results from two of the participating laboratories. This situation was only partly related to differences in calibration and mainly reflected the lower recoveries seen with the ultrafiltration of samples. These findings lead us to conclude that longitudinal monitoring of primary hyperoxaluria patients with deteriorating kidney function should be performed by a single consistent laboratory and the methodology used should always be defined. In addition, plasma oxalate concentrations reported in registry studies and those associated with the risk of systemic oxalosis in published studies need to be interpreted in light of the methodology used. A reference method and external quality assurance scheme for plasma oxalate analysis would be beneficial.
Abstract only
LBA391^
Background: Efficacy and safety of first-line FOLFOX4 plus either cetuximab (weekly or every two weeks) have been reported to be similar in 152 patients with KRAS exon 2 wt mCRC ...within the randomized phase II CECOG/CORE2 study. Recent analyses have shown that also mutations in KRAS exons 3/4 and NRAS (exons 2, 3, and 4) are associated with an inferior PFS and OS with EGFR-targeted monoclonal antibody containing therapy. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study were investigated. Methods: Tumor samples of 148 randomized KRAS exon 2 wild-type metastatic colorectal cancer patients were available for testing of additional mutations by conventional Sanger sequencing. Objective response rate (ORR), PFS and OS were compared in patients with KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) wild-type tumors RAS wt versus patients with mutations in KRAS (exons 3 and 4) or NRAS (exons 2, 3 and 4) RAS mt. Patients with BRAF mutations were excluded from this comparison. The Cochran-Mantel-Haenszel procedure was used to compare the ORR. Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze PFS and OS. Results: Of the 148 KRAS exon 2 wt patients 124 patients had RAS and BRAF wt tumors, 10 patients had RAS mutations only and 14 had only BRAF mutations. In the RAS wt and the RAS mt groups ORR was 61.3% (95% CI 52.1-69.9) and 40% (95%CI 12.2-73.8), (Odds ratio 0.43, p=0.1966). Median PFS was 9.7 months (95% CI 8.9-11.2) versus 7.2 months (95% CI 6.7-10.8) (hazard ratio HR=0.56, p=0.1135). Median OS was 28.5 months (95% CI 24.0-31.3) versus 16.3 months (95% CI 15.9-20.7), (HR=0.43, p=0.0199). The difference in OS remained statistically significant in the Cox model, if adjusted for significant confounding factors. ORR, PFS, and OS in BRAF mt and RAS mt patients were similar. Conclusions: RAS wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to RAS mt patients. This analysis supports the findings of other trials that RAS mutational analyses in metastatic CRC disease is recommended prior to initiation of an EGFR-targeted monoclonal antibody therapy. Clinical trial information: NCT00479752.
Micro-Abstract Metastatic colorectal cancer patients with KRAS exon 2 wild type tumors (codon 12 +13) were screened. Additional mutations at other KRAS and NRAS loci were identified. RAS mutations ...were detected in 7% and BRAF mutations in 9% of tumors. Patients with mutations at any of the RAS loci had worse response, progression-free survival, and overall survival. Mutation testing should be extended to the entire coding region of RAS genes.
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