BackgroundIt remains unclear if the increased colorectal neoplasia detection rate in inflammatory bowel disease (IBD) by high-definition (HD) dye-based chromoendoscopy compared with HD white-light endoscopy is due to enhanced contrast or increased inspection times. Longer withdrawal times may yield similar neoplasia detection rates as found by HD chromoendoscopy.ObjectiveTo compare colorectal neoplasia detection rates for HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy, using single-pass HD white-light endoscopy as an additional control group.DesignIn a multicentre, randomised controlled trial, IBD patients aged ≥18 years without active disease and scheduled for endoscopic surveillance were included. Patients were 2:2:1 randomised to HD white-light endoscopy with segmental re-inspection of each colonic segment (double pass), HD chromoendoscopy or single-pass HD white-light endoscopy. The primary outcome was colorectal neoplasia detection rate. Assuming equal colorectal neoplasia rates (non-inferiority margin of 10%) between segmental re-inspection and chromoendoscopy and superiority of segmental re-inspection vs single-pass HD white-light endoscopy, a sample size of 566 patients was required.ResultsIn total, 563 patients were analysed per-protocol. Colorectal neoplasia detection rates were 10.3% (n=24/234) for HD white-light endoscopy with segmental re-inspection and 13.1% (n=28/214) for HD chromoendoscopy. This confirmed non-inferiority to HD chromoendoscopy (Δ−2.8%, lower limit 95% CI −7.8, p<0.01). In addition, the number of detected colorectal neoplasia per 10 min of withdrawal time was similar between HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy (0.062 vs 0.058, p=0.83). Single-pass HD white-light endoscopy yielded a lower colorectal neoplasia rate (6.1%; n=7/115) than segmental re-inspection but this was not statistically significant (Δ4.1%, 95% CI −2.2:9.6%, p=0.19).ConclusionsHD white-light endoscopy with segmental re-inspection was non-inferior to HD chromoendoscopy for colorectal neoplasia detection in IBD patients. It can therefore be assumed that the benefit of HD chromoendoscopy may be explained by the longer withdrawal time and not necessarily the enhanced contrast. However, re-inspection per se did not lead to a significantly higher colorectal neoplasia rate than single-pass HD white-light endoscopy alone.

Rapid Arctic warming is accelerating permafrost thaw and mobilizing previously frozen organic carbon (OC) into waterways. Upon thaw, permafrost-derived OC can become susceptible to microbial degradation that may lead to greenhouse gas emissions (GHG), thus accelerating climate change. Abrupt permafrost thaw (e.g., riverbank erosion, retrogressive thaw slumps) occurs in areas rich in OC. Given the high OC content and the increase in frequency of abrupt thaw events, these environments may increasingly contribute to permafrost GHG emissions in the future. To better assess these emissions from abrupt permafrost thaw, we incubated thaw stream waters from an abrupt permafrost thaw site (Duvanny Yar, Siberia) and additionally, waters from their outflow to the Kolyma River. Our results show that CO2 release by volume from thaw streams was substantially higher than CO2 emissions from the river outflow waters, while the opposite was true for CO2 release normalized to the suspended sediment weight (gram dry weight). The CH4 emissions from both thaw streams and outflow waters were at a similar range, but an order of magnitude lower than those of CO2. Additionally, we show that nearshore riverbank waters differ in their biogeochemistry from thaw streams and Kolyma River mainstem: particles resemble thaw streams while dissolved fraction is more alike to the Kolyma River thalweg. In these waters dissolved OC losses are faster than in the river thalweg. Our incubations offer a first insight into the GHG release from permafrost thaw streams that connect exposed and degrading permafrost outcrops to larger river systems.

Erosion of permafrost coasts due to climate warming releases large quantities of organic carbon (OC) into the Arctic Ocean. While burial of permafrost OC in marine sediments potentially limits degradation, resuspension of sediments in the nearshore zone potentially enhances degradation and greenhouse gas production, adding to the "permafrost carbon feedback." Recent studies, focusing on bulk sediments, suggest that permafrost OC derived from coastal erosion is predominantly deposited close to shore. However, bulk approaches disregard sorting processes in the coastal zone, which strongly influence the OC distribution and fate. We studied soils and sediments along a transect from the fast-eroding shoreline of Herschel Island-Qikiqtaruk (Yukon, Canada) to a depositional basin offshore. Sample material was fractionated by density (1.8 g cm-3) and size (63 mu m), separating loose OC from mineral-associated OC. Each fraction was analyzed for element content (TOC, TN), carbon isotopes (delta 13C, Delta 14C), molecular biomarkers (n-alkanes, n-alkanoic acids, lignin phenols, cutin acids), and mineral surface area. The OC partitioning between fractions changes considerably along the transect, highlighting the importance of hydrodynamic sorting in the nearshore zone. Additionally, OC and biomarker loadings decrease along the land-ocean transect, indicating significant loss of OC during transport. However, molecular proxies for degradation show contrasting trends, suggesting that OC losses are not always well reflected in its degradation state. This study, using fraction partitioning that crosses land-ocean boundaries in a way not done before, aids to disentangle sorting processes from degradation patterns, and provides quantitative insight into losses of thawed and eroded permafrost OC. The Arctic coastline is vulnerable for erosion, since it mostly consist of permafrost (permanently frozen ground), which undergoes rapid warming due to climate change. Thaw and erosion of permafrost along the coast releases organic carbon (OC), that has been stored for millennia, into the ocean. There, in the ocean, this carbon can be degraded back into CO2, potentially enforcing climate warming, or it can settle to the sediments, and potentially be stored again for millennia. The permafrost and the sediment consist of particles, for example, sand, silt, and clay, and loose fragments of vegetation. In this study, we separated the OC that is associated with fine particles (silt and clay) from the loose fragments of organic matter. We observe that these two fractions of sediment have a very different composition and source, and end up somewhere else in the marine system. This study further shows that a large part of the OC associated with minerals (silt and clay) is lost during transport, but also that indicators for degradation show contrasting results. Overall, we highlight the importance of looking at sediment fractions separately, and also emphasize studying the transitional zone between land to ocean for the permafrost carbon cycle. Size and density fractionation of sediment organic carbon (OC) reveals substantial contrasts between different fractions and environmentsOC- and biomarker loading shows that a significant amount of terrestrial OC is lost along a land-ocean transectCombining methods in dynamic environments such as the nearshore zone is key in studying the fate of permafrost OC

Background and Aims: A novel multisegmented esophageal fully covered self-expandable metal stent (FCSEMS) was designed to reduce stent migration, which is seen in up to 30% of patients. The goal of this study was to evaluate the safety and efficacy fi cacy of the multisegmented FCSEMS. Methods: This multicenter prospective study aimed to include 30 patients undergoing palliative stent placement. Efficacy, fi cacy, defined fi ned as technically successful stent placement and dysphagia scores, and safety, defined fi ned as the number of adverse events (AEs) and serious AEs (SAEs), were measured. Results: The study was prematurely terminated due to safety concerns after including 23 patients (mean +/- standard deviation age, 72 +/- 10 years; 78% male). Stent placement was technically successful in 21 patients (91%), and dysphagia scores had improved in all patients with successful stent placement. SAEs were reported in 16 (70%) patients. Stent-related mortality occurred in 3 patients (13%). Conclusions: The multisegmented FCSEMS successfully treated malignant dysphagia. The study was prematurely terminated, however, because stent placement was associated with a relatively high SAE rate. (Clinical trial registration number: NCT04415463.) (Gastrointest Endosc 2024;99:1027-31.)

In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn’s disease (CD) in clinical and biochemical remission. To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. We included 109 patients, of which 60.6

Abstract Background Patients with colonic inflammatory bowel disease (IBD) undergo endoscopic surveillance to detect and remove colorectal neoplasia (CRN). Although high-definition dye-based chromo-endoscopy (HD-CE) is the recommended modality in guidelines, high-definition white light endoscopy (HD-WLE) with matched procedural time may yield similar neoplasia detection rates. We designed a non-blinded, randomized controlled trial in four academic hospitals aiming to compare three endoscopic surveillance techniques in IBD patients for the outcome of CRN detection rate. Methods Eligible patients were aged ≥18 years and scheduled for colitis-associated CRN surveillance according to Dutch IBD surveillance guidelines. Patients were excluded in case of insufficient bowel cleansing, active colitis, or if >50% of the colon was resected. Patients were randomly assigned (2:2:1) to undergo HD-WLE with segmental re-inspection (SR), HD-CE, or single pass HD-WLE. The primary outcome was CRN detection rate, defined as the proportion of procedures in which macroscopic CRN was detected. Secondary outcomes included the number of CRN and withdrawal time. To demonstrate non-inferiority of HD-WLE with SR compared to HD-CE (one-sided testing, α=0.05, 1−β=0.8, non-inferiority (NI) margin -10%), and superiority compared to single-pass HD-WLE (two-sided testing, estimated CRN detection rate of 24% and 12%, respectively1) with Mantel-Haenszel analyses, a total of 566 patients were needed. Results In total, 666 patients were randomized, 563 fulfilled all study criteria and were analysed per protocol (table 1). Of these, 51.8% were male, with a median age of 51 years (interquartile range 35-63). CRN detection rates were 9.8% for HD-WLE with SR, 13.1% for HD-CE, and 6.1% for single pass HD-WLE. HD-WLE with SR was non-inferior compared to HD-CE (Δ-3.1%, lower boundary of the 95% confidence interval (CI) -8.1 not exceeding the NI margin of -10%, p<.05). HD-WLE with SR was not superior compared to single-pass HD-WLE (Δ3.7%, 95% CI -2.5:9.1%, p=0.31). A significant difference was found between arms for the number of detected CRN (n=29 vs n=36 vs n=8 for HD-WLE with SR, HD-CE and single-pass HD-WLE, respectively (p=.04)) and withdrawal time (p=.03, table 1). One advanced lesion was detected (high-grade dysplasia in the HD-CE arm). Conclusion In this large, randomized controlled trial, HD-WLE with SR was non-inferior compared to HD-CE for CRN detection in IBD patients. HD-WLE with SR was not superior to single-pass HD-WLE, although this may have resulted from lower than expected neoplasia yields and subsequent lower power. These results suggest that HD-WLE with SR may provide a feasible alternative to HD-CE in clinical practice (NCT04291976). 1Imperatore et al. JCC 2019;13(6):714-24

Arctic warming is causing permafrost thaw and release of organic carbon (OC) to fluvial systems. Permafrost-derived OC can be transported downstream and degraded into greenhouse gases that may enhance climate warming. Susceptibility of OC to decomposition depends largely upon its source and composition, which vary throughout the seasonally distinct hydrograph. Most studies on carbon dynamics to date have focused on larger Arctic rivers, yet little is known about carbon cycling in lower-order rivers and streams. Here, we characterize the composition and sources of OC, focusing on less studied particulate OC (POC), in smaller waterways within the Kolyma River watershed. Additionally, we examine how watershed characteristics control carbon concentrations. In lower-order systems, we find rapid initiation of primary production in response to warm water temperatures during spring freshet, shown by decreasing δ13C-POC, in contrast to larger rivers. This results in CO2 uptake by primary producers and microbial degradation of mainly autochthonous OC. However, if terrestrially derived inorganic carbon is assimilated by primary producers, part of it is returned via CO2 emissions if the autochthonous OC pool is simultaneously degraded. As Arctic warming and hydrologic changes may increase OC transfer from smaller waterways to larger river networks, understanding carbon dynamics in smaller waterways is crucial.

BACKGROUND:Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. METHODS:The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score <5, faecal calprotectin <150 μg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 μg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting. FINDINGS:Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively. INTERPRETATION:The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. FUNDING:Netherlands Organisation for Health Research and Development.

Arctic rivers will be increasingly affected by the hydrological and biogeochemical consequences of thawing permafrost. During transport, permafrost-derived organic carbon (OC) can either accumulate in floodplain and shelf sediments or be degraded into greenhouse gases prior to final burial. Thus, the net impact of permafrost OC on climate will ultimately depend on the interplay of complex processes that occur along the source-to-sink system. Here, we focus on the Kolyma River, the largest watershed completely underlain by continuous permafrost, and marine sediments of the East Siberian Sea, as a transect to investigate the fate of permafrost OC along the land–ocean continuum. Three pools of riverine OC were investigated for the Kolyma main stem and five of its tributaries: dissolved OC (DOC), suspended particulate OC (POC), and riverbed sediment OC (SOC). They were compared with earlier findings in marine sediments. Carbon isotopes (δ13C, Δ14C), lignin phenol, and lipid biomarker proxies show a contrasting composition and degradation state of these different carbon pools. Dual C isotope source apportionment calculations imply that old permafrost-OC is mostly associated with sediments (SOC; contribution of 68±10 %), and less dominant in POC (38±8 %), whereas autochthonous primary production contributes around 44±10 % to POC in the main stem and up to 79±11 % in tributaries. Biomarker degradation indices suggest that Kolyma DOC might be relatively degraded, regardless of its generally young age shown by previous studies. In contrast, SOC shows the lowest Δ14C value (oldest OC), yet relatively fresh compositional signatures. Furthermore, decreasing mineral surface area-normalised OC- and biomarker loadings suggest that SOC might be reactive along the land–ocean continuum and almost all parameters were subjected to rapid change when moving from freshwater to the marine environment. This suggests that sedimentary dynamics play a crucial role when targeting permafrost-derived OC in aquatic systems and support earlier studies highlighting the fact that the land–ocean transition zone is an efficient reactor and a dynamic environment. The prevailing inconsistencies between freshwater and marine research (i.e. targeting predominantly DOC and SOC respectively) need to be better aligned in order to determine to what degree thawed permafrost OC may be destined for long-term burial, thereby attenuating further global warming.

Abstract. Arctic warming is causing permafrost thaw and release of organic carbon (OC) to fluvial systems. Permafrost-derived OC can be transported downstream and degraded into greenhouse gases that may enhance climate warming. Susceptibility of OC to decomposition depends largely upon its source and composition which varies throughout the seasonally distinct hydrograph. Most studies to date have focused on larger Arctic rivers, yet little is known about carbon dynamics in lower order rivers/streams. Here, we characterize composition and sources of OC, focusing on less studied particulate OC (POC), in smaller waterways within the Kolyma River watershed. Additionally, we examine how watershed characteristics control carbon concentrations. In lower order systems, we find rapid initiation of primary production in response to warm weather, shown by decreasing δ13C-POC, in contrast to larger rivers. As Arctic warming and hydrologic changes may increase OC transfer from smaller waterways through river networks this may intensify inland water carbon outgassing.

Outpatient visits and laboratory assessments are routinely scheduled every 3 to 4 months in thiopurine-treated patients with inflammatory bowel disease (IBD) to timely detect thiopurine-related adverse events (AEs). AEs that require therapy adjustment beyond 12 months of treatment are rare. This single-center prospective cohort study evaluated the safety of a reduced 6-monthly monitoring strategy in steroid-free patients with quiescent IBD on stable dose of azathioprine, mercaptopurine, or thioguanine monotherapy. The primary outcome was thiopurine-related AEs requiring therapy adjustments during a follow-up period of 24 months. Secondary outcomes included all AEs including laboratory toxicity, disease flares until 12 months, and the net monetary benefit from this strategy concerning IBD-related health care use. We enrolled 85 patients with IBD (median age 42 years, 61

BACKGROUND AND AIMS:We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN:We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS:We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION:When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER:ClinicalTrials.gov, number NCT03172377.

Major Arctic rivers are undergoing changes due to climate warming with higher discharge and increased amounts of solutes and organic carbon (OC) draining into rivers and coastal seas. Permafrost thaw mobilizes previously frozen OC to the fluvial network where it can be degraded into greenhouse gases and emitted to the atmosphere. Degradation of OC during downstream transport, especially of the particulate OC (POC), is however poorly characterized. Here, we quantified POC degradation in the Kolyma River, the largest river system underlain with continuous permafrost, during 9–15 d whole-water incubations (containing POC and dissolved OC—DOC) during two seasons: spring freshet (early June) and late summer (end of July). Furthermore, we examined interactions between dissolved and particulate phases using parallel incubations of filtered water (only DOC). We measured OC concentrations and carbon isotopes (δ13C, Δ14C) to define carbon losses and to characterize OC composition, respectively. We found that both POC composition and biodegradability differs greatly between seasons. During summer, POC was predominantly autochthonous (47%–95%) and degraded rapidly (∼33% loss) whereas freshet POC was largely of allochthonous origin (77%–96%) and less degradable. Gains in POC concentrations (up to 31%) were observed in freshet waters that could be attributed to flocculation and adsorption of DOC to particles. The demonstrated DOC flocculation and adsorption to POC indicates that the fate and dynamics of the substantially-sized DOC pool may shift from degradation to settling, depending on season and POC concentrations—the latter potentially acting to attenuate greenhouse gas emissions from fluvial systems. We finally note that DOC incubations without POC present may yield degradation estimates that do not reflect degradation in the in situ river conditions, and that interaction between dissolved and particulate phases may be important to consider when determining fluvial carbon dynamics and feedbacks under a changing climate.

Arctic rivers will be increasingly affected by the hydrological and biogeochemical consequences of thawing permafrost. During transport, permafrost-derived organic carbon (OC) can either accumulate in floodplain and shelf sediments or be degraded into greenhouse gases prior to final burial. Thus, the net impact of permafrost OC on climate will ultimately depend on the interplay of complex processes that occur along the source-to-sink system. Here, we focused on the Kolyma River, the largest watershed completely underlain by continuous permafrost, and marine sediments of the East Siberian Sea as a transect to investigate the fate of permafrost OC along the land-ocean continuum. Three pools of riverine OC were investigated for the Kolyma main stem and five of its tributaries: dissolved OC (DOC), suspended particulate OC (POC), and riverbed sediment OC (SOC) and compared to earlier findings in marine sediments. Carbon isotopes (δ13C, Δ14C), lignin phenol, and lipid biomarkers show a contrasting composition and degradation state of these different carbon pools. Dual isotope source apportionment calculations imply that old permafrost-OC is mostly associated with sediments (SOC; contribution of 68 ± 10 %), and less dominant in POC (38 ± 8 %), while autochthonous primary production contributes around 44 ± 10 % to POC in the main stem and up to 79 ± 11 % in tributaries. Biomarker degradation indices suggest that Kolyma DOC is relatively degraded, regardless of its generally young age shown by previous studies. In contrast, SOC shows the lowest Δ14C signal (oldest OC), yet relatively fresh compositional signatures. Furthermore, decreasing mineral surface area-normalised OC- and biomarker loadings suggest that SOC is reactive along the land-ocean continuum supporting the idea that floodplain and shelf sediments are efficient reactors. A better understanding of DOC and POC dynamics in Arctic rivers is still necessary, however, this study highlights that sedimentary dynamics play a crucial role when targeting permafrost-derived OC in aquatic systems. Chemical and physical processes (e.g. degradation, sorption) along fluvial-marine transects will determine to what degree thawed permafrost OC may be destined for long-term burial, therewith attenuating further global warming.

BACKGROUND:To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low.AIM:To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment.METHODS:Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed.RESULTS:In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring.CONCLUSION:Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval.

BACKGROUND:Both vedolizumab and ustekinumab can be considered for the treatment of Crohn's disease (CD) when anti-TNF treatment fails. However, head-to-head trials are currently not available or planned.AIM:To compare vedolizumab and ustekinumab in Crohn´s disease patients in a prospective registry specifically developed for comparative studies with correction for confounders.METHODS:Crohn´s disease patients, who failed anti-TNF treatment and started vedolizumab or ustekinumab in standard care as second-line biological, were identified in the observational prospective Dutch Initiative on Crohn and Colitis Registry. Corticosteroid-free clinical remission (Harvey Bradshaw Index ≤4), biochemical remission (C-reactive protein ≤5 mg/L and fecal calprotectin ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, and safety outcomes were compared after 52 weeks of treatment. To adjust for confounding and selection bias, we used multiple logistic regression and propensity score matching.RESULTS:In total, 128 vedolizumab- and 85 ustekinumab-treated patients fulfilled the inclusion criteria. After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (odds ratio [OR]: 2.58, 95% CI: 1.36-4.90, P = 0.004), biochemical remission (OR: 2.34, 95% CI: 1.10-4.96, P = 0.027), and combined corticosteroid-free clinical and biochemical remission (OR: 2.74, 95% CI: 1.23-6.09, P = 0.014), while safety outcomes (infections: OR: 1.26, 95% CI: 0.63-2.54, P = 0.517; adverse events: OR: 1.33, 95% CI: 0.62-2.81, P = 0.464; hospitalisations: OR: 0.67, 95% CI: 0.32-1.39, P = 0.282) were comparable between the two groups. The propensity score matched cohort with sensitivity analyses showed comparable results.CONCLUSIONS:Ustekinumab was associated with superior effectiveness outcomes when compared to vedolizumab, while safety outcomes were comparable after 52 weeks of treatment in CD patients who have failed anti-TNF treatment.

Arctic rivers will be increasingly affected by the hydrological and biogeochemical effects of thawing permafrost. During transport, permafrost thaw-derived organic carbon (OC) can be degraded into greenhouse gases and potentially add to further climate warming, or transported to the shelf seas and buried in marine sediments, attenuating this ‘permafrost carbon feedback’. To assess the transport pathways and fate of permafrost-OC, we focus on the river-shelf continuum of the Kolyma River, the largest river on Earth completely underlain by continuous permafrost. Three pools of riverine OC were investigated: dissolved OC (DOC), suspended particulate OC (POC), and river sediment OC (SOC). Preliminary results of bulk carbon isotopes (δ13C, Δ14C) and molecular biomarkers (lignin phenols, leaf wax lipids) show contrasts in composition and degradation state for these carbon pools. Old permafrost-OC seems to be mostly associated with SOC, and less dominant in POC. However, while SOC shows the oldest Δ14C signal, lignin phenol results (e.g., acid to aldehyde ratios) suggest this material is the least degraded. In contrast, DOC shows more degraded signal, even at the outflow of an active permafrost thaw site. Our study serves as a terrestrial extension to earlier investigated marine sediments from the Kolyma paleoriver transect in the East Siberian Sea. It also highlights the value of connecting terrestrial and marine observations to gain insight into the complete pathway of permafrost-OC, from the moment of thaw, via aquatic transport and degradation, towards storage in marine sediments.

Soil temperatures in permafrost (i.e. perennially frozen ground) are rising globally. The increasing temperatures accelerate permafrost thaw and release of organic carbon, that has been locked in permafrost soils since the last glacial period, to the contemporary carbon cycle. The potential remineralisation of organic carbon to greenhouse gases can contribute to further climate warming. Particulate organic carbon (POC) in the Kolyma River is older than dissolved organic carbon (DOC) thus serves as a good tracer for abrupt permafrost thaw (i.e. river bank erosion and thermokarst) that dominantly releases old POC. While dissolved organic carbon (DOC) mobilised from the old Yedoma outcrops on the banks of the Kolyma River is shown to be highly labile, vulnerability of POC to biodegradation is not yet known. In this study we aim to constrain degradation rates for POC in the Kolyma River. To capture seasonal variability of the POC pool and its degradation rate the incubation was conducted both during the spring freshet and in late summer (2019 and 2018, respectively). We incubated whole-water samples over 9 to 15 days and quantified POC (and DOC) loss over time, as well as dissolved inorganic carbon (DIC). The incubation was carried out in the dark. We also tracked changes in POC composition and age with carbon isotopes (d13C-OC, d13C-DIC, ∆14C). Preliminary results from 2018 suggest a decrease in POC concentrations of up to 30 % while those of DOC decrease by up to 11 %. The rate of POC degradation is nearly three times faster than DOC though the absolute amounts of DOC are in turn higher than those of POC (< 1 mg L-1 for POC and ~3 mg L-1 for DOC). Furthermore, the changes in d13C of POC, DOC and DIC suggest ongoing microbial degradation and conversion of organic carbon into inorganic carbon. These first estimates show that POC degrades fairly rapidly while transported in the Kolyma River. A better understanding of POC degradation along lateral flow paths is critical for improving our knowledge of permafrost thaw and its possible climate impacts in the future.

Collapse of permafrost coasts delivers large quantities of particulate organic carbon (POC) to Arctic coastal areas. With rapidly changing environmental conditions, sediment and organic carbon (OC) mobilization and transport pathways are also changing. Here, we assess the sources and sinks of POC in the highly dynamic nearshore zone of Herschel Island‐Qikiqtaruk (Yukon, Canada). Our results show that POC concentrations sharply decrease, from 15.9 to 0.3 mg L−1, within the first 100–300 m offshore. Simultaneously, radiocarbon ages of POC drop from 16,400 to 3,600 14C years, indicating rapid settling of old permafrost POC to underlying sediments. This suggests that permafrost OC is, apart from a very narrow resuspension zone (<5 m water depth), predominantly deposited in nearshore sediments. While long‐term storage of permafrost OC in marine sediments potentially limits biodegradation and its subsequent release as greenhouse gas, resuspension of fine‐grained, OC‐rich sediments in the nearshore zone potentially enhances OC turnover.