Methane (CH4) is produced in many natural systems that are vulnerable to change under a warming climate, yet current CH4 budgets, as well as future shifts in CH4 emissions, have high uncertainties. ...Climate change has the potential to increase CH4 emissions from critical systems such as wetlands, marine and freshwater systems, permafrost, and methane hydrates, through shifts in temperature, hydrology, vegetation, landscape disturbance, and sea level rise. Increased CH4 emissions from these systems would in turn induce further climate change, resulting in a positive climate feedback. Here we synthesize biological, geochemical, and physically focused CH4 climate feedback literature, bringing together the key findings of these disciplines. We discuss environment‐specific feedback processes, including the microbial, physical, and geochemical interlinkages and the timescales on which they operate, and present the current state of knowledge of CH4 climate feedbacks in the immediate and distant future. The important linkages between microbial activity and climate warming are discussed with the aim to better constrain the sensitivity of the CH4 cycle to future climate predictions. We determine that wetlands will form the majority of the CH4 climate feedback up to 2100. Beyond this timescale, CH4 emissions from marine and freshwater systems and permafrost environments could become more important. Significant CH4 emissions to the atmosphere from the dissociation of methane hydrates are not expected in the near future. Our key findings highlight the importance of quantifying whether CH4 consumption can counterbalance CH4 production under future climate scenarios.
Plain Language Summary
Methane is a powerful greenhouse gas, second only to carbon dioxide in its importance to climate change. Methane production in natural environments is controlled by factors that are themselves influenced by climate. Increased methane production can warm the Earth, which can in turn cause methane to be produced at a faster rate ‐ this is called a positive climate feedback. Here we describe the most important natural environments for methane production that have the potential to produce a positive climate feedback. We discuss how these feedbacks may develop in the coming centuries under predicted climate warming using a cross‐disciplinary approach. We emphasize the importance of considering methane dynamics at all scales, especially its production and consumption and the role microorganisms play in both these processes, to our understanding of current and future global methane emissions. Marrying large‐scale geophysical studies with site‐scale biogeochemical and microbial studies will be key to this.
Key Points
The key drivers of methane production and consumption are assessed for wetlands, marine and freshwaters, permafrost regions, and methane hydrates
The balance of microbial controlled methane production and consumption are critical to methane climate feedbacks in all environments
Wetlands and freshwater systems are likely to drive the methane climate feedback from natural settings in the coming century
Summary
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.
Vaccines are the most effective means available for preventing infectious diseases. However, vaccine-induced immune responses are highly variable between individuals and between populations in ...different regions of the world. Understanding the basis of this variation is, thus, of fundamental importance to human health. Although the factors that are associated with intra- and inter-population variation in vaccine responses are manifold, emerging evidence points to a key role for the gut microbiome in controlling immune responses to vaccination. Much of this evidence comes from studies in mice, and causal evidence for the impact of the microbiome on human immunity is sparse. However, recent studies on vaccination in subjects treated with broad-spectrum antibiotics have provided causal evidence and mechanistic insights into how the microbiota controls immune responses in humans.
The definition and classification for chronic kidney disease was proposed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) in 2002 and endorsed by the Kidney ...Disease: Improving Global Outcomes (KDIGO) in 2004. This framework promoted increased attention to chronic kidney disease in clinical practice, research and public health, but has also generated debate. It was the position of KDIGO and KDOQI that the definition and classification should reflect patient prognosis and that an analysis of outcomes would answer key questions underlying the debate. KDIGO initiated a collaborative meta-analysis and sponsored a Controversies Conference in October 2009 to examine the relationship of estimated glomerular filtration rate (GFR) and albuminuria to mortality and kidney outcomes. On the basis of analyses in 45 cohorts that included 1,555,332 participants from general, high-risk, and kidney disease populations, conference attendees agreed to retain the current definition for chronic kidney disease of a GFR <60ml/min per 1.73m2 or a urinary albumin-to-creatinine ratio >30mg/g, and to modify the classification by adding albuminuria stage, subdivision of stage 3, and emphasizing clinical diagnosis. Prognosis could then be assigned based on the clinical diagnosis, stage, and other key factors relevant to specific outcomes. KDIGO has now convened a workgroup to develop a global clinical practice guideline for the definition, classification, and prognosis of chronic kidney disease.
Summary
Background
Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC).
Aim
To evaluate effectiveness, safety and use of tofacitinib in daily practice.
...Methods
UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid‐free clinical remission (short clinical colitis activity index SCCAI ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid‐free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation.
Results
In total, 123 UC patients (95% anti‐TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12‐26). The proportion of patients in corticosteroid‐free clinical, biochemical, and combined corticosteroid‐free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval CI 0.11‐0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib‐related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9‐26), 18% (95% CI 8‐28) and 21% (95% CI 14‐39) respectively.
Conclusion
Tofacitinib is an effective treatment for UC after anti‐TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.
Abstract
Background and Aims
Ustekinumab is approved for the treatment of Crohn’s disease CD. Systematically registered prospective real-world data are scarce. We therefore aimed to study the ...effectiveness, safety and usage of ustekinumab for CD in everyday practice.
Methods
We prospectively enrolled CD patients initiating ustekinumab in regular care between December 2016 and January 2019. Clinical (Harvey Bradshaw Index HBI), biochemical (C-reactive protein CRP and faecal calprotectin FCP), extra-intestinal manifestations and, peri-anal fistula activity, ustekinumab dosage, concomitant medication use, and adverse events were documented at weeks 0, 12, 24, and 52. The primary outcome was corticosteroid-free clinical remission.
Results
In total, 221 CD patients were included (98.6% anti-tumour necrosis factor TNF and 46.6% vedolizumab exposed) with a median follow-up of 52.0 weeks interquartile range 49.3–58.4. Corticosteroid-free clinical remission rates at weeks 24 and 52 were 38.2% and 37.1%, respectively. An initial dosing schedule of 8 weeks, compared to 12 weeks, correlated with a lower discontinuation rate 20.0% vs 42.6%, p = 0.01, but comparable corticosteroid-free clinical remission at week 52 (46.3% q8w vs 34.6% q12w, p = 0.20). There was no clinical benefit of combination therapy after 52 weeks when compared to ustekinumab monotherapy combi 40.6% vs mono 36.0%, p = 0.64. At baseline, 28 patients had active peri-anal fistula, of whom 35.7% showed complete clinical resolution after 24 weeks. During follow-up we encountered six severe infections 3.5 per 100 patient-years, with all patients being on concomitant immunosuppressant therapies. Ustekinumab treatment discontinuation was observed in 75 33.9% patients mainly due to lack of response.
Conclusion
Ustekinumab is a relatively safe and effective treatment option for CD patients with prior failure of anti-TNF and anti-integrin therapies.
We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney ...disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15ml/min per 1.73m2 lower eGFR below a threshold of 45ml/min per 1.73m2 was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.
Introduction
Biologics serve as a cornerstone in psoriasis treatment, with low disease activity or sometimes even clinical remission as a realistic treatment outcome. So far, it is unclear whether ...biologics should be tapered when this target is achieved. Dose tapering could offer potential benefits by decreasing side effects, the burden of repetitive injections and costs of biological therapy. However, clinical guidelines on dose tapering of biologicals in psoriasis patients are lacking. This scoping review was conducted to provide an overview of the current literature on dose tapering and offer guidance for clinicians in daily clinical practice.
Methods
Dose tapering is defined as the administration of a lower dose per administration, or the prolongation of the regular dose interval, after initial treatment according to the standard dosing. Four electronic databases (PubMed, EMBASE, Cochrane, and Web of Science) were systematically searched for literature on tapering of biologics in adult patients with psoriasis from 1 January 2000.
Results
We included 19 original articles on biologic tapering in psoriasis patients: four randomized controlled trials and 15 observational studies. Tapering eligibility criteria, tapering strategies, tapering outcomes, and recapture of response after relapse were assessed. Furthermore, the available evidence on possible predictors for successful tapering, and the effect of tapering on safety, quality of life and costs is summarized. The definition of low disease activity as a measure for tapering eligibility varied widely. Beside tapering criteria, tapering strategies were also heterogeneous. Of note, quality-of-life measurements were barely integrated in the evaluation of tapering outcomes. Literature on regaining response after relapse due to tapering was limited, but restored remission has been described. The included studies did not proclaim a significant effect of tapering on the occurrence of (severe) adverse events. Even though cost savings have been reported, no proper cost-effectiveness analysis has been conducted yet.
Conclusion
Biologic tapering seems to be effective and safe in psoriasis patients with stable low disease activity or clinical remission. Available data on biologic dose tapering in patients with psoriasis are promising, but more research is warranted to fill the current gaps in knowledge.
Plain Language Summary
Biologics are effective in treating psoriasis amongst other diseases, such as rheumatoid arthritis and Crohn’s disease. However, biologics are costly, and can cause side effects, such as an increased risk of infection. In patients with rheumatoid arthritis, it is not uncommon to lower the dose of these biologics (also called “dose tapering”), once stable low disease activity, or even remission, is reached. However, in psoriasis patients, dose tapering of biologics is not common practice. In this “scoping review,” we provide an overview of the available literature on dose tapering of biologics in adult patients with plaque psoriasis in order to address the current gaps in literature. We found 19 studies that addressed dose tapering. These studies used different criteria to determine which patients were eligible for tapering, which led to various interpretations of tapering success. This made it difficult for us to draw general conclusions on which tapering criteria and strategies should be further investigated. Dose tapering seems to be effective and safe in patients with a stable low disease activity, although more (high-quality) research is needed. Future studies should focus on generating more data on long-term safety, finding predictors for successful tapering, calculating the cost-effectiveness of dose tapering, and evaluating dose tapering in the newest generation of biologics.
Introduction and Aims
Cognitive impairments in substance use disorder predict treatment outcome and are assumed to differ between substances. They often go undetected, thus the current study focuses ...on the prevalence of and differences in cognitive functioning across substances by means of a cognitive screen at the early stage of addiction treatment.
Design and Methods
The Montreal Cognitive Assessment was administered to outpatients seeking treatment for substance use disorder. Patient characteristics (age, years of regular use, polysubstance use, severity of dependence/abuse, depression, anxiety and stress) were also taken into account.
Results
A total of 656 patients were included (n = 391 used alcohol, n = 123 used cannabis, n = 100 used stimulants and n = 26 used opioids). The prevalence of cognitive impairments was 31%. Patients using alcohol had a lower total‐ and memory domain score than those using cannabis. Patients using opioids scored lower on visuospatial abilities than those using cannabis or stimulants. Younger patients scored higher than older patients. No effect was found for the other investigated characteristics.
Discussion and Conclusions
Given the high prevalence of cognitive impairments, standard screening at an early stage of treatment is important to determine the course of treatment and maximise treatment outcome. Caution is needed in interpreting results about opioids due to an underrepresentation of this patient group, and more research is needed on the effect of age on Montreal Cognitive Assessment performance.
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