Model-based data analysis of individual human postprandial plasma bile acid responses indicates a major role for the gallbladder and intestine

BACKGROUND: Bile acids are multifaceted metabolic compounds that signal to cholesterol, glucose, and lipid homeostasis via receptors like the Farnesoid X Receptor (FXR) and transmembrane Takeda G protein-coupled receptor 5 (TGR5). The postprandial increase in plasma bile acid concentrations is therefore a potential metabolic signal. However, this postprandial response has a high interindividual variability. Such variability may affect bile acid receptor activation. METHODS: In this study, we analyzed the inter- and intraindividual variability of fasting and postprandial bile acid concentrations during three identical meals on separate days in eight healthy lean male subjects using a statistical and mathematical approach. MAIN FINDINGS: The postprandial bile acid responses exhibited large interindividual and intraindividual variability. The individual mathematical models, which represent the enterohepatic circulation of bile acids in each subject, suggest that interindividual variability results from quantitative and qualitative differences of distal active uptake, colon transit, and microbial bile acid transformation. Conversely, intraindividual variations in gallbladder kinetics can explain intraindividual differences in the postprandial responses. CONCLUSIONS: We conclude that there is considerable inter- and intraindividual variation in postprandial plasma bile acid levels. The presented personalized approach is a promising tool to identify unique characteristics of underlying physiological processes and can be applied to investigate bile acid metabolism in pathophysiological conditions

Novel minimally invasive treatments for lower urinary tract symptoms: a systematic review and network meta-analysis

ABSTRACT Purpose: To review and compare the effectivity of novel minimally invasive treatments (MITs) to transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms (LUTS) in men. Methods: Medline, Embase, and Cochrane databases were searched from January 2010 to December 2022 for randomized controlled trials (RCTs) evaluating MITs, compared to TURP or sham, in men with LUTS. Studies were assessed by risk of bias tool, and evidence by GRADE. Functional outcomes by means of uroflowmetry and IPSS were the primary outcomes, safety and sexual function were secondary outcomes. As part of this review, a network meta-analysis (NMA) was conducted. MITs were ranked based on functional outcome improvement probability. Results: In total, 10 RCTs were included, evaluating aquablation, prostatic urethral lift, prostatic artery embolization (PAE), convective water vapor thermal treatment or temporary implantable nitinol device. All MITs showed a better safety profile compared to TURP. Functional outcome improvement following aquablation were comparable to TURP. In the NMA, aquablation was ranked highest, PAE followed with the second highest probability to improve functional outcomes. Other novel MITs resulted in worse functional outcomes compared to TURP. Level of evidence was low to very low. Conclusions: Five MITs for treatment of LUTS were identified. Aquablation is likely to result in functional outcomes most comparable to TURP. Second in ranking was PAE, a technique that does not require general or spinal anesthesia. MITs have a better safety profile compared to TURP. However, due to high study heterogeneity, results should be interpreted with caution

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis

Objective To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). Methods An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A–D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0–10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. Results Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4–9.6). Conclusions These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

Adalimumab drug and antidrug antibody levels do not predict flare risk after stopping adalimumab in RA patients with low disease activity

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Development of a model forecasting Dermanyssus gallinae's population dynamics for advancing Integrated Pest Management in laying hen facilities

The poultry red mite, Dermanyssus gallinae, is the most significant pest of egg laying hens in many parts of the world. Control of D. gallinae could be greatly improved with advanced Integrated Pest Management (IPM) for D. gallinae in laying hen facilities. The development of a model forecasting the pests’ population dynamics in laying hen facilities without and post-treatment will contribute to this advanced IPM and could consequently improve implementation of IPM by farmers. The current work describes the development and demonstration of a model which can follow and forecast the population dynamics of D. gallinae in laying hen facilities given the variation of the population growth of D. gallinae within and between flocks. This high variation could partly be explained by house temperature, flock age, treatment, and hen house. The total population growth variation within and between flocks, however, was in part explained by temporal variation. For a substantial part this variation was unexplained. A dynamic adaptive model (DAP) was consequently developed, as models of this type are able to handle such temporal variations. The developed DAP model can forecast the population dynamics of D. gallinae, requiring only current flock population monitoring data, temperature data and information of the dates of any D. gallinae treatment. Importantly, the DAP model forecasted treatment effects, while compensating for location and time specific interactions, handling the variability of these parameters. The characteristics of this DAP model, and its compatibility with different mite monitoring methods, represent progression from existing approaches for forecasting D. gallinae that could contribute to advancing improved Integrated Pest Management (IPM) for D. gallinae in laying hen facilities