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.
We present a tomographic cosmic shear analysis of the Kilo-Degree Survey (KiDS) combined with the VISTA Kilo-Degree Infrared Galaxy Survey. This is the first time that a full optical to near-infrared ...data set has been used for a wide-field cosmological weak lensing experiment. This unprecedented data, spanning 450 deg 2 , allows us to significantly improve the estimation of photometric redshifts, such that we are able to include robustly higher-redshift sources for the lensing measurement, and – most importantly – to solidify our knowledge of the redshift distributions of the sources. Based on a flat ΛCDM model we find S 8 ≡ σ 8 Ω m /0.3 = 0.737 +0.040 −0.036 in a blind analysis from cosmic shear alone. The tension between KiDS cosmic shear and the Planck-Legacy CMB measurements remains in this systematically more robust analysis, with S 8 differing by 2.3 σ . This result is insensitive to changes in the priors on nuisance parameters for intrinsic alignment, baryon feedback, and neutrino mass. KiDS shear measurements are calibrated with a new, more realistic set of image simulations and no significant B-modes are detected in the survey, indicating that systematic errors are under control. When calibrating our redshift distributions by assuming the 30-band COSMOS-2015 photometric redshifts are correct (following the Dark Energy Survey and the Hyper Suprime-Cam Survey), we find the tension with Planck is alleviated. The robust determination of source redshift distributions remains one of the most challenging aspects for future cosmic shear surveys.
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.
Patient Reported Outcome Measures (PROMs) are increasingly used in routine clinical practice to facilitate patients in sharing and discussing health-related topics with their clinician. This study ...focuses on the implementation experiences of healthcare professionals and patients during the early implementation phase of the newly developed Dutch set of dialysis PROMs and aims to understand the process of early implementation of PROMs from the users' perspectives.
This is a qualitative study among healthcare professionals (physicians and nursing staff: n = 13) and patients (n = 14) of which 12 were receiving haemodialysis and 2 peritoneal dialysis. Semi-structured interviews were used to understand the barriers and facilitators that both professionals and patients encounter when starting to implement PROMs.
The early PROM implementation process is influenced by a variety of factors that we divided into barriers and facilitators. We identified four barriers: patient´s indifference to PROMs, scepticism on the benefits of aggregated PROM data, the limited treatment options open to doctors and organizational issues such as mergers, organizational problems and renovations. We also describe four facilitators: professional involvement and patient support, a growing understanding of the use of PROMs during the implementation, quick gains from using PROMs such as receiving instant feedback and a clear ambition on patient care such as a shared view on patient involvement and management support.
In this qualitative study carried out during the early implementation phase of the Dutch dialysis PROM set, we found that patients did not yet consider the PROM set to be a useful additional tool to share information with their doctor. This was despite the professionals' primary reason for using PROMs being to improve patient-doctor communication. Furthermore, the perceived lack of intervention options was frustrating for some of the professionals. We found that nurses could be important enablers of further implementation because of their intensive relationship with dialysis patients.
We present cosmological parameter constraints from a tomographic weak gravitational lensing analysis of ~450 deg super( 2) of imaging data from the Kilo Degree Survey (KiDS). For a flat ... cold dark ...matter (...CDM) cosmology with a prior on H sub( 0) that encompasses the most recent direct measurements, we find S sub( 8) ... = 0.745 plus or minus 0.039. This result is in good agreement with other low-redshift probes of large-scale structure, including recent cosmic shear results, along with pre-Planck cosmic microwave background constraints. A 2.3... tension in S sub( 8) and 'substantial discordance' in the full parameter space is found with respect to the Planck 2015 results. We use shear measurements for nearly 15 million galaxies, determined with a new improved 'self-calibrating' version of lensfit validated using an extensive suite of image simulations. Four-band ugri photometric redshifts are calibrated directly with deep spectroscopic surveys. The redshift calibration is confirmed using two independent techniques based on angular cross-correlations and the properties of the photometric redshift probability distributions. Our covariance matrix is determined using an analytical approach, verified numerically with large mock galaxy catalogues. We account for uncertainties in the modelling of intrinsic galaxy alignments and the impact of baryon feedback on the shape of the non-linear matter power spectrum, in addition to the small residual uncertainties in the shear and redshift calibration. The cosmology analysis was performed blind. Our high-level data products, including shear correlation functions, covariance matrices, redshift distributions, and Monte Carlo Markov chains are available at http://kids.strw.leidenuniv.nl. (ProQuest: ... denotes formulae/symbols omitted.)
Lifestyle interventions remain the treatment of choice for patients with obesity and metabolic complications, yet are difficult to maintain and often lead to cycles of weight loss and regain (weight ...cycling). Literature on weight cycling remains controversial and we therefore investigated the association between weight cycling and metabolic complications using preexistent obese mice. Ldlr−/−.Leiden mice received a high‐fat diet (HFD) for 20 weeks to induce obesity. Subsequently, weight‐cycled mice were switched between the healthy chow diet and HFD for four 2‐week periods and compared to mice that received HFD for the total study period. Repeated weight cycling tended to decrease body weight and significantly reduced fat mass, whereas adipose tissue inflammation was similar relative to HFD controls. Weight cycling did not significantly affect blood glucose or plasma insulin levels yet significantly reduced plasma free fatty acid and alanine transaminase/aspartate transaminase levels. Hepatic macrovesicular steatosis was similar and microvesicular steatosis tended to be increased upon weight cycling. Weight cycling resulted in a robust decrease in hepatic inflammation compared to HFD controls while hepatic fibrosis and atherosclerosis development were not affected. These results argue against the postulate that repeated weight cycling leads to unfavorable metabolic effects, when compared to a continuous unhealthy lifestyle, and in fact revealed beneficial effects on hepatic inflammation, an important hallmark of non‐alcoholic steatohepatitis.
Overview of the effects of repeated weight cycling versus continuous high‐fat diet feeding on adipose tissue, muscle, liver, and vasculature.
Drug-resistant tuberculosis is a serious global health threat. Bedaquiline (BDQ) is a relatively new core drug, targeting the respiratory chain in Mycobacterium tuberculosis (Mtb). While mutations in ...the BDQ target gene, atpE, are rare in clinical isolates, mutations in the Rv0678 gene, a transcriptional repressor regulating the efflux pump MmpS5-MmpL5, are increasingly observed, and have been linked to worse treatment outcomes. Nevertheless, underlying mechanisms of (cross)-resistance remain incompletely resolved. Our study aims to distinguish resistance associated variants from other polymorphisms, by assessing the in vitro onset of mutations under drug pressure, combined with their impact on minimum inhibitory concentrations (MICs) and on protein stability. For this purpose, isolates were exposed in vitro to sub-lethal concentrations of BDQ or clofazimine (CFZ). Selected colonies had BDQ- and CFZ-MICs determined on 7H10 and 7H11 agar. Sanger sequencing and additional Deeplex Myc-TB and whole genome sequencing (WGS) for a subset of isolates were used to search for mutations in Rv0678, atpE and pepQ. In silico characterization of relevant mutations was performed using computational tools. We found that colonies that grew on BDQ medium had mutations in Rv0678, atpE or pepQ, while CFZ-exposed isolates presented mutations in Rv0678 and pepQ, but none in atpE. Twenty-eight Rv0678 mutations had previously been described among in vitro selected mutants or in patients' isolates, while 85 were new. Mutations were scattered across the Rv0678 gene without apparent hotspot. While most Rv0678 mutations led to an increased BDQ- and/or CFZ-MIC, only a part of them surpassed the critical concentration (69.1% for BDQ and 87.9% for CFZ). Among the mutations leading to elevated MICs for BDQ and CFZ, we report a synonymous Val1Val mutation in the Rv0678 start codon. Finally, in silico characterization of Rv0678 mutations suggests that especially the C46R mutant may render Rv0678 less stable.
Summary
Background
There are currently no independent data available comparing infliximab and etanercept for the treatment of psoriasis.
Objectives
To compare these biologics without funding from ...pharmaceutical companies.
Methods
Overall, 50 patients were randomized to etanercept (n = 23) 50 mg subcutaneously twice weekly or infliximab (n = 25) 5 mg kg−1 intravenously at week 0, 2, 6, 14 and 22. After 24 weeks, 19 patients stopped and 22 continued treatment and were followed up to week 48. The primary outcome was ≥ 75% improvement of Psoriasis Area and Severity Index (PASI 75) at week 24. The secondary outcomes included PASI 75 at week 6 (onset of action) and week 12, Investigator's Global Assessment (IGA), Patient Global Assessment, impact on quality of life (Skindex‐17 and SF‐36), Treatment Satisfaction Questionnaire of Medication, duration of remission, maintenance treatment and safety.
Results
At week 24, PASI 75 was achieved in 72% (infliximab) vs. 35% (etanercept) (P = 0·01). The onset of action was achieved in 52% (infliximab) and 4% (etanercept). At week 12, 76% (infliximab) and 22% (etanercept) achieved PASI 75 (P < 0·001). At week 24, IGA ‘clear or almost clear’ was observed in 76% (infliximab) and 30% (etanercept) (P = 0·01). Skindex‐17 symptom score was significantly better for infliximab. Maintenance treatment achieved PASI 75 for 67% (n = 6) infliximab vs. 50% (n = 5) etanercept, at week 48 (P = 0·65). Mild adverse events were reported in 76% (infliximab) vs. 66% (etanercept).
Conclusions
Infliximab showed a rapid and significant higher level of efficacy until week 24 compared with etanercept. Long‐term data showed no significant differences between both groups at week 48. Safety parameters were comparable.
What's already known about this topic?
Etanercept and infliximab are both effective and safe treatments for psoriasis.
No comparative long‐term data are available that are independent from pharmaceutical companies.
What does this study add?
The onset of action and physician‐reported efficacy for week 12 and 24 is significantly better for infliximab. There was less of a difference in efficacy for patient‐reported outcomes.
Long‐term data show no significant differences, based on the duration of remission after stopping treatment and maintenance treatment until week 48.
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Linked Comment: Burden. Br J Dermatol 2017; 176:565.
Context:
Anti-Müllerian hormone (AMH) is an accurate marker of ovarian reserve. However, sufficiently large sets of normative data from infancy to the end of reproductive life are scarce.
Objective:
...This study was an assessment of serum AMH levels in healthy females.
Subjects:
In 804 healthy females ranging from infancy until the end of the reproductive period, serum AMH levels were measured with an enzyme-linked immunometric assay. All adults had regular menstrual cycles. The majority was proven fertile and none of them had used oral contraceptive pills prior to study inclusion.
Results:
In the total cohort, AMH was inversely correlated with age (r = −0.24; P < 0.001). The age at which the maximum AMH value was attained was at 15.8 yr. In girls younger than 15.8 yr, serum AMH and age were positively correlated (r = +0.18; P = 0.007). Thereafter AMH levels remained stable (r = −0.33; P = 0.66), whereas from the age of 25.0 yr onward, an inverse correlation between AMH and age (r = −0.47; P < 0.001) was observed. At any given age, considerable interindividual differences in serum AMH levels were observed.
Conclusion:
During infancy AMH levels increase, whereas during adolescence, a plateau until the age of 25 yr was observed. From the age of 25 yr onward, serum AMH levels correlate inversely with age, implying that AMH is applicable as a marker of ovarian reserve only in women of 25 yr old and older. Our nomogram may facilitate counseling women on their reproductive potential.
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