BACKGROUND: The research on possible cerebral involvement in Crohn's disease (CD) has been largely marginalized and failed to capitalize on recent developments in magnetic resonance imaging (MRI). OBJECTIVE: This cross-sectional pilot study searches for eventual macrostructural and microstructural brain affection in CD in remission and early after the disease onset. METHODS: 14 paediatric CD patients and 14 healthy controls underwent structural, diffusion weighted imaging and quantitative relaxation metrics acquisition, both conventional free precession and adiabatic rotating frame transverse and longitudinal relaxation time constants as markers of myelination, iron content and cellular loss. RESULTS: While no inter-group differences in cortical thickness and relaxation metrics were found, lower mean diffusivity and higher intracellular volume fraction were detected in CD patients over vast cortical regions essential for the regulation of the autonomous nervous system, sensorimotor processing, cognition and behavior, pointing to wide-spread cytotoxic oedema in the absence of demyelination, iron deposition or atrophy. CONCLUSION: Although still requiring further validation in longitudinal projects enrolling larger numbers of subjects, this study provides an indication of wide-spread cortical oedema in CD patients very early after the disease onset and sets possible directions for further research.
- Publikační typ
- časopisecké články MeSH
Understanding potential differences in vaccine-induced protection between demographic subgroups is key for vaccine development. Vaccine efficacy evaluation across these subgroups in phase 2b or 3 clinical trials presents challenges due to lack of precision: such trials are typically designed to demonstrate overall efficacy rather than to differentiate its value between subgroups. This study proposes a method for estimating vaccine efficacy using immunogenicity (instead of vaccination status) as a predictor in time-to-event models. The method is applied to two datasets from immunogenicity sub-studies of vaccine phase 3 clinical trials for zoster and dengue vaccines. Results show that using immunogenicity-based estimation of efficacy in subgroups using time-to-event models is more precise than the standard estimation. Incorporating immune correlate data in time-to-event models improves precision in estimating efficacy (i.e., yields narrower confidence intervals), which can assist vaccine developers and public health authorities in making informed decisions.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Vaccine efficacy (VE) assessed in a randomized controlled clinical trial can be affected by demographic, clinical, and other subject-specific characteristics evaluated as baseline covariates. Understanding the effect of covariates on efficacy is key to decisions by vaccine developers and public health authorities. METHODS: This work evaluates the impact of including correlate of protection (CoP) data in logistic regression on its performance in identifying statistically and clinically significant covariates in settings typical for a vaccine phase 3 trial. The proposed approach uses CoP data and covariate data as predictors of clinical outcome (diseased versus non-diseased) and is compared to logistic regression (without CoP data) to relate vaccination status and covariate data to clinical outcome. RESULTS: Clinical trial simulations, in which the true relationship between CoP data and clinical outcome probability is a sigmoid function, show that use of CoP data increases the positive predictive value for detection of a covariate effect. If the true relationship is characterized by a decreasing convex function, use of CoP data does not substantially change positive or negative predictive value. In either scenario, vaccine efficacy is estimated more precisely (i.e., confidence intervals are narrower) in covariate-defined subgroups if CoP data are used, implying that using CoP data increases the ability to determine clinical significance of baseline covariate effects on efficacy. CONCLUSIONS: This study proposes and evaluates a novel approach for assessing baseline demographic covariates potentially affecting VE. Results show that the proposed approach can sensitively and specifically identify potentially important covariates and provides a method for evaluating their likely clinical significance in terms of predicted impact on vaccine efficacy. It shows further that inclusion of CoP data can enable more precise VE estimation, thus enhancing study power and/or efficiency and providing even better information to support health policy and development decisions.
- MeSH
- demografie statistika a číselné údaje MeSH
- klinické zkoušky, fáze III jako téma statistika a číselné údaje metody MeSH
- lidé MeSH
- logistické modely MeSH
- počítačová simulace MeSH
- randomizované kontrolované studie jako téma statistika a číselné údaje metody MeSH
- účinnost vakcíny * statistika a číselné údaje MeSH
- vakcinace statistika a číselné údaje metody MeSH
- vakcíny terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
Given the substantial dependence of neurons on continuous supply of energy, the distribution of major cerebral arteries opens a question whether the distance from the main supply arteries constitutes a modulating factor for the microstructural and functional properties of brain tissue. To tackle this question, multimodal MRI acquisitions of 102 healthy volunteers over the full adult age span were utilised. Relaxation along a fictitious field in the rotating frame of rank n = 4 (RAFF4), adiabatic T1ρ, T2ρ, and intracellular volume fraction (fICVF) derived from diffusion-weighted imaging were implemented to quantify microstructural (cellularity, myelin density, iron concentration) tissue characteristics and degree centrality and fractional amplitude of low-frequency fluctuations to probe for functional metrics. Inverse correlation of arterial distance with robust homogeneity was detected for T1ρ, T2ρ and RAFF4 for cortical grey matter and white matter, showing substantial complex microstructural differences between brain tissue close and farther from main arterial trunks. Albeit with wider variability, functional metrics pointed to increased connectivity and neuronal activity in areas farther from main arteries. Surprisingly, multiple of these microstructural and functional distance-based gradients diminished with higher age, pointing to uniformization of brain tissue with ageing. All in all, this pilot study provides a novel insight on brain regionalisation based on artery distance, which merits further investigation to validate its biological underpinnings.
- MeSH
- arterie MeSH
- bílá hmota * MeSH
- difuzní magnetická rezonance MeSH
- dospělí MeSH
- lidé MeSH
- magnetická rezonanční tomografie * metody MeSH
- mozek MeSH
- pilotní projekty MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
The advent of new, advanced quantitative MRI metrics allows for in vivo evaluation of multiple biological processes highly relevant for ageing. The presented study combines several MRI parameters hypothesised to detect distinct biological characteristics as myelin density, cellularity, cellular membrane integrity and iron concentration. 116 healthy volunteers, continuously distributed over the whole adult age span, underwent a multi-modal MRI protocol acquisition. Scatterplots of individual MRI metrics revealed that certain MRI protocols offer much higher sensitivity to early adulthood changes while plateauing in higher age (e.g., global functional connectivity in cerebral cortex or orientation dispersion index in white matter), while other MRI metrics provided reverse ability-stable levels in young adulthood with sharp changes with rising age (e.g., T1ρ and T2ρ). Nonetheless, despite the previously published validations of specificity towards microstructural biology based on cytoarchitectonic maps in healthy population or alterations in certain pathologies, several metrics previously hypothesised to be selective to common measures failed to show similar scatterplot distributions, pointing to further confounding factors directly related to age. Furthermore, other metrics, previously shown to detect different biological characteristics, exhibited substantial intercorrelations, be it due to the nature of the MRI protocol itself or co-dependence of relevant biological microstructural processes. All in all, the presented study provides a unique basis for the design and choice of relevant MRI parameters depending on the age group of interest. Furthermore, it calls for caution in simplistic biological inferences in ageing based on one simple MRI metric, even though previously validated under other conditions. Complex multi-modal approaches combining several metrics to extract the shared subcomponent will be necessary to achieve the desired goal of histological MRI.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Long-term results of kidney transplant (KTx) in older patients may differ from younger recipients owing to increased cardiovascular comorbidities. The study aimed to analyze surgical and nonsurgical complications that develop in the long-term follow-up period after KTx, and factors that influence results of KTx in recipients aged 60 years and older (≥60) compared with younger recipients (<60). METHODS: One hundred seventy-five patients aged ≥60 years and 175 patients aged <60 years who received a kidney graft from the same deceased donor were enrolled in the study. In the long-term follow-up period (3 months to 5 years after KTx) the incidence of surgical and nonsurgical complications, as well as patient and kidney graft survival, were compared. Additionally, the influence of early complications on patients and kidney graft survival was assessed. RESULTS: There were no differences between recipients aged ≥60 years compared with recipients aged <60 years in occurrence of surgical complications (graft artery stenosis: 0.6% vs 2.3%; ureter stenosis: 3.4% vs 1.1%; lymphocele: 6.9% vs 3.4%) and nonsurgical complications (urinary tract infection: 19.4% vs 23.4%; pneumonia: 8.6% vs 8.6%; cytomegalovirus infection: 6.3% vs 8%; new-onset diabetes after transplant: 16.6% vs 17.1%; cancer incidence: 5.7% vs 4.6%; acute rejection episode: 13.1% vs 17.1%). Five-year recipient survival was lower in a group of patients aged ≥60 years (death, 15.4% vs 8%; death with functioning graft, 12% vs 5.1%). CONCLUSIONS: The incidence of surgical and nonsurgical complications, as well as kidney-graft survival, in recipients aged ≥60 years in a 5-year follow-up period is comparable to younger recipients aged <60 years.
- MeSH
- ledviny MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- přežívání štěpu * MeSH
- příjemce transplantátu MeSH
- rejekce štěpu epidemiologie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- stenóza etiologie MeSH
- transplantace ledvin * metody MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
We analyze data on Silesian patients after kidney transplantation under competing events scenarios where time to death and time to graft failure are considered as absorbing competing events. Our objectives are to use model diagnostics in identifying violations of proportionality assumption under the framework of subdistribution and cause-specific hazards. We use the Fine-Gray proportional hazards model for the subdistribution. Under the cause-specific hazards (CSH) scenario we use the Cox proportional hazards model and Gray's time-varying coefficients model and available model diagnostics. We show that violation of proportional subdistribution hazards assumption may be conveniently identified using residual diagnostics and properly accounted for by involving time interactions with appropriate model predictors. We also show that although the nonproportional effects on cumulative incidence do not necessarily translate in those on cause-specific hazards, they often take place simultaneously, and a violation of the proportionality assumption needs to be checked rigorously. Time-varying effects have a profound impact on clinical inference under competing risks. They do not translate directly between the frameworks of subdistribution and cause-specific hazards because the cumulative incidence is obtained via integrating the cause-specific hazard weighted by the overall survival function. Also, a different definition of the risk set is in place under the cumulative incidence and CSH framework, respectively. However, a simultaneous violation of the proportionality assumption under both frameworks is still possible. Clinical inference may change considerably when such a violation occurs. Nonproportional effects may be properly identified under each framework using available model diagnostics.
- MeSH
- hodnocení rizik MeSH
- incidence MeSH
- ledviny MeSH
- lidé MeSH
- proporcionální rizikové modely MeSH
- rizikové faktory MeSH
- transplantace ledvin * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Probiotic administration seems to be a rational approach to promote maturation of the neonatal immune system. Mutual interaction of the microbiota with the host immune system is critical for the setting of appropriate immune responses including a tolerogenic one and thevmaintenance of homeostasis. On the other hand, our knowledge on the modes of actions of probiotics is still scarce. METHODS: In our study, probiotic strain Escherichia coli O83:K24:H31 (EcO83) was administered to neonates of allergic mothers (AMs; neonates with increased risk for allergy development) within 48 h after the delivery, and the impact of this early postnatal supplementation on allergy incidence and selected immune markers has been analyzed 10 years after the primary EcO83 administration. RESULTS: We have observed decreased allergy incidence in 10-year-old children supplemented with EcO83 (13 of 52 children were allergic) in comparison with non-supplemented children of AMs (16 of 42 children were allergic). The early postnatal EcO83 supplementation appeared to limit the allergy in the high-risk group (children of AMs) compared to that in the low-risk group (children of healthy mothers). Dendritic cells (DCs) in the peripheral blood of EcO83-supplemented children do not differ significantly in cell surface presence of CD83. The immunomodulatory capacity of EcO83 on DCs was tested in vitro as well. Both directly isolated myeloid and in vitro monocyte-derived DCs from cord blood increased CD83 expression together with interleukin (IL)-10 secretion after EcO83 stimulation. The effect of early postnatal EcO83 supplementation on the microbiota composition of 10-year-old children was characterized by next-generation sequencing, and we have not observed significant changes in the microbiota composition of EcO83-supplemented and non-supplemented children at the age of 10 years. CONCLUSIONS: Early postnatal EcO83 supplementation appears to lower allergy incidence in children of AMs. It seems that the beneficial effect of EcO83 is mediated via modulation of DC functional capacities without impacting the microbiota composition. Larger-scale studies will be necessary to confirm these preliminary findings.
- MeSH
- alergie * epidemiologie prevence a kontrola MeSH
- dendritické buňky MeSH
- dítě MeSH
- Escherichia coli fyziologie MeSH
- incidence MeSH
- lidé MeSH
- mikrobiota * MeSH
- monocyty MeSH
- novorozenec MeSH
- probiotika * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
