Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta-analysis of studies over the last ten years

More than 10 years ago, the first pilot observational study of imatinib discontinuation was reported in chronic myeloid leukaemia (CML) patients in deep molecular response (DMR). Several studies have been published since then, in patients treated with frontline imatinib, or second-generation tyrosine kinase inhibitors (TKI) in first or second line but also on second attempt of TKI discontinuation. Our objective was to estimate, through meta-analyses of the literature data, the probability of molecular recurrence (MolRec) in the time periods of 0–6, 6–12, 12–18 and 18–24 months after a first and second TKI discontinuation and the probability of re-acquisition of DMR after MolRec. The Medline and Scopus databases were searched up to April 2019. The studies were selected by three independent reviewers. Random-effect meta-analyses were conducted using the MetaXL software. The probability of MolRec in the time periods 0–6, 6–12, 12–18 and 18–24 months after the first attempt was respectively 35%, 8%, 3% and 3%, whereas the probability of MolRec in the time periods 0-6, 6-12 and 12-18 after the second attempt was 48%, 27% and 12% respectively. Re-acquisition of a DMR was observed in 90% of patients. Most of the MolRec occur during the first six months in case of a first attempt, whereas the second MolRec occurs over a larger window of time.     

Functional traits explain variation in plant life history strategies

Ecologists seek general explanations for the dramatic variation in species abundances in space and time. An increasingly popular solution is to predict species distributions, dynamics, and responses to environmental change based on easily measured anatomical and morphological traits. Trait-based approaches assume that simple functional traits influence fitness and life history evolution, but rigorous tests of this assumption are lacking, because they require quantitative information about the full lifecycles of many species representing different life histories. Here, we link a global traits database with empirical matrix population models for 222 species and report strong relationships between functional traits and plant life histories. Species with large seeds, long-lived leaves, or dense wood have slow life histories, with mean fitness (i.e., population growth rates) more strongly influenced by survival than by growth or fecundity, compared with fast life history species with small seeds, short-lived leaves, or soft wood. In contrast to measures of demographic contributions to fitness based on whole lifecycles, analyses focused on raw demographic rates may underestimate the strength of association between traits and mean fitness. Our results help establish the physiological basis for plant life history evolution and show the potential for trait-based approaches in population dynamics.Recent evidence for global patterns of functional variation in plants, such as the leaf economics spectrum (1, 2), the wood economics spectrum (3), and the seed size–seed number tradeoff (4, 5), has convinced many ecologists that functional traits offer the best available approach for achieving a general predictive understanding of communities and ecosystems (6, 7). Trait-based approaches are now being used to predict the outcome of community assembly (8–10), global vegetation dynamics (11), and the rate of ecosystem processes (6, 12–14). A central assumption of trait-based ecology is that morphological traits determine physiological performance, which influences vital rates and determines individual fitness and life history evolution (15, 16). However, because of the challenge of quantifying the contribution of traits to fitness, the assumed links between functional traits and life history have not been fully tested.Research in tropical and Mediterranean forests has revealed cross-species relationships between functional traits and the survival and growth rates of individuals (3, 17–24). Although these relationships provide evidence that functional traits influence vital rates, they offer only limited insight into associations between those traits and individual fitness and life history. Vital rates (e.g., survival and fecundity) represent fitness components, but their influence on mean fitness, defined as the population growth rate (λ), is best understood in the context of the full lifecycle of a species (25, 26). A significant negative correlation between wood density and individual growth (18) might not translate into a significant effect on mean fitness if individual growth has little influence on λ. Conversely, a weak relationship between a functional trait and another vital rate could have a significant effect on mean fitness if that vital rate has a strong influence on λ. Perturbation analyses, such as the sensitivities and elasticities frequently applied to matrix projection models (27), address this problem by quantifying the contribution of vital rates to λ (28), making it possible to characterize a species'' overall life history in terms of the relative importance of survival, individual growth, and fecundity to mean fitness. Species with slow life histories have population growth rates with high elasticities to survival, whereas species with fast life histories have relatively higher elasticities to individual growth or fecundity (29, 30).Armed with vital rate elasticities, we can test quantitative hypotheses about whether functional tradeoffs scale up to generate life history tradeoffs. For example, plants can allocate their reproductive effort to provision a few large seeds, which tolerate low light and resource availability and have a high survival probability, or they can spread their reproductive effort among many small seeds, maximizing fitness under high resource availability (31, 32). If this functional tradeoff at the seedling stage translates into a life history tradeoff, seed mass should be positively related to the elasticity of the population growth rate to survival and negatively related to elasticities to individual growth and fecundity. The leaf economics spectrum represents another allocation tradeoff. Species can construct long-lived, well-defended leaves that are often favored in low resource environments or build leaves that assimilate carbon quickly under conditions of high resource availability but are prone to rapid tissue loss (1, 33). Species with slow leaf economics traits, such as long leaf lifespans, low specific leaf area (SLA), and low leaf N, might also lead slow lives, characterized by high elasticities to survival and low elasticities to individual growth and recruitment. A wood economics spectrum also exists: species with dense wood tend to have higher survival but lower relative growth rates than species with soft wood (3, 34). Elasticities to survival should increase with wood density, whereas elasticities to individual growth and fecundity should decrease.The main obstacle in testing these hypotheses is availability of the detailed demographic data necessary to describe a species’ full lifecycle and estimate vital rate elasticities. We overcame this limitation by crossing the TRY Global Plant Traits Database (35) with the COMPADRE Plant Matrix Database (www.compadre-db.org/), a collection of published matrix population models. This approach produced a dataset of 222 plant species spanning a global range of biomes and perennial growth forms (Table S1), for which we have at least one functional trait measurement as well as a matrix population model that we used to calculate the elasticity of the population growth rate to each of the three vital rates: survival, growth, and fecundity (30).Our primary objective was to evaluate the ability of functional traits to explain variation across species in life history, which we quantified with vital rate elasticities. Our secondary objective was to evaluate whether inferences about life history can be drawn directly from the raw vital rates, which would save researchers the considerable time and effort required to parameterize population models and calculate elasticities. We used two statistical approaches to quantify relationships between vital rate elasticities and seed mass, wood density, and leaf economics traits (leaf lifespan, SLA, and leaf N). Dirichlet regression is a multivariate approach that accounts for the fact that the survival, growth, and fecundity elasticities for each species sum to one but does not account for phylogenetic relationships. Phylogenetic generalized least squares (PGLS) regression ignores the nonindependence of the elasticities but accounts for phylogenetic relationships. We repeated both types of regressions with plant growth form and then biome included as covariates to confirm that trait effects did not simply represent differences between trees and herbaceous species or plants adapted to different environments.     

Does Anatomy Explain the Origin of a Leak after Sleeve Gastrectomy?

Background

Sleeve gastrectomy is a bariatric surgical procedure that may result in particular morbidity or mortality due to gastric fistula in the proximal part of the gastric tube. Two theories are currently proposed to explain this specific leak location. The vascular theory attributes the leaks to reduced perfusion in the gastric tube, and the mechanical theory suggests the etiology as gastric tube hyper-pressure due to pyloric conservation. The aim of this study was to map the arterial gastric vascular supply on fresh cadavers after performing sleeve gastrectomy to evaluate the effect of vascular changes on gastric leakage.

Methods

We performed sleeve gastrectomies on 11 cadaveric trunks with a detailed anatomical study of the gastric vascular supply after latex injection in the three branches arising from the celiac trunk.

Results

In 55 % of cases, the sleeve procedure changed the gastric vascular supply. In 9.1 %, it divided the three left gastric artery branches arising from the lesser curvature. Few changes were noted in the antrum or pylorus.

Conclusions

This anatomical study demonstrates that the vascular supply of the proximal part of the gastric tube can be damaged by a sleeve procedure, which can sever one or more of the branches arising from the left gastric artery. Such weakness could be exacerbated by disparities in vascular supply. The uninterrupted vascular supply of the antrum and pylorus may explain the preferential localization of the fistula to the proximal part of the gastric tube.     

Mutations in the telomere capping complex in bone marrow failure and related syndromes

Dyskeratosis congenita and its variants have overlapping phenotypes with many disorders including Coats plus, and their underlying pathology is thought to be one of defective telomere maintenance. Recently, biallelic CTC1 mutations have been described in patients with syndromes overlapping Coats plus. CTC1, STN1 and TEN1 are part of the telomere-capping complex involved in maintaining telomeric structural integrity. Based on phenotypic overlap we screened 73 genetically uncharacterized patients with dyskeratosis congenita and related bone marrow failure syndromes for mutations in this complex. Biallelic CTC1 mutations were identified in 6 patients but none in either STN1 or TEN1. We have expanded the phenotypic spectrum associated with CTC1 mutations and report that intracranial and retinal abnormalities are not a defining feature, as well as showing that the effect of these mutations on telomere length is variable. The study also demonstrates the lack of disease-causing mutations in other components of the telomere-capping complex.     

Chronic stress induces transient spinal neuroinflammation,triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia

Chronic stressful events induce biochemical, physiological and psychological changes, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression. Using repeated social defeat as a stressful event model, we show that this preclinical paradigm induces a transient increase in the expression of the genes encoding the pro-inflammatory molecules iNOS and COX-2. We provide the first demonstration that chronic stress affects spinal plasticity through a mechanism involving local neuroinflammation. The functional consequences of such neuroinflammation are associated with a transient decrease in the mechanical nociceptive threshold. Administration of the cholecystokinin(CCK)-2 receptor antagonist, CI-988, directly into the Rostral Ventromedial Medulla reverses the chronic stress-induced decrease in the nociceptive threshold. These data strongly suggest that chronic stress induces a spinal neuroinflammation associated with transient sensory hypersensitivity involving the activation of CCK-dependent nociceptive descending facilitatory pathways. Pharmacological data show that chronic social stress-induced long-lasting state of anxiety is not responsible for maintaining the spinal neuroinflammation and, therefore, for the associated sensory hypersensitivity. Conversely, an evaluation of pain-related behavior in the formalin model indicates that anxiety is directly related to prolonged hyperalgesia prevented by systemic benzodiazepine or CCK-2 receptor antagonist treatments. The present study highlights the adverse effects of chronic stress on spinal neuroinflammation triggering sensory hypersensitivity. Exploration of this phenomenon points out the divergence between pain sensitivity and anxiety-induced hyperalgesia, which is in agreement with clinical observations. Altogether, these data open up new perspectives for clinical research devoted to the evaluation and treatment of pain in anxio-depressive patients.     

Characteristics and development of therapeutic patient education in rheumatoid arthritis: Analysis of the 2003–2008 literature

ObjectiveThe aim of this study is to point out the recent characteristics and developments of therapeutic patient education (TPE) in rheumatoid arthritis through an analysis of the international articles published from 2003 to 2008.MethodStudies were selected from major databases, using the following keywords: rheumatoid arthritis, patient education, self-management, programs. Three authors independently reviewed each study and selected the data using the patient education research categories (PERC). Articles consistently related to patient education in rheumatoid arthritis (37 among 109) were included.ResultsThe selected articles have been published in 23 scientific journals. The majority of them concern TPE for adult patients with rheumatoid arthritis. TPE is delivered in several structures and group education represents the most widespread educational strategy mainly provided by a multiprofessional team. There are two types of programs: educational, aiming to make the patient competent in the daily management of his disease and psycho-educational ones, aiming to improve coping and to decrease stress, anxiety and depression. Twenty-eight studies show the effectiveness of TPE on the basis of bio-clinical, educational, psychosocial, economical criteria, but the majority of these positive results are observed in short-term. Barriers to TPE are linked to cultural and socio-economic factors.ConclusionA large number of studies still assess the positive effects of TPE. Nowadays, the problems of short-term efficacy of TPE and the cultural and social barriers to this practice have become a major issue for research.     

Using EMGs and kinematics data to study the take-off technique of experts and novices for a pole vaulting short run-up educational exercise

This study attempts to characterise the electromyographic activity and kinematics exhibited during the performance of take-off for a pole vaulting short run-up educational exercise, for different expertise levels. Two groups (experts and novices) participated in this study. Both groups were asked to execute their take-off technique for that specific exercise. Among the kinematics variables studied, the knee, hip and ankle angles and the hip and knee angular velocities were significantly different. There were also significant differences in the EMG variables, especially in terms of (i) biceps femoris and gastrocnemius lateralis activity at touchdown and (ii) vastus lateralis and gastrocnemius lateralis activity during take-off. During touchdown, the experts tended to increase the stiffness of the take-off leg to decrease braking. Novices exhibited less stiffness in the take-off leg due to their tendency to maintain a tighter knee angle. Novices also transferred less energy forward during take-off due to lack of contraction in the vastus lateralis, which is known to contribute to forward energy transfers. This study highlights the differences in both groups in terms of muscular and angular control according to the studied variables. Such studies of pole vaulting could be useful to help novices to learn expert's technique.     

Characterization by culture and molecular analysis of the microbial diversity of a deep subsurface gas storage aquifer

The bacterial diversity of a subsurface water sample collected from a gas storage aquifer in an Upper Jurassic calcareous formation was investigated by culture of microorganisms and construction of a 16S rRNA gene library. Both culture and molecular techniques showed that members of the phyla Firmicutes and class δ-proteobacteria dominated the bacterial community. The presence of hydrogen-utilizing autotrophic bacteria including sulfate reducers (e.g. Desulfovibrio aespoeensis) and homoacetogens (e.g. Acetobacterium carbinolicum) suggested that CO₂ and H₂ are the main carbon and energy sources sustaining a nutrient-limited subsurface lithoautotrophic microbial ecosystem (SLiME). Gram-positive SRB belonging to the genus Desulfotomaculum, frequently observed in subsurface environments, represented 25% of the clone library and 4 distinct phylotypes. No Archaea were detected by both experimental approaches.Water samples were collected in an area of the rauracian geological formation located outside the maximum seasonal extension of underground gas storage. Considering the observed microbial diversity, there is no evidence of any influence on the microbial ecology of the aquifer in the surroundings of maximum extension reached by the gas bubble of the underground storage, which should have resulted from the introduction of exogenous carbon and energy sources in a nutrient-limited ecosystem.