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Background Skeletal muscle mass (SMM) loss is common in metastatic colorectal cancer (mCRC) patients and associated with poor clinical outcomes, including increased treatment‐related toxicities and reduced survival. Muscle loss may contribute to reduced health‐related quality of life (HRQoL), including fatigue. Our aim was to study associations between changes in SMM and concomitant changes in patient‐reported HRQoL. Methods This was a secondary analysis of mCRC patients in the CAIRO3 randomized clinical trial who were—after initial treatment—randomized between maintenance treatment with capecitabine plus bevacizumab (CAP‐B) and observation until first disease progression (PD1). Included patients had computed tomography images for SMM quantification, together with HRQoL assessments available at randomization and PD1. Changes in SMM (categorized as >2% loss, stable, and >2% gain) and HRQoL were computed between randomization and PD1. Changes in HRQoL score >10 points were considered clinically relevant. Associations between SMM and HRQoL changes were studied by multiple linear regression models. We also investigated whether associations differed by treatment arm for global health and the 13 other HRQoL subscales. Results Of 221 patients included (mean age 63.5 ± 8.4 years), 24% lost, 27% remained stable, and 49% gained SMM. At randomization, mean global health status was 73.5 ± 15.9 in the CAP‐B arm and 75.1 ± 17.5 in the observation arm (P = 0.48). A stable or gain in SMM was significantly associated with a clinically relevant improvement in global health status (9.9 and 14.7 points, respectively), compared with patients who lost SMM. From the subscales that did not show significant differences between the two treatment arms, we found significant and clinically relevant associations for stable or gain in SMM with improved role functioning (12.0 and 17.9, respectively) and with less fatigue (−10.0 and −15.0, respectively) and pain (−16.3 for SMM gain). From the subscales that did show significantly different associations with SMM between the two treatment arms, we only found significant results in the observation arm. Here, associations were found for stable or gain in SMM with clinically relevant improved physical (12.4 for SMM gain), cognitive (10.7 and 9.7, respectively), and social functioning (15.5 and 15.6, respectively) as well as reduced appetite loss (−28.5 and −30.7, respectively). Conclusions In mCRC, SMM preservation during CAP‐B and observation treatment is associated with significant and clinically relevant improvements in global health status and multiple functional and symptom scales. Studies are warranted to investigate whether interventions targeting SMM lead to improved HRQoL, fewer symptoms, and better functioning.

International audience; Climate change affects forest ecosystem processes and related services due to climate variability. These might affect ecosystem functioning, especially productivity. Regarding management issues, mixed stands are considered a relevant option to maintain forest cover and ecosystem services under climate change. However, the possibility to maintain these mixed stands with management actions with positive effects on forest functioning under climate change remains uncertain and deserves further investigations. Relying on a simulation-based study with a forest gap model (ForCEEPS), we thus addressed the following questions: (1) Are monospecific stands vulnerable to climate change? (2) Would mixed stands significantly mitigate climate change effects on forest productivity and wood production under climate change? (3) Would conversion to mixed stand management affect significantly forest productivity and wood production under climate change compare to monospecific management? In this study, we quantified potential climate change effect (using RCP 8.5 and present climate) and management’s effect in the French Alps, focusing on five species (Fagus sylvatica, Abies alba, Picea abies, Pinus sylvestris, and Quercus pubescens). We tested different scenarios, with various composition, structure, or environmental conditions, under climate change. These simulations showed that monospecific stands currently growing in stressful conditions would be vulnerable to climate change. Managing mixed stands or conversion from pure to mixed stands would make it possible to maintain higher productivity in the long term than monospecific stands, depending on the species and the sites considered. Our results will feed into discussion on forest management in the context of climate change.

International audience; Climate change modifies ecosystem processes directly through its effect on environmental conditions, but also indirectly by changing community composition. Theoretical studies and grassland experiments suggest that diversity may increase and stabilize communities’ productivity over time. Few recent studies on forest ecosystems suggested the same pattern but with a larger variability between the results. In this paper, we aimed to test stabilizing diversity effect for two kinds of mixtures (Fagus sylvatica–Quercus pubescens and F. sylvatica–Abies alba), and to assess how climate may affect the patterns. We used tree ring data from forest plots triplets distributed along a latitudinal gradient across French Alps, adapting NBE approach to study temporal stability. We found that diversity effect on stability in productivity varies with stand composition. Most beech-fir stands showed a greater stability in productivity over time than monocultures, while beech-oak stands showed a less stable productivity. Considering nonadditive effects, no significant trends were found, regardless of the type of mixed stands considered. We further highlighted that these patterns could be partially explained by asynchrony between species responses (notably to variation in temperature or precipitation), overyielding and climatic conditions. We also showed that the intensity of the diversity effect on stability varies along the ecological gradient, consistently with the stress gradient hypothesis for beech in beech-oak forests, but not for beech-fir forests. This study showed the importance of the species identity on the relationships between diversity, climate and stability of forest productivity. Better depicting diversity and composition effects on forest ecosystem functioning appears to be crucial for forest managers to promote forest adaptation and maintain timber resource in the context of ongoing climate change.

International audience; In the context of climate change, it remains unclear whether mixed-species forests will help mitigate the impacts of future droughts and, if so, through which processes. As European beech (Fagus sylvatica L.) is one of the major European species, it is crucial to evaluate its response to drought when mixed with species with contrasted functional traits and in contrasted climatic conditions, particularly at the limit of its climatic range. This study aimed to (i) characterize the effects of tree species interactions on the drought exposure of beech in southeastern France, and (ii) determine whether belowground water uptake complementarity underlies these effects. We focused on beech-silver fir (Abies alba Mill.) and beech-pubescent oak (Quercus pubescens Willd.) forests across six sites in the French pre-Alps, a region at the limit of the climatic range for beech. We used a triplet approach to compare the tree-ring carbon isotope composition (δ 13 C) of these species in pure and two-species mixed stands during a period of dry years, and used water hydrogen isotope composition (δ 2 H) in the xylem to identify water uptake sources. Overall, we found no clear mixture effect pattern on beech physiological functioning among sites and triplets. In beech-fir sites, mixing beech with fir had no effect on beech δ 13 C values during dry years. In beech-oak sites, mixture effects on beech were mostly neutral, although sometimes beech suffered from a stronger exposure to drought in mixed stands. Our study emphasizes the impact of the tree sampling design on the outcome of studies on forest biodiversity-ecosystem functioning relationships. Limiting tree sampling to dominant trees when analyzing stand-level relationships may bias these outcomes. We evidenced differences in water uptake sources between beech and fir, but not between beech and oak during a dry summer. However, these patterns did not help explain the lack of species mixture effects, or existence thereof, at the triplet scale. Our study demonstrates that managing beech in mixed stands with silver fir or pubescent oak at the limit of beech climatic range does not buffer drought impacts on beech during dry years. In the long term, with more frequent extreme droughts, promoting beech-fir mixtures will not be detrimental to beech drought response, while beech may suffer in mixtures with pubescent oak.

International audience; 1. Over the coming decades, the predicted increase in frequency and intensity of extreme events such as droughts is likely to have a strong effect on forest functioning. Recent studies have shown that species mixing may buffer the temporal variability of productivity. However, most studies have focused on temporal stability of productivity, while species mixing may also affect forest resilience to extreme events. Our understanding of mechanisms underlying species mixing effects on forest stability and resilience remains limited because we ignore how changes from intraspecific to interspecific interactions in the neighbourhood of a given tree might affect its stability and resilience to extreme drought (i.e. response during and after this drought). This is crucial to better understand forests' response to climate change and how diversity may help maintain forest functioning.2. Here we analysed how local intra-or interspecific interactions may affect the temporal stability and resilience to drought of individual trees in French mountain forests, using basal area increment data over the previous 20 years for Fagus sylvatica, Abies alba and Quercus pubescens. We analysed the effect of interspecific competition on (a) the temporal stability and (b) the resilience to drought (resistance and recovery) of individual tree radial growth.3. We found no significant interspecific competition effect on temporal stability, but species-specific effects on tree growth resilience to drought. There was a positive effect of heterospecific proportion on the drought resilience of Q. pubescens, a negative effect for A. alba and no effect for F. sylvatica. These differences may be related to interspecific differences in water use or rooting depth.4. Synthesis: In this study, we showed that stand composition influences individual tree growth resilience to drought, but this effect varied depending on the species and its physiological responses. Our study also highlighted that a lack of biodiversity effect on long-term stability might hide important effects on short-term resilience to extreme climatic events. This may have important implications in the face of climate change.

Background Low skeletal muscle index (SMI) in metastatic colorectal cancer (mCRC) patients is associated with poor outcomes. The prognostic impact of SMI changes during consecutive palliative systemic treatments is unknown. Methods This is a retrospective analysis of the phase 3 CAIRO3 study. The CAIRO3 study randomized 557 patients between maintenance capecitabine + bevacizumab (CAP‐B) or observation, after six cycles capecitabine + oxaliplatin + bevacizumab (CAPOX‐B). Upon first disease progression (PD1), CAPOX‐B was reintroduced until second progression (PD2). SMI was assessed by computed tomography (CT) (total 1355 scans). SMI and body mass index (BMI) changes were analyzed for three time‐periods; p1: during initial CAPOX‐B, p2: randomization to PD1, and p3: PD1 to PD2. The association between absolute and change in SMI and BMI (both per 1 standard deviation) during p1‐p3, with PD1, PD2, and survival was studied by Cox regression models. Results This analysis included 450 of the 557 patients randomized in the CAIRO3 study. Mean SMI decreased during p1: mean −0.6 SMI units [95% CI −1.07;‐0.26] and p3: −2.2 units [−2.7;‐1.8], whereas during p2, SMI increased + 1.2 units [0.8‐1.6]. BMI changes did not reflect changes in SMI. SMI loss during p2 and p3 was significantly associated with shorter survival (HR 1.19 [1.09‐1.35]; 1.54 [1.31‐1.79], respectively). Sarcopenia at PD1 was significantly associated with early PD2 (HR 1.40 [1.10‐1.70]). BMI loss independent of SMI loss was only associated with shorter overall survival during p3 (HR 1.35 [1.14‐1.63]). Conclusions In mCRC patients, SMI loss during palliative systemic treatment was related with early disease progression and reduced survival. BMI did not reflect changes in SMI and could not identify patients at risk of poor outcome during early treatment lines.

Every year, several epizooties of equine influenza (EI) are reported worldwide. However, no EI case has been identified in France between 2015 and late 2018, despite an effective field surveillance of the pathogen and the disease. Vaccination against equine influenza virus (EIV) remains to this day one of the most effective methods to prevent or limit EI outbreaks and the lack of detection of the pathogen could be linked to vaccination coverage. The aim of this study was to evaluate EI immunity and vaccine coverage in France through a large-scale serological study. A total of 3004 archived surplus serums from French horses of all ages, breeds and sexes were selected from four different geographical regions and categories (i.e., sanitary check prior to exportation, sale, breeding protocol or illness diagnosis). EIV-specific antibody response was measured by single radial hemolysis (SRH) and an EIV-nucleoprotein (NP) ELISA (used as a DIVA test). Overall immunity coverage against EIV infection (i.e., titers induced by vaccination and/or natural infection above the clinical protection threshold) reached 87.6%. The EIV NP ELISA results showed that 83% of SRH positive serum samples from young horses (&le, 3 years old) did not have NP antibodies, which indicates that the SRH antibody response was likely induced by EI vaccination alone (the HA recombinant canarypoxvirus-based EI vaccine is mostly used in France) and supports the absence of EIV circulation in French horse populations between 2015 and late 2018, as reported by the French equine infectious diseases surveillance network (RESPE). Results from this study confirm a strong EI immunity in a large cohort of French horses, which provides an explanation to the lack of clinical EI in France in recent years and highlights the success of vaccination against this disease. However, such EI protection has been challenged since late 2018 by the incursion in the EU of a Florida Clade 1 sub-lineage EIV (undetected in France since 2009), which is also reported here.

International audience; Equine herpesvirus 1 (EHV-1) is an Alphaherpesvirus infecting not only horses but also other equid and non-equid mammals. It can cause respiratory distress, stillbirth and neonatal death, abortion, and neurological disease. The different forms of disease induced by EHV-1 infection can have dramatic consequences on the equine industry, and thus the virus represents a great challenge for the equine and scientific community. This report describes the progress of a major EHV-1 outbreak that took place in Normandy in 2009, during which the three forms of disease were observed. A collection of EHV-1 strains isolated in France and Belgium from 2012 to 2018 were subsequently genetically analysed in order to characterise EHV-1 strain circulation. The open reading frame 30 (ORF30) non-neuropathogenic associated mutation A2254 was the most represented among 148 samples analysed in this study. ORF30 was also sequenced for 14 strains and compared to previously published sequences. Finally, a more global phylogenetic approach was performed based on a recently described Multilocus Sequence Typing (MLST) method. French and Belgian strains were clustered with known strains isolated in United Kingdom and Ireland, with no correlation between the phylogeny and the time of collection or location. This new MLST approach could be a tool to help understand epidemics in stud farms.

Background Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first‐line maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose‐limiting toxicities (DLTs) during CAP‐B and CAPOX‐B. Methods Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs. Results One hundred eighty‐two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP‐B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX‐B. At the start of CAP‐B and CAPOX‐B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non‐sarcopenic at the start of CAP‐B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX‐B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2). Sarcopenia at the start of CAP‐B was not associated with DLTs [relative risk 0.87 (95% confidence interval 0.64–1.19)], whereas patients with >2% SMI loss had a significantly higher risk of DLTs [1.29 (1.01–1.66)]. At the start of subsequent CAPOX‐B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss [1.78 (1.06–3.01)] or sarcopenia [1.75 (1.08–2.86)]. After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX‐B [sarcopenia vs. non‐sarcopenic: 0.86 (0.69–1.08) and SMI loss vs. stable/gain: 0.83 (0.65–1.07)]. In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs. Conclusions In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.

Preliminary results from a large scale seroepidemiological study we conducted in 2018, involving 3000 French horses, reveals that equine influenza vaccination is well established, with 90 per cent of the studied population possessing antibody titres above the protection threshold against clinical signs of disease and 60 per cent virus shedding.1 The predominant use in France of the recombinant canarypox virus equine influenza vaccine ProteqFlu-Te (Boehringer Ingelheim/Merial), the only fully updated equine influenza vaccine licensed in the EU with DIVA (differentiating infected from vaccinated animal) capability, allowed us to confirm that the measured equine influenza immunological status was mostly attributed to equine influenza vaccination, with little immunological …

As climate change should lead to an increase in the vulnerability and the sensitivity of forests to extreme climatic events, quantifying and predicting their response to more severe droughts remains a key task for foresters. Furthermore, recent works have suggested that tree diversity may affect forest ecosystem functioning, including their response to extreme events. In this study we aimed at testing whether the growth response of forest stands to stressful climatic events varied between mixed and monospecific stands, under various environmental conditions. We focused on beech-fir forests (Fagus sylvatica [L.] and Abies alba [L.]) and beech-oak forests (F. sylvatica [L.] and Quercus pubescent [L.]) in the French Alps. We used a dendrochronological dataset sampled in forest plots organized by triplets (one mixture and two monospecific stands) distributed in six sites along a latitudinal gradient. We tested (1) whether stand diversity (two-species stands vs monospecific stands) modulates the stands’ response to drought events in terms of productivity, (2) whether species identity may drive the diversity effect on resistance and recovery, and (3) whether this can be explained by interspecific interactions. We found that (1) interspecific differences in response to extreme drought events (possibly due to interspecific differences in hydraulic characteristics) can induce a mixture effect on stand growth, although it appeared (2) to be strongly depending on species identity (positive effect only found for beech-fir mixed stands), while (3) there were no significant non-additive effects of diversity on stand resistance and recovery, except for some specific cases. Overall, our study shows that promoting selected mixed stands management may buffer extreme drought effect on stand productivity.

Background: Evidence is increasing that severe skeletal muscle (SM) loss (sarcopenia) is associated with reduced overall survival (OS) in mCRC pts. We recently found, using data of the randomized phase 3 CAIRO3 study (Lancet, 2015), that SM loss was related to shorter time to progression during first line maintenance treatment (Tx) with capecitabine+bevacizumab (CAP-B) or observation. Subsequently, SM loss during more intensive reinduction Tx by adding oxaliplatin (CAPOX-B) was associated to shorter overall survival (ASCO, 2017). As a potential risk factor for reduced survival we explored whether sarcopenia was associated with dose reductions at start of CAPOX-B reinduction Tx and dose limiting toxicities (DLT) during CAPOX-B reinduction Tx. Methods: Here, CAIRO3 pts were included who received CAPOX-B reinduction Tx. DLT were defined as any dose delay, reduction, or discontinuation of systemic treatment because of reported CTCAE (v3.0) toxicities at start or during Tx. Poisson regression models adjusted for relevant confounders were used to study the association between sarcopenia and DLT. Results: A total of 254 pts received CAPOX-B reinduction Tx. 39% of pts were sarcopenic and compared to normal SM pts we found no statistically significant differences in age and sex (sarcopenic vs normal SM: mean age 63.6±9.1 vs 61.9±8.5 yrs, p=.20 and 39% vs 31% females p=.31). BMI was significantly lower in sarcopenic pts, but pts were on average still overweight (25.9±3.8 vs 27.2±3.8 p=.01). Overall, 67% experienced ≥1 DLT. At start of CAPOX-B, 25% had already received a dose reduction and the risk of dose reduction at start was significantly higher for sarcopenic compared to normal SM pts (RR 1.8 95%CI 1.08-2.90). Despite more frequent dose reductions at start, sarcopenic pts did not have a significantly lower risk of DLT during CAPOX-B Tx (RR sarcopenic vs normal SM pts 0.86 95% CI 0.46-1.45). Conclusions: Sarcopenia was significantly associated with dose reductions at start of CAPOX-B reinduction Tx, and not with DLT during CAPOX-B reinduction Tx. Possible explanations for dose reductions at start might be more frequent toxicities during previous Tx including neuropathy.

The authors gratefully acknowledge all members of the animal facilities from Theix's INRA center for their valuable assistance in conducting this study; We investigated the impact of vitamin D deficiency and repletion on muscle anabolism in old rats. Animals were fed a control (1 IU vitamin D3/g, ctrl, n=20) or a vitamin D-depleted diet (VDD; 0 IU, n=30) for 6 months. A subset was thereafter sacrificed in the control (ctrl6) and depleted groups (VDD6). Remaining control animals were kept for 3 additional months on the same diet (ctrl9), while a part of VDD rats continued on a depleted diet (VDD9) and another part was supplemented with vitamin D (5 IU, VDS9). The ctr16 and VDD6 rats and the ctr19, VDD9 and VDS9 rats were 21 and 24 months old, respectively. Vitamin D status, body weight and composition, muscle strength, weight and lipid content were evaluated. Muscle protein synthesis rate (fractional synthesis rate; FSR) and the activation of controlling pathways were measured. VDD reduced plasma 25(OH)-vitamin D, reaching deficiency (

International audience; While the spatial pattern of the highly pathogenic avian influenza H5N1 virus has been studied throughout Southeast Asia, little is known on the spatial risk factors for avian influenza in Africa. In the present paper, we combined serological data from poultry and remotely sensed environmental factors in the Lake Alaotra region of Madagascar to explore for any association between avian influenza and landscape variables. Serological data from cross-sectional surveys carried out on poultry in 2008 and 2009 were examined together with a Landsat 7 satellite image analysed using supervised classification. The dominant landscape features in a 1-km buffer around farmhouses and distance to the closest water body were extracted. A total of 1,038 individual bird blood samples emanating from 241 flocks were analysed, and the association between avian influenza seroprevalence and these landcape variables was quantified using logistic regression models. No evidence of the presence of H5 or H7 avian influenza subtypes was found, suggesting that only low pathogenic avian influenza (LPAI) circulated. Three predominant land cover classes were identified around the poultry farms: grassland savannah, rice paddy fields and wetlands. A significant negative relationship was found between LPAI seroprevalence and distance to the closest body of water. We also found that LPAI seroprevalence was higher in farms characterised by predominant wetlands or rice landscapes than in those surrounded by dry savannah. Results from this study suggest that if highly pathogenic avian influenza H5N1 virus were introduced in Madagascar, the environmental conditions that prevail in Lake Alaotra region may allow the virus to spread and persist.

ScopeIn recent years, there has been a growing body of evidence pointing to an effect of vitamin D on muscle mass and function. Our aim was to investigate the combined effect of 1,25(OH)(2)-vitamin D-3 (1,25(OH)(2)D-3) with anabolic factors insulin and leucine on protein fractional synthesis rate (FSR) and regulation in the mouse C2C12 myotube. Methods and resultsAfter differentiation, myotubes were cultured in 1,25(OH)(2)D-3 solutions at 0, 1, or 10 nM for 72 h. Cells were treated by l-[1-C-13]valine and puromycin in presence or not of leucine and insulin, and protein FSR was determined by measuring tracer enrichments and puromycin incorporation in proteins, respectively. Protein expression and phosphorylation state of insulin receptor (IR), Akt, GSK3, mTOR, p70 S6 kinase, rpS6, and 4EBP1 were measured by Western blot. Transcript levels of IR and 1,25(OH)(2)D-3 receptor (VDR) were determined by qPCR. 1,25(OH)(2)D-3 (10 nM) with leucine and insulin increased protein FSR in C2C12 myotubes (14-16%). IR and VDR mRNA expression was increased with 1,25(OH)(2)D-3 treatment. The Akt/mTOR-dependent pathway was activated by insulin and leucine and further enhanced by 1,25(OH)(2)D-3. Conclusion1,25(OH)(2)D-3 sensitizes the Akt/mTOR-dependant pathway to the stimulating effect of leucine and insulin, resulting in a further activation of protein synthesis in murine C2C12 skeletal myotubes.