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Ecosystems are under pressure from multiple human disturbances whose impact may vary depending on environmental context. We experimentally evaluated variation in the separate and combined effects of the loss of a key functional group (canopy algae) and physical disturbance on rocky shore ecosystems at nine locations across Europe. Multivariate community structure was initially affected (during the first three to six months) at six locations but after 18 months, effects were apparent at only three. Loss of canopy caused increases in cover of non-canopy algae in the three locations in southern Europe and decreases in some northern locations. Measures of ecosystem functioning (community respiration, gross primary productivity, net primary productivity) were affected by loss of canopy at five of the six locations for which data were available. Short-term effects on community respiration were widespread, but effects were rare after 18 months. Functional changes corresponded with changes in community structure and/or species richness at most locations and times sampled, but no single aspect of biodiversity was an effective predictor of longer-term functional changes. Most ecosystems studied were able to compensate in functional terms for impacts caused by indiscriminate physical disturbance. The only consistent effect of disturbance was to increase cover of non-canopy species. Loss of canopy algae temporarily reduced community resistance to disturbance at only two locations and at two locations actually increased resistance. Resistance to disturbance-induced changes in gross primary productivity was reduced by loss of canopy algae at four locations. Location-specific variation in the effects of the same stressors argues for flexible frameworks for the management of marine environments. These results also highlight the need to analyse how species loss and other stressors combine and interact in different environmental contexts.

Aim To investigate some of the environmental variables underpinning the past and present distribution of an ecosystem engineer near its poleward range edge. Location >500 locations spanning >7,400 km around Ireland. Methods We collated past and present distribution records on a known climate change indicator, the reef‐forming worm Sabellaria alveolata (Linnaeus, 1767) in a biogeographic boundary region over 182 years (1836–2018). This included repeat sampling of 60 locations in the cooler 1950s and again in the warmer 2000s and 2010s. Using species distribution modelling, we identified some of the environmental drivers that likely underpin S. alveolata distribution towards the leading edge of its biogeographical range in Ireland. Results Through plotting 981 records of presence and absence, we revealed a discontinuous distribution with discretely bounded sub‐populations, and edges that coincide with the locations of tidal fronts. Repeat surveys of 60 locations across three time periods showed evidence of population increases, declines, local extirpation and recolonization events within the range, but no evidence of extensions beyond the previously identified distribution limits, despite decades of warming. At a regional scale, populations were relatively stable through time, but local populations in the cold Irish Sea appear highly dynamic and vulnerable to local extirpation risk. Contemporary distribution data (2013–2018) computed with modelled environmental data identified specific niche requirements which can explain the many distribution gaps, namely wave height, tidal amplitude, stratification index, then substrate type. Main conclusions In the face of climate warming, such specific niche requirements can create environmental barriers that may prevent species from extending beyond their leading edges. These boundaries may limit a species’ capacity to redistribute in response to global environmental change.

Marine organisms inhabiting environments where p CO 2 /pH varies naturally are suggested to be relatively resilient to future ocean acidification. To test this hypothesis, the effect of elevated p CO 2 was investigated in the articulated coralline red alga Corallina elongata from an intertidal rock pool on the north coast of Brittany (France), where p CO 2 naturally varied daily between 70 and 1000 μatm. Metabolism was measured on algae in the laboratory after they had been grown for 3 weeks at p CO 2 concentrations of 380, 550, 750 and 1000 μatm. Net and gross primary production, respiration and calcification rates were assessed by measurements of oxygen and total alkalinity fluxes using incubation chambers in the light and dark. Calcite mol % Mg/Ca ( m Mg/Ca) was analysed in the tips, branches and basal parts of the fronds, as well as in new skeletal structures produced by the algae in the different p CO 2 treatments. Respiration, gross primary production and calcification in light and dark were not significantly affected by increased p CO 2 . Algae grown under elevated p CO 2 (550, 750 and 1000 μatm) formed fewer new structures and produced calcite with a lower m Mg/Ca ratio relative to those grown under 380 μatm. This study supports the assumption that C. elongata from a tidal pool, where p CO 2 fluctuates over diel and seasonal cycles, is relatively robust to elevated p CO 2 compared to other recently investigated coralline algae.

A key challenge in research linking biodiversity and ecosystem functioning is to incorporate the trophic interactions that characterise natural systems. There is a particular shortage of studies investigating consumer species richness and composition (identity) effects in the context of ecosystem development (or succession). We manipulated the richness and composition of an assemblage of molluscan grazers (Patella ulyssiponensis,Gibbula umbilicalisandLittorina littorea) added to rock pools denuded of existing biota. We created monocultures and all possible multispecies combinations in a substitutive design, and ran a field experiment for 13 mo. We used 2 separate nested analyses to isolate the roles of species richness, species composition nested within levels of species richness and the specific effect of the limpetP. ulyssiponensis, a putative key species. We found no evidence that the biomass or productivity of the developing macroalgal assemblage was affected by grazer richness or species composition nested within richness levels. Rather, the presence ofP. ulyssiponensis, irrespective of the presence of other grazer species, acted to suppress mean values of these response variables. Biomass and productivity were not strongly related, showing that they provide unique information on ecosystem functioning in this system. Macroalgal species richness was also reduced byP. ulyssiponensis, and correlated positively with macroalgal biomass, indicating a link between these response variables. Macroalgal species composition was largely insensitive to either species richness or the presence ofP. ulyssiponensis, but responded to particular combinations of species within levels of these factors. The key role ofP. ulyssiponensisin determining ecosystem functioning is apparent from our results, but we note that consumer species richness may play an important role under more heterogeneous conditions.

Marine organisms inhabiting environments where pC[O.sub.2]/pH varies naturally are suggested to be relatively resilient to future ocean acidification. To test this hypothesis, the effect of elevated pC[O.sub.2] was investigated in the articulated coralline red alga Corallina elongata from an intertidal rock pool on the north coast of Brittany (France), where pC[O.sub.2] naturally varied daily between 70 and 1000 µatm. Metabolism was measured on algae in the laboratory after they had been grown for 3 weeks at pC[O.sub.2] concentrations of 380, 550, 750 and 1000 µatm. Net and gross primary production, respiration and calcification rates were assessed by measurements of oxygen and total alkalinity fluxes using incubation chambers in the light and dark. Calcite mol % Mg/Ca (mMg/Ca) was analysed in the tips, branches and basal parts of the fronds, as well as in new skeletal structures produced by the algae in the different pC[O.sub.2] treatments. Respiration, gross primary production and calcification in light and dark were not significantly affected by increased pC[O.sub.2]. Algae grown under elevated pC[O.sub.2] (550, 750 and 1000 µatm) formed fewer new structures and produced calcite with a lower mMg/Ca ratio relative to those grown under 380 µatm. This study supports the assumption that C. elongata from a tidal pool, where pC[O.sub.2] fluctuates over diel and seasonal cycles, is relatively robust to elevated pC[O.sub.2] compared to other recently investigated coralline algae.

Background Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10 , overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. Methods Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111 In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90 Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90 Y-OTSA-101 for radionuclide therapy. Results From January 2012 to June 2015, 20 pts. (median age 43 years [21–67]) with advanced SS were enrolled. Even though 111 In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90 Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. Conclusions Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111 In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90 Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90 Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. Trial registration The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β1-adrenoceptor antagonist with a β2-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg per day. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.

Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed.