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The epaulette shark, Hemiscyllium ocellatum, is a small, reef-dwelling, benthic shark that—using its paired fins—can walk, both in and out of water. Within the reef flats, this species experiences short periods of elevated CO2 and hypoxia as well as fluctuating temperatures as reef flats become isolated with the outgoing tide. Past studies have shown that this species is robust (i.e., respiratory and metabolic performance, behavior) to climate change-relevant elevated CO2 levels as well as hypoxia and anoxia tolerant. However, epaulette shark embryos reared under ocean warming conditions hatch earlier and smaller, with altered patterns and coloration, and with higher metabolic costs than their current-day counterparts. Findings to date suggest that this species has adaptations to tolerate some, but perhaps not all, of the challenging conditions predicted for the 21st century. As such, the epaulette shark is emerging as a model system to understand vertebrate physiology in changing oceans. Yet, few studies have investigated the kinematics of walking and swimming, which may be vital to their biological fitness, considering their habitat and propensity for challenging environmental conditions. Given that neonates retain embryonic nutrition via an internalized yolk sac, resulting in a bulbous abdomen, while juveniles actively forage for worms, crustaceans, and small fishes, we hypothesized that difference in body shape over early ontogeny would affect locomotor performance. To test this, we examined neonate and juvenile locomotor kinematics during the three aquatic gaits they utilize—slow-to-medium walking, fast walking, and swimming—using 13 anatomical landmarks along the fins, girdles, and body midline. We found that differences in body shape did not alter kinematics between neonates and juveniles. Overall velocity, fin rotation, axial bending, and tail beat frequency and amplitude were consistent between early life stages. Data suggest that the locomotor kinematics are maintained between neonate and juvenile epaulette sharks, even as their feeding strategy changes. Studying epaulette shark locomotion allows us to understand this—and perhaps related—species’ ability to move within and away from challenging conditions in their habitats. Such locomotor traits may not only be key to survival, in general, as a small, benthic mesopredator (i.e., movements required to maneuver into small reef crevices to avoid aerial and aquatic predators), but also be related to their sustained physiological performance under challenging environmental conditions, including those associated with climate change—a topic worthy of future investigation.

One hundred twenty crossbred steers were allotted to six weight blocks. Within each block, steers were allotted to one of four pens in a randomized complete block design (5 head per pen, 24 total pens). Treatments were low forage control diets (LFC) or high forage diets supplemented with soybean oil (HFO), without or with anabolic implant in 2 × 2 factorial arrangement. As compared with LFC, HFO reduced dry matter intake and average daily gain, without affecting the gain:feed ratio. Feeding HFO also decreased dressing yield and backfat thickness, with no impact on the longissimus dorsi area and Warner-Bratzler shear force. Meat from steers fed HFO contained greater relative proportion of cis-9, cis-12 18:2, cis-9, trans-11 18:2, and cis-9, cis-12, cis-15 18:3 as compared with LFC. Implanted steers had greater dry matter intake, average daily gain, and gain:feed ratio. Implants improved dressing yield, tended to increase the longissimus dorsi area, decreased backfat thickness, and increased meat Warner-Bratzler shear force. Meat from implanted steers contained greater relative concentration of cis-9, cis-12 18:2 and cis-9, cis-12, cis-15 18:3, without affecting cis-9, trans-11 18:2, as compared with non-implanted animals. No interaction of diet by implant was observed for these variables.

Given the vulnerability of early life stages to predation, many species elicit antipredator responses to predator-associated cues (e.g. alarm cues, necromones). However, the response used may vary between predatory stimuli. Antipredator responses, while ostensibly enhancing survival, are costly, either resulting in missed opportunities (e.g. foraging) through decreased activity and crypsis strategies (i.e. predator avoidance) or incurring high energetic costs through the use of generalized stress responses and increased activity (i.e. predator evasion). Juvenile Port Jackson sharks, Heterodontus portusjacksoni, were exposed to the scent of dead conspecifics (conspecific necromones) coupled with a simulated predator chase to determine the energetic effects of a predator ‘attack’. When exposed to necromone cues alone, juvenile sharks depressed their oxygen uptake rates for up to 3 h following exposure, indicating that they used crypsis to avoid detection by predators. However, when forced to swim and evade a predator, sharks increased their oxygen uptake rates, regardless of whether or not they were exposed to predatory cues. Juvenile sharks exposed to conspecific necromones may primarily rely on strategies that depress activity to avoid detection by predators; however, if forced to evade capture they use energetically costly escape strategies similar to typical ‘fight or flight’ responses.

Highly variable thermal environments, such as coral reef flats, are challenging for marine ectotherms and are thought to invoke the use of behavioural strategies to avoid extreme temperatures and seek out thermal environments close to their preferred temperatures. Common to coral reef flats, the epaulette shark (Hemiscyllium ocellatum) possesses physiological adaptations to hypoxic and hypercapnic conditions, such as those experienced on reef flats, but little is known regarding the thermal strategies used by these sharks. We investigated whether H. ocellatum uses behavioural thermoregulation (i.e., movement to occupy thermally favourable microhabitats) or tolerates the broad range of temperatures experienced on the reef flat. Using an automated shuttlebox system, we determined the preferred temperature of H. ocellatum under controlled laboratory conditions and then compared this preferred temperature to 6 months of in situ environmental and body temperatures of individual H. ocellatum across the Heron Island reef flat. The preferred temperature of H. ocellatum under controlled conditions was 20.7 +/- 1.5 degrees C, but the body temperatures of individual H. ocellatum on the Heron Island reef flat mirrored environmental temperatures regardless of season or month. Despite substantial temporal variation in temperature on the Heron Island reef flat (15-34 degrees C during 2017), there was a lack of spatial variation in temperature across the reef flat between sites or microhabitats. This limited spatial variation in temperature creates a low-quality thermal habitat limiting the ability of H. ocellatum to behaviourally thermoregulate. Behavioural thermoregulation is assumed in many shark species, but it appears that H. ocellatum may utilize other physiological strategies to cope with extreme temperature fluctuations on coral reef flats. While H. ocellatum appears to be able to tolerate acute exposure to temperatures well outside of their preferred temperature, it is unclear how this, and other, species will cope as temperatures continue to rise and approach their critical thermal limits. Understanding how species will respond to continued warming and the strategies they may use will be key to predicting future populations and assemblages.

Many species with broad distributions are exposed to different thermal regimes which often select for varied phenotypes. This intraspecific variation is often overlooked but may be critical in dictating the vulnerability of different populations to environmental change. We reared Port Jackson shark (Heterodontus portusjacksoni) eggs from two thermally discrete populations (i.e. Jervis Bay and Adelaide) under each location's present-day mean temperatures, predicted end-of-century temperatures and under reciprocal-cross conditions to establish intraspecific thermal sensitivity. Rearing temperatures strongly influenced ṀO2 Max and critical thermal limits, regardless of population, indicative of acclimation processes. However, there were significant population-level effects, such that Jervis Bay sharks, regardless of rearing temperature, did not exhibit differences in ṀO2 Rest , but under elevated temperatures exhibited reduced maximum swimming activity with step-wise increases in temperature. In contrast, Adelaide sharks reared under elevated temperatures doubled their ṀO2 Rest , relative to their present-day temperature counterparts; however, maximum swimming activity was not influenced. With respect to reciprocal-cross comparisons, few differences were detected between Jervis Bay and Adelaide sharks reared under ambient Jervis Bay temperatures. Similarly, juveniles (from both populations) reared under Adelaide conditions had similar thermal limits and swimming activity (maximum volitional velocity and distance) to each other, indicative of conserved acclimation capacity. However, under Adelaide temperatures, the ṀO2 Rest of Jervis Bay sharks was greater than that of Adelaide sharks. This indicates that the energetics of cooler water population (Adelaide) is likely more thermally sensitive than that of the warmer population (Jervis Bay). While unique to elasmobranchs, these data provide further support that by treating species as static, homogeneous populations, we ignore the impacts of thermal history and intraspecific variation on thermal sensitivity. With climate change, intraspecific variation will manifest as populations move, demographics change or extirpations occur, starting with the most sensitive populations.

The consequences of human influence can arise in vertebrates as primary, secondary, or even tertiary stressors and may be especially detrimental for slow growing species with long generation times (i.e., K-selected species). Here, we review the impacts of both direct and indirect human interactions on the reproductive biology of elasmobranchs. Within direct human influence, capture-induced stress from fisheries bycatch and poor coastal management practices leading to habitat destruction and pollution are among the most impactful on elasmobranch reproduction. Capture-induced stress has been shown to negatively influence offspring and reproductive capacity via capture-induced parturition as well as by disrupting the reproductive physiology of adults. Habitat degradation impacts essential ecosystems that are necessary for the development of young elasmobranchs. Pollutants such as heavy metals, legacy pesticides, and flame retardants have been traced through elasmobranch reproduction; however, the long-term effects of these exogenous chemicals are yet to be determined. Furthermore, within indirect human impacts, climate change-mediated influences (e.g., ocean warming and acidification) can impact development, physiological processes, and behavioral patterns necessary for essential tasks such as foraging, growth, reproduction, and ultimately survival. Here, we also present a case study, where data regarding temperature and incubation time from 28 egg-laying elasmobranch species were examined to show relevance of such data in predicting how suitable (e.g., via maximum threshold temperatures) habitats will be for skate and shark development in the coming century. Concomitantly, this information highlights areas for future research that will help inform better management as well as climate change forecasting for this threatened group of aquatic vertebrates.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR)= 1.02 (0.66-1.58), two-sided P= 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR= 0.95 (0.59-1.52), P= 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade =3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Biotin (B

Temperature has a profound effect on all life and a particularly influential effect on ectotherms, such as fishes. Amphibious fishes have a variety of strategies, both physiological and/or behavioural, to cope with a broad range of thermal conditions. This study examined the relationship between prolonged (5 weeks) exposure to a range of temperatures (22, 25, 28, or 32 degrees C) on oxygen uptake rate and movement behaviours (i.e., thermoregulation and emergence) in a common amphibious fish, the barred mudskipper (Periophthalmus argentilneatuis). At the highest temperature examined (32 degrees C, approximately 5 degrees C above their summer average temperatures), barred mudskippers exhibited 33.7-97.7% greater oxygen uptake rates at rest ((M) over dotO(2Rest)), emerged at a higher temperature (CTe; i.e., a modified critical thermal maxima (CTMax) methodology) of 41.3 +/- 0.3 degrees C relative to those maintained at 28, 25, or 22 degrees C. The 32 degrees C-maintained fish also ceased movement activity at the highest holding temperature suggesting that prolonged submergence at elevated temperatures is physiologically and energetically stressful to the individual. Using exhaustive exercise protocols with and without air exposure to simulate a predatory chase, the time to recovery was examined for all individuals. When submerged, mudskippers required 2.5x longer recovery time to return to resting oxygen uptake from exhaustive exercise than those fully emerged in air. Oxygen uptake data revealed that air exposure did not accrue oxygen debt, thereby allowing faster return to resting oxygen consumption rates. If the option to emerge was not available, mudskippers preferentially sought more benign water temperatures (26.7 +/- 2.1 degrees C), resembling those experienced by these fish during the Austral autumn, regardless of prolonged exposure higher or lower temperatures. These results add to our understanding of the strategies that amphibious fishes may use to mitigate extra costs associated with living in warm waters, and could be the key to understanding how such species will cope with increasing temperatures in the future.

Young animals, especially those developing within eggs, are extremely vulnerable to predation risk given their immobility, small size and limited functionality of developing sensory systems. Embryos from a range of taxa can detect predator cues and use antipredator responses to reduce risk; however, little is known about this capacity in elasmobranchs, especially regarding olfactory detection. Embryonic Port Jackson sharks (Heterodontus portusjacksoni) were exposed to elasmobranch and teleost odours across key developmental stages to investigate their capacity to detect and discern between cues. Oxygen uptake rates were measured as a proxy for antipredator response and to estimate their energetic costs. Earlier developmental stages exhibited limited responses, regardless of the odour, likely associated with an undeveloped sensory system. However, older shark embryos depressed oxygen uptake rates (i.e. crypsis responses) when exposed to teleost cues, but showed little response to elasmobranch cues. In contrast, hatchlings exhibited minimal responses to teleost cues but a significant increase in oxygen uptake rates when exposed to elasmobranch odours, indicative of a general stress response in preparation for escape. Collectively, our data suggest that embryonic sharks can differentiate between odour cues and elicit various responses, but this ability is limited by their developing sensory capacity.

Wave-induced surge conditions are found in shallow marine ecosystems worldwide; yet, few studies have quantified how cyclical surges may affect free swimming animals. Here, we used a recently adapted respirometry technique to compare the energetic costs of a temperate fish species (Cymatogaster aggregata) swimming against a steady flow versus cyclical unidirectional and bidirectional surges in which unsteady swimming (such as accelerating, decelerating and turning) occurs. Using oxygen uptake (ṀO(2)) as an estimate of energetic costs, our results reveal that fish swimming in an unsteady (i.e. cyclical) unidirectional flow showed no clear increase in costs when compared to a steady flow of the same average speed, suggesting that costs and savings from cyclical acceleration and coasting are near equal. Conversely, swimming in a bidirectional cyclical flow incurred significantly higher energetic costs relative to a steady, constant flow, likely due to the added cost of turning around to face the changing flow direction. On average, we observed a 50% increase in ṀO(2) of fish station holding within the bidirectional flow (227.8 mg O(2) kg(−1) h(−1)) compared to a steady, constant flow (136.1 mg O(2) kg(−1) h(−1)) of the same mean velocity. Given wave-driven surge zones are prime fish habitats in the wild, we suggest the additional costs fish incur by station holding in a bidirectional cyclical flow must be offset by favourable conditions for foraging and reproduction. With current and future increases in abiotic stressors associated with climate change, we highlight the importance of incorporating additional costs associated with swimming in cyclical water flow in the construction of energy budgets for species living in dynamic, coastal habitats.

Wave-induced surge conditions are found in shallow marine ecosystems worldwide; yet, few studies have quantified how cyclical surges may affect free swimming animals. Here, we used a recently adapted respirometry technique to compare the energetic costs of a temperate fish species (Cymatogaster aggregata) swimming against a steady flow versus cyclical unidirectional and bidirectional surges in which unsteady swimming (such as accelerating, decelerating and turning) occurs. Using oxygen uptake (ṀO2) as an estimate of energetic costs, our results reveal that fish swimming in an unsteady (i.e. cyclical) unidirectional flow showed no clear increase in costs when compared to a steady flow of the same average speed, suggesting that costs and savings from cyclical acceleration and coasting are near equal. Conversely, swimming in a bidirectional cyclical flow incurred significantly higher energetic costs relative to a steady, constant flow, likely due to the added cost of turning around to face the changing flow direction. On average, we observed a 50% increase in ṀO2 of fish station holding within the bidirectional flow (227.8 mg O2 kg−1 h−1) compared to a steady, constant flow (136.1 mg O2 kg−1 h−1) of the same mean velocity. Given wave-driven surge zones are prime fish habitats in the wild, we suggest the additional costs fish incur by station holding in a bidirectional cyclical flow must be offset by favourable conditions for foraging and reproduction. With current and future increases in abiotic stressors associated with climate change, we highlight the importance of incorporating additional costs associated with swimming in cyclical water flow in the construction of energy budgets for species living in dynamic, coastal habitats.

Background Exclusive enteral nutrition (EEN) is an established induction treatment for active Crohn’s disease (CD) with a proposed mechanism of action involving the gut microbiome. We have previously shown that CD-TREAT diet, a food-based diet with similar dietary profile to EEN, improves rat ileitis and replicates the effect of EEN on the gut microbiome of healthy volunteers and animal models. Here, we test the efficacy of CD-TREAT diet to induce clinical remission in active CD. Methods This is an open-label study in children (wPCDAI≥12.5) and adults (HBI≥5) with active CD. Primary outcome was clinical response (wPCDAI fall≥17.5; HBI fall≥3) or clinical remission (wPCDAI< 12.5; HBI Results 25 children, [age, 14.4 (12.5,15.7) years] and 32 adults, [age, 32.6 (24.2,43.9) years] were treated. 7 (12%) failed treatment and n=10 (18%) dropped out during the first 2 weeks of treatment due to palatability issues. In patients who completed 8 weeks of CD-TREAT course (n=40), 85% and 78% achieved clinical response and remission, respectively. CD-TREAT diet improved QoL in children [IMPACT-III score, baseline: 136 (122,143) vs 8weeks: 148 (133,153), p50% FC reduction. Median FC levels decreased significantly? in the group of patients (n=22) who had undetectable GIP at 4 or 8 weeks [mg/kg FC, baseline: 1190 (361,1129); 8weeks: 534 (92,1230), p Conclusion CD-TREAT diet improved disease activity indices and QoL in the majority of patients who completed treatment and decreased FC in those who were most likely to be compliant. Future RCT should aim to compare CD-TREAT with other induction treatments and improve meal variety and palatability to improve compliance and reduce drop-out rates.

Following a lack of detected change in white shark Carcharodon carcharias L. 1758 diet and nutritional condition attributed to the interaction with the cage-diving industry, Lusseau and Derous (Tourism Management, 2019, 75, 547-549) cautioned the use of muscle lipids and fatty acids in this context, advocating for other biomarkers. This study provides additional evidence from peer-reviewed literature to contend the usefulness of elasmobranch muscle fatty acid profiles to detail diet and habitat use. It also presents findings from a controlled experiment on captive Port Jackson sharks Heterodontus portusjacksoni (Meyer 1793) whereby long-term (daily for 33 days) 3 min exhaustive chase exercise changed muscle lipid class profiles, supporting its use to infer nutritional condition after activities such as interactions with wildlife tourism operators. Conversely, the unaltered muscle fatty acid and lipid content suggests their use in trophic ecology is not confounded by activities such as interacting with tourism operators, remaining useful biomarkers to investigate diet and habitat use.

Introduction L’utilisation des anti-PD1/PDL1 en oncologie thoracique est associe a un large eventail d’effets secondaires immuno-medies. Les atteintes neurologiques concerneraient 4,2 % des patients avec des presentations cliniques tres variees. L’objectif de ce travail est d’analyser les caracteristiques cliniques et evolutives des patients avec cancer bronchopulmonaire developpant une encephalite immuno-medie sous anti-PD1/PDL1. Methodes Il s’agit d’une etude retrospective multicentrique analysant les caracteristiques cliniques, biologiques, therapeutiques et evolutives de patients ayant presente une encephalite pour laquelle une imputabilite directe de l’immunotherapie a ete retenue. Resultats L’analyse porte sur 7 patients, inclus par 5 centres : tous de sexe masculin, tous tabagiques, âge moyen : 64,6 (48–77) ans, histologie : adenocarcinome dans 86 % des cas. Respectivement 4 et 3 patients sont traites par immunotherapie en 1er et 2e ligne (pembrolizumab n = 3, nivolumab n = 3, atezolizumab n = 1). Un seul patient presentait des localisations metastatiques cerebrales a l’initiation de l’immunotherapie. Le nombre moyen d’injections d’immunotherapie avant l’apparition des symptomes neurologiques etait de 7 (1–22). Les signes neurologiques les plus frequents etaient : confusion (71 %), syndrome extra-pyramidal (57 %) fievre (43 %). Les analyses du liquide cephalorachidien retrouvaient un liquide lymphocytaire, une hyperproteinorachie et une hyperglycorachie dans 86 % des cas. L’ensemble des analyses bacteriologiques et virologiques etait toute negative. Tous les patients ont eu une IRM cerebrale avec injection de gadolinium considere dans tous les cas comme normale sauf chez un patient avec des hypersignaux FLAIR au niveau de la face interne des lobes temporaux evocateurs d’une encephalite limbique ; 2 patients ont necessite des soins en reanimation. Tous les patients ont ete traites par corticotherapie avec des schemas de traitement tres variables et un delai moyen d’introduction de 9,8 jours (6–18). Dans 6 cas cette corticotherapie a permis une amelioration rapide de la symptomatologie sans sequelles. Le dernier patient, chez qui le delai d’introduction de la corticotherapie a ete le plus long est decede. L’immunotherapie n’a ete reprise chez aucun des patients. Conclusion Les encephalites immuno-medies constituent une complication rare mais grave de l’immunotherapie anti-PD1/PDL1 avec un pronostic qui est bon lorsque la prise en charge, en particulier l’administration de la corticotherapie est precoce.

Ocean warming can induce physiological and behavioural effects in marine predators that can cascade through ecosystems. A lack of understanding of the effects of elevated temperature on shark behaviour remains an impediment to forecasting ecosystem-wide impacts. Port Jackson shark eggs were incubated and reared at current and projected end-of-century temperatures (+ 3 °C). We tested juvenile’s learning ability with a quantity discrimination task. The mortality rate of sharks reared in warm water was 41.7% compared with no mortality in the present-day sharks. Contrary to expectations, our results suggest that surviving hatchlings from the elevated-temperature group took fewer days to reach learning criterion and had a higher proportion of correct choice compared with hatchlings reared under present conditions. Additionally, this is the first data suggesting that sharks can discriminate different quantities. Our results seem to indicate that learning and behaviour might play a role in allowing elasmobranchs to overcome some of the deleterious effects of climate warming, but further research is needed to fully comprehend these findings. The world’s oceans are warming at an unprecedented rate, which will impair development and alter physiological and behavioural traits in marine predators. Learning may play a leading role in allowing apex and mesopredators to adapt to a rapidly changing environment; however, no studies have tested the impacts of ocean warming in their learning abilities. We incubated and reared Port Jackson shark eggs at current and projected end-of-century temperatures (+ 3 °C). Contrary to expectations, surviving juveniles from the elevated-temperature group showed better learning performance, potentially adding learning ability to a growing list of traits that incubation temperature can modify during early development in marine predators. Our results were not entirely negative; it is possible that increased learning performance might allow apex and mesopredators to increase foraging efficiency and match increased energetic demands caused by elevated temperature.

International audience; BackgroundProgrammed cell death-ligand 1 (PD-L1) is a checkpoint receptor that facilitates immune evasion by tumor cells, through interaction with programmed cell death-1 (PD-1), a receptor expressed by T-cells. Durvalumab is an anti-PD-L1 monoclonal antibody that blocks PD-L1 interaction with PD-1 on T-cells, countering the tumor's immune-evading tactics. Phase I/II studies demonstrated durable responses and manageable tolerability in heavily pre-treated patients with non-small cell lung cancer (NSCLC).MethodsThis phase II study is designed to administrate three durvalumab IV infusions (10 mg/kg at day 1, 15, 29) before surgery, to patients with pathologically confirmed NSCLC, clinical stage IB (> 4 cm) or stage II, ≥ 18 years of age, WHO performans status 0–1, without selection on PD-L1 expression. Preoperative chemotherapy and radiation therapy are not permitted. The primary objective is feasibility of complete surgical resection. Major pathological response on surgical tissue, defined as 10% or less remaining tumor cells, will be a secondary objective. Additional secondary objectives include tolerance, adverse effects, delay between start of treatment and surgery, response rate (RECIST 1.1), metabolic response rate, postoperative adverse events, disease-free survival and overall survival. A rate of complete resection < 85% (P0) is considered unacceptable. P1 hypothesis is of 95%, and with a study power of 90% and an alpha risk of 5% (two-steps Fleming's procedure), 81 patients are required.Expected resultsTo establish whether neoadjuvant immunotherapy is feasible and could improve the survival of patients with early-stage NSCLC.; État des connaissancesProgrammed cell death-ligand 1 (PD-L1) est une protéine membranaire facilitant l’échappement tumoral vis-à-vis de l’immunité. Le durvalumab est un anticorps monoclonal bloquant l’interaction PD-L1/PD-1 entre lymphocytes T et cellules tumorales, ayant montré des réponses durables et une toxicité acceptable en phase I/II dans les cancers bronchiques non à petites cellules (CBNPC) métastatiques.MéthodesDans cette étude de phase II, 3 perfusions de durvalumab (10 mg/kg à j1, j15, j29) sont administrées en néo-adjuvant à des patients ≥ 18 ans, indice de performance (PS) 0–1, ayant un CBNPC de stade clinique IB (> 4 cm) ou II. La chimiothérapie et la radiothérapie préopératoire ne sont pas permises. L’objectif principal est la faisabilité d’une résection chirurgicale complète. Un taux de résection complète < 85 % (P0) est considéré comme inacceptable. Avec une hypothèse P1 de 95 %, une puissance de 90 % et un risque alpha de 5 %, 81 patients sont nécessaires. La réponse histologique majeure (≤ 10 % de cellules tumorales résiduelles sur la pièce opératoire) est un objectif secondaire. Les autres objectifs sont le délai entre traitement et chirurgie, les taux de réponse radiologique et métabolique, les évènements indésirables, la survie sans récidive et globale.Résultats attendusL’immunothérapie néo-adjuvante est faisable et pourrait améliorer la survie des CBNPC de stade précoce.

{Extract} The transition from swimming to walking was an important event in the evolution of tetrapods. To understand this transition, researchers have studied movement in many extinct and extant aquatic and semi-aquatic species. The epaulette shark Hemiscillum ocellatum uses slow-to-medium walking, fast walking, and swimming forms of aquatic locomotion. We described kinematic differences between the three gaits in neonate (n=6) and juvenile (n=6) sharks hatched and reared in the laboratory. Neonates retain nutrition from an internal yolk until they develop a consistent feeding schedule (~35d post-hatch). They are then classified as juveniles, foraging for worms, crustaceans, and small fish. We hypothesized that changes in diet and feeding habits would affect gait performance between neonates and juveniles. Using video tracking software and 13 anatomical landmarks along the fins, girdles, and body mid-line, whole body velocity, duty factor, fin frequency, girdle rotation, and body curvature were calculated to identify characteristic movements of the gaits for each shark. Velocity was greater in neonates when compared to juveniles across all gaits; however, both groups increased velocity from walking to swimming. Regardless of gait, pelvic girdles had a greater range of motion than pectoral girdles for both neonates and juveniles. In juveniles, regardless of gait, the contralateral sides of the pectoral and pelvic girdles were synchronized during lateral excursions. Neonates, however, exhibited overlapping of ipsilateral sides of the girdles. Understanding the transition from neonate to juvenile locomotory forms in this species could provide insight on the water to land transition of tetrapods.

Certain patients being treated with Suboxone™ or Subutex™ can exhibit very high buprenorphine and low norbuprenorphine concentrations in urine. Very high buprenorphine can interfere with buprenorphine-D4 used as an internal standard, causing errors in norbuprenorphine determination by gas chromatography-mass spectrometry (GC-MS). We used a modified method of Wu et al. to introduce norbuprenorphine-D3 as a separate internal standard for norbuprenorphine. This allowed us to accurately measure norbuprenorphine in neat urine specimens when buprenorphine is present in extremely high concentrations. Laboratories measuring buprenorphine and metabolite by GC-MS may face this problem if their clientele includes patients being treated with other medications that interfere with the cytochrome p450 CYP 3A4-mediated conversion of buprenorphine to norbuprenorphine.

Tropical coral reef flats can be 3–4 °C warmer than surrounding deeper reef slopes, and some experience daily temperature fluctuations of up to 12 °C, which will be exacerbated as global temperatures continue to rise. Epaulette sharks (Hemiscyllium ocellatum), predominantly found on reef flats, may have evolved behavioural and/or physiological strategies to mitigate the effects of these dramatic temperature fluctuations. Here, juvenile sharks were acclimated, for at least 6 weeks, to average summer temperatures (28 °C) or predicted end-of-century summer temperatures (32 °C) to investigate the effects of elevated temperatures on growth, survival, and the use of movement to thermoregulate. In addition, sharks experience seasonal temperature changes; therefore, the upper critical thermal limits were determined for adult, wild sharks during both summer and winter months. We found that regardless of acclimation temperature, juveniles maintained the same food consumption rates (~ 5% body mass every other day), but for those living at 32 °C, this resulted in significantly decreased growth rates (body mass and total length). During winter months, maximum habitat temperatures (~ 24 °C) are far below adult sharks’ critical thermal limits (35.92 ± 0.21 °C). During summer months, maximum habitat temperatures (~ 35 °C) are closer to adult critical thermal limits (38.85 ± 0.31 °C). When estimating thermoregulatory behaviour of juvenile sharks maintained at 28 °C, those sharks examined in winter exhibited no thermoregulatory behaviour, while those examined in summer actively sought to control their thermal exposure, preferring 30.7 ± 1.04 °C (day) and 28.54 ± 0.75 °C (night). Furthermore, after acclimation to predicted end-of-century conditions, these same sharks behaviourally sought out 32.94 ± 0.46 °C (day) and 30.74 ± 0.68 °C (night); despite the cost of decreased growth and/or survival. Sharks maintained in control conditions had a mortality rate of 33% during the initial 90-day period of exposure, while mortality was 100% in those sharks exposed to elevated conditions. Ultimately, as ocean temperatures continue to rise, the distribution and abundance patterns for epaulette sharks and many other coral reef species are likely to change if trade-offs associated with acclimation outweigh the benefits of moving to more favourable habitats.

Climate change is warming the world’s oceans at an unprecedented rate. Under predicted end-of-century temperatures, many teleosts show impaired development and altered critical behaviors, including behavioral lateralisation. Since laterality is an expression of brain functional asymmetries, changes in the strength and direction of lateralisation suggest that rapid climate warming might impact brain development and function. However, despite the implications for cognitive functions, the potential effects of elevated temperature in lateralisation of elasmobranch fishes are unknown. We incubated and reared Port Jackson sharks at current and projected end-of-century temperatures and measured preferential detour responses to left or right. Sharks incubated at elevated temperature showed stronger absolute laterality and were significantly biased towards the right relative to sharks reared at current temperature. We propose that animals reared under elevated temperatures might have more strongly lateralized brains to cope with deleterious effects of climate change on brain development and growth. However, far more research in elasmobranch lateralisation is needed before the significance of these results can be fully comprehended. This study provides further evidence that elasmobranchs are susceptible to the effects of future ocean warming, though behavioral mechanisms might allow animals to compensate for some of the challenges imposed by climate change.

Background Statins are widely prescribed to the elderly in primary prevention (PP) and secondary prevention (SP) of cardiovascular diseases, although data on the benefits of this therapeutic class in patients over 65 years remain rare. They are not harmless because of their serious side-effects, and drug interaction, especially to polymedicated patients. Purpose This study was designed to evaluate statin prescriptions in our hospital. Material and methods This observational study was performed from June to September 2017 in geriatric units. Inclusion criteria were: age over 65 years and statin prescription. Data collected were: cardiovascular risk factors; age at statin introduction; dosage; indication; side-effects’ occurrence; and side-effects’ risk factors. Results In our study, 86 patients were included, with 2.3 [1–4] cardiovascular risk factors per patient. Median age was 83 years (66–98). Statins were prescribed in PP for 34 patients and in SP for 52 (40 after stroke, 12 after myocardial infarction). Statins introduction in patients over 80 years’ old represented 23% of patients (five in PP, 15 in SP). We reported eight cases of side-effects: one hepatic cytolysis, six falls and one fainting fit leading to rhabdomyolysis increased by statins. For those patients, one treatment was discontinued definitively and three temporarily, two had a reduction in dosage and two had no modification. According to current recommendations (French Medicine Agency, European Society of Cardiology), statins in PP could be re-evaluated in 28 patients (82. 4%): three statins’ introduction in patients over 80 years’ old, one with low cardiovascular risk factor (i.e. only one), 17 with important non-cardiovascular comorbidities (i.e. at least three), two with side-effects and five with several of these criteria combined. Besides, statins in SP could be re-evaluated in 53 patients (100%): 23 with low-life expectancy (90 years old’ and above), 24 with low-life expectancy and important comorbidities, three with low-life expectancy and side-effects, and three with several criteria. Conclusion This study leads to a reconsideration of the use of statins in patients over 80 years’ old in order to limit iatrogenic risks. We will propose prescribers to re-evaluate treatment when it is not appropriate. Further studies could allow the definition of precise limits in the use of statins in patients over 80 years’ old and to create a score to guide the decision. No conflict of interest