Penguin biogeography along the West Antarctic Peninsula: Testing the canyon hypothesis with Palmer LTER observations

The West Antarctic Peninsula (WAP) is home to large breeding colonies of the ice-dependent Antarctic Adélie penguin (Pygoscelis adeliae). Although the entire inner continental shelf is highly productive, with abundant phytoplankton and krill populations, penguin colonies are distributed heterogeneously along the WAP (Ducklow et al., 2013, in this issue). This ecological conundrum targets a long-standing question of interest: what environmental factors structure the locations of Adélie penguin "hot spots" throughout the WAP

Central place foragers select ocean surface convergent features despite differing foraging strategies

Discovering the predictors of foraging locations can be challenging, and is often the critical missing piece for interpreting the ecological significance of observed movement patterns of predators. This is especially true in dynamic coastal marine systems, where planktonic food resources are diffuse and must be either physically or biologically concentrated to support upper trophic levels. In the Western Antarctic Peninsula, recent climate change has created new foraging sympatry between Adélie (Pygoscelis adeliae) and gentoo (P. papua) penguins in a known biological hotspot near Palmer Deep canyon. We used this recent sympatry as an opportunity to investigate how dynamic local oceanographic features affect aspects of the foraging ecology of these two species. Simulated particle trajectories from measured surface currents were used to investigate the co-occurrence of convergent ocean features and penguin foraging locations. Adélie penguin diving activity was restricted to the upper mixed layer, while gentoo penguins often foraged much deeper than the mixed layer, suggesting that Adélie penguins may be more responsive to dynamic surface convergent features compared to gentoo penguins. We found that, despite large differences in diving and foraging behavior, both shallow-diving Adélie and deeper-diving gentoo penguins strongly selected for surface convergent features. Furthermore, there was no difference in selectivity for shallow- versus deep-diving gentoo penguins. Our results suggest that these two mesopredators are selecting surface convergent features, however, how these surface signals are related to subsurface prey fields is unknown

Winter and spring controls on the summer food web of the coastal West Antarctic Peninsula

Understanding the mechanisms by which climate variability affects multiple trophic levels in food webs is essential for determining ecosystem responses to climate change. Here we use over two decades of data collected by the Palmer Long Term Ecological Research program (PAL-LTER) to determine how large-scale climate and local physical forcing affect phytoplankton, zooplankton and an apex predator along the West Antarctic Peninsula (WAP). We show that positive anomalies in chlorophyll-a (chl-a) at Palmer Station, occurring every 4-6 years, are constrained by physical processes in the preceding winter/spring and a negative phase of the Southern Annular Mode (SAM). Favorable conditions for phytoplankton included increased winter ice extent and duration, reduced spring/summer winds, and increased water column stability via enhanced salinity-driven density gradients. Years of positive chl-a anomalies are associated with the initiation of a robust krill cohort the following summer, which is evident in Adelie penguin diets, thus demonstrating tight trophic coupling. Projected climate change in this region may have a significant, negative impact on phytoplankton biomass, krill recruitment and upper trophic level predators in this coastal Antarctic ecosystem

Penguin Biogeography Along the West Antarctic Peninsula Testing the Canyon Hypothesis with Palmer LTER Observations

The West Antarctic Peninsula (WAP) is home to large breeding colonies of the ice-dependent Antarctic Adélie penguin (Pygoscelis adeliae). Although the entire inner continental shelf is highly productive, with abundant phytoplankton and krill populations, penguin colonies are distributed heterogeneously along the WAP (Ducklow et al., 2013, in this issue). This ecological conundrum targets a long-standing question of interest: what environmental factors structure the locations of Adélie penguin “hot spots” throughout the WAP

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The interaction between island geomorphology and environmental parameters drives Adélie penguin breeding phenology on neighboring islands near Palmer Station, Antarctica

Despite many studies on Adélie penguin breeding phenology, understanding the drivers of clutch initiation dates (CIDs, egg 1 lay date) is limited or lacks consensus. Here, we investigated Adélie penguin CIDs over 25&nbsp;years (1991-2016) on two neighboring islands, Torgersen and Humble (&lt;1&nbsp;km apart), in a rapidly warming region near Palmer Station, Antarctica. We found that sea ice was the primary large-scale driver of CIDs and precipitation was a secondary small-scale driver that fine-tunes CID to island-specific nesting habitat geomorphology. In general, CIDs were earlier (later) when the spring sea ice retreat was earlier (later) and when the preceding annual ice season was shorter (longer). Island-specific effects related to precipitation and island geomorphology caused greater snow accumulation and delayed CIDs by ~2&nbsp;days on Torgersen compared to Humble Island. When CIDs on the islands were similar, conditions were mild with less snow across breeding sites. At Torgersen Island, the negative relationship between CID and breeding success highlights detrimental effects of delayed breeding and/or snow on penguin fitness. Past phenological studies reported a relationship between air temperature and CID, assumed to be related to precipitation, but we found air temperature was more highly correlated to sea ice, revealing a misinterpretation of temperature effects. Finally, contrasting trends in CIDs based on temporal shifts in regional sea ice patterns revealed trends toward earlier CIDs (4-6&nbsp;day advance) from 1979 to 2009 as the annual ice season shortened, and later CIDs (7-10&nbsp;day delay) from 2010 to 2016 as the annual ice season lengthened. Adélie penguins tracked environmental conditions with flexible breeding phenology, but their life history remains vulnerable to subpolar weather conditions that can delay CIDs and decrease breeding success, especially on landscapes where geomorphology facilitates snow accumulation