Background and Purpose
Lasmiditan is a novel selective 5‐HT1F receptor agonist, recently approved for acute treatment of migraine. 5‐HT1F receptors are widely expressed in the CNS and ...trigeminovascular system. Here, we have explored the therapeutic effects of 5‐HT1F receptor activation in preclinical models of migraine and cluster headache.
Experimental Approach
Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal–autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal–autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5‐HT1F receptors in human post‐mortem tissue and of several 5‐HT1 receptor subtypes in specific tissue beds.
Key Results
Lasmiditan dose‐dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus‐evoked activation of the trigeminal–autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5‐HT1F receptor in several structures relevant for migraine and cluster headache.
Conclusion and Implications
Our data suggest that lasmiditan acts, at least in part, as an anti‐migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks.
LINKED ARTICLES
This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc
The physical interactions between ice sheets and the atmosphere and ocean around them are major factors in determining the state of the climate system, yet many current Earth System models omit them ...entirely or treat them very simply. In this work we describe how models of the Greenland and Antarctic ice sheets have been incorporated into the global U.K. Earth System model (UKESM1) via substantial technical developments with a two‐way coupling that passes fluxes of energy and water, and the topography of the ice sheet surface and ice shelf base, between the component models. File‐based coupling outside the running model executables is used throughout to pass information between the components, which we show is both physically appropriate and convenient within the UKESM1 structure. Ice sheet surface mass balance is computed in the land surface model using multi‐layer snowpacks in subgrid‐scale elevation ranges and compares well to the results of regional climate models. Ice shelf front discharge forms icebergs, which drift and melt in the ocean. Ice shelf basal mass balance is simulated using the full three‐dimensional ocean model representation of the circulation in ice‐shelf cavities. We show a range of example results, including from simulations with changes in ice sheet height and thickness of hundreds of meters, and changes in ice sheet grounding line and land‐terminating margin of many tens of kilometres, demonstrating that the coupled model is computationally stable when subject to significant changes in ice sheet geometry.
Plain Language Summary
Loss of mass from the ice sheets on Greenland and Antarctica makes an important contribution to global mean sea level (GMSL) rise, and one that will increase significantly in the coming decades and centuries. Our limited ability to predict exactly how the Earth's ice sheets will interact with the changing climate is the main reason we cannot say with confidence whether GMSL will rise by tens of centimeters or a meter or more in this century alone. One way to develop our understanding is to build tools capable of modeling the co‐evolution of ice sheets and climate, a difficult task made yet more challenging by the wide range of spatial‐ and time‐scales that need to be considered to model these systems simultaneously. UKESM1 is a state‐of‐the‐art Earth System model used to predict future climate change. Our work allows UKESM1 to be run with interactive models of the Greenland and Antarctic ice sheets. This is a new and complex model, and there are still problems to solve before such tools can be used to produce complete projections of GMSL rise. Our work nevertheless allows us to investigate new areas of climate physics in ways that have not been possible before.
Key Points
A CMIP6 Earth System Model has been coupled to interactive models of both the Greenland and Antarctic ice sheets for the first time
Substantial technical challenges have been overcome, our solutions and their limitations are described
Our system simulates climate and ice sheet physics reasonably well, and is computationally stable when subject to extreme ice sheet retreat
Suture zones are abundant on Antarctic ice shelves and widely observed to impede fracture propagation, greatly enhancing ice-shelf stability. Using seismic and radar observations on the Larsen C Ice ...Shelf of the Antarctic Peninsula, we confirm that such zones are highly heterogeneous, consisting of multiple meteoric and marine ice bodies of diverse provenance fused together. Here we demonstrate that fracture detainment is predominantly controlled by enhanced seawater content in suture zones, rather than by enhanced temperature as previously thought. We show that interstitial seawater can reduce fracture-driving stress by orders of magnitude, promoting both viscous relaxation and the development of micro cracks, the incidence of which scales inversely with stress intensity. We show how simple analysis of viscous buckles in ice-penetrating radar data can quantify the seawater content of suture zones and their modification of the ice-shelf's stress regime. By limiting fracture, enhancing stability and restraining continental ice discharge into the ocean, suture zones act as vital regulators of Antarctic mass balance.
Warm ocean waters drive rapid ice‐shelf melting in the Amundsen Sea. The ocean heat transport toward the ice shelves is associated with the Amundsen Undercurrent, a near‐bottom current that flows ...eastward along the shelf break and transports warm waters onto the continental shelf via troughs. Here we use a regional ice‐ocean model to show that, on decadal time scales, the undercurrent's variability is baroclinic (depth‐dependent). Decadal ocean surface cooling in the tropical Pacific results in cyclonic wind anomalies over the Amundsen Sea. These wind anomalies drive a westward perturbation of the shelf‐break surface flow and an eastward anomaly (strengthening) of the undercurrent, leading to increased ice‐shelf melting. This contrasts with shorter time scales, for which surface current and undercurrent covary, a barotropic (depth‐independent) behavior previously assumed to apply at all time scales. This suggests that interior ocean processes mediate the decadal ice‐shelf response in the Amundsen Sea to climate forcing.
Plain Language Summary
The West Antarctic Ice Sheet is losing mass, causing sea level rise. Most of this loss occurs in the Amundsen Sea Embayment, due to melting of coastal glaciers by warm ocean waters. These warm waters are transported toward the glaciers by the Amundsen Undercurrent, a near‐seafloor eastward‐flowing current located at the boundary between the deep ocean and the shallower seas around Antarctica. Changes in the undercurrent thus regulate the amount of heat available to melt the glaciers. Here, we use a model to assess the undercurrent's variability on time scales of decades, as decadal ocean forcing drives periods of enhanced ice‐sheet retreat. Contrary to previous work, our model shows that wind fluctuations, associated with surface temperature changes in the tropical Pacific, lead to changes in the interior ocean density field on decadal time scales. Decadal anomalous cyclonic atmospheric circulation over the Amundsen Sea, associated with cooling in the tropical Pacific, accelerates the near‐surface ocean flow westward, but also accelerates the eastward‐flowing undercurrent and enhances glacial melting. Our work suggests that previous assumptions about the decadal oceanic response of the Amundsen Sea to wind variability might need to be reconsidered, with implications for melting of West Antarctic glaciers.
Key Points
Our modeled decadal strengthening of the Amundsen Undercurrent corresponds with increase in ice‐shelf basal melting
Undercurrent variability on decadal time scales is predominantly baroclinic (i.e., anticorrelated with the surface flow variability)
At decadal timescales, this model shows enhanced ice‐shelf melting under westward wind anomalies, a reverse relationship to previous studies
The Antarctic Ice Sheet will play a crucial role in the evolution of global mean sea level as the climate warms. An interactively coupled climate
and ice sheet model is needed to understand the ...impacts of ice–climate feedbacks during this evolution. Here we use a two-way coupling between the
UK Earth System Model and the BISICLES (Berkeley Ice Sheet Initiative for Climate at Extreme Scales) dynamic ice sheet model to investigate Antarctic ice–climate interactions under two climate change
scenarios. We perform ensembles of SSP1–1.9 and SSP5–8.5 (Shared Socioeconomic Pathway) scenario simulations to 2100, which we believe are the first such simulations with a
climate model that include two-way coupling of atmosphere and ocean models to dynamic models of the Greenland and Antarctic ice sheets. We focus our
analysis on the latter. In SSP1–1.9 simulations, ice shelf basal melting and grounded ice mass loss from the Antarctic Ice Sheet are generally lower
than present rates during the entire simulation period. In contrast, the responses to SSP5–8.5 forcing are strong. By the end of the 21st century,
these simulations feature order-of-magnitude increases in basal melting of the Ross and Filchner–Ronne ice shelves, caused by intrusions of masses of warm
ocean water. Due to the slow response of ice sheet drawdown, this strong melting does not cause a substantial increase in ice discharge
during the simulations. The surface mass balance in SSP5–8.5 simulations shows a pattern of strong decrease on ice shelves, caused by increased
melting, and strong increase on grounded ice, caused by increased snowfall. Despite strong surface and basal melting of the ice shelves, increased
snowfall dominates the mass budget of the grounded ice, leading to an ensemble mean Antarctic contribution to global mean sea level of a fall of
22 mm by 2100 in the SSP5–8.5 scenario. We hypothesise that this signal would revert to sea-level rise on longer timescales, caused by the
ice sheet dynamic response to ice shelf thinning. These results demonstrate the need for fully coupled ice–climate models in reducing the
substantial uncertainty in sea-level rise from the Antarctic Ice Sheet.
Abstract
We assess the impact of El Niño‐induced wind changes on seasonal West Antarctic sea ice concentrations using reanalysis data and sea ice observations. A novel ice budget analysis reveals ...that in autumn a previously identified east‐west dipole of sea ice concentration anomalies is formed by dynamic and thermodynamic processes in response to El Niño‐generated circulation changes. The dipole features decreased (increased) concentration in the Ross Sea (Amundsen and Bellingshausen Seas). Thermodynamic processes and feedback make a substantial contribution to ice anomalies in all seasons. The eastward propagation of this anomaly is partly driven by mean sea ice drift rather than anomalous winds. Our results demonstrate that linkages between sea ice anomalies and atmospheric variability are highly nonlocal in space and time. Therefore, we assert that caution should be applied when interpreting the results of studies that attribute sea ice changes without accounting for such temporally and spatially remote linkages.
Key Points
A novel sea ice budget analysis is used to assess the causes of a West Antarctic sea ice anomaly dipole during El Niño events
A dipole forms in autumn due to anomalous winds. Its subsequent progression is controlled by thermodynamic feedback and mean sea ice drift
This demonstrates for the first time that linkages between sea ice anomalies and atmospheric variability are nonlocal in space and time
Open-ocean polynyas in the Weddell Sea of Antarctica are the product of deep convection, which transports Warm Deep Water (WDW) to the surface and melts sea ice or prevents its formation. These ...polynyas occur only rarely in the observational record but are a near-permanent feature of many climate and ocean simulations. A question not previously considered is the degree to which the Weddell polynya affects the nearby Filchner–Ronne Ice Shelf (FRIS) cavity. Here we assess these effects using regional ocean model simulations of the Weddell Sea and FRIS, where deep convection is imposed with varying area, location, and duration. In these simulations, the idealized Weddell polynyas consistently cause an increase in WDW transport onto the continental shelf as a result of density changes above the shelf break. This leads to saltier, denser source waters for the FRIS cavity, which then experiences stronger circulation and increased ice shelf basal melting. It takes approximately 14 years for melt rates to return to normal after the deep convection ceases. Weddell polynyas similar to those seen in observations have a modest impact on FRIS melt rates, which is within the range of simulated interannual variability. However, polynyas that are larger or closer to the shelf break, such as those seen in many ocean models, trigger a stronger response. These results suggest that ocean models with excessive Weddell Sea convection may not be suitable boundary conditions for regional models of the Antarctic continental shelf and ice shelf cavities.
Coastal areas are highly diverse, ecologically rich, regions of key socio-economic activity, and are particularly sensitive to sea-level change. Over most of the 20th century, global mean sea level ...has risen mainly due to warming and subsequent expansion of the upper ocean layers as well as the melting of glaciers and ice caps. Over the last three decades, increased mass loss of the Greenland and Antarctic ice sheets has also started to contribute significantly to contemporary sea-level rise. The future mass loss of the two ice sheets, which combined represent a sea-level rise potential of ∼65 m, constitutes the main source of uncertainty in long-term (centennial to millennial) sea-level rise projections. Improved knowledge of the magnitude and rate of future sea-level change is therefore of utmost importance. Moreover, sea level does not change uniformly across the globe and can differ greatly at both regional and local scales. The most appropriate and feasible sea level mitigation and adaptation measures in coastal regions strongly depend on local land use and associated risk aversion. Here, we advocate that addressing the problem of future sea-level rise and its impacts requires (i) bringing together a transdisciplinary scientific community, from climate and cryospheric scientists to coastal impact specialists, and (ii) interacting closely and iteratively with users and local stakeholders to co-design and co-build coastal climate services, including addressing the high-end risks.
Purpose
This study aims to determine if the hospital efficiency, safety and health outcomes are equal in patients who receive bariatric surgery in government-funded hospitals (GFH) versus privately ...funded hospitals (PFH).
Materials and Methods
This is a retrospective observational study of prospectively maintained data from the Australia and New Zealand Bariatric Surgery Registry of 14,862 procedures (2134 GFH and 12,728 PFH) from 33 hospitals (8 GFH and 25 PFH) performed in Victoria, Australia, between January 1st, 2015, and December 31st, 2020. Outcome measures included the difference in efficacy (weight loss, diabetes remission), safety (defined adverse event and complications) and efficiency (hospital length of stay) between the two health systems.
Results
GFH treated a higher risk patient group who were older by a mean (SD) 2.4 years (0.27),
P
< 0.001; had a mean 9.0 kg (0.6) greater weight at time of surgery,
P
< 0.001; and a higher prevalence of diabetes at day of surgery OR = 2.57 (CI
95%
2.29–2.89),
P
< 0.001. Despite these baseline differences, both GFH and PFH yielded near identical remission of diabetes which was stable up to 4 years post-operatively (57%). There was no statistically significant difference in defined adverse events between the GFH and PFH (OR = 1.24 (CI
95%
0.93–1.67),
P
= 0.14). Both healthcare settings demonstrated that similar covariates affect length of stay (LOS) (diabetes, conversion bariatric procedures and defined adverse event); however, these covariates had a greater effect on LOS in GFH compared to PFH.
Conclusions
Bariatric surgery performed in GFH and PFH yields comparable health outcomes (metabolic and weight loss) and safety. There was a small but statistically significant increased LOS following bariatric surgery in GFH.
Graphical Abstract
Glaciers in the Amundsen Sea Embayment of West Antarctica are rapidly retreating and contributing to sea level rise. Ice loss is occurring primarily via exposure to warm ocean water, which varies in ...response to local wind variability. There is evidence that retreat was initiated in the mid-20th century, but the perturbation that may have triggered retreat remains unknown. A leading hypothesis is that large pressure and wind anomalies in the 1940s drove exceptionally strong oceanic ice-shelf melting. However, the characteristics, drivers, and rarity of the atmospheric event remain poorly constrained. We investigate the 1940s atmospheric event using paleoclimate reconstructions and climate model simulations. The reconstructions show that large westerly wind anomalies occurred from ∼1938–1942, a combined response to the very large El Niño event from 1940–1942 and other variability beginning years earlier. Climate model simulations provide evidence that events of similar magnitude and duration may occur tens to hundreds of times per 10 kyr of internal climate variability (∼0.2 to 2.5 occurrences per century). Our results suggest that the 1940s westerly event is unlikely to have been exceptional enough to be the sole explanation for the initiation of Amundsen Sea glacier retreat. Additional factors are likely needed to explain the onset of retreat in West Antarctica, such as naturally arising variability in ocean conditions prior to the 1940s or anthropogenically driven trends since the 1940s.
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