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Summary Low-frequency distributed acoustic sensing (LF-DAS) exploits the optical phase shift of Rayleigh backscatter in fiber-optic cables to obtain distributed measurements of changes in strain and temperature. Fiber-optic cables are often installed for multistage hydraulic fracture diagnostics in horizontal wells. LF-DAS in an untreated well provides far-field strain measurements, while offset wells are hydraulically fractured. Such a configuration is called crosswell LF-DAS sensing. Crosswell LF-DAS measurements have proved useful in diagnosing fracture hits, fracture azimuth, planarity, cluster efficiency, fracture propagation rates, and the dynamic distance to the fracture front. In contrast, in-well LF-DAS is conducted on the actively fractured well. Due to cool fracture fluid being injected at high injection rates, the strain component of the LF-DAS response is largely obscured by temperature changes. In permanent fiber-optic cable installations, distributed temperature sensing (DTS) is often conducted simultaneously with LF-DAS. An opportunity exists to decouple the temperature and strain components of LF-DAS sensors to observe strain changes on in-well LF-DAS. The LF-DAS response is modeled as linearly dependent on strain and temperature changes. Theoretical LF-DAS temperature and strain sensitivity coefficients are derived based on the changes to the index of refraction and length of the fiber. Using the DTS measurements, temperature changes are computed, smoothed, filtered, and compared to the LF-DAS response. Crossplots of the in-well LF-DAS measurements and temperature changes from DTS measurements far from the actively fractured region are used to validate the theoretical sensitivity coefficients. Uncertainty in the temperature component of the LF-DAS response is quantified. The difficulty in corresponding the different spatial and temporal resolutions of the DTS and LF-DAS measurements is overcome by comparing the responses over a moving temporal and spatial window. If the LF-DAS response at the center of the window agrees with the DTS response within uncertainty, the measurement is filtered out. After filtering, the remaining nonzero in-well LF-DAS measurements are due to changes in strain. The data are then visualized in waterfall plots. The results indicate that the theoretical and observed strain and temperature coefficients agree within 10%. After the temperature component of the in-well LF-DAS response is extracted, the remaining nonzero measurements are located primarily within the actively treated region. Locations with peaks in the strain response are interpreted to indicate fracture initiation points. These fracture initiation points are compared with in-well DTS and high-frequency DAS noise measurements across multiple stages to better understand fracture initiation along the horizontal well.

The 4.2kyr event saw major changes in civilizations across the world, often attributed to climate change and widespread drought. Indeed, there are high quality palaeohydrological proxies that seem to document a significant drying at this time in Egypt, the Indus Valley and in the Near East. In Mesopotamia, settlements were abandoned, agricultural practices shifted and the Akkadian Empire ended. Climate model simulations covering 5000-3000 years ago are able to reproduce much of the evidence for Holocene climate change and some of the key reductions in mid-late Holocene precipitation. However, unlike some other regions, the annual mean rainfall in Mesopotamia at 4.2kyr is similar to the adjoining millennia. The climate model simulates significant droughts during this time, but these are within the range seen both before and after.The end of the middle Holocene saw rapid population growth in Mesopotamia, with significant urban centres putting pressure on local resources. Although the models suggest no significant change in climate, the archaeological evidence shows the exploitation of a dryer landscape, both in existing sites and new urban centres in dryer regions. This time also sees changing agricultural practices and the loss of available sources of wood. Vegetation models suggest little impact of climate change on the natural landscape, although drought years bring major losses in net primary productivity. However, human activities in Mesopotamia could have affected the landscape and exacerbated the impacts of existing drought cycles. We suggest that an unexceptional drought, combined with a large population and anthropogenic impacts on the landscape contributed to significant societal change in Mesopotamia at 4.2kyr.

Localized radial patterns have been observed in the vegetation of semi-arid ecosystems, often as localized patches of vegetation or in the form of ‘fairy circles’. We consider stationary localized radial solutions to a reduced model for dryland vegetation on flat terrain. By considering certain prototypical pattern-forming systems, we prove the existence of three classes of localized radial patterns bifurcating from a Turing instability. We also present evidence for the existence of localized gap solutions close to a homogeneous instability. Additionally, we numerically solve the vegetation model and use continuation methods to study the bifurcation structure and radial stability of localized radial spots and gaps. We conclude by investigating the effect of varying certain parameter values on the existence and stability of these localized radial patterns.

Summary Fiber-optic cables cemented outside of the casing of an unconventional well measure crosswell strain changes during fracturing of neighboring wells with low-frequency distributed acoustic sensing (LF-DAS). As a hydraulic fracture intersects an observation well instrumented with fiber-optic cables, the fracture fluid injected at ambient temperatures can cool a section of the sensing fiber. Often, LF-DAS and distributed temperature sensing (DTS) cables are run in tandem, enabling the detection of such cooling events. The increasing use of LF-DAS for characterizing unconventional hydraulic fracture completions demands an investigation of the effects of temperature on the measured strain response by LF-DAS. Researchers have demonstrated that LF-DAS can be used to extract the temporal derivative of temperature for use as a differential-temperature-gradient sensor. However, differential-temperature-gradient sensing is predicated on the ability to filter strain components out of the optical signal. In this work, beginning with an equation for optical phase shift of LF-DAS signals, a model relating strain, temperature, and optical phase shift is explicitly developed. The formula provides insights into the relative strength of strain and temperature effects on the phase shift. The uncertainty in the strain-rate measurements due to thermal effects is estimated. The relationship can also be used to quantify uncertainties in differential-temperature-gradient sensors due to strain perturbations. Additionally, a workflow is presented to simulate the LF-DAS response accounting for both strain and temperature effects. Hydraulic fracture geometries are generated with a 3D fracture simulator for a multistage unconventional completion. The fracture width distributions are imported by a displacement discontinuity method (DDM) program to compute the strain rates along an observation well. An analytic model is used to approximate the temperature in the fracture. Using the derived formulae for optical phase shift, the model outputs are then used to compute the LF-DAS response at a fiber-optic cable, enabling the generation of waterfall plots including both strain and thermal effects. The model results suggest that before, during, and immediately following a fracture intersecting a well instrumented with fiber, the strain on the fiber drives the LF-DAS signal. However, at later times, as completion fluid cools the observation well, the temperature component of the LF-DAS signal can be equal to or exceed the strain component. The modeled results are compared to a published field case in an attempt to enhance the interpretation of LF-DAS waterfall plots. Finally, we propose a sensing configuration to identify the events when “wet fractures” (fractures with fluids) intersect the observation well.

Size is fundamentally important in individual planktic foraminifers as it determines the number of offspring and hence reproductive success. Over evolutionary timescales, individuals tend to increase in size, altering the average size of assemblages; in the last million years, individuals were larger than at any other time in the geological record. This pattern is specifically driven by size increases in tropical and subtropical taxa in the Plio-Pleistocene. Here we use a taxon-free approach to assess what facilitated this novelty and to quantify the response of planktic foraminifers to both long and short time-scale environmental changes. We focus on the Pliocene, a time interval characterized by the closure of the Central American Seaway (CAS) and the short glaciation at marine isotope stage (MIS) M2. We measured size in foraminiferal assemblages using automated microscopy across 24 globally distributed PRISM locations, from subpolar to tropical environments. The 95th percentile was calculated on the maximum diameter measurements of 1.28 million specimens. Although there is a slight decrease in the average size of the assemblage in the high latitudes from the Early to Late Pliocene, with minimal changes in the tropics, results indicate little to no effect on foraminiferal size across MIS M2. The results show an unexpected stability and resilience against the reorganization of the tropical oceans associated with the closure of the CAS.

Low-frequency distributed acoustic sensing (LF-DAS) exploits the optical phase shift of Rayleigh backscatter in fiber optic cables to obtain distributed measurements of changes in strain and temperature. Fiber optic cables are often installed for multistage hydraulic fracture diagnostics in horizontal wells. LF- DAS in an untreated well provides far-field strain measurements while offset wells are hydraulically fractured. Such a configuration is called cross-well LF-DAS sensing. Cross-well LF-DAS measurements have proven useful to diagnose frac hits, fracture azimuth, planarity, cluster efficiency, fracture propagation rates, and the dynamic distance to the fracture front. In contrast, in-well LF-DAS is conducted on the actively fractured well. Due to cool fracture fluid being injected at high injection rates, the strain component of the LF-DAS response is largely obscured by temperature changes. In permanent fiber optic cable installations, distributed temperature sensing (DTS) is often conducted simultaneously with LF- DAS. An opportunity exists to decouple the temperature and strain components of LF-DAS sensors to observe strain changes on in-well LF-DAS.The LF-DAS response is modeled as linearly dependent on strain and temperature changes. Theoretical LF-DAS temperature and strain sensitivity coefficients are derived based on changes to the index of refraction and length of the fiber. Using the DTS measurements, temperature changes are computed, smoothed, filtered, and compared to the LF-DAS response. Cross-plots of the in-well LF-DAS measurements and temperature changes from DTS measurements far from the actively fractured region are used to validate the theoretical sensitivity coefficients. Uncertainty in the temperature component of the LF-DAS response is quantified. The difficulty in corresponding the different spatial and temporal resolutions of the DTS and LF-DAS measurements is overcome by comparing the responses over a moving temporal and spatial window. If the LF-DAS response at the center of the window agrees with the DTS response within uncertainty, the measurement is filtered out. After filtering, the remaining non-zero in-well LF-DAS measurements are due to changes in strain. The data is then visualized in waterfall plots. The results indicate that the theoretical and observed strain and temperature coefficients agree within 10%. After the temperature component of the in-well LF-DAS response is extracted, the remaining non-zero measurements are located primarily within the actively treated region. Locations with peaks in the strain response are interpreted to indicate fracture initiation points. These fracture initiation points are compared with in-well DTS and high frequency DAS noise measurements across multiple stages to better understand fracture initiation along the horizontal well.

In spin-density-functional theory (SDFT) for noncollinear magnetic materials, the Kohn-Sham system features exchange-correlation (xc) scalar potentials and magnetic fields. The significance of the xc magnetic fields is not very well explored; in particular, they can give rise to local torques on the magnetization, which are absent in standard local and semilocal approximations. Exact benchmark solutions for a five-site extended Hubbard lattice at half filling and in the presence of spin-orbit coupling are compared with SDFT results obtained using orbital-dependent exchange-only approximations. The magnetization dynamics following short-pulse excitations is found to be reasonably well described in the exchange-only approximation for weak to moderate interactions. For stronger interactions and near transitions between magnetically ordered and frustrated phases, exchange and correlation torques tend to compensate each other and must both be accounted for., Comment: 9 pages, 6 figures

This paper describes the evaluation of a longitudinal peer-support program developed to address loneliness and isolation among low-income, urban community-dwelling older adults in San Francisco. Our objective was to determine barriers, challenges, and successful strategies in implementation of the program. In-depth qualitative interviews with clients ( n = 15) and peers ( n = 6) were conducted and analyzed thematically by program component. We identified barriers and challenges to engagement and outlined strategies used to identify clients, match them with peers, and provide support to both peers and clients. We found that peers played a flexible, non-clinical role and were perceived as friends. Connections to community resources helped when clients needed additional support. We also documented creative strategies used to maintain inter-personal connections during the COVID-19 pandemic. This study fills a gap in understanding how a peer-support program can be designed to address loneliness and social isolation, particularly in low-income, urban settings.

Healthy hearts use more fatty acids (FA) than glucose for ATP synthesis but diabetic cardiomyopathy (DbCM) occurs with higher FA dependency. It remains controversial whether glucotoxicity or lipotoxicity or both account for DbCM. We recently discovered that insulin signaling inhibition and eventual FOXO1 activation stimulate cardiac KLF5 expression, which drives lipotoxicity and causes cardiac dysfunction. In the present study, we investigated the relative contribution of glucose in the activation of cardiac KLF5 and DbCM. We induced Type-1 diabetes (T1D) in C57BL/6 mice via intraperitoneal injections of streptozotocin (STZ). In contrast to late-stage diabetes (12 weeks post-STZ), cardiac KLF5 mRNA and protein levels were not increased in the early T1D stage (4 weeks post-STZ) although mice have mild cardiac dysfunction already. Seahorse analysis in adult cardiomyocytes isolated from mice with early T1D showed higher glucose and lower FA dependency compared to non-diabetic mice and mice in late T1D. To confirm whether hyperglycemia causes cardiac dysfunction, we treated diabetic mice with Dapagliflozin (DAPA, SGLT2 inhibitor) or STF-31, a GLUT1 inhibitor. These treatments restored normal dependency on fatty acids and prevented cardiac dysfunction. GC-MS analysis showed that the reversal of fuel dependency from glucose to fatty acids in late T1D is accompanied by increased glucose content opposite to the early T1D. Accordingly cardiac KLF5 is increased in late T1D, accompanied by severe cardiac dysfunction. The expression changes of KLF5 are mirrored by transcriptional activity of FOXO1 -shown by expression of FOXO1 targets- in early and late T1D. The changes in transcriptional activity are accompanied by differential FOXO1 acetylation, which is controlled by Sirtuin-1 and modulates its DNA affinity. Analysis of mouse cardiac tissue in early T1D and a human cardiomyocyte cell line (AC16) that was treated with high glucose showed higher Sirtuin-1 expression and stronger protein-protein interaction with FOXO1. To this end, mice that were subjected to treatment with either DAPA or STF31 for 12 Wks had improved cardiac function, lower cardiac KLF5 expression and decreased expression of cardiac KLF5 gene targets. Interestingly, GLUT1 mRNA levels were increased in late T1D compared to early T1D. Cardiomyocyte-specific KLF5 overexpression or adenovirus-mediated KLF5 overexpression in AC16 cells stimulated GLUT1 expression. Collectively, in early T1D, hearts rely more on glucose utilization in mitochondria. In late T1D, SIRT1-FOXO1-KLF5 axis causes lipotoxicity and subsequent induction of GLUT1 expression that contributes to glucotoxicity. Inhibition of GLUT1-dependent glucose uptake alleviates diabetic cardiomyopathy via inhibition of both early glucose dependency and late KLF5 activation.

We address the ethics of scenarios in which one party (the ‘agent’) entraps, intentionally tempts or intentionally tests the virtue of another (the ‘target’). We classify, in a new manner, three distinct types of acts that are of concern, namely acts of entrapment, of (mere) intentional temptation and of (mere) virtue testing. Our classification is, for each kind of scenario, of itself neutral concerning the question whether the agent acts permissibly (and concerning the extent to which the target is culpable). We explain why acts of entrapment are more ethically objectionable than like acts of (mere) intentional temptation and why these, in turn, are more ethically objectionable than like acts of (mere) virtue testing. Along the way, we scrutinize, and eventually reject, the view that acts of entrapment are ethically unacceptable because intentional temptation is involved in entrapment. (The article touches upon, but is not about, the question of culpability.)

Alzheimer’s disease (AD) is a neurodegenerative disorder, the most common form of dementia. AD is characterised by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) in the brain, in association with neuronal loss and synaptic failure, causing cognitive deficits. Accurate and early diagnosis is currently unavailable in lifespan, hampering early intervention of potential new treatments. Visual deficits have been well documented in AD patients, and the pathological changes identified in the brain are also believed to be found in the retina, an integral part of the central nervous system. Retinal changes can be detected by real-time non-invasive imaging, due to the transparent nature of the ocular media, potentially allowing an earlier diagnosis as well as monitoring disease progression and treatment outcome. Animal models are essential for AD research, and this review has a focus on retinal changes in various transgenic AD mouse models with retinal imaging and immunohistochemical analysis as well as therapeutic effects in those models. We also discuss the limitations of transgenic AD models in clinical translations.

The pore habits of gas hydrate in natural sediment matrices provide essential clues for understanding physical (mechanical, thermal, hydraulic, and electrical) properties of hydrate-bearing sediments, yet there are no tools that can directly visualize the pore habits of natural gas hydrate other than indirect interpretation based on core-scale or field-scale observations. A significant challenge is to obtain a mini-core from pressure cores retrieved from natural reservoirs for high-resolution micro-CT (computed tomography) scans while maintaining pressure and temperature conditions required for stability of gas hydrate during all operational steps including manipulation, cutting, transferring, sub-coring and CT scanning. We present a new set of tools for pore-scale micro-CT imaging of natural hydrate-bearing sediments while maintaining pressure and temperature control. The tests with laboratory-prepared cores and pressure cores successfully demonstrate the capability of this set of tools to subsample a mini-core from pressure cores, transfer the mini-core to an X-ray transparent core holder, and conduct micro-CT scans. Successfully obtained CT images prove the functionality of this set of tools.

Retinal neurodegeneration causes irreversible vision loss, impairing quality of life. By targeting neurotoxic conditions, such as oxidative stress and ischemia, neuroprotectants can slow or stop sight loss resulting from eye disease. Despite limimted clinical use of neuroprotectants, there are several promising compounds in early clinical trials (pre-phase III) which may fulfil new therapeutic roles. Search terms relating to neuroprotection and eye disease were used on ClinicalTrials.gov to identify neuroprotective candidates.Research supporting neuroprotection in eye diseases is focused on, ranging from preclinical to phase II, according to the ClinicalTrials.gov database. The compounds discussed are explored in terms of future clinical applications.The major challenge in neuroprotection research is translation from basic research to the clinic. A number of potential neuroprotectants have progressed to ophthalmology clinical trials in recent years, with defined mechanisms of action - saffron and CoQ10 - targeting mitochondria, and both CNTF and NGF showing anti-apoptotic effects. Enhancements in trial design and patient cohorts in proof-of-concept trials with enriched patient populations and surrogate endpoints should accelerate drug development. A further important consideration is optimising drug delivery to improve individualised management and patient compliance. Progress in these areas means that neuroprotective strategies have a much improved chance of translational success.

The Pliocene Model Intercomparison Project (PlioMIP) is one of the most successful MIPs in palaeoclimatology. Over two phases since 2008, PlioMIP has co-ordinated the experimental design and publication strategy of the community, which has included an increasing number of climate models and modelling groups from around the world. It has engaged with the palaeo-data community in order to foster new data synthesis, supporting the construction of new model boundary conditions as well as to facilitate new data/model comparisons. Given the long implementation period for a new phase it is necessary to define the broad parameters of PlioMIP3 now. Here we present different potential components of a new science plan. This incorporates feedback gained from PlioMIP participants following the online PlioMIP2 showcase event in 2021. PlioMIP3 will continue to have balanced scientific portfolio across both Pliocene for Pliocene and Pliocene for Future agendas. It will continue to carefully consider the competing demands of the overall effort required to complete experiments, and to be a part of the project, versus having the ability to introduce new and existing elements to enhance scientific exploration and understanding of the Pliocene. We propose the retention of the PlioMIP2 core experiment (Eoi400), but an extension to Core requirements to include either (or both) an experiment focussed on the Early Pliocene, or an alternative Eoi400 simulation. These additions will (a) allow an intercomparison of Early and Late Pliocene warm intervals and help build research connections and synergies with the MioMIP project, and (b) through removal of some of the largest palaeogeographic differences introduced between the PlioMIP2 and 1 (the closure of the Bering Strait and Canadian Archipelago and the exposure of the Sahul and Sunda Shelves), create a time slice simulation for 3.205 Ma (MIS KM5c) with minimal palaeogeographic variations from the modern. This will enhance the palaeo to future scientific connection, and enable an exploration of the significance of palaeogeographic uncertainties on climate simulations. In addition, we propose a number of optional experiments across 2 tiers of additional activity that incorporate simulations designed to enhance our understanding of Climate Sensitivity, as well as incorporating the radiative forcing potentially stemming from non-CO2 greenhouse gases. For the first time, we have introduced orbital sensitivity experiments into the science plan examining both Northern Hemisphere minimum and maximum insolation forcing, as well as a specific simulation using dynamic vegetation models. Finally, we have proposed an experiment designed to examine the potential significance of East Antarctic Ice Sheet boundary condition uncertainty, which would help inform a new phase of the Pliocene Ice Sheet Model Intercomparison Project.

The large glacial period that immediately precedes the mid-Pliocene Warm Period (mPWP) is a ~0.6‰ benthic oxygen isotope shift at 3.3Ma, known as M2. The excursion is roughly equivalent to 60m of sea level drop or 40msle (metres sea level equivalent) more ice than today. However, there is significant uncertainty in both these values and the potential locations of any large volumes of ice. Previous modelling studies have either used Last Glacial Cycle analogues for the M2 ice sheets or failed to reproduce the large Northern Hemisphere ice sheets implied by global ice volume proxies. Here we present new climate and ice sheet models simulating the M2 glacial period, by lowering Pliocene atmospheric carbon dioxide concentrations and selecting specific Pliocene orbital forcing. These climates are sufficiently cold to produce ice sheets in North America and northern Europe within our modelling framework. The largest components of these ice masses are centred over regions with significant landscape differences between Pliocene and present day, including the Hudson Bay, Canadian Archipelago and Barents Sea. This suggests that the M2 glacial may have had very different initiation locations to the most recent glacial cycles and that Pliocene palaeogeographic changes may be key to understanding the M2 glacial.

A long-standing challenge for mid-Pliocene climate simulations is large underestimation of simulated surface warming in the Nordic Seas in comparison to sea surface temperature (SST) proxy records (e.g. Dowsett et al., 2013; McClymont et al., 2020). Previous modelling studies have proposed that geographic changes in the Barents-Kara Sea are of great importance for surface temperature change in the Nordic Seas (e.g., Hill, 2015). That is, changing the Barents Sea from a marine to a subaerial setting can give rise to evident warming in the Nordic Seas. Nevertheless, this geographic change has so far not been well considered in the Pliocene Modelling Intercomparison Project (Haywood et al., 2016 a,b), potentially due to the lack of quantitative reconstruction of this paleogeographic change. Recently, Lien et al. (2022) provided such reconstruction, which enables a test of the impact of a subaerial Barents Sea on mid-Pliocene climate. Based on iCESM1.2, we accordingly conducted sensitivity experiments where we changed bathymetry in the eastern Nordic Sea and topography in the Barents-Kara Sea region in a setup of otherwise unaltered PRISM4 mid-Pliocene boundary conditions (Dowsett et al., 20016). Our results hint that a subaerial Barents-Kara Sea might contribute to a reduction of the data-model SST mismatch during the mid-Pliocene. References: Dowsett, H., Foley, K., Stoll, D., et al., 2013. Sea Surface Temperature of the Mid-Piacenzian Ocean: A Data-Model Comparison: Science Reports, vol. 3. https://doi.org/10.1038/srep02013. Dowsett, H., Dolan, A., Rowley, D., Moucha, R., Forte, A. M., Mitrovica, J. X., Pound, M., Salzmann, U., Robinson, M., Chandler, M., Foley, K., and Haywood, A., 2016. The PRISM4 (mid-Piacenzian) paleoenvironmental reconstruction, Clim. Past, 12, 1519–1538, https://doi.org/10.5194/cp-12-1519-2016. Haywood, A.M., Dowsett, H.J., Dolan, A.M., 2016a. Integrating geological archives and climate models for the mid-Pliocene warm period. Nat. Commun. 7, 10646. https://doi.org/10.1038/ncomms10646. Haywood, A.M., Dowsett, H.J., Dolan, A.M., Rowley, D., Abe-Ouchi, A., Otto-Bliesner, B., Chandler, M.A., Hunter, S.J., Lunt, D.J., Pound, M., Salzmann, U.,2016b. The Pliocene model Intercomparison project (PlioMIP) phase 2: scientific objectives and experimental design. Clim. Past 12, 663e675. https://doi.org/10.5194/cp-12-663-2016. Hill, D.J., 2015. The non-analogue nature of Pliocene temperature gradients. Earth Planet Sci. Lett. 425, 232e241. https://doi.org/10.1016/j.epsl.2015.05.044 Lien, Ø. F., Hjelstuen, B. O.; Zhang, X.; Sejrup H. P., 2022. Late Plio-Pleistocene evolution of the Eurasian Ice Sheets inferred from sediment input along the northeastern Atlantic continental margin. Quat. Sci. Rev. 282, 107433. https://doi.org/10.1016/j.quascirev.2022.107433 McClymont, E. L., Ford, H. L., Ho, S. L., Tindall, J. C., Haywood, A. M., Alonso-Garcia, M., Bailey, I., Berke, M. A., Littler, K., Patterson, M. O., Petrick, B., Peterse, F., Ravelo, A. C., Risebrobakken, B., De Schepper, S., Swann, G. E. A., Thirumalai, K., Tierney, J. E., van der Weijst, C., White, S., Abe-Ouchi, A., Baatsen, M. L. J., Brady, E. C., Chan, W.-L., Chandan, D., Feng, R., Guo, C., von der Heydt, A. S., Hunter, S., Li, X., Lohmann, G., Nisancioglu, K. H., Otto-Bliesner, B. L., Peltier, W. R., Stepanek, C., and Zhang, Z., 2020: Lessons from a high-CO2 world: an ocean view from ∼ 3 million years ago, Clim. Past, 16, 1599–1615, https://doi.org/10.5194/cp-16-1599-2020.

Some legal theorists say that legal entrapment to commit a crime is incoherent. So far, there is no satisfactorily precise statement of this objection in the literature: it is obscure even as to the type of incoherence that is purportedly involved. (Perhaps consequently, substantial assessment of the objection is also absent.) We aim to provide a new statement of the objection that is more precise and more rigorous than its predecessors. We argue that the best form of the objection asserts that, in attempting to entrap, law-enforcement agents lapse into a form of practical incoherence that involves the attempt simultaneously to pursue contrary ends. We then argue that the objection, in this form, encompasses all cases of legal entrapment only if it is supplemented by appeal to the premise that law-enforcement agents have an absolute duty never to create crimes.

The Bayesian decision-analytic approach to trial design uses prior distributions for treatment effects, updated with likelihoods for proposed trial data. Prior distributions for treatment effects based on previous trial results risks sample selection bias and difficulties when a proposed trial differs in terms of patient characteristics, medication adherence, or treatment doses and regimens. The aim of this study was to demonstrate the utility of using pharmacometric-based clinical trial simulation (CTS) to generate prior distributions for use in Bayesian decision-theoretic trial design. The methods consisted of four principal stages: a CTS to predict the distribution of treatment response for a range of trial designs; Bayesian updating for a proposed sample size; a pharmacoeconomic model to represent the perspective of a reimbursement authority in which price is contingent on trial outcome; and a model of the pharmaceutical company return on investment linking drug prices to sales revenue. We used a case study of febuxostat versus allopurinol for the treatment of hyperuricemia in patients with gout. Trial design scenarios studied included alternative treatment doses, inclusion criteria, input uncertainty, and sample size. Optimal trial sample sizes varied depending on the uncertainty of model inputs, trial inclusion criteria, and treatment doses. This interdisciplinary framework for trial design and sample size calculation may have value in supporting decisions during later phases of drug development and in identifying costly sources of uncertainty, and thus inform future research and development strategies.

Glaucoma remains the leading cause of irreversible blindness. Although the loss of retinal ganglion cells (RGCs) is an established hallmark of glaucoma, reduction of intraocular pressure (IOP) is a...

Neuroprotection in glaucoma is any medical treatment by which decline in visual function can be slowed or prevented by supporting the health and survival of neural cells, independent of lowering of intraocular pressure (IOP). This is achieved by targeting mechanisms to inhibit or delay retinal ganglion cell death and promote cell survival pathways. Despite demonstrating promising results in preclinical trials, many neuroprotective strategies have failed to show success in subsequent clinical trials. Of the clinical trials performed, many have been hampered by slow disease progression and questions surrounding biomarker sensitivity. Adaptive clinical trial design, enriched populations and the use of state-of-the-art clinical endpoints are required to improve assessment of therapeutic efficacy. We review the neuroprotective strategies in glaucoma that have been investigated in clinical trials, and appraise experimental designs, the strength of the original hypotheses and preceding work to examine why so few candidates have successfully translated into clinical research.

Summary Most wells in carbonate reservoirs are stimulated. Because of their low cost and simpler operations, acid-stimulation methods are usually preferred if they are sufficient. Matrix acidizing can effectively stimulate carbonate reservoirs, often resulting in skin factors on the order of −3 to −4. In low confining stress and hard rocks, acid fracturing can yield better results than matrix acidizing. However, acid fracturing is less effective in high permeability, high confining stress, or soft rocks. There is a combination of parameters, among them permeability, confining stress, and rock geomechanical properties, that can be used as criteria to decide whether matrix acidizing or acid fracturing is the best acid-stimulation technique for a given scenario. This study compares the productivity of matrix-acidized and acid-fractured wells in carbonate reservoirs. The criterion used to decide the preferred method is the largest productivity obtained using the same volume of acid for both operations. The productivity of the acid-fractured wells is estimated using a fully coupled acid-fracturing simulator, which integrates the geomechanics (fracture propagation), pad and acid transport, heat transfer, temperature effect on reaction rate, effect of wormhole propagation on acid leakoff, and finally calculates the well productivity by simulating the flow in the reservoir toward the acid fracture. Using this simulator, the acid-fracturing operation is optimized, resulting in the operational conditions (injection rate, type of fluid, amount of pad, and so forth) that lead to the best possible acid fracture that can be created with a given amount of acid. The productivity of the matrix-acidized wells is estimated using the most recent wormhole-propagation models scaled up to field conditions. Results are presented for different types of rock and reservoir scenarios, such as shallow and deep reservoirs, soft and hard limestones, chalks, and dolomites. Most of the presented results considered vertical wells. A theoretical extension to horizontal wells is also presented using analytical considerations. For each type of reservoir rock and confining stress, there is a cutoff permeability less than which acid fracturing results in a more productive well; at higher than this cutoff permeability, matrix acidizing should be preferred. This result agrees with the general industry practice, and the estimated productivity agrees with the results obtained in the field. However, the value of the cutoff permeability changes for each case, and simple equations for calculating it are presented. For example, for harder rocks or shallower reservoirs, acid fracturing is more efficient up to higher permeabilities than in softer rocks or at deeper depths. This method provides an engineered criterion to decide the best acid-stimulation method for a given carbonate reservoir. The decision criterion is presented for several different scenarios. A simplified concise analytical decision criterion is also presented: a single dimensionless number that incorporates all pertinent reservoir properties and determines which stimulation method yields the most productive well, without needing any simulations.

Anthropogenic activity is changing Earth’s climate and ecosystems in ways that are potentially dangerous and disruptive to humans. Greenhouse gas concentrations in the atmosphere continue to rise, ensuring these changes will be felt for centuries beyond 2100, the current benchmark for prediction. Estimating the effects of past, current, and potential future emissions to only 2100 is therefore shortsighted. Critical problems for food production and climate-forced ‘survival’ migration are projected to arise well before 2100 raising questions regarding the habitability of some regions of the Earth after the turn of the century. To highlight the need for more distant horizon scanning, we model climate change to 2500 under a suite of emission scenarios and quantify associated projections of crop viability and heat stress. Together, our projections show global climate impacts significantly increase after 2100 without rapid mitigation. As a result, projections of climate and its effects on human well-being and associated governance and policy must be framed beyond 2100.