Initial Conditions for Bubble Universes

The "bubble universes" of Coleman and De Luccia play a crucial role in string cosmology. Since our own Universe is supposed to be of this kind, bubble cosmology should supply definite answers to the long-standing questions regarding cosmological initial conditions. In particular, it must explain how an initial singularity is avoided, and also how the initial conditions for Inflation were established. We argue that the simplest non-anthropic approach to these problems involves a requirement that the spatial sections defined by distinguished bubble observers should not be allowed to have arbitrarily small volumes. Casimir energy is a popular candidate for a quantum effect which can ensure this, but [because it violates energy conditions] there is a danger that it could lead to non-perturbative instabilities in string theory. We make a simple proposal for the initial conditions of a bubble universe, and show that our proposal ensures that the system is non-perturbatively stable. Thus, low-entropy conditions can be established at the beginning of a bubble universe without violating the Second Law of thermodynamics and without leading to instability in string theory. These conditions are inherited from the ambient spacetime.Comment: Further clarifications; 28 pages including three eps files. This is the final [accepted for publication] versio

Survey of highly non-Keplerian orbits with low-thrust propulsion

Celestial mechanics has traditionally been concerned with orbital motion under the action of a conservative gravitational potential. In particular, the inverse square gravitational force due to the potential of a uniform, spherical mass leads to a family of conic section orbits, as determined by Isaac Newton, who showed that Kepler‟s laws were derivable from his theory of gravitation. While orbital motion under the action of a conservative gravitational potential leads to an array of problems with often complex and interesting solutions, the addition of non-conservative forces offers new avenues of investigation. In particular, non-conservative forces lead to a rich diversity of problems associated with the existence, stability and control of families of highly non-Keplerian orbits generated by a gravitational potential and a non-conservative force. Highly non-Keplerian orbits can potentially have a broad range of practical applications across a number of different disciplines. This review aims to summarize the combined wealth of literature concerned with the dynamics, stability and control of highly non-Keplerian orbits for various low thrust propulsion devices, and to demonstrate some of these potential applications

Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis. Methods: In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01752634. Findings: Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42–13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25–13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14–4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. Interpretation: Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder

Natural hazards in Australia : storms, wind and hail

Current and potential future storm-related wind and hail hazard in Australia is reviewed. Confidence in the current incidence of wind hazard depends upon the type of storm producing the hazard. Current hail hazard is poorly quantified in most regions of Australia. Future projections of wind hazard indicate decreases in wind hazard in northern Australia, increases along the east coast and decreases in the south, although such projections are considerably uncertain and are more uncertain for small-scale storms than for larger storms. A number of research gaps are identified and recommendations made

A novel method to allow noninvasive, longitudinal imaging of the murine immune system in vivo

In vivo imaging has revolutionized understanding of the spatiotemporal complexity that subserves the generation of successful effector and regulatory immune responses. Until now, invasive surgery has been required for microscopic access to lymph nodes (LNs), making repeated imaging of the same animal impractical and potentially affecting lymphocyte behavior. To allow longitudinal in vivo imaging, we conceived the novel approach of transplanting LNs into the mouse ear pinna. Transplanted LNs maintain the structural and cellular organization of conventional secondary lymphoid organs. They participate in lymphocyte recirculation and exhibit the capacity to receive and respond to local antigenic challenge. The same LN could be repeatedly imaged through time without the requirement for surgical exposure, and the dynamic behavior of the cells within the transplanted LN could be characterized. Crucially, the use of blood vessels as fiducial markers also allowed precise re-registration of the same regions for longitudinal imaging. Thus, we provide the first demonstration of a method for repeated, noninvasive, in vivo imaging of lymphocyte behavior

Changes in lipid levels and incidence of cardiovascular events following tofacitinib treatment in patients with psoriatic arthritis: a pooled analysis acrossphase III and long‐term extension studies

Objective: The risk of cardiovascular disease (CVD) is higher in patients with psoriatic arthritis (PsA) compared to the general population. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Because tofacitinib increases circulating lipid levels in some patients, we evaluated CVD risk factors and major adverse cardiovascular events (MACE) in patients with active PsA receiving tofacitinib 5 or 10 mg twice daily plus conventional synthetic disease‐modifying antirheumatic drugs. Methods: Data were pooled from 2 phase III studies (Efficacy and Safety of Tofacitinib in Psoriatic Arthritis [OPAL Broaden] and Tofacitinib in Patients with Psoriatic Arthritis With Inadequate Response to TNF Inhibitors [OPAL Beyond]) and 1 ongoing long‐term extension (Open‐Label Extension Study of Tofacitinib in Psoriatic Arthritis [OPAL Balance], data cutoff January 2017; database not locked). Outcomes included fasting lipid levels, blood pressure, hypertension‐related adverse events (AEs; including hypertension, high blood pressure, and increased blood pressure), and MACE. Results: Overall, 783 tofacitinib‐treated patients were included. Percentage increases from baseline in low‐density lipoprotein cholesterol (LDL‐c) and high‐density lipoprotein cholesterol (HDL‐c) levels ranged from 9% to 14% for tofacitinib 5 mg and 10 mg at 3 and 6 months; no meaningful changes in LDL‐c:HDL‐c or total cholesterol:HDL‐c ratios were observed. Blood pressure remained stable for 24 months. Fifty‐eight patients (7.4%) had hypertension‐related AEs; none were fatal (incidence rate [IR] per 100 patient‐years 4.81 [95% confidence interval (95% CI) 3.65–6.22]). Five patients (0.6%) had MACE (IR 0.24 [95% CI 0.05–0.70]); 2 were fatal. Conclusion: Serum lipid level increases at month 3 following tofacitinib treatment in PsA were consistent with observations in rheumatoid arthritis and psoriasis. The IR of hypertension‐related AEs and MACE was low; long‐term follow‐up is ongoing

Resolution of Lithium Deposition versus Intercalation of Graphite Anodes in Lithium Ion Batteries: An In Situ Electron Paramagnetic Resonance Study

From Wiley via Jisc Publications RouterHistory: received 2021-05-07, rev-recd 2021-07-02, pub-electronic 2021-08-13Article version: VoRPublication status: PublishedFunder: Engineering and Physical Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000266; Grant(s): EP/R023034/1, NS/A000055/1, FIRG001 (EP/S003053/1)Abstract: In situ electrochemical electron paramagnetic resonance (EPR) spectroscopy is used to understand the mixed lithiation/deposition behavior on graphite anodes during the charging process. The conductivity, degree of lithiation, and the deposition process of the graphite are reflected by the EPR spectroscopic quality factor, the spin density, and the EPR spectral change, respectively. Classical over‐charging (normally associated with potentials ≤0 V vs. Li+/Li) are not required for Li metal deposition onto the graphite anode: Li deposition initiates at ca. +0.04 V (vs. Li+/Li) when the scan rate is lowered to 0.04 mV s−1. The inhibition of Li deposition by vinylene carbonate (VC) additive is highlighted by the EPR results during cycling, attributed to a more mechanically flexible and polymeric SEI layer with higher ionic conductivity. A safe cut‐off potential limit of +0.05 V for the anode is suggested for high rate cycling, confirmed by the EPR response over prolonged cycling

Research and Education in Computational Science and Engineering

Over the past two decades the field of computational science and engineering (CSE) has penetrated both basic and applied research in academia, industry, and laboratories to advance discovery, optimize systems, support decision-makers, and educate the scientific and engineering workforce. Informed by centuries of theory and experiment, CSE performs computational experiments to answer questions that neither theory nor experiment alone is equipped to answer. CSE provides scientists and engineers of all persuasions with algorithmic inventions and software systems that transcend disciplines and scales. Carried on a wave of digital technology, CSE brings the power of parallelism to bear on troves of data. Mathematics-based advanced computing has become a prevalent means of discovery and innovation in essentially all areas of science, engineering, technology, and society; and the CSE community is at the core of this transformation. However, a combination of disruptive developments---including the architectural complexity of extreme-scale computing, the data revolution that engulfs the planet, and the specialization required to follow the applications to new frontiers---is redefining the scope and reach of the CSE endeavor. This report describes the rapid expansion of CSE and the challenges to sustaining its bold advances. The report also presents strategies and directions for CSE research and education for the next decade.Comment: Major revision, to appear in SIAM Revie

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors:a systematic review

Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.</p

Scalar dark energy models mimicking Λ\LambdaCDM with arbitrary future evolution

Dark energy models with various scenarios of evolution are considered from the viewpoint of the formalism for the equation of state. It is shown that these models are compatible with current astronomical data. Some of the models presented here evolve arbitrarily close to $\Lambda$CDM up to the present, but diverge in the future into a number of different possible asymptotic states, including asymptotic de-Sitter (pseudo-rip) evolution, little rips with disintegration of bound structures, and various forms of finite-time future singularities. Therefore it is impossible from observational data to determine whether the universe will end in a future singularity or not. We demonstrate that the models under consideration are stable for a long period of time (billions of years) before entering a Little Rip/Pseudo-Rip induced dissolution of bound structures or before entering a soft finite-time future singularity. Finally, the physical consequences of Little Rip, Type II, III and Big Crush singularities are briefly compared.Comment: 15 pages, 1 figure, version to appear in Physics Letters