Classical and quantum modifications of gravity

Einstein’s General Relativity has been our best theory of gravity for nearly a century, yet we know it cannot be the final word. In this thesis, we consider modifications to General Relativity, motivated by both high and low energy physics. In the quantum realm, we focus on Horava gravity, a theory which breaks Lorentz invariance in order to obtain good ultraviolet physics by adding higher spatial derivatives to the action (improving propagator behaviour in loops) but not temporal (avoiding Ostrogradski ghosts). By using the Stückelberg trick, we demonstrate the necessity of introducing a Lorentz violating scale into the theory, far below the Planck scale, to evade strong coupling concerns. Using this formalism we then show explicitly that Horava gravity breaks the Weak Equivalence Principle, for which there are very strict experimental bounds. Moving on to considering matter in such theories, we construct DiffF(M) invariant actions for both scalar and gauge fields at a classical level, before demonstrating that they are only consistent with the Equivalence Principle in the case that they reduce to their covariant form. This motivates us to consider the size of Lorentz violating effects induced by loop corrections of Horava gravity coupled to a Lorentz invariant matter sector. Our analysis reveals potential light cone fine tuning problems, in addition to evidence that troublesome higher order time derivatives may be generated. At low energies, we demonstrate a class of theories which modify gravity to solve the cosmological constant problem. The mechanism involves a composite metric with the square root of its determinant a total derivative or topological invariant, thus ensuring pieces of the action proportional to the volume element do not contribute to the dynamics. After demonstrating general properties of the proposal, we work through a specific example, demonstrating freedom from Ostrogradski ghosts at quadratic order (in the action) on maximally symmetric backgrounds. We go on to demonstrate sufficient conditions for a theory in this class to share a solution space equal to that of Einstein’s equations plus a cosmological constant, before determining the cosmology these extra solutions may have when present

Classical and quantum modifications of gravity

Einstein’s General Relativity has been our best theory of gravity for nearly a century, yet we know it cannot be the final word. In this thesis, we consider modifications to General Relativity, motivated by both high and low energy physics. In the quantum realm, we focus on Horava gravity, a theory which breaks Lorentz invariance in order to obtain good ultraviolet physics by adding higher spatial derivatives to the action (improving propagator behaviour in loops) but not temporal (avoiding Ostrogradski ghosts). By using the Stückelberg trick, we demonstrate the necessity of introducing a Lorentz violating scale into the theory, far below the Planck scale, to evade strong coupling concerns. Using this formalism we then show explicitly that Horava gravity breaks the Weak Equivalence Principle, for which there are very strict experimental bounds. Moving on to considering matter in such theories, we construct DiffF(M) invariant actions for both scalar and gauge fields at a classical level, before demonstrating that they are only consistent with the Equivalence Principle in the case that they reduce to their covariant form. This motivates us to consider the size of Lorentz violating effects induced by loop corrections of Horava gravity coupled to a Lorentz invariant matter sector. Our analysis reveals potential light cone fine tuning problems, in addition to evidence that troublesome higher order time derivatives may be generated. At low energies, we demonstrate a class of theories which modify gravity to solve the cosmological constant problem. The mechanism involves a composite metric with the square root of its determinant a total derivative or topological invariant, thus ensuring pieces of the action proportional to the volume element do not contribute to the dynamics. After demonstrating general properties of the proposal, we work through a specific example, demonstrating freedom from Ostrogradski ghosts at quadratic order (in the action) on maximally symmetric backgrounds. We go on to demonstrate sufficient conditions for a theory in this class to share a solution space equal to that of Einstein’s equations plus a cosmological constant, before determining the cosmology these extra solutions may have when present

Stability of a bi-layer free film: simultaneous or individual rupture events?

We consider the stability of a long free film of liquid composed of two immiscible layers of differing viscosities, where each layer experiences a van der Waals force between its interfaces. We analyse the different ways the system can exhibit interfacial instability when the liquid layers are sufficiently thin. For an excess of surfactant on one gas–liquid interface the coupling between the layers is relatively weak and the instability manifests as temporally separated rupture events in each layer. Conversely, in the absence of surfactant the coupling between the layers is much stronger and the instability manifests as rupture of both layers simultaneously. These features are consistent with recent experimental observations

Cleaning up the cosmological constant

We present a novel idea for screening the vacuum energy contribution to the overall value of the cosmological constant, thereby enabling us to choose the bare value of the vacuum curvature empirically, without any need to worry about the zero-point energy contributions of each particle. The trick is to couple matter to a metric that is really a composite of other fields, with the property that the square-root of its determinant is the integrand of a topological invariant, and/or a total derivative. This ensures that the vacuum energy contribution to the Lagrangian is non-dynamical. We then give an explicit example of a theory with this property that is free from Ostrogradski ghosts, and is consistent with solar system physics and cosmological tests.Comment: 8 pages, typos corrected and more text added, version accepted for publication in JHE

Lymph node homing cells biologically enriched for γδ T cells express multiple genes from the T19 repertoire

Sheep γδ T cells have been shown serologically to express T19, a membrane protein of 180-200 kDa which is a member of the scavenger receptor superfamily. Previous work from this laboratory resulted in the detection of a multigene family of T19-like genes in the sheep genome. In this study nucleotide sequences from several T19 genes were determined and are reported along with the corresponding segments of a number of expressed mRNA molecules. A segment of a single sheep T19-like gene was sequenced and these data, along with the corresponding sequences from cloned T19-like cDNA molecules from sheep and cow, were used to design an ollgonucleotide primer system suitable for amplification of corresponding segments of many T19 genes and their cDNAs. Between 30 and 40% of cloned T19 genes were amenable to amplification using the selected primers, and sequence analysis of cloned PCR products confirmed that different T19 genes encode unique amino acid sequences. The expression of multiple T19 genes was established using cDNA molecules obtained from a single sample of sheep lymphocyte mRNA. The possible role of the T19 family of genes is discusse

Lessons from the decoupling limit of Horava gravity

We consider the so-called "healthy" extension of Horava gravity in the limit where the Stuckelberg field decouples from the graviton. We verify the alleged strong coupling problem in this limit, under the assumption that no large dimensionless parameters are put in by hand. This follows from the fact that the dispersion relation for the Stuckelberg field does not have the desired z = 3 anisotropic scaling in the UV. To get the desired scaling and avoid strong coupling one has to introduce a low scale of Lorentz violation and retain some coupling between the graviton and the Stuckelberg field. We also make use of the foliation preserving symmetry to show how the Stuckelberg field couples to some violation of energy conservation. We source the Stuckelberg field using a point particle with a slowly varying mass and show that two such particles feel a constant attractive force. In this particular example, we see no Vainshtein effect, and violations of the Equivalence Principle. The latter is probably generic to other types of source and could potentially be used to place lower bounds on the scale of Lorentz violation.Comment: 18 pages, 1 figure. Version to appear in JHEP. Conclusions with respect to strong coupling modified - our strong coupling analysis does not apply to a low scale of Lorentz violation. Expanded Equivalence Principle violation discussion, noting it presents a challenge to low scale Lorentz violation, exactly the scenario designed to cure strong coupling. Other minor corrections and references adde

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570