Braneworld black holes and black strings

This thesis involves the study of strong and weak gravity phenomenology within the braneworld paradigm. We begin with a general overview of the hypothesised concept of extra spatial dimensions and explain why they are so interesting. Turning next to the topic of classical four-dimensional black holes, we discuss their formation via gravitational collapse and indicate some of the strong observational evidence of their existence. We then merge the two independent theories of extra dimensions and black holes together to form braneworld black holes. Focusing our attention on two distinct braneworld scenarios, we examine the effects produced from either strong or weak gravity. The prospect of obtaining experimental verification of the existence of additional spacelike dimensions in the upcoming ground-based accelerators, makes the theoretical research of braneworld gravity within this thesis even more enticing. We start with a non-perturbative approach to look for exact, spherically symmetric star or black hole solutions on a Randall-Sundrum brane from the perspective of the five-dimensional spacetime. By fixing the background, we explore the permissible braneworld trajectories within it that correspond to a braneworld observer, the solutions of the brane Tolmann-Oppenheimer-Volkoff equations. A variety of static gravitating matter sources on the brane are obtained in a range of different backgrounds. Our final aim is a consistent brane embedding in a Schwarzschild- Anti de Sitter spacetime as these solutions are potential candidates for brane stars or black holes. The weak and dominant energy conditions determine the physically sensible solutions which have the interpretation of braneworld stars. We then study time-dependent trajectories as a possible description of time-dependent braneworld black holes. This work is then generalised by relaxing the simplifying assumption of Z(_2)-symmetry, previously imposed around the brane. Non-Z(_2) symmetric spacetimes are applicable in processes which concern only one side of the brane, for example black hole recoil or the emission of Hawking radiation. We determine that a subset of the allowed brane trajectories in an asymmetric background are exactly the same as the Z(_2)-symmetric case. Next, we explore perturbative gravity in the Hofava-Witten model of heterotic M-theory. The study of scalar and gravitational fluctuations determines that the radion mode is coupled to the bulk scalar field, indicating only one single degree of freedom. Our analysis also determines the instability of a black string. We then compute the complete mass spectrum of the graviton mode. Using the five-dimensional gravitational physics, we determine what the gravitational interaction an observer on the braneworld would perceive. This analysis involves the computation of the Newtonian potential between two test masses on the visible brane, together with the four-dimensional tensor structure of the massless graviton propagator. Finally, as an application to the earlier work, we comment on work which is in progress: the study of possible brane black hole solutions in low energy heterotic M-theory

On black holes in heterotic braneworlds

We explore the problem of braneworld black holes in the heterotic braneworld scenario of Lukas, Ovrut, Stelle and Waldram (LOSW). We show that black string solutions are unstable, and demonstrate some unusual asymptotics in the linearized metric. We also solve the fully coupled brane and bulk Einstein equations, finding an exact, though singular, solution which corresponds to a brane black hole in which the branes spike apart at the Schwarzschild radius.Comment: 20 pages, 3 figure

Braneworld stars and black holes

We look for spherically symmetric star or black hole solutions on a Randall-Sundrum brane from the perspective of the bulk. We take a known bulk solution, and analyse possible braneworld trajectories within it that correspond, from the braneworld point of view, to solutions of the brane Tolman-Oppenheimer-Volkoff equations. Our solutions are therefore embedded consistently into a full bulk solution. We find the full set of static gravitating matter sources on a brane in a range of bulk spacetimes, analyzing which can correspond to physically sensible sources. Finally, we look at time-dependent trajectories in a Schwarzschild--anti de Sitter spacetime as possible descriptions of time-dependent braneworld black holes, highlighting some of the general features one might expect, as well as some of the difficulties involved in getting a full solution to the question.Comment: 39 pages, 15 figure

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.

Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

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