Immunotherapy-Associated Uveitis

Novel immunotherapies used to treat some cancers, such as checkpoint inhibitors and target therapies of B-RAF protooncogene and mitogen-activated protein kinase (BRAF/MEK), have been strongly associated with adverse events related to immune dysregulation. These effects are known as immune-related adverse events (irAEs). Uveitis is among the known irAEs, and it occurs in approximately 1% of patients using these therapies. The uveitis observed in these patients ranges from anterior, intermediate, to panuveitis. If irAEs are severe, current recommendations are to stop immunotherapy treatment and simultaneously treat the uveitis with steroids (local or systemic). These oncologic immunotherapies have proved to show positive results in cancer treatment. Their use has increased with time, showing ocular side effects that were not reported previously. It is important that ophthalmologists and non-ophthalmologists are aware of these agents and their potential ocular side effects for timely diagnosis and adequate management. This chapter will review different immunotherapies and their potential ocular manifestations and how to diagnose, monitor, and manage these patients

One in a Billion: MSSM-like D-Brane Statistics

Continuing our recent work hep-th/0411173, we study the statistics of four-dimensional, supersymmetric intersecting D-brane models in a toroidal orientifold background. We have performed a vast computer survey of solutions to the stringy consistency conditions and present their statistical implications with special emphasis on the frequency of Standard Model features. Among the topics we discuss are the implications of the K-theory constraints, statistical correlations among physical quantities and an investigation of the various statistical suppression factors arising once certain Standard Model features are required. We estimate the frequency of an MSSM like gauge group with three generations to be one in a billion.Comment: 36 pages, 12 figures; v2: typos corrected, one ref. added; v3: minor changes, version to appear in JHE

Four-dimensional String Compactifications with D-Branes, Orientifolds and Fluxes

This review article provides a pedagogical introduction into various classes of chiral string compactifications to four dimensions with D-branes and fluxes. The main concern is to provide all necessary technical tools to explicitly construct four-dimensional orientifold vacua, with the final aim to come as close as possible to the supersymmetric Standard Model. Furthermore, we outline the available methods to derive the resulting four-dimensional effective action. Finally, we summarize recent attempts to address the string vacuum problem via the statistical approach to D-brane models.Comment: 331 pages, 7 figures, review prepared for Physics Reports, please send constructive comments to: [email protected], v2: refs added, v3: final version to appear in Phys. Rep

Modified Gravity and Cosmology

In this review we present a thoroughly comprehensive survey of recent work on modified theories of gravity and their cosmological consequences. Amongst other things, we cover General Relativity, Scalar-Tensor, Einstein-Aether, and Bimetric theories, as well as TeVeS, f(R), general higher-order theories, Horava-Lifschitz gravity, Galileons, Ghost Condensates, and models of extra dimensions including Kaluza-Klein, Randall-Sundrum, DGP, and higher co-dimension braneworlds. We also review attempts to construct a Parameterised Post-Friedmannian formalism, that can be used to constrain deviations from General Relativity in cosmology, and that is suitable for comparison with data on the largest scales. These subjects have been intensively studied over the past decade, largely motivated by rapid progress in the field of observational cosmology that now allows, for the first time, precision tests of fundamental physics on the scale of the observable Universe. The purpose of this review is to provide a reference tool for researchers and students in cosmology and gravitational physics, as well as a self-contained, comprehensive and up-to-date introduction to the subject as a whole.Comment: 312 pages, 15 figure

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Uveitic Glaucoma

Uveitic glaucoma is a complex disease whose pathogenesis and treatment differ greatly from other glaucoma syndromes. Intraocular pressure elevation can be due to open-angle, closed-angle, or mixed mechanisms and steroid-induced processes. Up to 20% of patients with uveitis develop glaucoma. It is important to adequately recognize the differences in the treatment of this disease to accurately manage both glaucoma and ocular inflammation. We provide a review of the most common inflammatory etiologies that cause glaucoma and different treatment modalities used to manage it, both medical and surgical

Use of biologic response modifiers for the management of ocular inflammatory conditions

Ocular inflammatory conditions can be challenging to manage due to their prolonged and complicated nature. While the mainstay treatment for most cases is oral or topical corticosteroids, it is very important that physicians know how other medications such as biologic response modifiers (biologics) could be used in certain cases. Through illustrative cases, we discuss how treatment with biologics can be helpful in the management of three challenging patients with ocular inflammatory conditions. We review and discuss, (1) a 60-year-old male with granulomatosis with polyangiitis and bilateral anterior scleritis who required rituximab; (2) a 25-year-old male with refractory, idiopathic, bilateral chronic panuveitis and retinal vasculitis, which was controlled with adalimumab after treatment failure with oral and topical corticosteroids, cyclosporine, and methotrexate; and (3) a 44-year-old female with unilateral blindness and juvenile psoriatic arthritis-related intermediate uveitis, who required adalimumab to control her complication of persistent macular edema. These cases highlight the considerations that are required when clinicians are faced with the need to commence biologic therapy for patients with refractory ocular inflammation