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Over a period of 5 years, the Innovative Medicines Initiative PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) project has addressed key research questions relevant to the science of safety signal detection. The results of studies conducted into quantitative signal detection in spontaneous reporting, clinical trial and electronic health records databases are summarised and 39 recommendations have been formulated, many based on comparative analyses across a range of databases (e.g. regulatory, pharmaceutical company). The recommendations point to pragmatic steps that those working in the pharmacovigilance community can take to improve signal detection practices, whether in a national or international agency or in a pharmaceutical company setting. PROTECT has also pointed to areas of potentially fruitful future research and some areas where further effort is likely to yield less.

Birdshot chorioretinopathy (BCR) is a rare form of chronic, bilateral, posterior uveitis with a distinctive clinical phenotype, and a strong association with HLA-A29. It predominantly affects people in middle age. Given its rarity, patients often encounter delays in diagnosis leading to delays in adequate treatment, and thus risking significant visual loss. Recent advances have helped increase our understanding of the underlying autoimmune mechanisms involved in disease pathogenesis, and new diagnostic approaches such as multimodality imaging have improved our ability to both diagnose and monitor disease activity. Whilst traditional immunosuppressants may be effective in BCR, increased understanding of immune pathways is enabling development of newer treatment modalities, offering the potential for targeted modulation of immune mediators. In this review, we will discuss current understanding of BCR and explore recent developments in diagnosis, monitoring and treatment of this disease.Synonyms for BCR: Birdshot chorioretinopathy, Birdshot retinochoroiditis, Birdshot retino-choroidopathy, Vitiliginous choroiditis.Orphanet number: ORPHA179OMIM: 605808.

Background Rosuvastatin (Crestor), a new, highly efficacious statin, has demonstrated dose-dependent low-density lipoprotein cholesterol (LDL-C) reductions of up to 65% in a dose-ranging programme with doses of 1 to 80 mg. Design A randomized, double-blind multicentre trial compared rosuvastatin with commonly used starting doses of pravastatin and simvastatin to determine relative efficacy in LDL-C reduction and impact on other lipid parameters in primary hypercholesterolaemia. Methods and results A total of 502 patients (≥ 18 years; LDL-C ≥ 4.14 mmol/l [160mg/dl] and <6.50mmol/l [250mg/dl] and triglycerides <4.52 mmol/l [400mg/dl]) were randomized to 12 weeks of rosuvastatin 5 mg (n=120) or 10mg (n=115), pravastatin 20 mg (n=137) or simvastatin 20 mg (n=130). Rosuvastatin 5 and 10mg reduced LDL-C by 42 and 49%, respectively, compared with 28% for pravastatin (P< 0.001 versus both rosuvastatin doses) and 37% for simvastatin (P<0.01 versus rosuvastatin 5mg; P < 0.001 versus 10mg). National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) goals were achieved by 87% of rosuvastatin 10mg patients, 71% of rosuvastatin 5 mg patients, 53% of pravastatin patients, and 64% of simvastatin patients; similar proportions of patients achieved NCEP ATP III goals. European Atherosclerosis Society (EAS) goals were achieved by 83, 63, 20 and 50% of patients, respectively. All study treatments were well tolerated. Conclusions Both doses of rosuvastatin were more effective than pravastatin and simvastatin in meeting NCEP ATP II and EAS LDL-C targets. Rosuvastatin 10mg was more effective than pravastatin and simvastatin in meeting NCEP ATP III targets.

Eye disease can be devastating. The most feared impact is sight loss, but in a number of ophthalmic conditions, there can be wide-ranging systemic, psychological, emotional and social effects of both the disease and its treatment. External tests of visual function, such as visual acuity, are inadequate to understand the overall impact of ophthalmic disease on a patient’s functional vision or daily life. This can lead to a discordance between the patient’s priorities and perspective on the one hand and the efforts of clinicians and other stakeholders on the other hand. In this review, we discuss how the patient is uniquely placed to understand the impact of the disease and can use that position to transform ophthalmic care at the individual and collective level, from research to care delivery. We highlight how the “patient voice” can contribute to key areas, including priority setting in the research agenda, communicating the wide-ranging impact of disease and its treatment as assessed through qualitative research, identifying the outcome measures that matter to the patient through core outcome set development and reporting these outcomes through appropriate patient-reported outcome measures. We also consider the increasing power of the patient voice on health institutions, ranging from broadcasting an individual’s experience of care he/she has received to patient societies influencing future health policy. Finally, we reflect on the challenges that need to be overcome for the patient voice to increasingly influence and improve the delivery of eye care in the future.

To combine "extramacular" and "enhanced depth" optical coherence tomographic (OCT) scanning protocols to facilitate enhanced characterization of patients with birdshot chorioretinopathy. Methods: Spectral-domain OCT images were prospectively collected from 24 eyes of 12 patients with birdshot chorioretinopathy. The images were acquired both from the macula and from 4 peripheral locations: superior and inferior to the temporal vascular arcades, nasal to the optic disc, and temporal to the macula. All images were obtained using enhanced depth scanning protocols. Qualitative and quantitative assessments were performed and compared with those from healthy, agematched controls. Results: Generalized loss of the photoreceptor inner segment/outer segment junction was seen more frequently on extramacular OCT image sets. Focal loss of the inner segment/outer segment junction was seen most commonly on inferior extramacular images. Generalized thinning and loss of retinal architecture, accompanied by outer retinal hyperreflective foci, were also commonly seen on extramacular scans. Assessment of choroidal morphology included thinning/absence of the Sattler layer, generalized thinning, discrete hyperreflective foci, focal depigmentation, and the presence of suprachoroidal hyporeflective space. The mean (SD) foveal choroidal thickness was significantly less for patients with birdshot chorioretinopathy (276 [101] m) than for controls (337 [74] m) (P =.04). Conclusions: The OCT images obtained outside the macula often show significant retinal and choroidal changes in cases for which conventional OCT scans appear unremarkable. Use of extramacular scanning may thus allow improved phenotyping of uveitic disorders such as birdshot chorioretinopathy. Evaluation of the photoreceptor inner segment/outer segment junction, using this approach, may be of value for monitoring disease activity in clinical practice and as a surrogate end point in clinical trials.

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ObjectiveTo better understand ozanimod's mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod's effect on circulating leukocyte subsets in patients with relapsing multiple sclerosis.MethodsAn open-label pharmacodynamic study randomized patients to oral ozanimod hydrochloride (HCl) 0.5 (n = 13) or 1 mg/d (n = 11) for ∼12 weeks (including 7-day dose escalation). Circulating leukocyte subsets were quantified using flow cytometry (days 28, 56, and 85) and epigenetic cell counting (days 2, 5, 28, 56, and 85) and compared with baseline (day 1) using descriptive statistics.ResultsOzanimod caused dose-dependent reductions in absolute lymphocyte counts. Observed by both methodologies, circulating CD19+ B- and CD3+ T-cell counts were reduced by >50% with ozanimod HCl 0.5 mg and >75% with 1 mg at day 85. Based on flow cytometry, ozanimod HCl 1 mg showed greater decreases in CD4+ than CD8+ T cells, greater decreases in both CD4+ and CD8+ central memory vs effector memory T cells, and reductions in mean CD4+ and CD8+ naive T cells by ≥90% at day 85. In the flow cytometry analysis, changes in monocytes, natural killer, and natural killer T cells were minimal. Using epigenetic cell counting, greater reductions for Th17 than T regulatory cells were determined.ConclusionOzanimod induced dose-dependent reductions in circulating B- and T-cell counts and differential effects on naive and memory CD4+ and CD8+ T cells and CD19+ B cells. Data characterized with both a novel epigenetic cell-counting method and flow cytometry support ozanimod's MOA.Clinical trial registration:clinicaltrials.govNCT02797015.