Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease.

BACKGROUND: Many physicians retain reservations regarding the routine prescription of renin-angiotensin blockade (RAB) in patients with atheromatous renovascular disease (ARVD). Conversely, these patients are in most need of the cardio- and renal protection offered by RAB. This reservation is mostly because of fear of precipitating acute renal deterioration. We aimed to study whether RAB can be used safely in ARVD patients and whether it altered their outcome. METHODS: Prospective observational study of all ARVD patients presenting to our tertiary referral centre from 1999-2009. Data capture included usage and tolerability of RAB, and correlation with endpoints of cardiovascular events, dialysis or death. RESULTS: Six hundred and twenty-one subjects were available for analysis. Mean age (SD) of the cohort was 71.3 (8.8) years, median (interquartile range) follow-up 3.1 (2.1, 4.8), range 0.2-10.61 years. Seventy-four patients had an intolerance to RAB at study entry. When utilized prospectively, RAB was tolerated in 357 of 378 patients (92%), and this was even seen in 54/69 (78.3%) patients with bilateral>60% renal artery stenosis (RAS) or occlusion. Patients (4/21) who were intolerant of RAB during follow-up (and 12 retrospectively intolerant), underwent renal revascularization which facilitated safe use of these medications post-procedure. On multivariate time-adjusted analysis, patients receiving RAB were significantly less likely to die (P=0.02). CONCLUSION: RAB is well tolerated even in patients with bilateral severe RAS and reduced mortality in a large group of ARVD patients. We recommend all ARVD patients be considered for RAB therapy unless an absolute contra-indication exists. Intolerance of these agents due to renal dysfunction should be considered an emerging indication for renal revascularization to facilitate their re-introduction.

Determining the needs of ophthalmic trainees entering into specialist training and how they can be met.

Problem: Starting ophthalmic specialty training can be daunting as new basic clinical examination and surgical skills must be acquired before meaningful assessment of patients can begin. No formal clinical induction currently exists with the aim to teach clinical and practical skills to new starters. Aim and objectives: To determine the experience and needs of ophthalmic trainees entering into specialist training. Using this information we developed and implemented a clinical skills training programme for Ophthalmology ST1s. Intervention: Using SMART objectives, PDSA cycles and Chartered Institute of Personnel Development guidance we implemented a clinical skills induction week. Pre-course skills evaluation took place in the form of a questionnaire in order to tailor the course content to the skill level of the group. Course material was made and simulation techniques devised for teaching practical skills. Qualitative data was collected via a pre- and post-course questionnaire. Outcome: All 9 participants rated the course as "extremely useful" it increased their confidence in terms of commencing clinical ophthalmology. 100% of participants felt that this course should be delivered to new ST1s. All participants reported improved confidence in managing ophthalmic emergencies and their clinical skills technique. Lessons learned: A sustainable induction programme was implemented tailored to the prior experience and skills of ST1 trainees. All participants felt it improved their confidence and clinical skills prior to commencing clinical activities. Basic clinical skills can be taught in a cost effective manner early on in postgraduate training.

Clinical Effectiveness of Intravitreal Fluocinolone Acetonide (FAc) (ILUVIEN™) in Patients with Diabetic Macular Oedema (DMO) Refractory to Prior Therapy: The Manchester Experience.

INTRODUCTION: Diabetic macular oedema (DMO) remains a significant cause of sight loss in the UK. Despite macular laser and anti-VEGF agents, a large proportion of patients remain with persistent DMO. We present our results of using 0.19 mg fluocinolone acetonide (FAc) intravitreal implant in this cohort with up to 3 years of follow-up. METHODS: This is a single-centre retrospective review of patients treated with FAc implant for refractory DMO. The primary efficacy end point was visual acuity and secondary efficacy end point was central retinal thickness (CRT) on OCT. A primary safety end point was a rise in IOP requiring treatment. RESULTS: Twenty-one eyes were identified with an average follow-up of 27 months (6-36 months). Visual acuity change from baseline was - 0.1 ETDRS letters at year 1 (n = 13), 8.1 letters at year 2 (n = 13) and 10.7 letters at year 3 (n = 10). CRT improved by - 132.1 µm at year 1 (n = 15), - 172.8 µm at year 2 (n = 13) and - 157.8 µm at year 3 (n = 10). Five eyes (24%) required further anti-VEGF during follow-up and two (9.5%) required further focal laser. IOP rise requiring treatment was noted in eight eyes (38%). Seven were steroid induced. One was caused by rubeotic glaucoma. Six (75%) were managed medically and the remaining two also required surgery. CONCLUSION: This data add to the limited real-world data on FAc in DMO with 3 years of follow-up. Vision and macular architectures both improved at varying rates over 3 years in patients with refractory DMO. IOP rise is a risk but, in the majority, it can be managed medically.

Development of motavizumab, an ultra-potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract.

Respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis and pneumonia in infants and children. Currently, palivizumab is the only approved monoclonal antibody (mAb) for prophylaxis of RSV. However, a small percentage of patients are not protected by palivizumab; in addition, palivizumab does not inhibit RSV replication effectively in the upper respiratory tract. We report here the development and characterization of motavizumab, an ultra-potent, affinity-matured, humanized mAb derived from palivizumab. Several palivizumab variants that enhanced the neutralization of RSV in vitro by up to 44-fold were generated; however, in vivo prophylaxis of cotton rats with these antibodies conferred only about a twofold improvement in potency over palivizumab. This unexpected small increase of in vivo potency was caused by poor serum pharmacokinetics and lung bio-availability that resulted from unexpectedly broad tissue binding. Subsequent analyses revealed that changes at three amino acids arising from the affinity maturation markedly increased the non-specific binding to various tissues. Our results suggested that k(on)-driven mutations are more likely to initiate non-specific binding events than k(off)-driven mutations. Reversion of these three residues to the original sequences greatly diminished the tissue binding. The resulting mAb, motavizumab, binds to RSV F protein 70-fold better than palivizumab, and exhibits about a 20-fold improvement in neutralization of RSV in vitro. In cotton rats, at equivalent concentrations, motavizumab reduced pulmonary RSV titers to up to 100-fold lower levels than did palivizumab and, unlike palivizumab, motavizumab very potently inhibited viral replication in the upper respiratory tract. This affinity-enhanced mAb is being investigated in pivotal clinical trials. Importantly, our engineering process offers precious insights into the improvement of other therapeutic mAbs.

Ultra-potent antibodies against respiratory syncytial virus: effects of binding kinetics and binding valence on viral neutralization.

We describe here the selection of ultra-potent anti-respiratory syncytial virus (RSV) antibodies for preventing RSV infection. A large number of antibody variants derived from Synagis (palivizumab), an anti-RSV monoclonal antibody that targets RSV F protein, were generated by a directed evolution approach that allowed convenient manipulation of the binding kinetics. Palivizumab variants with about 100-fold slower dissociation rates or with fivefold faster association rates were identified and tested for their ability to neutralize virus in a microneutralization assay. Our data reveal a major differential effect of the association and dissociation rates on the RSV neutralization, particularly for intact antibodies wherein the association rate plays the predominant role. Furthermore, we found that antibody binding valence also plays a critical role in mediating the viral neutralization through a mechanism that is likely unrelated to antibody size or binding avidity. We applied an iterative mutagenesis approach, and thereafter were able to identify palivizumab Fab variants with up to 1500-fold improvement and palivizumab IgG variants with up to 44-fold improvement in the ability to neutralize RSV. These anti-RSV antibodies likely will offer great clinical potential for RSV immunoprophylaxis. In addition, our findings provide insights into engineering potent antibody therapeutics for other disease targets.