The effects of new topical treatments on management of glaucoma in Scotland:An examination of ophthalmological health care

Background: The management of glaucoma has been changed in the past decade by the introduction of new drugs. The impact of these changes on clinical care of patients was examined by examining operation and prescribing rates for glaucoma in four geographical areas of Scotland for the years 1994 to 1999. Methods: A retrospective analysis of national health statistics: primary care prescribing data, hospital derived operation rates, consultant numbers, optometrist numbers, and eye test data, expressed by estimated population at risk of glaucoma. The outcome measures were prescribing volume and cost for glaucoma medications, and operation rates, corrected for population estimated to be at risk of glaucoma (PEG), for trabeculectomy, for Scotland as a whole, and for four geographical "regions" (north east, south east, central, and south west Scotland). Results: Prescribed items per 1000 population estimated to have glaucoma (PEG) increased by 24.9% between 1994 and 1999. This was above the general increase in prescribing in Scotland (17.8%). This increase varied in the four health regions evaluated (14.3% to 31.9%). Prescribing of topical ß blockers increased little (6.4%), but there was a large increase in the use of new products (topical prostaglandins, carbonic anhydrase inhibitors, and a agonists), at the expense of miotics (47.7% fall), and older sympathomimetics. This change in prescribing pattern was accompanied by a 61.5% increase in cost (range 42.2% to 73.4% in the four regions). New drugs accounted for more than half of total glaucoma expenditure in 1999. Operation rates (corrected for PEG) fell by 45.9% (range 43.1 to 58.6%) between 1994 and 1999. Other indicators suggested increased activity in ophthalmic areas (for example, cataract operations, eye tests, numbers of optometrists and ophthalmic surgeons all increased). Within north east Scotland operation rates decreased and prescribing increased less than in other regions, both from lowest regional baseline in 1994. Conclusions: The introduction of new drug classes has had dramatic effects on the prescribing of glaucoma treatments. There has been a decline in older treatments and an increase in new agents, which has been associated with a large reduction in operation rates for glaucoma in Scotland over 6 years. Comparison of prescribing and operation data indicates regional differences in healthcare delivery for glaucoma.

An in vitro study of the radiobiological effects of flattening filter free radiotherapy treatments

Flattening filter free (FFF) linear accelerators allow for an increase in instantaneous dose-rate of the x-ray pulses by a factor of 2-6 over the conventional flattened output. As a result, radiobiological investigations are being carried out to determine the effect of these higher dose-rates on cell response. The studies reported thus far have presented conflicting results, highlighting the need for further investigation. To determine the radiobiological impact of the increased dose-rates from FFF exposures a Varian Truebeam medical linear accelerator was used to irradiate two human cancer cell lines in vitro, DU-145 prostate and H460 non-small cell lung, with both flattened and FFF 6 MV beams. The fluence profile of the FFF beam was modified using a custom-designed Nylon compensator to produce a similar dose profile to the flattened beam (6X) at the cell surface but at a higher instantaneous dose-rate. For both cell lines there appeared to be no significant change in cell survival. Curve fitting coefficients for DU145 cells irradiated with constant average dose-rates were 6X: alpha = 0.09 +/- 0.03, beta = 0.03 +/- 0.01 and 6FFF: alpha = 0.14 +/- 0.13, beta = 0.03 +/- 0.02 with a significance of p = 0.75. For H460 cells irradiated with the same instantaneous dose-rate but different average dose-rate the fit coefficients were 6FFF (low dose-rate): alpha = 0.21 +/- 0.11, 0.07 +/- 0.02 and 6FFF (high dose-rate): alpha = 0.21 +/- 0.16, 0.07 +/- 0.03, with p = 0.79. The results indicate that collective damage behaviour does not occur at the instantaneous dose-rates investigated here and that the use of either modality should result in the same clinical outcome, however this will require further validation in vivo.

Thermomechanical analyses of ultrasonic welding process using thermal and acoustic softening effects

Ultrasonic welding process is a rapid manufacturing process used to weld thin layers of metal at low temperatures and low energy consumption. Experimental results have shown that ultrasonic welding is a combination of both surface (friction) and volume (plasticity) softening effects. In the presented work, a very first attempt has been made to simulate the ultrasonic welding of metals by taking into account both of these effects (surface and volume). A phenomenological material model has been proposed which incorporates these two effects (i.e. surface and volume). The thermal softening due to friction and ultrasonic (acoustic) softening has been included in the proposed material model. For surface effects a friction law with variable coefficient of friction dependent upon contact pressure, slip, temperature and number of cycles has been derived from experimental friction tests. Thermomechanical analyses of ultrasonic welding of aluminium alloy have been performed. The effects of ultrasonic welding process parameters, such as applied load, amplitude of ultrasonic vibration, and velocity of welding sonotrode on the friction work at the weld interface are being analyzed. The change in the friction work at the weld interface has been explained on the basis of softening (thermal and acoustic) of the specimen during the ultrasonic welding process. In the end, a comparison between experimental and simulated results has been presented showing a good agreement. © 2008 Elsevier Ltd. All rights reserved.

Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial

Background: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. Methods: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Findings: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91). Interpretation: Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought.

Mucociliary clearance in cystic fibrosis: Physiology and pharmacological treatments

The understanding of how mutations of the cystic fibrosis gene results in recurrent infection and the development of bronchiectasis is now well established. This review examines aspects of lung pathophysiology specifically, abnormal mucociliary clearance, inflammation and infection which are the basis of the daily symptoms encountered by people with cystic fibrosis. Other components of the lung epithelium and their potential contribution to cystic fibrosis disease are discussed. Therapeutic interventions which aim to target abnormal mucociliary clearance are summarized. © 2011 Elsevier Ltd.

Pharmacological treatments in ARDS; a state-of-the-art update

Despite its high incidence and devastating outcomes, acute respiratory distress syndrome (ARDS) has no specific treatment, with effective therapy currently limited to minimizing potentially harmful ventilation and avoiding a positive fluid balance. Many pharmacological therapies have been investigated with limited success to date. In this review article we provide a state-of-the-art update on recent and ongoing trials, as well as reviewing promising future pharmacological therapies in ARDS.

Evaluating Many Treatments and Biomarkers in Oncology: A New Design

There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.