Shieldsbak3037

To evaluate the safety and effectiveness of the Flow Redirection Endoluminal Device (FRED) flow diverter in support of an application for Food and Drug Administration approval in the USA.

145 patients were enrolled in a prospective, single-arm multicenter trial. Patients with aneurysms of unfavorable morphology for traditional endovascular therapies (large, wide-necked, fusiform, etc) were included. The trial was designed to demonstrate non-inferiority in both safety and effectiveness, comparing trial results with performance goals (PGs) established from peer-reviewed published literature. The primary safety endpoint was death or major stroke (National Institutes of Health Stroke Scale score ≥4 points) within 30 days of the procedure, or any major ipsilateral stroke or neurological death within the first year. The primary effectiveness endpoint was complete occlusion of the target aneurysm with ≤50% stenosis of the parent artery at 12 months after treatment, and in which an alternative treatment of the target intracranial aneurysm had not been performed.

145 patients underwent attempted placement of a FRED device, and one or more devices were placed in all 145 patients. 135/145 (93%) had a single device placed. Core laboratory adjudication deemed 106 (73.1%) of the aneurysms large or giant. A safety endpoint was experienced by 9/145 (6.2%) patients, successfully achieving the safety PG of <15%. The effectiveness PG of >46% aneurysm occlusion was also achieved, with the effectiveness endpoint being met in 80/139 (57.6%) CONCLUSION As compared with historically derived performance benchmarks, the FRED flow diverter is both safe and effective for the treatment of appropriately selected intracranial aneurysms.

NCT01801007.

NCT01801007.Nitrosamines have gained unexpected attention again, triggered by their discovery at significant concentrations in some active pharmaceutical ingredients (APIs) excipients. Regulatory agencies not only expect the marketing authorization holders to include a nitrosamine risk assessment in their drug development process but to also apply it retrospectively on the marketed drug product. As part of this risk assessment, all possible sources of nitrosamines need to be evaluated. This review provides the chemical background of nitrosamines and elastomeric formulations, the current regulatory status in the pharmaceutical and other industries and discusses analytical challenges of nitrosamine measurement. This evaluation of elastomeric components as a potential nitrosamine source proposes how this information can be used in a drug product risk assessment. Lay abstract Nitrosamines are a group of chemical substances that in many cases have been shown to be carcinogenic. They can form in many ways, from acidic conditions in the human stomach to high temperatures during food preparation. They are also known to be generated during beer brewing and smoking of cigarettes, and naturally exist in the air, soil and our water supply. In the past years, they have also been discovered as impurities in drug products. Extensive investigations have been initiated to find the root causes, whereby all possible sources are included. One of these sources are elastomers, since they are used as primary packaging components in syringe, cartridge and vial systems. This review provides the chemical background of nitrosamines and elastomeric formulations, the current regulatory status in the pharmaceutical and other industries and discusses analytical challenges of nitrosamine measurement. This evaluation of elastomeric components as a potential nitrosamine source proposes how this information can be used in a drug product risk assessment.The fill-finish process of highly concentrated protein formulations poses several technical challenges and in particular the filling process is critical to ensure filling accuracy. As highly concentrated formulations comprise a significant non-volatile fraction, drying of drug product at the filling nozzle may occur during line interruptions. In many cases, this is a result of dripping at the filling nozzle and dependent on environmental factors. The dried product may be picked up by the units after filling interruption and although in small quantities, the effect of drying on the quality of the drug product is currently unclear. We investigated the drying phenomenon of a highly concentrated monoclonal antibody formulation (120 mg/mL) and studied drying kinetics and associated aggregation propensity. To this regard, we established a robust method simulating the drying process dependent on environmental conditions such as relative humidity and air flow. We revealed that drying kinetics were characterized by an initial fast evaporation phase, which was shorter for lower relative humidity and air flow, followed by a plateau phase. Protein aggregation particularly increased during the plateau phase and was positively correlated with relative humidity. Drying kinetics and aggregate formation were modeled using Hill's equation. We highlight that drying phenomena are relevant for small-volume drug products (magnitude of 100-200 μL) in particular for dosing accuracy, but less critical for larger fill volumes in the milliliter range. Especially for the latter, they might be negligible if the dried product can fully dissolve in the first units after filling interruption and in case of consistent drug product quality because of adequate formulation choice. Ultimately, we summarize technical options to avoid drying phenomena of highly concentrated protein formulations and emphasize the importance of adequate pump parameter setting.There are many drivers to intensify the manufacturing of vaccines. The emergence of SARS-CoV-2 has only added to them. Since the pandemic began, we are seeing an acceleration of vaccine development and approval, including application of novel prophylactic vaccine modalities. We have also seen an increase in the appreciation and general understanding of what had been a somewhat obscure discipline. Concurrently, there has been great interest in the application of new understandings and technology to the intensification of biopharmaceutical processes in general. The marriage of these developments defines the field of vaccine manufacturing process intensification. Difficulties in its implementation include the many disparate vaccine types- from conjugate to hybrid to nucleic-acid based. Then, there are the respective and developing manufacturing methods, modes, and platforms- from fermentation of transformed bacteria to the bioreactor culture of recombinant animal cells to production of virus-like particles in transgenic plants. Advances are occurring throughout the biomanufacturing arena, from process development (PD) techniques to manufacturing platforms, materials, equipment, and facilities. Bioprocess intensification refers to systems for producing more product per cell, time, volume, footprint, or cost. The need for vaccine manufacturing process intensification is being driven by desires for cost control, process efficiency, and the heightened pressures of pandemic response. We are seeing great interest in the power of such disciplines as synthetic biology, process simplification, continuous bioprocessing, and digital techniques in the optimization of vaccine PD and manufacturing. Other powerful disciplines here include process automation, improved monitoring, optimized culture materials, and facility design. The intent of this short commentary is to provide a brief review, and a few examples of the exciting advances in the equipment, technology and processes supporting this activity.Paraproteinaemic neuropathies comprise a heterogeneous group of neuro-haematological conditions with some distinct neurological, haematological and systemic phenotypes. The spectrum of disease varies from mild to severe, indolent to rapidly progressive and from small fibre sensory involvement to dramatic sensorimotor deficits. The haematological association may be overlooked, resulting in delayed treatment, disability, impaired quality of life and increased mortality. However, the presence of an irrelevant benign paraprotein can sometimes lead to inappropriate treatment. In this review, we outline our practical approach to paraproteinaemic disorders, discuss the utility and limitations of diagnostic tests and the distinctive clinical phenotypes and touch on the complex multidisciplinary management approaches.

Lung cancer has a poor prognosis that varies internationally when assessed by the two major histological subgroups (non-small cell (NSCLC) and small cell (SCLC)).

236 114 NSCLC and 43 167 SCLC cases diagnosed during 2010-2014 in Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK were included in the analyses. One-year and 3-year age-standardised net survival (NS) was estimated by sex, histological type, stage and country.

One-year and 3-year NS was consistently higher for Canada and Norway, and lower for the UK, New Zealand and Ireland, irrespective of stage at diagnosis. Three-year NS for NSCLC ranged from 19.7% for the UK to 27.1% for Canada for men and was consistently higher for women (25.3% in the UK; 35.0% in Canada) partly because men were diagnosed at more advanced stages. International differences in survival for NSCLC were largest for regional stage and smallest at the advanced stage. For SCLC, 3-year NS also showed a clear female advantage with the highest being for Canada (1ion practice, as well as differences in histological verification, staging and coding across jurisdictions.Changes in the distribution and abundance of invasive species can have far-reaching ecological consequences. Programs to control invaders are common but gauging the effectiveness of such programs using carefully controlled, large-scale field experiments is rare, especially at higher trophic levels. Experimental manipulations coupled with long-term demographic monitoring can reveal the mechanistic underpinnings of interspecific competition among apex predators and suggest mitigation options for invasive species. We used a large-scale before-after control-impact removal experiment to investigate the effects of an invasive competitor, the barred owl (Strix varia), on the population dynamics of an iconic old-forest native species, the northern spotted owl (Strix occidentalis caurina). Isradipine mw Removal of barred owls had a strong, positive effect on survival of sympatric spotted owls and a weaker but positive effect on spotted owl dispersal and recruitment. After removals, the estimated mean annual rate of population change for spotted owls stabilized in areas with removals (0.2% decline per year), but continued to decline sharply in areas without removals (12.1% decline per year). The results demonstrated that the most substantial changes in population dynamics of northern spotted owls over the past two decades were associated with the invasion, population expansion, and subsequent removal of barred owls. Our study provides experimental evidence of the demographic consequences of competitive release, where a threatened avian predator was freed from restrictions imposed on its population dynamics with the removal of a competitively dominant invasive species.