Accurate and precise viral quantification for rapid vaccine development in- process production monitoring using Radiance® Laser Force Cytology\u3csup\u3eTM

The biopharmaceutical world is evolving rapidly, bringing with it the need for technologies to support this fast-paced and changing environment. Trends in biomanufacturing are moving towards shortened development cycles as companies balance increased productivity requirements with the goal of reducing costs while at the same time ensuring production consistencies are met and batch out of specification (OOS) and failure events are minimized. LumaCyte’s Radiance® instrument using Laser Force Cytology™ (LFC), a combination of advanced optics and microfluidics to rapidly analyze single cells based upon their intrinsic biochemical and biophysical cellular properties and without the need for antibodies or labels. Subtle cellular changes can be precisely captured with Radiance’s automated workflow enabling new capabilities for measuring real-time product quality attributes to support R&D, process development and manufacturing needs across the biopharmaceutical industry. In this poster, LumaCyte demonstrates how tedious infectivity assays such as plaque and TCID50 can be replaced by Radiance’s rapid viral infectivity quantification assay to provide significant shorter time to result (TTR), reduced labor, and improved data quality and consistency. In addition, the bioproduction of vaccines, viral vectors or VLPs can be monitored in real-time, enabling rapid optimization of key processes and increasing process knowledge. As a result, product yield can be increased using the same inputs and the likelihood of OOS events can be reduced. Radiance applications in oncolytic virus research and neutralization assays are presented as well. Overall, LFC delivers faster TTR and improved data quality for vaccine analytics from R&D to manufacturing

Infiltration/cure modeling of resin transfer molded composite materials using advanced fiber architectures

A model was developed which can be used to simulate infiltration and cure of textile composites by resin transfer molding. Fabric preforms were resin infiltrated and cured using model generated optimized one-step infiltration/cure protocols. Frequency dependent electromagnetic sensing (FDEMS) was used to monitor in situ resin infiltration and cure during processing. FDEMS measurements of infiltration time, resin viscosity, and resin degree of cure agreed well with values predicted by the simulation model. Textile composites fabricated using a one-step infiltration/cure procedure were uniformly resin impregnated and void free. Fiber volume fraction measurements by the resin digestion method compared well with values predicted using the model

Laser force cytology for rapid quantification of viral infectivity

The quantification of viral infectivity is an integral step at multiple stages in the process of virally producing recombinant protein, studying the mechanism of viral infection, and developing vaccines. Accurate measurements of infectivity allow for consistent infection and expansion, maximum yield, and assurance that time or environmental conditions have not degraded product quality. Traditional methods to assess infectivity, including the end-point dilution assay (TCID50) and viral plaque assay, are slow, labor intensive, and can vary depending upon the skill and experience of the user. Application of Laser Force Cytology (LFC) for the rapid detection and quantification of viral infection will be presented and discussed for several viral systems in the context of improving the development and production of vaccines. LumaCyte’s Radiance™ instrument is an automated cell analyzer and sorter that measures the optical force, size, shape, and deformability and captures images of single cells. By measuring the intrinsic properties of single cells, cellular changes due to viral infection can be rapidly and objectively quantitated. LFC is very sensitive to agents that perturb cellular structures or change biochemical composition. High quality viral infectivity measurements can be made in a fraction of the time, labor, and cost of traditional assays such as plaque or endpoint dilution. For in-process automated bioreactor monitoring, infectivity can be measured by Radiance in near real-time throughout the process, allowing critical feedback control and optimization. The measurement speed and data quality of LFC / Radiance serve to enhance vaccine development, process optimization/scale-up, and manufacturing to ultimately improve the delivery of vaccines to patients

Balancing the Benefits and Risks of 2 Doses of Dabigatran Compared With Warfarin in Atrial Fibrillation

ObjectivesThis study sought to compare the net clinical benefit of dabigatran 110 mg bid and 150 mg bid with that of warfarin in patients with atrial fibrillation (AF).BackgroundIn patients with AF, dabigatran 110 mg bid and 150 mg bid are associated with similar rates of death. However, the higher dose reduces ischemic stroke and increases bleeding compared with the lower dose. Therefore, there is uncertainty about how to evaluate the overall benefit of the 2 doses.MethodsIn 18,113 AF patients in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial, we used a previously developed method for integrating ischemic and bleeding events as “ischemic stroke equivalents” in order to compare a weighted benefit of 2 doses of dabigatran with each other, and with that of warfarin.ResultsCompared with warfarin, there was a significant decrease in ischemic stroke equivalents with both dabigatran doses: –0.92 per 100 patient years (95% confidence interval [CI]: –1.74 to −0.21, p = 0.02) with dabigatran 110 mg bid and –1.08 (95% CI: –1.86 to −0.34, p = 0.01) with dabigatran 150 mg bid. There was no significant difference in ischemic stroke equivalents between the 2 doses: –0.16 (95% CI: –0.80 to 0.43) comparing dabigatran 150 mg bid with 110 bid. When including death in the weighted benefit calculations, the results were similar.ConclusionsOn a group level both doses of dabigatran as compared with warfarin have similar benefits when considering a weighted estimate including both efficacy and safety. The similar overall benefits of the 2 doses of dabigatran versus warfarin support individualizing the dose based on patient characteristics and physician and patient preferences. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600

The impact of early hypoglycemia and blood glucose variability on outcome in critical illness

INTRODUCTION: In critical illness, the association of hypoglycemia, blood glucose (BG) variability and outcome are not well understood. We describe the incidence, clinical factors and outcomes associated with an early hypoglycemia and BG variability in critically ill patients. METHODS: Retrospective interrogation of prospectively collected data from the Australia New Zealand Intensive Care Society Adult Patient Database on 66184 adult admissions to 24 intensive care units (ICUs) from 1 January 2000 to 31 December 2005. Primary exposure was hypoglycemia (BG or= 12.0 mmol/L) within 24 hours of admission. Primary outcome was all-cause mortality. RESULTS: The cumulative incidence of hypoglycemia and BG variability were 13.8% (95% confidence interval (CI) = 13.5 to 14.0; n = 9122) and 2.9% (95%CI = 2.8 to 3.0, n = 1913), respectively. Several clinical factors were associated with both hypoglycemia and BG variability including: co-morbid disease (P < 0.001), non-elective admissions (P < 0.001), higher illness severity (P < 0.001), and primary septic diagnosis (P < 0.001). Hypoglycemia was associated with greater odds of adjusted ICU (odds ratio (OR) = 1.41, 95% CI = 1.31 to 1.54) and hospital death (OR = 1.36, 95% CI = 1.27 to 1.46). Hypoglycemia severity was associated with 'dose-response' increases in mortality. BG variability was associated with greater odds of adjusted ICU (1.5, 95% CI = 1.4 to 1.6) and hospital (1.4, 95% CI = 1.3 to 1.5) mortality, when compared with either hypoglycemia only or neither. CONCLUSIONS: In critically ill patients, both early hypoglycemia and early variability in BG are relatively common, and independently portend an increased risk for mortality

Vereckei criteria as a diagnostic tool amongst emergency medicine residents to distinguish between ventricular tachycardia and supra-ventricular tachycardia with aberrancy

SummaryBackgroundAccurate electrocardiographic (ECG) differentiation of ventricular tachycardia (VT) from supraventricular tachycardia with aberrancy (SVT-A) on ECG is key to therapeutic decision-making in the emergency department (ED) setting.ObjectiveThe goal of this study was to test the accuracy and agreement of emergency medicine residents to differentiate VT from SVT-A using the Vereckei criteria.MethodsSix emergency medicine residents volunteered to participate in the review of 114 ECGs from 86 patients with a diagnosis of either VT or SVT-A based on an electrophysiology study. The resident reviewers initially read 12-lead ECGs blinded to clinical information, and then one week later reviewed a subset of the same 12-lead ECGs unblinded to clinical information.ResultsOne reviewer was excluded for failing to follow study protocol and one reviewer was excluded for reviewing less than 50 blinded ECGs. The remaining four reviewers each read 114 common ECGs blinded to clinical data and their diagnostic accuracy for VT was 74% (sensitivity 70%, specificity 80%), 75% (sensitivity 76%, specificity 73%), 61% (sensitivity 81%, specificity 25%), and 68% (sensitivity 84%, specificity 40%). The intraclass correlation coefficient (ICC) was 0.31 (95% CI 0.22–0.42). Eliminating two of the four reviewers who left a disproportionately high number of ECGs unclassified resulted in an increase in overall mean diagnostic accuracy (70–74%) and agreement (0.31–0.50) in the two remaining reviewers. Three reviewers read 45 common ECGs unblinded to clinical information and had accuracies for VT 93%, 93% and 78%.ConclusionThe new single lead Vereckei criteria, when applied by emergency medicine residents achieved only fair-to-good individual accuracy and moderate agreement. The addition of clinical information resulted in substantial improvement in test characteristics. Further improvements (accuracy and simplification) of algorithms for differentiating VT from SVT-A would be helpful prior to clinical implementation

Effects of Language Context on Ratings of Shy and Unsociable Behaviors in English Language Learning Children

Purpose The primary goal of this study was to explore the effect of the language context on the socially withdrawn behaviors of school aged-children who are English Language Learners (ELLs) from middle to high SES backgrounds. This is one of the first studies to address the frequently confused concepts of shyness and unsociability as independent constructs within the ELL population. This study also investigated the feasibility of an experimental parent and child questionnaire that examines shyness and unsociability across native and English speaking contexts. Method Children and parents (34 ELL and 37 native English speaking) were administered an experimental questionnaire examining shy and unsociable behavior in native language and English-speaking contexts. Results Parents and children from the ELL group reported significantly higher ratings of shy behavior in English versus native language contexts, whereas unsociable ratings did not differ across language contexts. Conclusions Shyness and unsociability are distinguishable behaviors in ELL children and these constructs should be considered when examining withdrawal. Additionally, examining ELL children’s behavior across language contexts provides a valuable method for investigating language influenced behavioral problems. This study demonstrates the need for service providers to evaluate behavior across subtype and language context before pathologizing withdrawal in ELL children

‘Nothing about us without us’ : disabled people determining their human rights through the UNCRPD

The human rights and fundamental freedoms of disabled persons are set out in the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD). This paper firstly focuses on the importance of the involvement of disabled people at all levels of decision-making. The second part of the paper identifies those aspects of the UNCRPD that reflect the direct involvement of disabled people. Finally, it considers how human rights bodies can best build on this specific aspect of the UNCRPD in order to realize the potential of the Convention as a determining factor in affirming disabled people rights in an effective and meaningful manner.peer-reviewe

Challenges in Australian policy processes for disinvestment from existing, ineffective health care practices

Background Internationally, many health care interventions were diffused prior to the standard use of assessments of safety, effectiveness and cost-effectiveness. Disinvestment from ineffective or inappropriately applied practices is a growing priority for health care systems for reasons of improved quality of care and sustainability of resource allocation. In this paper we examine key challenges for disinvestment from these interventions and explore potential policy-related avenues to advance a disinvestment agenda. Results We examine five key challenges in the area of policy driven disinvestment: 1) lack of resources to support disinvestment policy mechanisms; 2) lack of reliable administrative mechanisms to identify and prioritise technologies and/or practices with uncertain clinical and cost-effectiveness; 3) political, clinical and social challenges to removing an established technology or practice; 4) lack of published studies with evidence demonstrating that existing technologies/practices provide little or no benefit (highlighting complexity of design) and; 5) inadequate resources to support a research agenda to advance disinvestment methods. Partnerships are required to involve government, professional colleges and relevant stakeholder groups to put disinvestment on the agenda. Such partnerships could foster awareness raising, collaboration and improved health outcome data generation and reporting. Dedicated funds and distinct processes could be established within the Medical Services Advisory Committee and Pharmaceutical Benefits Advisory Committee to, a) identify technologies and practices for which there is relative uncertainty that could be the basis for disinvestment analysis, and b) conduct disinvestment assessments of selected item(s) to address existing practices in an analogous manner to the current focus on new and emerging technology. Finally, dedicated funding and cross-disciplinary collaboration is necessary to build health services and policy research capacity, with a focus on advancing disinvestment research methodologies and decision support tools. Conclusion The potential over-utilisation of less than effective clinical practices and the potential under-utilisation of effective clinical practices not only result in less than optimal care but also fragmented, inefficient and unsustainable resource allocation. Systematic policy approaches to disinvestment will improve equity, efficiency, quality and safety of care, as well as sustainability of resource allocation.Adam G Elshaug, Janet E Hiller, Sean R Tunis and John R Mos