Economic and operational appraisal of an allogeneic CAR T-cell bioprocess

Allogeneic CAR T-cell therapies face a variety of challenges from a processing point of view. Pressures to deliver cell therapies at affordable prices demand the development of efficient and cost-effective manufacturing strategies and process technologies for the manufacture of such products. Consideration must be paid to both financial and operational aspects of bioprocess designs from the early stages of product development. This work presents the application of a decisional tool to a case study which describes the manufacture of an allogeneic CAR T-cell therapy. The tool, developed at University College London, is able to quantitatively evaluate bioprocess designs from both a financial and an operational perspective. In this instance the tool has been used to carry out mass balances and equipment sizing calculations in order to compute resource utilisation and cost of goods (COG) for a range of bioprocess designs. Scenario analyses have been used to pinpoint future process improvements that result in feasible manufacturing COG. Furthermore, multi-attribute decision making (MADM) has been employed in order to allow the appraisal of optimal bioprocess designs from both a financial and an operational perspective. The tool outputs provide COG breakdowns for bioprocess designs at a range of annual demands and dose sizes. MADM has been used to provide quantitative output values to key financial and operational performance metrics. Further to this, key process bottlenecks and economic drivers have been identified; these provide a basis for the focus of future process improvements. This work presents a computational technique that can be used to drive effective decision making early on in the development of allogeneic CAR T-cell therapy bioprocesses

Dense, Parsec-Scale Clumps near the Great Annihilator

We report on Combined Array for Research in Millimeter-Wave Astronomy (CARMA) and James Clerk Maxwell Telescope (JCMT) observations toward the Einstein source 1E 1740.7-2942, a LMXB commonly known as the "Great Annihilator." The Great Annihilator is known to be near a small, bright molecular cloud on the sky in a region largely devoid of emission in 12-CO surveys of the Galactic Center. The region is of interest because it is interior to the dust lanes which may be the shock zones where atomic gas from HI nuclear disk is converted into molecular gas. We find that the region is populated with a number of dense (n ~ 10^5 cm^-3) regions of excited gas with small filling factors, and estimate that up to 1-3 x 10^5 solar masses of gas can be seen in our maps. The detection suggests that a significant amount of mass is transported from the shock zones to the GC star-forming regions in the form of small, dense bundles.Comment: 26 pages, 7 figures, accepted for publication by the Astrophysical Journal, abstract abridge

The prosequence of procaricain forms an α-helical domain that prevents access to the substrate-binding cleft

AbstractBackground Cysteine proteases are involved in a variety of cellular processes including cartilage degradation in arthritis, the progression of Alzheimer's disease and cancer invasion: these enzymes are therefore of immense biological importance. Caricain is the most basic of the cysteine proteases found in the latex of Carica papaya. It is a member of the papain superfamily and is homologous to other plant and animal cysteine proteases. Caricain is naturally expressed as an inactive zymogen called procaricain. The inactive form of the protease contains an inhibitory proregion which consists of an additional 106 N-terminal amino acids; the proregion is removed upon activation.Results The crystal structure of procaricain has been refined to 3.2 å resolution; the final model consists of three non-crystallographically related molecules. The proregion of caricain forms a separate globular domain which binds to the C-terminal domain of mature caricain. The proregion also contains an extended polypeptide chain which runs through the substrate-binding cleft, in the opposite direction to that of the substrate, and connects to the N terminus of the mature region. The mature region does not undergo any conformational change on activation.Conclusions We conclude that the rate-limiting step in the in vitro activation of procaricain is the dissociation of the prodomain, which is then followed by proteolytic cleavage of the extended polypeptide chain of the proregion. The prodomain provides a stable scaffold which may facilitate the folding of the C-terminal lobe of procaricain

Accountability and Transparency of Entrepreneurial Journalism: Unresolved ethical issues in crowdfunded journalism projects

Crowdfunding is a new business model in which journalists rely—and depend—on (micro-) payments by a large number of supporters to finance their reporting. In this form of entrepreneurial journalism the roles of publisher, fundraiser and journalist often overlap. This raises questions about conflicts of interest, accountability and transparency. The article presents the results of selected case studies in four different European countries—Germany (Krautreporter), Italy (Occhidellaguerra), the United Kingdom (Contributoria) and the Netherlands (De Correspondent)—as well as one US example (Kickstarter). The study used a two-step methodological approach: first a content analysis of the websites and the Twitter accounts with regard to practices of media accountability, transparency and user participation was undertaken. The aim was to investigate how far ethical challenges in crowdfunded entrepreneurial journalism are accounted for. Second, we present findings from semi-structured interviews with journalists from each crowdfunding. The study provides evidence about the ethical issues in this area, particularly in relation to production transparency and responsiveness. The study also shows that in some cases of crowdfunding (platforms), accountability is outsourced and implemented only through the audience participation

Compassion, Dominance/Submission, and Curled Lips: A Thematic Analysis of Dacryphilic Experience

Paraphilias are often discussed in the psychological literature as pathological problems, yet relatively little research exists that looks into non-pathological paraphilias (i.e., non-normative sexual interests). Empirical evidence suggests that many individuals incorporate a range of non-normative sexual interests into their sexual lifestyles. Dacryphilia is a non-normative sexual interest that involves enjoyment or arousal from tears and crying, and to date has never been researched empirically. The present study set out to discover the different interests within dacryphilia and explore the range of dacryphilic experience. A set of online interviews was carried out with individuals with dacryphilic preferences and interests (six females and two males) from four countries. The data were analysed for semantic and latent themes using thematic analysis. The respondents' statements focused attention on three distinct areas that may be relevant to the experience of dacryphilia: (i) compassion; (ii) dominance/submission; and (iii) curled-lips. The data provided detailed descriptions of features within all three interests, which are discussed in relation to previous quantitative and qualitative research within emotional crying and tears, and the general area of non-normative sexual interests. The study suggests new directions for potential research both within dacryphilia and with regard to other non-normative sexual interests

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy

Background: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight threatening complications of diabetes mellitus and leading causes of adult onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes. Methods: Caucasian Australians with type 2 diabetes were evaluated in a genome wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates. Results: The top ranked SNP for DME was rs1990145 (p = 4.10 x 10(-6), OR = 2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p = 3.87 x 10(-6), OR = 0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p = 0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK.2 (p = 0.007) in the PDR cohort. Conclusion: This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology

Influenza Vaccine Effectiveness against Hospitalisation with Confirmed Influenza in the 2010-11 Seasons: A Test-negative Observational Study

Immunisation programs are designed to reduce serious morbidity and mortality from influenza, but most evidence supporting the effectiveness of this intervention has focused on disease in the community or in primary care settings. We aimed to examine the effectiveness of influenza vaccination against hospitalisation with confirmed influenza. We compared influenza vaccination status in patients hospitalised with PCR-confirmed influenza with patients hospitalised with influenza-negative respiratory infections in an Australian sentinel surveillance system. Vaccine effectiveness was estimated from the odds ratio of vaccination in cases and controls. We performed both simple multivariate regression and a stratified analysis based on propensity score of vaccination. Vaccination status was ascertained in 333 of 598 patients with confirmed influenza and 785 of 1384 test-negative patients. Overall estimated crude vaccine effectiveness was 57% (41%, 68%). After adjusting for age, chronic comorbidities and pregnancy status, the estimated vaccine effectiveness was 37% (95% CI: 12%, 55%). In an analysis accounting for a propensity score for vaccination, the estimated vaccine effectiveness was 48.3% (95% CI: 30.0, 61.8%). Influenza vaccination was moderately protective against hospitalisation with influenza in the 2010 and 2011 seasons

Anomalies in the theory of viscous energy losses due to shear in rotational MEMS resonators.

In this paper, the effect of viscous wave motion on a micro rotational resonator is discussed. This work shows the inadequacy of developing theory to represent energy losses due to shear motion in air. Existing theory predicts Newtonian losses with little slip at the interface. Nevertheless, experiments showed less effect due to Newtonian losses and elevated levels of slip for small gaps. Values of damping were much less than expected. Novel closed form solutions for the response of components are presented. The stiffness of the resonator is derived using Castigliano's theorem, and viscous fluid motion above and below the resonator is derived using a wave approach. Analytical results are compared with experimental results to determine the utility of existing theory. It was found that existing macro and molecular theory is inadequate to describes measured responses

Genetic study of Diabetic Retinopathy: recruitment methodology and analysis of baseline characteristics

ARC and NHMRC funded authors may self-archive the author accepted version of their paper (authors manuscript) after a 12-month embargo period from publication in an open access institutional repository.BACKGROUND: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence, caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study sample to be used for genome-wide association (GWAS) analysis to detect genetic risk variants of DR. METHODS: 1669 participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. Individuals with T2DM had disease duration of at least 5 years, and were taking oral hypoglycemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. RESULTS: 683 diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR (NPDR), proliferative DR (PDR) or diabetic macular edema (DME) were included in this analysis. 812 individuals with DM but no DR or minimal NPDR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and BMI. DME was associated with T2DM (p<0.001), whereas PDR was associated with T1DM (p<0.001). CONCLUSIONS: Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered GWAS to detect genetic risk variants for DR.This work was funded by a grant from the Ophthalmic Research Institute of Australia, and Project Grant #595918 from the National Health and Medical Research Council (NHMRC) of Australia. JEC is supported in part by a NHMRC Practitioner Fellowship and KPB by a Career Development Fellowship. Research conducted at Moorfields Eye Hospital was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology