Implementing connected processes at-scale - Challenges and opportunities for streamlining operations

In response to increased demands placed on biopharmaceutical manufacturers to diversify portfolios and to reduce costs, bioprocesses are being intensified to allow for significant protein production in ≤2,000L single-use bioreactors. Many biopharmaceutical manufacturers are maturing continuous bioprocessing platforms to meet these demands. Hardware, which was once thought to be novel and high-risk for failure, is now being proven as robust at-scale. When coupled with single-use technology, these processes enable biomanufacturing facilities to be built faster at a lower cost, with more flexibility for reconfiguration and support of regional manufacturing. Many challenges remain to achieving this final vision including liquid management for large-scale perfusion operations, overcoming product sieving decay often encountered in filtration-based cell retention devices, and bioburden control for long duration operations. In a collaborative case study, Merck & Co., Inc. and Just Biotherapeutics will demonstrate a strategy leveraging fully single-use equipment and connected operations for an extended duration at manufacturing-scale (500L). This presentation will highlight bioreactor performance with the deployment of media concentrate technology to ease the logistical, staffing and space constraints of a traditional perfusion process, as well as implementation of large-scale microfiltration membranes for cell retention with consistently high protein transmission. In addition, data will be presented not only on the performance of a linked continuous multi-column protein A chromatography capture step, but also bioburden monitoring from multiple points in the process. Advancements implemented during this campaign as well as valuable lessons learned will open the door to further expanding the continuous boundary of connected operations and continuous bioprocessing

The meaning of knowing what is to be known

The aim of this article is to contribute to an articulated language of knowing, which we consider as a key aspect of teachers' professional work. We describe three examples of how the meaning of knowing some specific learning objects can be studied and described. The three learning objects are: to be able to evaluate technical solutions, to be able to perform a house-hop and to be able to act with presence. Phenomenographic analyses of data from the pre-tests carried out within the frame of so called Learning Studies resulted in descriptions of different ways of knowing as well as different aspects of the specific knowns that must be discerned in order to develop the knowing.Cet article a pour objectif de contribuer à un langage articulé du savoir, que nous considérons comme un aspect central du travail des enseignants. Nous décrivons trois exemples de la manière dont on peut étudier et décrire le sens du savoir dans le cadre d'objets d'apprentissage spécifiques. Les trois objets d'apprentissage sont : la capacité à évaluer des solutions techniques, la capacité à effectuer une figure appelée « house-hop » et la capacité à agir « avec présence ». Les analyses phénoménographiques des données issues des tests préliminaires qui ont été menés dans le cadre des études sur l'apprentissage ont permis de mettre en exergue différentes formes de savoirs ainsi que différents aspects des connaissances spécifiques que l'on doit discerner afin de construire le savoir

Use of a Web-Based Dietary Assessment Tool (RiksmatenFlex) in Swedish Adolescents: Comparison and Validation Study

BACKGROUND: A Web-based dietary assessment tool-RiksmatenFlex-was developed for the national dietary survey of adolescents in Sweden. OBJECTIVE: This study aimed to describe the Web-based method RiksmatenFlex and to test the validity of the reported dietary intake by comparing dietary intake with 24-hour dietary recalls (recall interviews), estimated energy expenditure, and biomarkers. METHODS: Adolescents aged 11-12, 14-15, and 17-18 years were recruited through schools. In total, 78 students had complete dietary information and were included in the study. Diet was reported a few weeks apart with either RiksmatenFlexDiet (the day before and a random later day) or recall interviews (face-to-face, a random day later by phone) in a cross-over, randomized design. At a school visit, weight and height were measured and blood samples were drawn for biomarker analyses. Students wore an accelerometer for 7 days for physical activity measurements. Dietary intake captured by both dietary methods was compared, and energy intake captured by both methods was compared with the accelerometer-estimated energy expenditure (EEest). Intake of whole grain wheat and rye and fruit and vegetables by both methods was compared with alkylresorcinol and carotenoid concentrations in plasma, respectively. RESULTS: The mean of the reported energy intake was 8.92 (SD 2.77) MJ by RiksmatenFlexDiet and 8.04 (SD 2.67) MJ by the recall interviews (P=.01). Intake of fruit and vegetables was 224 (169) g and 227 (150) g, and whole grain wheat and rye intake was 12.4 (SD 13.2) g and 12.0 (SD 13.1) g, respectively; the intakes of fruit and vegetables as well as whole grain wheat and rye did not differ between methods. Intraclass correlation coefficients ranged from 0.57 for protein and carbohydrates to 0.23 for vegetables. Energy intake by RiksmatenFlexDiet was overreported by 8% (P=.03) but not by the recall interviews (P=.53) compared with EEest. The Spearman correlation coefficient between reported energy intake and EEest was 0.34 (P=.008) for RiksmatenFlexDiet and 0.16 (P=.21) for the recall interviews. Spearman correlation coefficient between whole grain wheat and rye and plasma total alkylresorcinol homologs was 0.36 (P=.002) for RiksmatenFlexDiet and 0.29 (P=.02) for the recall interviews. Spearman correlations between intake of fruit and vegetables and plasma carotenoids were weak for both dietary tools. The strongest correlations were observed between fruit and vegetable intake and lutein/zeaxanthin for RiksmatenFlexDiet (0.46; P<.001) and for recall interviews (0.28; P=.02). CONCLUSIONS: RiksmatenFlexDiet provides information on energy, fruit, vegetables, and whole grain wheat and rye intake, which is comparable with intake obtained from recall interviews in Swedish adolescents. The results are promising for cost-effective dietary data collection in upcoming national dietary surveys and other studies in Sweden. Future research should focus on how, and if, new technological solutions could reduce dietary reporting biases

Beyond plant blindness: seeing the importance of plants for a sustainable world

In recent years an interdisciplinary nexus has been generated around what it means to experience life as a plant. From the science of plant behaviours, plant language and meaning-making to plant-based philosophy, plant enquiries are crossing disciplinary and conceptual boundaries. The everyday life of a plant can appear to be static and silent to human perception. And yet, as modern science narratives tell their stories, we are realising that plants live in complex, and often social worlds. Removing plants from the human view makes it easier for us to exploit them and appears accordingly to reduce our ability to see into their worlds. In this research study we ask how, by taking a different view through an interdisciplinary lens, might we improve our understanding and sensitivity to the lives of plants? Thus, our research contributes to policy contexts in which society cannot afford its citizens to be plant blind to contemporary conservation issues

Effects of similar intakes of marine n-3 fatty acids from enriched food products and fish oil on cardiovascular risk markers in healthy human subjects

There is convincing evidence that consumption of fish and fish oil rich in long-chain (LC) n-3 PUFA (n-3 LCPUFA), EPA (20 : 5n-3) and DHA (22 : 6n-3) reduce the risk of CHD. The aim of the present study was to investigate whether n-3 LCPUFA-enriched food products provide similar beneficial effects as fish oil with regard to incorporation into plasma lipids and effects on cardiovascular risk markers. A parallel 7-week intervention trial was performed where 159 healthy men and women were randomised to consume either 34 g fish pâté (n 44), 500 ml fruit juice (n 38) or three capsules of concentrated fish oil (n 40), all contributing to a daily intake of approximately 1 g EPA and DHA. A fourth group did not receive any supplementation or food product and served as controls (n 37). Plasma fatty acid composition, serum lipids, and markers of inflammation and oxidative stress were measured. Compared with the control group, plasma n-3 LCPUFA and EPA:arachidonic acid ratio increased equally in all intervention groups. However, no significant changes in blood lipids and markers of inflammation and oxidative stress were observed. In conclusion, enriched fish pâté and fruit juice represent suitable delivery systems for n-3 LCPUFA. However, although the dose given is known to reduce the risk of CVD, no significant changes were observed on cardiovascular risk markers in this healthy populatio

Predictive maps in rats and humans for spatial navigation

Much of our understanding of navigation comes from the study of individual species, often with specific tasks tailored to those species. Here, we provide a novel experimental and analytic framework integrating across humans, rats, and simulated reinforcement learning (RL) agents to interrogate the dynamics of behavior during spatial navigation. We developed a novel open-field navigation task ("Tartarus maze") requiring dynamic adaptation (shortcuts and detours) to frequently changing obstructions on the path to a hidden goal. Humans and rats were remarkably similar in their trajectories. Both species showed the greatest similarity to RL agents utilizing a "successor representation," which creates a predictive map. Humans also displayed trajectory features similar to model-based RL agents, which implemented an optimal tree-search planning procedure. Our results help refine models seeking to explain mammalian navigation in dynamic environments and highlight the utility of modeling the behavior of different species to uncover the shared mechanisms that support behavior

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexit

A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension