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  • 1
    Online Resource
    Online Resource
    MDPI AG ; 2022
    In:  Histories Vol. 2, No. 4 ( 2022-10-26), p. 457-465
    In: Histories, MDPI AG, Vol. 2, No. 4 ( 2022-10-26), p. 457-465
    Abstract: Since the history of fieldwork emerged as a self-conscious area of study within the history of science, especially during the last quarter century, it has expanded its focus on place and practice into an ever wider range of disciplines, social and environmental settings, scales, analytical frameworks, and connections with adjacent disciplines and sub-disciplines. After reviewing some of the foundational scholarly works on the history of scientific fieldwork, this essay identifies and discusses some important recent patterns in scholarship. Historians of fieldwork have increasingly attempted to connect their work to other disciplines such as geography, and to other historical subfields such as environmental history, agricultural history, and the history of capitalism, with increasing success at cross-fertilization despite ongoing tensions arising from significant methodological differences. At the same time, scholars have not only linked their work to a wider variety of social and environmental places, including colonial and postcolonial settings, as well as extreme environments, but have also striven more deliberately to understand the emergence of knowledge through fieldwork at larger scales beyond the local, such as regional, continental, oceanic, and global environments. Scholars have also sought to understand more about the intersection of fieldwork with indigenous, folk, vernacular, and experiential knowledge.
    Type of Medium: Online Resource
    ISSN: 2409-9252
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 3042181-0
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  • 2
    Online Resource
    Online Resource
    MDPI AG ; 2014
    In:  International Journal of Environmental Research and Public Health Vol. 11, No. 8 ( 2014-08-06), p. 7896-7917
    In: International Journal of Environmental Research and Public Health, MDPI AG, Vol. 11, No. 8 ( 2014-08-06), p. 7896-7917
    Type of Medium: Online Resource
    ISSN: 1660-4601
    Language: English
    Publisher: MDPI AG
    Publication Date: 2014
    detail.hit.zdb_id: 2175195-X
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  • 3
    In: Cancers, MDPI AG, Vol. 14, No. 3 ( 2022-01-18), p. 468-
    Abstract: In breast cancer, the promising efficacy of farnesyltransferase inhibitors (FTIs) in preclinical studies is in contrast to only limited effects in clinical Phase II–III trials. The objective of this study was to explore the clinical relevance of farnesyltransferase β-subunit (FNTB) single nucleotide promoter polymorphisms (FNTB-173 6G 〉 5G (rs3215788), -609 G 〉 C (rs11623866) and -179 T 〉 A (rs192403314)) in early breast cancer. FNTB genotyping was performed by pyrosequencing in 797 patients from a prospective multicentre observational PiA trial (NCT 01592825). In the total cohort, the FNTB-173 6G 〉 5G polymorphism was an independent predictor of RFI (HR = 0.568; 95% CI = 0.339–0.949, p = 0.031), OS (HR = 0.629; 95% CI = 0.403–0.980, p = 0.040) and BCSS (HR = 0.433; 95% CI = 0.213–0.882; p = 0.021), whereas the FNTB-609 G 〉 C polymorphism was an independent predictor of RFI (HR = 0.453; 95% CI = 0.226–0.910, p = 0.026) and BCSS (HR = 0.227; 95% CI = 0.075–0.687, p = 0.009). Subtype analysis revealed the independent prognostic relevance of FNTB promoter polymorphisms, particularly in TNBC but not in luminal or HER2-positive intrinsic subtypes. Finally, we used electrophoretic mobility shift assays (EMSAs) to confirm in vitro that the polymorphism FNTB-173 6G 〉 5G resulted in the differential binding of nuclear proteins from five different breast cancer cell lines. This is the first study on breast cancer suggesting that FNTB promoter polymorphisms (i) are independent prognostic biomarkers, particularly in patients with early TNBC, and (ii) could modulate FNTB’s transcriptional activity.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 4
    In: Water, MDPI AG, Vol. 7, No. 12 ( 2015-06-12), p. 2796-2820
    Type of Medium: Online Resource
    ISSN: 2073-4441
    Language: English
    Publisher: MDPI AG
    Publication Date: 2015
    detail.hit.zdb_id: 2521238-2
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  • 5
    In: Children, MDPI AG, Vol. 9, No. 9 ( 2022-09-04), p. 1349-
    Abstract: Background: The purpose of the study was to investigate and describe neurovascular complications and mid-term clinical outcomes of operatively managed fractures of the distal humerus in a paediatric population. Neurovascular injuries are common in these fractures, but reports about their implications for mid-term clinical outcomes is sparse. Methods: A single-centre retrospective study was conducted at a university teaching hospital investigating paediatric patients who underwent operative management of a distal humerus fracture between 2014 and 2018. Patient demographics, fracture classification, pre-, peri- and postoperative neurovascular complications were investigated. Mid-term follow up clinical examination and functional scoring using QuickDASH, the Broberg and Morrey Score (BMS), the Mayo Elbow Performance Score (MEPS) and the Numeric Rating Scale were performed. Results: A total of 84 patients were identified, of which 34 met the inclusion criteria and were available for follow-up clinical examination. The average time to follow-up was 150 weeks (1049.44 days ± 448.54). Ten primary traumatic neurovascular complications were identified, the majority of which involved the median nerve. Primary traumatic dissection of the brachial artery was recorded in three patients. Secondary iatrogenic nerve injury was documented in five patients after previously normal clinical examination. At follow-up, the average QuickDASH score was 3.0 ± 4.3, BMS was 98.6 ± 3.4 and MEPS was 97.1 ± 3.3 points. Conclusions: The mid-term clinical outcome following surgical management of distal humerus fractures is excellent. There is, however, a considerable frequency of both primary and secondary neurovascular complications, which must be considered when opting to treat these injuries surgically.
    Type of Medium: Online Resource
    ISSN: 2227-9067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2732685-8
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  • 6
    In: Processes, MDPI AG, Vol. 10, No. 9 ( 2022-09-05), p. 1783-
    Abstract: Vaccine supply has a bottleneck in manufacturing capacity due to operation personnel and chemicals needed. Assessment of existing mRNA (messenger ribonucleic acid) vaccine processing show needs for continuous manufacturing processes. This is enabled by strict application of the regulatory demanded quality by design process based on digital twins, process analytical technology, and control automation strategies in order to improve process transfer for manufacturing capacity, reduction out-of-specification batch failures, qualified personnel training and number, optimal utilization of buffers and chemicals as well as speed-up of product release. In this work, process control concepts, which are necessary for achieving autonomous, continuous manufacturing, for mRNA manufacturing are explained and proven to be ready for industrialization. The application of the process control strategies developed in this work enable the previously pointed out benefits. By switching from batch-wise to continuous mRNA production as was shown in previous work, which was the base for this study, a potential cost reduction by a factor 5 (i.e., from EUR 0.380 per dose to EUR 0.085 per dose) is achievable. Mainly, based on reduction of personnel (factor 30) and consumable (factor 7.5) per campaign due to the significant share of raw materials in the manufacturing costs (74–97). Future research focus following this work may be on model-based predictive control to gain further optimization potential of potential batch failure and out of specification (OOS) number reduction.
    Type of Medium: Online Resource
    ISSN: 2227-9717
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720994-5
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  • 7
    In: Processes, MDPI AG, Vol. 10, No. 9 ( 2022-09-15), p. 1868-
    Abstract: mRNA-based therapeutics are predicted to have a bright future. Recently, a B2C study was published highlighting the critical bottlenecks of mRNA manufacturing. The study focused on supply bottlenecks of various chemicals as well as shortages of skilled personnel. The assessment of existing messenger ribonucleic acid (mRNA) vaccine processing shows the need for continuous manufacturing processes that are capable of about 80% chemical reduction and more than 70% personnel at factor five more efficient equipment utilization. The key technology to solve these problems is both a higher degree of automation and the maximization of process throughput. In this paper, the application of a quality-by-design process development approach is demonstrated, using process models as digital twins. Their systematic application leads to both robust optimized process parameters, with an increase in productivity of up to 108%, and sophisticated control concepts, preventing batch failures and minimizing the operating workload in terms of personnel and chemicals’ consumption. The approach thereby provides a data-driven decision basis for the industrialization of such processes, which fulfills the regulatory requirements of the approval authorities and paves the way for PAT integration. In the process investigated, it was shown that conventional PID-based controls can regulate fluctuations in the input streams sufficiently well. Model-based control based on digital twins may have potential above all in a further increase in productivity, but is not mandatory to implement for the industrialization of continuous mRNA manufacturing.
    Type of Medium: Online Resource
    ISSN: 2227-9717
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720994-5
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  • 8
    In: Processes, MDPI AG, Vol. 11, No. 3 ( 2023-03-02), p. 745-
    Abstract: The production of messenger ribonucleic acid (mRNA) and other biologics is performed primarily in batch mode. This results in larger equipment, cleaning/sterilization volumes, and dead times compared to any continuous approach. Consequently, production throughput is lower and capital costs are relatively high. Switching to continuous production thus reduces the production footprint and also lowers the cost of goods (COG). During process development, from the provision of clinical trial samples to the production plant, different plant sizes are usually required, operating at different operating parameters. To speed up this step, it would be optimal if only one plant with the same equipment and piping could be used for all sizes. In this study, an efficient solution to this old challenge in biologics manufacturing is demonstrated, namely the qualification and validation of a plant setup for clinical trial doses of about 1000 doses and a production scale-up of about 10 million doses. Using the current example of the Comirnaty BNT162b2 mRNA vaccine, the cost-intensive in vitro transcription was first optimized in batch so that a yield of 12 g/L mRNA was achieved, and then successfully transferred to continuous production in the segmented plug flow reactor with subsequent purification using ultra- and diafiltration, which enables the recycling of costly reactants. To realize automated process control as well as real-time product release, the use of appropriate process analytical technology is essential. This will also be used to efficiently capture the product slug so that no product loss occurs and contamination from the fill-up phase is 〈 1%. Further work will focus on real-time release testing during a continuous operating campaign under autonomous operational control. Such efforts will enable direct industrialization in collaboration with appropriate industry partners, their regulatory affairs, and quality assurance. A production scale-operation could be directly supported and managed by data-driven decisions.
    Type of Medium: Online Resource
    ISSN: 2227-9717
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2720994-5
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  • 9
    In: Processes, MDPI AG, Vol. 11, No. 5 ( 2023-05-12), p. 1480-
    Abstract: Many fundamental decisions in the process design of a separation task are conducted in an early stage where, unfortunately, process simulation does not have the highest priority. Subsequently, during the setup of the digital twin, dedicated experiments are carried out in the design space that was established earlier. These experiments are most often too complicated to conduct directly. This paper addresses the idea of a combined approach. The early-stage buffer screening and optimization experiments were planned with the Design of Experiments, carried out and then analyzed statistically to extract not only the best buffer composition but also the crucial model parameters, in this case the isotherm dependency on the buffer composition. This allowed the digital twin to predict the best buffer composition, and if the model-predicted control was applied to keep the process at the optimal productivity at a predetermined purity. The methodology was tested with an industrial peptide purification step.
    Type of Medium: Online Resource
    ISSN: 2227-9717
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2720994-5
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  • 10
    In: Processes, MDPI AG, Vol. 10, No. 5 ( 2022-04-27), p. 866-
    Abstract: The development and adoption of digital twins (DT) for Quality-by-Design (QbD)-based processes with flexible operating points within a proven acceptable range (PAR) and automation through Advanced Process Control (APC) with Process Analytical Technology (PAT) instead of conventional process execution based on offline analytics and inflexible process set points is one of the great challenges in modern biotechnology. Virus-like particles (VLPs) are part of a line of innovative drug substances (DS). VLPs, especially those based on human immunodeficiency virus (HIV), HIV-1 Gag VLPs, have very high potential as a versatile vaccination platform, allowing for pseudotyping with heterologous envelope proteins, e.g., the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As enveloped VLPs, optimal process control with minimal hold times is essential. This study demonstrates, for the first time, the use of a digital twin for the overall production process of HIV-1 Gag VLPs from cultivation, clarification, and purification to lyophilization. The accuracy of the digital twins is in the range of 0.8 to 1.4% in depth filtration (DF) and 4.6 to 5.2% in ultrafiltration/diafiltration (UFDF). The uncertainty due to variability in the model parameter determination is less than 4.5% (DF) and less than 3.8% (UFDF). In the DF, a prediction of the final filter capacity was demonstrated from as low as 5.8% (9mbar) of the final transmembrane pressure (TMP). The scale-up based on DT in chromatography shows optimization potential in productivity up to a factor of 2. The schedule based on DT and PAT for APC has been compared to conventional process control, and hold-time and process duration reductions by a factor of 2 have been achieved. This work lays the foundation for the short-term validation of the DT and PAT for APC in an automated S7 process environment and the conversion from batch to continuous production.
    Type of Medium: Online Resource
    ISSN: 2227-9717
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720994-5
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