End‐to‐end continuous bioprocessing: impact on facility design, cost of goods and cost of development for monoclonal antibodies

This article presents a systematic approach to evaluate the business case for continuous processing that captures trade-offs between manufacturing and development costs for monoclonal antibodies (mAbs). A decisional tool was built that integrated cost of goods (COG) with cost of development models and new equipment sizing equations tailored to batch, hybrid and end-to-end continuous processes. The COG analysis predicted that single-use continuous facilities (sized using a dedicated DSP train per bioreactor) offer more significant commercial COG savings over stainless steel batch facilities at annual demands of 100-500 kg (~35%), compared to tonnage demands of 1-3 tons (~±10%) that required multiple parallel continuous trains. Single-use batch facilities were found to compete with continuous options on COG only at 100 kg/year. For the scenarios where batch and continuous facilities offered similar COG, the analysis identified the windows of operation required to reach different COG savings with thresholds for the perfusion rate, volumetric productivity and media cost. When considering the project lifecycle cost, the analysis indicated that while end-to-end continuous facilities may struggle to compete on development costs, they become more cost-effective than stainless steel batch facilities when considering the total out-of-pocket cost across both drug development and commercial activities. This article is protected by copyright. All rights reserved

Pulse radiolysis study of 2-mercapto-benzothiazole-a corrosion inhibitor

Pulse radiolysis of 2-Mercaptobenzothiazole (2-MBT) has been undertaken in aqueous solution. The semi-oxidized species formed at pH 4.5 due to the reaction of OH•, Br2 •- and N3• and at pH 10.5 with OH• yielded a spectrum with λmax = 348 and 595 nm. These semi-oxidized species were able to oxidize phenothiazine drugs (E°=0.8 V). Reducing species such as eaq-, CO2 •- and H• atoms react with 2-MBT resulting in the formation of a transient having λmax = 350 nm and reducing in nature. Kinetic and spectroscopic data of interest are reported

Complexes of Some Transition Metal with 2-Benzoyl thiobenzimidazole and 1,10-Phenanthroline and Studying their Antibacterial Activity

Mixed ligands of 2-benzoyl Thiobenzimiazole (L1) with 1,10-phenanthroline (L2) complexes of Cr(III) , Ni(II) and Cu(II) ions were prepared. The ligand and the complexes were isolated and characterized in solid state by using FT-IR, UV-Vis spectroscopy, 1H, 13C-NMR, flame atomic absorption, elemental micro analysis C.H.N.S, magnetic susceptibility , melting points and conductivity measurements. 2-Benzoyl thiobenzimiazole behaves as bidenetate through oxygen atom of carbonyl group and nitrogen atom of imine group. From the analyses Octahedral geometry was suggested for all prepared complexes. A theoretical treatment of ligands and their metal complexes in gas phase were studied using HyperChem-8 program, moreover, ligands in gas phase also has been studied using Gaussian program (GaussView Currently Available Version (5.0.9) along with Gaussian 09 which was the latest in the Gaussian series of programs). The antibacterial activity of the prepared complexes have been determined and compared with that of the ligand and the standard metronidazole

Calcium-independent stimulation of membrane fusion and SNAREpin formation by synaptotagmin I

Ñeurotransmitter release requires the direct coupling of the calcium sensor with the machinery for membrane fusion. SNARE proteins comprise the minimal fusion machinery, and synaptotagmin I, a synaptic vesicle protein, is the primary candidate for the main neuronal calcium sensor. To test the effect of synaptotagmin I on membrane fusion, we incorporated it into a SNARE-mediated liposome fusion assay. Synaptotagmin I dramatically stimulated membrane fusion by facilitating SNAREpin zippering. This stimulatory effect was topologically restricted to v-SNARE vesicles (containing VAMP 2) and only occurred in trans to t-SNARE vesicles (containing syntaxin 1A and SNAP-25). Interestingly, calcium did not affect the overall fusion reaction. These results indicate that synaptotagmin I can directly accelerate SNARE-mediated membrane fusion and raise the possibility that additional components might be required to ensure tight calcium coupling

Improved defect detection using adaptive leaky NLMS filter in guided-wave testing of pipelines

Ultrasonic guided wave (UGW) testing of pipelines allows long range assessments of pipe integrity from a single point of inspection. This technology uses a number of arrays of transducers, linearly placed apart from each other to generate a single axisymmetric wave mode. The general propagation routine of the device results in a single time domain signal, which is then used by the inspectors to detect the axisymmetric wave for any defect location. Nonetheless, due to inherited characteristics of the UGW and non-ideal testing conditions, non-axisymmetric (flexural) waves will be transmitted and received in the tests. This adds to the complexity of results’ interpretation. In this paper, we implement an adaptive leaky normalized least mean square (NLMS) filter for reducing the effect of non-axisymmetric waves and enhancement of axisymmetric waves. In this approach, no modification in the device hardware is required. This method is validated using the synthesized signal generated by a finite element model (FEM) and real test data gathered from laboratory trials. In laboratory trials, six different sizes of defects with cross-sectional area (CSA) material loss of 8% to 3% (steps of 1%) were tested. To find the optimum frequency, several excitation frequencies in the region of 30–50 kHz (steps of 2 kHz) were used. Furthermore, two sets of parameters were used for the adaptive filter wherein the first set of tests the optimum parameters were set to the FEM test case and, in the second set of tests, the data from the pipe with 4% CSA defect was used. The results demonstrated the capability of this algorithm for enhancing a defect’s signal-to-noise ratio (SNR).NSIRC and Brunel Universit

Quality of medical training and emigration of physicians from India

<p>Abstract</p> <p>Background</p> <p>Physician 'brain drain' negatively impacts health care delivery. Interventions to address physician emigration have been constrained by lack of research on systematic factors that influence physician migration. We examined the relationship between the quality of medical training and rate of migration to the United States and the United Kingdom among Indian medical graduates (1955–2002).</p> <p>Methods</p> <p>We calculated the fraction of medical graduates who emigrated to the United States and the United Kingdom, based on rankings of medical colleges and universities according to three indicators of the quality of medical education (a) student choice, (b) academic publications, and (c) the availability of specialty medical training.</p> <p>Results</p> <p>Physicians from the top quintile medical colleges and of universities were 2 to 4 times more likely to emigrate to the United States and the United Kingdom than graduates from the bottom quintile colleges and universities.</p> <p>Conclusion</p> <p>Graduates of institutions with better quality medical training have a greater likelihood of emigrating. Interventions designed to counter loss of physicians should focus on graduates from top quality institutions.</p

Prostate cancer incidence across stage, NCCN risk groups, and age before and after USPSTF Grade D recommendations against prostateâ specific antigen screening in 2012

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153721/1/cncr32604.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153721/2/cncr32604_am.pd

Supporting families and carers of people living with multiple sclerosis: A rapid realist review and realist evaluation

Gillian Baer - ORCID: 0000-0002-1528-2851 https://orcid.org/0000-0002-1528-2851Christina Buckton - ORCID: 0000-0002-6004-4334 https://orcid.org/0000-0002-6004-4334Brendan McCormack - ORCID: 0000-0001-8525-8905 https://orcid.org/0000-0001-8525-8905Submitted manuscript added 2021-07-20.Supportive interventions are needed for family and carers of people with MS. A Rapid Realist Review and Realist Evaluation explored what helps, who it helps, when and how. Literature analysis was synthesised with thematic analysis of qualitative interviews and focus groups with 49 family and carers of people with MS. The resulting model summarised a family of interventions that could help people develop their capabilities and expand their resources, for more positive outcomes. This may prevent or delay a ‘tipping point’ where capacity to care is overwhelmed by caring roles.https://doi.org/10.1332/239788220X160209386931015pubpub

A refined risk stratification scheme for clinical stage 1 NSGCT based on evaluation of both embryonal predominance and lymphovascular invasion

Background: Active surveillance is an increasingly accepted approach for managing patients with germ-cell tumors (GCTs) after an orchiectomy. Here we investigate a time-to-relapse stratification scheme for clinical stage 1 (CS1) nonseminoma GCT (NSGCT) patients according to factors associated with relapse and identify a group of patients with a lower frequency and longer time-to-relapse who may require an alternative surveillance strategy. Patients and methods: We analyzed 266 CS1 GCT patients from the IRB-approved DFCI GCT database that exclusively underwent surveillance following orchiectomy from 1997 to 2013. We stratified NSGCT patients according to predominance of embryonal carcinoma (EmbP) and lymphovascular invasion (LVI), using a 0, 1, and 2 scoring system. Cox regression and conditional risk analysis were used to compare each NSGCT group to patients in the seminomatous germ-cell tumor (SGCT) category. Median time-to-relapse values were then calculated among those patients who underwent relapse. Relapse-free survival curves were generated using the Kaplan–Meier method. Results: Fifty (37%) NSGCT and 20 (15%) SGCT patients relapsed. The median time-to-relapse was 11.5 versus 6.3 months for the SGCT and NSGCT groups, respectively. For NSGCT patients, relapse rates were higher and median timeto- relapse faster with increasing number of risk factors (RFs). Relapse rates (%) and median time-to-relapse (months) were 25%/8.5 months, 41%/6.8 months and 78%/3.8 months for RF0, RF1 and RF2, respectively. We found a statistically significant difference between SGCT and patients with one or two RFs (P < 0.001) but not between SGCT and NSGCT RF0 (P = 0.108). Conclusion: NSGCT patients grouped by a risk score system based on EmbP and LVI yielded three groups with distinct relapse patterns -and patients with neither EmbP nor LVI appear to behave similar to SGCT.C. A. Lago-Hernandez, H. Feldman, E. O, Donnell, B. A. Mahal, V. Perez, S. Howard, M. Rosenthal, S. C. Cheng, P. L. Nguyen, C. Beard, A. V. D, Amico, C. J. Sweene

An optimised assay for quantitative, high-throughput analysis of polysialyltransferase activity

YesThe polysialyltransferases are biologically important glycosyltransferase enzymes responsible for the biosynthesis of polysialic acid, a carbohydrate polymer that plays a critical role in the progression of several diseases, notably cancer. Having improved the chemical synthesis and purification of the fluorescently-labelled DMB-DP3 acceptor, we report optimisation and validation of a highly sensitive cell-free high-throughput HPLC-based assay for assessment of human polysialyltransferase activity