Definition of a platform continuous capture scale down model and link to scale-up for monoclonal antibody clinical manufacturing

Definition and scale-up of a batch chromatography process is based on a few main variables such as linear velocity, column loading, and bed height, which are scaled proportionally to column volume. Continuous chromatography consists of multiple columns with column loading and washes/elution/regeneration occurring simultaneously. The definition of a small scale method for continuous chromatography can be extremely complex due to the extensive number of method variables. Limited knowledge exists for development of a scale down and up strategy for continuous chromatography. This abstract should provide some insight into case studies on integration of continuous operations and scale-up, which is one of the themes of the integrated continuous biomanufacturing (ICB) conference. This presentation will describe a strategy for definition of a platform continuous capture scale down model and scale-up pathway. The platform continuous capture step utilizes periodic counter-current chromatography (PCC) for operation of affinity chromatography in a semi-continuous manner. A scale down model for the PCC step was defined and simplified to the following three ranges of harvested cell culture fluid (HCCF) titers: ≤ 2 g/L, 2.5-8 g/L, and 8.5-13 g/L. For each of the three titer ranges, the following variable setpoints are changed based on the specific HCCF titer range: step linear velocity, number of columns, column size, and ΔUV. After these setpoints are inputted into the algorithm, PCC method variables, such as sample loading flowrate, loop time, number of loops and cycles, throughput (g/L/hr), and time cycle, will populate to finish the method design. This PCC scale down model was utilized to scale-up to a bioreactor range of 500-2000L. Quality results showed a good correlation between scale down model and scale-up data. Additional parameters for the 2000L scale-up run included assessment of cleaning and drug substance stability. The cleaning results of the continuous chromatography skid showed passing bioburden, endotoxin, and conductivity. Drug substance stability was also maintained for a year, which was the study duration. This data set proves the PCC small scale model data is representative of the scale-up quality results. In addition, targets such as skid cleanability and DS stability met specifications, which supports the scale-up package for implementation of a platform continuous capture step into a purification process for clinical mAb manufacturing

Quantifying social performance: A review with implications for further work

Human social performance has been a focus of theory and investigation for more than a century. Attempts to quantify social performance have focused on self-report and non-social performance measures grounded in intelligence-based theories. An expertise framework, when applied to individual differences in social interaction performance, offers novel insights and methods of quantification that could address limitations of prior approaches. The purposes of this review are 3-fold. First, to define the central concepts related to individual differences in social performance, with a particular focus on the intelligence-based framework that has dominated the field. Second, to make an argument for a revised conceptualization of individual differences in social–emotional performance as a social expertise. In support of this second aim, the putative components of a social–emotional expertise and the potential means for their assessment will be outlined. To end, the implications of an expertise-based conceptual framework for the application of computational modeling approaches in this area will be discussed. Taken together, expertise theory and computational modeling methods have the potential to advance quantitative assessment of social interaction performance

Haemoptysis in pregnancy caused by a well-differentiated fetal adenocarcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Haemoptysis in pregnancy is frequently assumed to be caused by a pulmonary embolism. However, it can also be an indicator of serious pathology.</p> <p>Case presentation</p> <p>We report the case of a 27-year-old Caucasian woman who presented with haemoptysis in pregnancy that was discovered to be caused by a well-differentiated fetal adenocarcinoma of the lung.</p> <p>Conclusion</p> <p>This case demonstrates the importance of establishing an accurate diagnosis when a pregnant woman presents with haemoptysis and that more serious pathology should be considered if the clinical symptoms persist and/or the presumed diagnosis of pulmonary embolism is not confirmed.</p

The regenerating skeletal muscle niche drives satellite cell return to quiescence

Skeletal muscle stem cells, or satellite cells (SCs), are essential to regenerate and maintain muscle. Quiescent SCs reside in an asymmetric niche between the basal lamina and myofiber membrane. To repair muscle, SCs activate, proliferate, and differentiate, fusing to repair myofibers or reacquiring quiescence to replenish the SC niche. Little is known about when SCs reacquire quiescence during regeneration or the cellular processes that direct SC fate decisions. We find that most SCs reacquire quiescence 5&ndash;10 days after muscle injury, following differentiation and fusion of most cells to regenerate myofibers. Single-cell sequencing of myogenic cells in regenerating muscle identifies SCs reacquiring quiescence and reveals that noncell autonomous signaling networks influence SC fate decisions during regeneration. SC transplantation experiments confirm that the regenerating environment influences SC fate. We define a window for SC repopulation of the niche, emphasizing the temporal contribution of the regenerative muscle environment on SC fate. &nbsp;</p

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow— stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers. SIGNIFICANCE: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics.</p

Inflation Inequality in Europe

We analyze cross-household inflation dispersion in Europe using fictitious monthly inflation rates for several household categories (grouped according to income levels, household size, socio-economic status, age) for the period from 1997 to 2008. Our analysis is carried out on a panel of 23 up to 27 household-specific inflation rates per country for 15 countries. In the first part of the paper, we employ time series and related non-stationary panel approaches to shed light on cross-country differences in inflation inequality with respect to the number of driving forces in the panel. In particular, we focus on the degree of persistence of the household-specific inflation rates and their the adjustment behaviour towards the inflation rate of a representative household. In the second part of the paper, we pool over the full sample of all countries and test if and by how much certain household categories across Europe are more prone to significant inflation differentials and significant differences in the volatility of inflation. Furthermore we search for the presence of clusters with respect to inflation susceptibility. On the national level, we find evidence for the existence of one main driving factor driving the non-stationarity of the panel and evidence for a single co-integration vector. Persistence of deviations, however, is high, and the adjustment speed towards the representative household is low. Even if there is no concern about a long-run stable distribution, at least in the short- to medium run deviations tend to last. On the European level, we find small but significant differences (mainly along income levels), we can separate 5 clusters and two main driving forces for the differences in the overall panel. All in all, even if differences are relatively small, they are not negligible and persistent enough to represent a serious matter of debate for economic and social policy

Stability of the vaginal, oral, and gut microbiota across pregnancy among African American women: the effect of socioeconomic status and antibiotic exposure

Objective A growing body of research has investigated the human microbiota and pregnancy outcomes, especially preterm birth. Most studies of the prenatal microbiota have focused on the vagina, with fewer investigating other body sites during pregnancy. Although pregnancy involves profound hormonal, immunological and metabolic changes, few studies have investigated either shifts in microbiota composition across pregnancy at different body sites or variation in composition at any site that may be explained by maternal characteristics. The purpose of this study was to investigate: (1) the stability of the vaginal, oral, and gut microbiota from early (8–14 weeks) through later (24–30 weeks) pregnancy among African American women according to measures of socioeconomic status, accounting for prenatal antibiotic use; (2) whether measures of socioeconomic status are associated with changes in microbiota composition over pregnancy; and (3) whether exposure to prenatal antibiotics mediate any observed associations between measures of socioeconomic status and stability of the vaginal, oral, and gut microbiota across pregnancy. Methods We used paired vaginal, oral, or gut samples available for 16S rRNA gene sequencing from two time points in pregnancy (8–14 and 24–30 weeks) to compare within-woman changes in measures of alpha diversity (Shannon and Chao1) and beta-diversity (Bray–Curtis dissimilarity) among pregnant African American women (n = 110). Multivariable linear regression was used to examine the effect of level of education and prenatal health insurance as explanatory variables for changes in diversity, considering antibiotic exposure as a mediator, adjusting for age, obstetrical history, and weeks between sampling. Results For the oral and gut microbiota, there were no significant associations between measures of socioeconomic status or prenatal antibiotic use and change in Shannon or Chao1 diversity. For the vaginal microbiota, low level of education (high school or less) was associated with an increase in Shannon and Chao1 diversity over pregnancy, with minimal attenuation when controlling for prenatal antibiotic use. Conversely, for within-woman Bray–Curtis dissimilarity for early compared to later pregnancy, low level of education and prenatal antibiotics were associated with greater dissimilarity for the oral and gut sites, with minimal attenuation when controlling for prenatal antibiotics, and no difference in dissimilarity for the vaginal site. Conclusions Measures of maternal socioeconomic status are variably associated with changes in diversity across pregnancy for the vaginal, oral, and gut microbiota, with minimal attenuation by prenatal antibiotic exposure. Studies that evaluate stability of the microbiota across pregnancy in association with health outcomes themselves associated with socioeconomic status (such as preterm birth) should incorporate measures of socioeconomic status to avoid finding spurious relationships

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

Specific antenatal interventions for Black, Asian and Minority Ethnic (BAME) pregnant women at high risk of poor birth outcomes in the United Kingdom: a scoping review

Background: Disparity exists in maternal and infant birth outcomes of Black and Minority Ethnic (BAME) women giving birth in the United Kingdom (UK) compared to the majority. There is therefore a need to reconsider existing maternity service provision to ensure culturally competent services. The purpose of this scoping review was to ascertain what specific maternity interventions have been implemented in the UK for BAME women (2004–2014) so that increased awareness of the need and scope of specific maternity interventions for BAME women can be identified. Methods: A scoping review was conducted in order to determine the evidence base. It was determined that no prior systematic reviews had been conducted and it was apparent that literature in this field was sparse. Scoping review is an ideal method when literature is likely to be heterogeneous and the research field relatively unexplored. A keyword strategy was used implementing population (P), intervention (I), comparison (C) and outcomes (O). Results: An initial 2188 papers were identified. Following screening and review, only 5 heterogeneous papers remained suitable and were included. The included interventions employed sample sizes of N = 160-1441, examined a range of different outcome measures and were delivered across different parts of the UK with high numbers of BAME residents. Conclusions: There is a lack of rigorous research interventions and practice interventions which are currently documented, of specific maternity interventions which are aimed to address culturally competent maternity services and the sharing of best practice addressing the increased risks of BAME women delivering in the UK