Socioeconomic Status and Group Belonging: Evidence from Early-Nineteenth-Century Colonial West Africa

This study provides a novel analysis of occupational stratification in Sierra Leone from a historical perspective. By employing census data for early-nineteenth-century colonial Sierra Leone, the present study offers a valuable snapshot of a colony characterized by a heterogenous population of indigenous and migratory origin. The study shows that an association between colonial group categorization and socioeconomic status existed despite the colony being of very recent foundation implying a hierarchical structure of the society. Although Europeans and “mulattoes” occupied most high-status positions, as common in the colonies, indigenous immigrants were also represented in high socioeconomic strata thanks to the opportunities stemming from long- and short-distance trading. However, later arrivals, especially liberated slaves, belonged within the lowest socioeconomic strata of the society and worked as farmers or unskilled labor, suggesting that the time component may also have influence socioeconomic opportunities.

Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor microenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy through a variety of mechanisms. Efforts to target MDSCs by blocking CXCR2 is an active area of research as a method for improving existing and novel immunotherapy strategies. As immunotherapies gain approval for a wider array of clinical indications, it will become even more important to understand the efficacy of CXCR2 inhibition in combating immunotherapy resistance at different stages of tumor progression.

Exploiting the STAT3 Nexus in Cancer-Associated Fibroblasts to Improve Cancer Therapy

The tumor microenvironment (TME) is composed of a heterogenous population of cells that exist alongside the extracellular matrix and soluble components. These components can shape an environment that is conducive to tumor growth and metastatic spread. It is well-established that stromal cancer-associated fibroblasts (CAFs) in the TME play a pivotal role in creating and maintaining a growth-permissive environment for tumor cells. A growing body of work has uncovered that tumor cells recruit and educate CAFs to remodel the TME, however, the mechanisms by which this occurs remain incompletely understood. Recent studies suggest that the signal transducer and activator of transcription 3 (STAT3) is a key transcription factor that regulates the function of CAFs, and their crosstalk with tumor and immune cells within the TME. CAF-intrinsic STAT3 activity within the TME correlates with tumor progression, immune suppression and eventually the establishment of metastases. In this review, we will focus on the roles of STAT3 in regulating CAF function and their crosstalk with other cells constituting the TME and discuss the utility of targeting STAT3 within the TME for therapeutic benefit.

TP6.1.9 Prolonged post-operative stay following emergency and elective laparoscopic cholecystectomies and its contributing factors

Aims Patients who undergo laparoscopic cholecystectomy (LC) for gallstone disease are a heterogenous population with many variables involved in their management. The aim was to identify the proportion of patients who have a prolonged post-operative stay (PPS; >3days) following elective and emergency LC and the variables that most contribute to PPS. Methods We retrospectively collected data for all patients who underwent an elective and emergency LC across three surgical units from 2015 to 2020. Rates of PPS were compared between elective and emergency groups and variables associated with PPS were identified using multivariate logistic regression models. Results 2769 patients were included in the study (median age, 53years(range, 13-92); M:F,1:2.7; emergency:elective,1:3.6) The rate of PPS was higher in the emergency versus elective group (25.1% versus 6.6%; p<0.0001). Pain was one of the major causes in both groups. In the elective group, factors associated with PPS included cholecystitis (OR,1.96; p=0.008), previous gallstone related admissions (OR,1.48; p=0.008), pre-operative ERCP (OR,3.58;p<0.0001), ASA (OR,1.82; p=0.001) and age (years) (OR,1.03;p=0.001). In the emergency group, factors associated with PPS include cholecystitis (OR,5.3;p<0.0001), ASA (OR,1.96; p = 0.01) and pre-operative ERCP (OR,4.44;p=0.001). Conclusions The rate of PPS following laparoscopic cholecystectomy is significant, particularly in the emergency group. Although the possibility of PPS cannot be avoided, patient information regarding the possibility of PPS is important, particularly for those at risk. The risk factors for PPS should be used to guide surgical decision making and should be followed by targeted management of these patients including optimised pain relief.

Prediction of arrhythmia susceptibility through mathematical modeling and machine learning

At present, the QT interval on the electrocardiographic (ECG) waveform is the most common metric for assessing an individual’s susceptibility to ventricular arrhythmias, with a long QT, or, at the cellular level, a long action potential duration (APD) considered high risk. However, the limitations of this simple approach have long been recognized. Here, we sought to improve prediction of arrhythmia susceptibility by combining mechanistic mathematical modeling with machine learning (ML). Simulations with a model of the ventricular myocyte were performed to develop a large heterogenous population of cardiomyocytes (n = 10,586), and we tested each variant’s ability to withstand three arrhythmogenic triggers: 1) block of the rapid delayed rectifier potassium current (IKr Block), 2) augmentation of the L-type calcium current (ICaL Increase), and 3) injection of inward current (Current Injection). Eight ML algorithms were trained to predict, based on simulated AP features in preperturbed cells, whether each cell would develop arrhythmic dynamics in response to each trigger. We found that APD can accurately predict how cells respond to the simple Current Injection trigger but cannot effectively predict the response to IKr Block or ICaL Increase. ML predictive performance could be improved by incorporating additional AP features and simulations of additional experimental protocols. Importantly, we discovered that the most relevant features and experimental protocols were trigger specific, which shed light on the mechanisms that promoted arrhythmia formation in response to the triggers. Overall, our quantitative approach provides a means to understand and predict differences between individuals in arrhythmia susceptibility.

Covid and social distancing with a heterogenous population

Motivated by the Covid-19 epidemic, we build a SIR model with private decisions on social distancing and population heterogeneity in terms of infection-induced fatality rates, and calibrate it to UK data to understand the quantitative importance of these assumptions. Compared to our model, the calibrated benchmark version with constant mean contact rate significantly over-predicts the mean contact rate, the death toll, herd immunity and prevalence peak. Instead, the calibrated counterfactual version with endogenous social distancing but no heterogeneity massively under-predicts these statistics. We use our calibrated model to understand how the impact of mitigating policies on the epidemic may depend on the responses these policies induce across the various population segments. We find that policies that shut down some of the essential sectors have a stronger impact on the death toll than on infections and herd immunity compared to policies that shut down non-essential sectors. Furthermore, there might not be an after-wave after policies that shut down some of the essential sectors are lifted. Restrictions on social distancing can generate welfare gains relative to the case of no intervention. Milder but longer restrictions on less essential activities might be better in terms of these welfare gains than stricter but shorter restrictions, whereas the opposite might be the case for restrictions on more essential activities. Finally, shutting down some of the more essential sectors might generate larger welfare gains than shutting down the less essential sectors.

Coordination of endothelial cell positioning and fate specification by the epicardium

The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.

Large red cell-derived membrane particles are major contributors to hypercoagulability in sickle cell disease

Sickle cell disease (SCD) is one of the most common inherited single gene disorders. Polymerisation of sickle hemoglobin results in erythrocytes that are inflexible and adherent, leading to coagulation, vascular and cellular activation and resultant blood vessel blockage. Previous studies have observed elevated numbers of red cell-derived particles (RCDP), also denoted extracellular vesicles, in SCD plasma. Here, imaging flow cytometry was used to quantify all RCDP in SCD plasma. A more heterogenous population of RCDP was observed than previously reported. Significantly, large right side-out red cell macrovesicles (MaV), 7 µm in diameter, were identified. Most RCDP were right side-out but a minor population of inside-out vesicles was also present. Electron micrographs confirmed the heterogenous nature of the RCDP detected. All MaV are decorated with prothrombotic phosphatidylserine (PS) and their removal from plasma lengthened clotting times by more than three-fold. Removal of all right side-out RCDP from SCD patient plasma samples resulted in a seven-fold increase in clotting time. These results indicate that MaV comprise a large area of prothrombotic membrane and are thus major contributors to hypercoagulation in SCD. Consequently, controlled removal of MaV and PS exposed RCDP from plasma could provide a novel therapy for managing this disease.

Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation

Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.