Human lymph node fibroblastic reticular cells maintain heterogeneous characteristics in culture.

Fibroblastic reticular cells (FRCs) are mesenchymal stromal cells in human lymph nodes (LNs) playing a pivotal role in adaptive immunity. Several FRC subsets have been identified, yet it remains to be elucidated if their heterogeneity is maintained upon culture. Here, we established a protocol to preserve and culture FRCs from human LNs and characterized their phenotypic profile in fresh LN suspensions and upon culture using multispectral flow cytometry. We found nine FRC subsets in fresh human LNs, independent of donor, of which four persisted in culture throughout several passages. Interestingly, the historically FRC-defining marker podoplanin (PDPN) was not present on all FRC subsets. Therefore, we propose that CD45negCD31neg human FRCs are not restricted by PDPN expression, as we found CD90, BST1, and CD146/MCAM to be more widely expressed. Together, our data provide insight into FRC heterogeneity in human LNs, enabling further investigation into the function of individual FRC subsets.

What choices of visual correction do people make for recreational running?

PURPOSE: Recreational runners who need refractive visual correction will need to choose the type of visual correction (spectacles, contact lenses, or no correction) to wear when running. The prevalence of correction choices and distinguishing demographic features associated with these choices of correction were investigated. METHODS: A 26-item online questionnaire covering demographics, running habits, and visual corrections used was answered by 941 people. Participants were aged 18 years or older, considered themselves a recreational runner and reported needing refractive correction for everyday life. Bivariate analyses and binary logistic regression were used to determine the variables independently associated with including or avoiding types of correction for running. RESULTS & CONCLUSIONS: Participants ran an average of 3.8times, 3.6hours, and 33.4km per week. Running habits were not associated with type of visual correction, suggesting that visual correction does not present a barrier to participating in recreational running. Solely using spectacles for running was the most common choice (38.8%) and they were worn for running at least sometimes by 65.8%. Fewer people wore spectacles for running than for general purposes (98.9%), suggesting spectacles have limitations for running. Spectacle wear for running was significantly associated with not having contact lenses available and longer duration of wearing visual correction. Running without correction was a common choice, with 15.5% of the sample only running without correction, and 26.2% running at least sometimes without their visual correction. Not wearing correction was significantly associated with not having contact lenses, a shorter duration of wearing visual correction, and a lower myopic refractive error. Contact lenses were the sole correction for running for 15.6% and were worn for running at least sometimes by 40.5%. Contact lenses were significantly more likely to be used by women and younger runners. Signposting runners to contact lenses if this has not previously been considered is recommended.

Immunogenicity of COVID-19 vaccines in patients with follicular lymphoma receiving frontline chemoimmunotherapy.

Immune responses to primary COVID-19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016-004010-10). COVID-19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide-based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS-CoV-2 spike protein using the Abbott Architect and interferon-gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T-cell responses. Within the FL cohort, multivariable analysis identified low pre-treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T-cell responses, and bendamustine and high/intermediate FLIPI-2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID-19 vaccines in FL patients is influenced by multiple disease- and treatment-related factors, among which B-cell depletion showed differential effects on antibody and T-cell responses.

In vitro immunity: an overview of immunocompetent organ-on-chip models.

Impressive advances have been made to replicate human physiology in vitro over the last few years due to the growth of the organ-on-chip (OoC) field in both industrial and academic settings. OoCs are a type of microphysiological system (MPS) that imitates functional and dynamic aspects of native human organ biology on a microfluidic device. Organoids and organotypic models, ranging in their complexity from simple single-cell to complex multi-cell type constructs, are being incorporated into OoC microfluidic devices to better mimic human physiology. OoC technology has now progressed to the stage at which it has received official recognition by the Food and Drug Administration (FDA) for use as an alternative to standard procedures in drug development, such as animal studies and traditional in vitro assays. However, an area that is still lagging behind is the incorporation of the immune system, which is a critical element required to investigate human health and disease. In this review, we summarise the progress made to integrate human immunology into various OoC systems, specifically focusing on models related to organ barriers and lymphoid organs. These models utilise microfluidic devices that are either commercially available or custom-made. This review explores the difference between the use of innate and adaptive immune cells and their role for modelling organ-specific diseases in OoCs. Immunocompetent multi-OoC models are also highlighted and the extent to which they recapitulate systemic physiology is discussed. Together, the aim of this review is to describe the current state of immune-OoCs, the limitations and the future perspectives needed to improve the field.

Small molecule induced STING degradation facilitated by the HECT ligase HERC4.

Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its' involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING, suggesting potential therapeutic applications.

Evaluation of shaft angle to ball-to-target line as a predictor of horizontal delivery plane angle in the golf swing.

The shaft angle to the ball-to-target line at various points in the golf swing is used by coaches as an indication of the horizontal delivery plane angle (HPA). The aim of the current study was to understand to what degree this simplified method of using the shaft orientation can predict the orientation of the HPA. Fifty-two male golfers hit 40 drives each in an indoor biomechanics laboratory. Between-subject regression models were created for the relationship between the HPA and the shaft angle to the ball-to-target line at three different swing positions. Additionally, single subject regression models were created for each subject for the small variables. The only significant between-subjects regression model was for mid-downswing (Adjusted R2 = 89.5%, RMSE = 2.41°); however, this was deemed not accurate enough to distinguish differences between typical driver and wedge HPA. The only shaft position to have significant single-subject regression models for all participants was mid-downswing. The mean RMSE for those models was determined to be low enough to distinguish typical driver and wedge swing planes within individuals. Overall, the shaft angle was only deemed accurate enough to predict the HPA within individual subjects, and only for mid-downswing.

An Organotypic Human Lymph Node Model Reveals the Importance of Fibroblastic Reticular Cells for Dendritic Cell Function.

BACKGROUND: Human lymph node (HuLN) models have emerged with invaluable potential for immunological research and therapeutic application given their fundamental role in human health and disease. While fibroblastic reticular cells (FRCs) are instrumental to HuLN functioning, their inclusion and recognition of importance for organotypic in vitro lymphoid models remain limited. METHODS: Here, we established an in vitro three-dimensional (3D) model in a collagen-fibrin hydrogel with primary FRCs and a dendritic cell (DC) cell line (MUTZ-3 DC). To study and characterise the cellular interactions seen in this 3D FRC-DC organotypic model compared to the native HuLN; flow cytometry, immunohistochemistry, immunofluorescence and cytokine/chemokine analysis were performed. RESULTS: FRCs were pivotal for survival, proliferation and localisation of MUTZ-3 DCs. Additionally, we found that CD1a expression was absent on MUTZ-3 DCs that developed in the presence of FRCs during cytokine-induced MUTZ-3 DC differentiation, which was also seen with primary monocyte-derived DCs (moDCs). This phenotype resembled HuLN-resident DCs, which we detected in primary HuLNs, and these CD1a- MUTZ-3 DCs induced T cell proliferation within a mixed leukocyte reaction (MLR), indicating a functional DC status. FRCs expressed podoplanin (PDPN), CD90 (Thy-1), CD146 (MCAM) and Gremlin-1, thereby resembling the DC supporting stromal cell subset identified in HuLNs. CONCLUSION: This 3D FRC-DC organotypic model highlights the influence and importance of FRCs for DC functioning in a more realistic HuLN microenvironment. As such, this work provides a starting point for the development of an in vitro HuLN.

Evaluating consistency of physical activity and exercise prescription in the UK for people with diabetes - a Delphi study.

Introduction: Increased physical activity is recommended as a cost-effective measure to tackle long-term management of people with diabetes, but research on interventions lacks consistency in terms of effective duration and modality. Methods: The aim of this study was to evaluate expert consensus on exercise and physical activity prescription via a three-round Delphi study conducted with 45 UK-based health and fitness professionals experienced in prescribing exercise or physical activity to people with diabetes. Results: The majority of items put forward to the panel reached consensus with 70% or above voting these items as important, but the details of the type, duration and/or modality of exercise or physical activity prescription within these items often contradicted each other, suggesting that patients are receiving inconsistent advice. The range of different exercise prescription found in this study suggests that patients are being given inconsistent and potentially confusing advice, which may affect their participation in exercise and long-term lifestyle change. Conclusion: More consistent promotion of advice from healthcare and fitness professionals may help with increasing physical activity in this participant group and achieving long term behavior change, reducing patient symptoms as well as reducing the cost to the National Health Service (NHS).

A família ameaçada: violência doméstica nas Américas / The threatened family: domestic violence in the Americas

Vários capítulos deste livro ressaltam os custos significativos que a violência doméstica impõe às mulheres que sofrem abuso e à sociedade como um todo. Essas estimativas preocupantes não deveriam causar paralisia ou inação; pelo contrário, deveriam galvanizar nossa vontade de dar passos concretos para lidar com o problema. Os autores deste livro fornecem orientação sobre como começar, descrevendo estratégias eficazes para reduzir os níveis de violência doméstica e prestar atendimento às mulheres vítimas de maus-tratos. Além disso, identificam lacunas no conhecimento atual que precisam ser sanadas a fim de que se chegue à erradicação da violência. (AU).