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In the contemporary era of cancer immunotherapy, an abundance of clinical and translational studies have reported radiotherapy (RT) and immunotherapies as a viable option for immunomodulation of many cancer subtypes, with many related clinical trials ongoing. In locally advanced disease, chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma (OAC), however, the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative setting.To immunophenotype OAC patients' immune checkpoint (IC) expression with and without radiation and evaluate the effects of checkpoint blockade on cell viability.In the contemporary era of cancer immunotherapy, an abundance of studies have demonstrated that combination RT and IC inhibitors (ICIs) are effective in the immunomodulation of many cancer subtypes, with many related clinical trials ongoing. Although surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC, the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative setting. The aim of this body of work was to immunophenotype OAC patients' IC expression with and without radiation and to establish the impact of checkpoint blockade on cell viability. This study was a hybrid combination ofWe identified that conventional dosing and hypofractionated approaches resulted in increased IC expression (PD-1, PD-L1, TIM3, TIGIT)The findings of the current study demonstrate synergistic potential for the use of ICIs and ionising radiation to potentiate established anti-tumour responses in the neoadjuvant setting and is of particular interest in those with advanced disease, adverse features of tumour biology and poor treatment responses to conventional therapies.

Background: Down syndrome (DS) is associated with increased risk for Alzheimer’s disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38–61 years). Results: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. Conclusion: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

Heterologous effects of vaccines are mediated by 'trained immunity' whereby myeloid cells are metabolically and epigenetically reprogrammed resulting in heightened responses to subsequent insults. Adenovirus vaccine vector has been reported to induce trained immunity in mice. Therefore, we sought to determine if the ChAdOx1 nCoV-19 vaccine (AZD1222), which uses an adenoviral vector, could induce trained immunity in vivo in humans.Ten healthy volunteers donated blood on the day before receiving the ChAdOx1 nCoV-19 vaccine and on day 14, 56 and 90 post vaccination. Monocytes were purified from PBMC; cell phenotype was determined by flow cytometry, expression of metabolic enzymes were quantified by RT-qPCR and production of cytokines and chemokine in response to stimulation ex vivo were analyzed by multiplex ELISA.Monocyte frequency and count were increased in peripheral blood up to 3 months post vaccination compared with their own pre-vaccine control. Expression of HLA-DR, CD40 and CD80 was enhanced on monocytes for up to 3 months following vaccination. Moreover, monocytes had increased expression of glycolysis-associated enzymes 2 months post vaccination. Upon stimulation ex vivo with unrelated antigens, monocytes produced increased IL-1β, IL-6, IL-10, CXCL1, and MIP-1α, and decreased TNF, compared with pre-vaccine controls. Resting monocytes produced more IFN-γ, IL-18, and MCP-1 up to 3 months post vaccination compared with pre-vaccine controls.These data provide evidence for the induction of trained immunity following a single dose of the ChAdOx1 nCoV-19 vaccine.This work was funded by The Health Research Board (EIA-2019-010) and Science Foundation Ireland Strategic Partnership Programme (Proposal ID 20/SPP/3685).

Environmental remediation of polluted sites in developing communities often faces difficulties due to the misalignment of project objectives with the needs and interests of local communities, establishment of unrealistic expectations for the outcome of the project, and failure to account for the available resources in the community itself. Remediation decisions favor technical data and technical solutions as the main means of determining remediation options, requiring significant investment and local capacity that are often not found in developing communities. Often these systems fail to account for the social aspects in environmental management and remediation. In contrast, new approaches in local knowledge-based solutions focus on pre-existing environmental management initiatives to establish objectives that are meaningful to the community itself. “Positive deviance” – or the idea that there are solutions already in communities that are successful at addressing challenges despite the barriers that a community faces – are often overlooked during project design and implementation. Identifying examples of positive deviance and working with community members who are well versed in local challenges, available resources, and local capacity presents opportunities for community members to establish project objectives and provides the foundation for future environmental management projects in the area. We present a case study of artisanal and small-scale gold mining (ASGM) in the Andes municipality, Antioquia, Colombia and local initiatives to overcome community-identified environmental pollutants. Through a series of semi-structured interviews, surveys, and site visits, we identified community perception of environmental pollutants, management techniques for mining waste, and grassroots initiatives that were locally developed to address them. Through key communication and interaction between innovators with identified positive deviance projects, technical experts, and other miners facing similar challenges, innovative projects that account for the social, political, and economic realities of a developing community can become widespread, leading to improved environmental and social conditions.

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC., After recovery from acute SARS-CoV-2 infection, mice exhibit chronic lung disease similar to some humans, allowing for testing of therapeutics.

Residential relocation (RR) is associated with behavior problems and cognitive delays in school-age children. Little is known regarding effects of RR on early childhood development. The data from this study were collected from 2011 to 2016 through the Cincinnati Home Injury Prevention and Literacy Promotion Trial. The purpose of the current study was to identify factors associated with RR and determine effects of RR on early childhood development in a cohort of mother/child dyads (n = 424). High RR was relocating ≥ 3 times over the 24-month study period. Differences in baseline characteristics and early childhood development, measured by the Ages and Stages Questionnaire (ASQ) and MacArthur Bates Communicative Development Inventory, according to relocations, were estimated by negative binomial regression and logistic regression, respectively. Participants moved on average 1.46 times over 24 months. Relocations decreased by 0.05 for each year of increasing maternal age. Mothers with college degrees moved 0.72 fewer times than those with a high school diploma or less. Mothers living alone moved 0.47 fewer times than their counterparts. Mothers who could not count on someone to loan them $1000 and those with food insecurity more (0.41) than their counterparts (0.50). Odds of scoring in the bottom-tertile for the communication domain of the ASQ was significantly higher in those relocating ≥ 3 times. High RR was associated with concern for delayed language development at 24-month follow-up in some, but not all models. Early intervention may be more successful if primary care physicians and community health professionals collaborate to link families at risk of high RR to relevant community based resources.

Background: \ud Reports of HLA incompatible (HLAi) kidney transplant outcomes are inconclusive, especially in the context of lower level Donor Specific Antibodies (DSA).\ud \ud Methods: \ud Multi-centre national cohort study of HLAi kidney transplant recipients matched in 1:2 ratio with HLA compatible (HLAc) kidney transplant recipients. HLAi defined as DSA identified by Luminex. Antibody mediated rejection (AMR) and transplant-survival were analysed using Kaplan-Meier plots. Propensity score (PS) matching was used to compare recipient and transplant survival between groups.\ud \ud Results: \ud We included 61 HLAi and 122 HLAc recipients; mean age 46 years; 60% female. MFIT0: 3327 (IQR 1352 – 6458), 23 (38%) were Flow cytometry crossmatch positive (FC-XMPOS). DSAPOS/FC-XMPOS transplantation carried an increased risk of AMR at 1 year (52%) compared to DSAPOS/FC-XMNEG (27%) and HLAc (0%). Unadjusted death censored graft loss at 3 years was 13% (HLAi) and 8% (HLAc). Three-year patient survival was 95% in HLAc, 84% in DSAPOS/FC-XMNEG and 69% in DSAPOS/FC-XMPOS recipients; 58% of HLAi deaths were infection-related. HLA incompatibility was associated with a decreased 3-year survival in our PS-matched cohort.\ud \ud Conclusion: \ud In kidney transplantation, DSA and positive FC-XM carries an increased risk of AMR. Despite inferior transplant and survival outcomes compared to HLAc transplantation, it remains a realistic option for highly sensitised patients facing prolonged waiting times and reduced survival on dialysis.

Neutrophils are implicated in the pathogenesis of many diseases involving inflammation. Neutrophils are also critical to host defence and have a key role in the innate immune response to infection. Despite their efficiencies against a wide range of pathogens however, their ability to contain and combatMycobacterium tuberculosis(Mtb) in the lung remains uncertain and contentious. The host response to Mtb infection is very complex, involving the secretion of various cytokines and chemokines from a wide variety of immune cells, including neutrophils, macrophages, monocytes, T cells, B cells, NK cells and dendritic cells. Considering the contributing role neutrophils play in the advancement of many diseases, understanding how an inflammatory microenvironment affects neutrophils, and how neutrophils interact with other immune cells, particularly in the context of the infected lung, may aid the design of immunomodulatory therapies. In the current review, we provide a brief overview of the mechanisms that underpin pathogen clearance by neutrophils and discuss their role in the context of Mtb and non-Mtb infection. Next, we examine the current evidence demonstrating how neutrophils interact with a range of human and non-human immune cells and how these interactions can differentially prime, activate and alter a repertoire of neutrophil effector functions. Furthermore, we discuss the metabolic pathways employed by neutrophils in modulating their response to activation, pathogen stimulation and infection. To conclude, we highlight knowledge gaps in the field and discuss plausible novel drug treatments that target host neutrophil metabolism and function which could hold therapeutic potential for people suffering from respiratory infections.

Selectively targeting facets of neutrophil function could benefit infectious and inflammatory diseases. Amara et al. report on a compound which blocks human neutrophil activation by activating the glycolytic enzyme phosphofructokinase, liver-type (PFKL). Altering glucose fate by modulating this key enzymatic step could dramatically alter the function and fate of phagocytes.

Purpose The purpose of this study was to examine how combinations of adverse childhood events (ACEs) contribute to the risk of postpartum depression and the mediating role of prenatal social support. Methods The Adverse Childhood Experiences Scale Questionnaire and the Edinburgh Postnatal Depression Scale Questionnaire were used to measure the study's exposure and outcome. Among a cohort of 419 mothers enrolled in a home visiting (HV) program, latent class analyses were used to identify classes of ACEs exposure. General linear models assessed the risk of postpartum depression, and prenatal social support was examined as a mediator. Results Four distinct classes of ACE exposure were identified. On the Edinburgh Postnatal Depression scale, mothers who were classified in Classes 1–3 scored higher by 2.6–4.4 points compared with women in Class 0. ACE class was found to be indirectly associated with postpartum depression scores through prenatal social support. Conclusions Identifying combinations of ACEs in an HV program has the potential to improve the characterization of ACEs among low-income perinatal women in the United States. Elucidating how these combinations contribute to the risk of postpartum depression has the potential to identify women at increased risk, which can help HV programs prioritize prevention efforts.

In developing countries, remediation projects are predominantly implemented in areas with imminent risks due to human exposure routes. Projects experience challenges due to funding constraints deri...