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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.

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.

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...

HLA-DR, an MHC class II molecule that mediates antigen presentation, is a favourable prognostic indicator in colorectal cancer (CRC). However, the dynamics and location of HLA-DR expression during CRC development are unclear. We aimed to define HLA-DR expression by immunohistochemistry in colorectal epithelium and stromal tissue at different stages of cancer development, assessing non-neoplastic colorectal adenocarcinoma–adjacent tissue, adenomas and carcinoma tissues, and to associate HLA-DR levels with clinical outcomes. Patients with higher than median HLA-DR expression survived at least twice as long as patients with lower expression. This association was significant for HLA-DR staining in the colorectal carcinoma epithelium (n = 152, p = 0.011, HR 1.9, 95% CI 1.15–3.15) and adjacent non-neoplastic epithelium (n = 152, p n = 63, p = 0.015, HR 3.6, 95% CI 1.279–10.25) and stroma (n = 63, p = 0.018, HR 5.07, 95% CI 1.32–19.49). HLA-DR was lower in carcinoma tissue compared to matched adenomas (n = 35), in epithelium (p p n = 101) compared to early stage (n = 105), in epithelium (p p p

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer's mouse model with late plaque development. In 18-month-old APP

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia touching plaques, neighboring plaques, and far from plaques in 18-month-oldAPPNLF/NLFknock-in mice with and without the Alzheimer’s disease risk mutationTrem2R47H/R47H. We report that, inAppNLF/NLFmice, expression of 35/55 PIGs, is exclusively upregulated in microglia that are touching plaques. In 7 PIGs includingTrem2this upregulation is prevented by theTrem2R47H/R47Hmutation. Unlike in young mice, knockin of theTrem2R47H/R47Hmutation does not significantly decrease theTrem2expression but decreases protein levels by 20% in the absence of plaques. On plaques, despite the mutation preventing increased gene expression, TREM2 protein levels increased by 1.6-fold (compared to 3-fold withTrem2WT/WT) and microglial density increased 20-fold compared to 30-fold. Hence microglia must touch plaques beforeTrem2gene expression is increased but small changes in protein expression can increase microglia density without a change in gene expression.

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant's structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations (i.e. healthy individuals without DS) which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable (CS-DS), mild cognitive impairment (MCI-DS), and dementia (DEM-DS)) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to the individually-based MRI segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the individually-based MRI segmentations by using DS group atlases that aligns with a participant's disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the individually-based MRI segmentations than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using diagnose-specific atlases matching disease status. All atlases are made publicly available for the research community.HighlightDown syndrome (DS) joint-label-fusion atlases provide accurate positron emission tomography (PET) amyloid measurements.A disorder-specific DS atlas is better than a neurotypical atlas for PET quantification.It is not necessary to use a disease-state-specific atlas for quantification in aged DS.Dorsal striatum results vary, possibly due to this region and dementia progression.

Numerous dietary quality indices exist to help quantify overall dietary intake and behaviors associated with positive health outcomes. Most indices focus solely on biomedical factors and nutrient or food intake, and exclude the influence of important social and environmental factors associated with dietary intake. Using the Diet Quality Index- International as one sample index to illustrate our proposed holistic conceptual framework, this critical review seeks to elucidate potential adaptations to dietary quality assessment by considering—in parallel—biomedical, environmental, and social factors. Considering these factors would add context to dietary quality assessment, influencing post-assessment recommendations for use across various populations and circumstances. Additionally, individual and population-level evidence-based practices could be informed by contextual social and environmental factors that influence dietary quality to provide more relevant, reasonable, and beneficial nutritional recommendations.

Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also directly affect cells of the immune system, altering their immune function. As use of these antimicrobials has been the mainstay of TB therapy for over fifty years now, it is more important than ever to understand how these antimicrobials affect key pathways of the immune system. One such central pathway, which underpins the immune response to a variety of infections, is immunometabolism, namely glycolysis and oxidative phosphorylation (OXPHOS). We hypothesise that in addition to their direct bactericidal effect on Mycobacterium tuberculosis (Mtb), current TB antimicrobials can modulate immunometabolic profiles and alter mitochondrial function in primary human macrophages. Human monocyte-derived macrophages (hMDMs) were differentiated from PBMCs isolated from healthy blood donors, and treated with four first-line and six second-line TB antimicrobials three hours post stimulation with either iH37Rv-Mtb or lipopolysaccharide (LPS). 24 h post stimulation, baseline metabolism and mitochondrial function were determined using the Seahorse Extracellular Flux Analyser. The effect of these antimicrobials on cytokine and chemokine production was also assayed using Meso Scale Discovery Multi-Array technology. We show that some of the TB antimicrobials tested can significantly alter OXPHOS and glycolysis in uninfected, iH37Rv-Mtb, and LPS-stimulated hMDMs. We also demonstrate how these antimicrobial-induced immunometabolic effects are linked with alterations in mitochondrial function. Our results show that TB antimicrobials, specifically clofazimine, can modify host immunometabolism and mitochondrial function. Moreover, clofazimine significantly increased the production of IL-6 in human macrophages that were stimulated with iH37Rv-Mtb. This provides further insight into the use of some of these TB antimicrobials as potential host-directed therapies in patients with early and active disease, which could help to inform TB treatment strategies in the future.

In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phagocytosed by macrophages in the airways. Mtb infected macrophages upregulate aerobic glycolysis and effector functions to try to kill the bacteria. Our lab has previously shown that human macrophages produce lactate in response to infection with Mtb. Although lactate has largely been considered a waste product of aerobic glycolysis, we hypothesised that the presence of extracellular lactate would impact subsequent immunometabolic responses and modulate macrophage function. We demonstrate that the presence of exogenous lactate has an immediate effect on the cellular metabolism of resting human macrophages; causing a decrease in extracellular acidification rate (ECAR; analogous to the rate of glycolysis) and an increase in the oxygen consumption rate (OCR; analogous to oxidative phosphorylation). When lactate-treated macrophages were stimulated with Mtb or LPS, glycolysis proceeds to increase immediately upon stimulation but oxidative phosphorylation remains stable compared with untreated cells that display a decrease in OCR. This resulted in a significantly reduced ECAR/OCR ratio early in response to stimulation. Since altered metabolism is intrinsically linked to macrophage function, we examined the effect of lactate on macrophage cytokine production and ability to kill Mtb. Lactate significantly reduced the concentrations of TNF and IL-1β produced by human macrophages in response to Mtb but did not alter IL-10 and IL-6 production. In addition, lactate significantly improved bacillary clearance in human macrophages infected with Mtb, through a mechanism that is, at least in part, mediated by promoting autophagy. These data indicate that lactate, the product of glycolysis, has a negative feedback effect on macrophages resulting in an attenuated glycolytic shift upon subsequent stimulation and reduced pro-inflammatory cytokine production. Interestingly, this pro-resolution effect of lactate is associated with increased capacity to kill Mtb.

Fourier Transform Infrared (FTIR) based chemical imaging is a powerful, non‐destructive and label‐free biophotonic technique, which spatially acquires bio‐molecularly relevant information in histopathology. Cancer detection with objective chemical imaging techniques is relatively well established, though detection of pre‐cancer stages within a continuum from normal tissue to cancer remains challenging. Here machine learning with chemical imaging was used to provide an objective classification pipeline for oesophageal tissues pathologically classified as normal, oesophagitis, dysplasia, Barrett's disease and cancer. Spectral images were segmented using a k‐means cluster validity indices approach and clustered spectra were classified using partial least squares discriminant analysis. Classification performances approached a receiver operator characteristic area‐under‐the‐curve (ROC‐AUC) of 0.90 for binary classification tasks (eg, normal vs Barrett's). Isolated histopathological substructures were identified which delivered a ROC‐AUC in of ~0.69 in classifying into each of the five‐classes. This work may provide the means to assist pathologist diagnoses of intermediate pre‐cancer stages.

Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59years), cognitively intact aging (73-95years) and age-matched AD cases. To identify "anti-aging/AD" transcription patterns associated with physical activity, probesets significantly associated with both physical activity and aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2210 probesets significant in both data sets, nearly 95% showed opposite transcription patterns with physical activity compared with aging/AD. The majority (>70%) of these anti-aging/AD genes showed increased expression with physical activity and decreased expression in aging/AD. Enrichment analysis of the anti-aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling, and spine plasticity. Anti-aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function (notably negative regulation of transcription). These data reveal that physical activity is associated with a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

Renal transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of NMSC in general, non-transplant setting, can predict risk of, and time to post-transplant skin cancer. Genetic variants, reaching pre-defined p-value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) non-transplant GWAS. Using these genome-wide association studies, BCC and SCC PRS were calculated for each sample across three European-ancestry renal-transplant cohorts (n=889) and tested as predictors of case:control status and time to NMSC post-transplant. BCC PRS calculated at p-value threshold 1x10 was the most significant predictor of case:control status of NMSC post-transplant (OR=1.65; adjusted P=0.0008; AUC(full model adjusted for clinical predictors and PRS)=0.81). SCC PRS at p-value threshold 1x10 was the most significant predictor of time to post-transplant NMSC (adjusted P=8.15x10 ; HR=1.42, concordance (full model)=0.74). PRS of non-transplant NMSC is predictive of case:control status and time to NMSC post-transplant. These results are relevant to how genomics can risk stratify patients to help develop personalised treatment regimens. This article is protected by copyright. All rights reserved.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer’s Coordinating Center (n = 129) and Alzheimer’s Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T1w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer’s disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer’s Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer’s Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer’s disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis.

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

ObjectiveBrain atrophy is associated with degenerative neuropathologies as well as clinical status of dementia. Whether dementia influences atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies.MethodsWe used data from National Alzheimer’s Coordinating Center (NACC, N=129) and Alzheimer’s Disease Neuroimaging Initiative (ADNI, N=47) participants with suitable in-vivo 3D-T1w MRI and autopsy data. We determined dementia status at visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer’s disease neuropathology, hippocampal sclerosis, Lewy Bodies, cerebral amyloid angiopathy, atherosclerosis. Voxel-based morphometry (VBM) identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analyzed. We used multiple linear regression models adjusted for neuropathologies and demographic variables.ResultsWe found strong associations for dementia with volumes of the hippocampus, amygdala, and parahippocampus (semi-partial correlations≥0.28, PConclusionEven after accounting for the most common neuropathologies, dementia still had among the strongest correlations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to clinical status of dementia as opposed to Alzheimer’s or other neuropathologies.

The Warburg effect, defined as increased glycolysis and decreased oxidative phosphorylation, occurs in murine macrophages following LPS stimulation and is required for activation. There are differences between human and murine macrophage metabolic responses to stimulation, with peak metabolite concentrations occurring earlier in humans than mice. Complex changes occur in the human immune system with age, resulting in the very young and the very old being more susceptible to infections. Anti-bacterial immune responses in umbilical cord immune cells are considered deficient but there is a paucity of data on the role that metabolism plays. We hypothesized that metabolic responses in human macrophages occur early during activation. In addition, we hypothesized that umbilical cord derived macrophages have an altered immunometabolic response compared with adult macrophages. We demonstrate that adult and cord blood monocyte derived macrophages (MDM) immediately increase glycolysis in response to stimulation with LPS or Mycobacterium tuberculosis (Mtb), however only adult MDM decrease oxidative phosphorylation. At 24 hours post stimulation, glycolysis remains elevated in both adult and cord blood MDM, oxidative phosphorylation remains unchanged in the cord blood MDM and has normalized in the adult MDM stimulated with Mtb. However, LPS stimulated adult MDM have increased oxidative phosphorylation at 24 hours, illustrating differences in metabolic responses to different stimuli, time-dependent variation in responses and differences in macrophage metabolism in adults compared with umbilical cord blood. We compared the phenotype and function of macrophages derived from adult or cord blood. Cord blood MDM secreted less TNF following Mtb stimulation and more IL-6 following LPS stimulation compared with adult MDM. Our findings demonstrate that whilst cord blood MDM exhibit an immediate increase in glycolytic flux in response to stimulation, similar to adult MDM, cord blood MDM do not concomitantly decrease oxygen consumption. This indicates that adult macrophages shift to Warburg metabolism immediately after stimulation, but cord blood macrophages do not. Understanding the differences in the metabolic profiles of macrophages over a human lifetime will enable the translation of immunometabolism into effective immuno-supportive therapies that could potentially be targeted at vulnerable populations, such as the very old and the very young.

For over 50 years, patients with drug-sensitive and drug-resistant tuberculosis have undergone long, arduous, and complex treatment processes with several antimicrobials. With the prevalence of drug-resistant strains on the rise and new therapies for tuberculosis urgently required, we assessed whether manipulating iron levels in macrophages infected with mycobacteria offered some insight into improving current antimicrobials that are used to treat drug-resistant tuberculosis. We investigated if the iron chelator, desferrioxamine, can support the function of human macrophages treated with an array of second-line antimicrobials, including moxifloxacin, bedaquiline, amikacin, clofazimine, linezolid and cycloserine. Primary human monocyte-derived macrophages were infected with Bacillus Calmette-Guérin (BCG), which is pyrazinamide-resistant, and concomitantly treated for 5 days with desferrioxamine in combination with each one of the second-line tuberculosis antimicrobials. Our data indicate that desferrioxamine used as an adjunctive treatment to bedaquiline significantly reduced the bacterial load in human macrophages infected with BCG. Our findings also reveal a link between enhanced bactericidal activity and increases in specific cytokines, as the addition of desferrioxamine increased levels of IFN-γ, IL-6, and IL-1β in BCG-infected human monocyte-derived macrophages (hMDMs) treated with bedaquiline. These results provide insight, and an in vitro proof-of-concept, that iron chelators may prove an effective adjunctive therapy in combination with current tuberculosis antimicrobials.

Research suggests a link between Alzheimer’s Disease in Down Syndrome (DS) and the overexpression of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant’s structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable, mild cognitive impairment (MCI-DS), and dementia) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to our ground truth individual MRI-based segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the ground truth by using DS group atlases that aligns with a participant’s disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the ground truth than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using a disease-state specific atlas. All atlases are made publicly available for the research community.AbbreviationsAD, DS, Aβ, DSG, CS-DS, CS-NT, LOOCV, ROI, MSE, MRI, PET, JLF, CS, MCI-DS, DEM.

Almost 140 years after its discovery, tuberculosis remains the leading infectious cause of death globally. For half a century, patients with drug-sensitive and drug-resistant tuberculosis have undergone long, arduous, and complex treatment processes with several antimicrobials that primarily function through direct bactericidal activity. Long-term utilization of these antimicrobials has been well-characterized and associated with numerous toxic side-effects. With the prevalence of drug-resistant strains on the rise and new therapies for tuberculosis urgently required, a more thorough understanding of these antimicrobials is a necessity. In order to progress from the "one size fits all" treatment approach, understanding how these antimicrobials affect mitochondrial function and bioenergetics may provide further insight into how these drugs affect the overall functions of host immune cells during tuberculosis infection. Such insights may help to inform future studies, instigate discussion, and help toward establishing personalized approaches to using such antimicrobials which could help to pave the way for more tailored treatment regimens. While recent research has highlighted the important role mitochondria and bioenergetics play in infected host cells, only a small number of studies have examined how these antimicrobials affect mitochondrial function and immunometabolic processes within these immune cells. This short review highlights how these antimicrobials affect key elements of mitochondrial function, leading to further discussion on how they affect bioenergetic processes, such as glycolysis and oxidative phosphorylation, and how antimicrobial-induced alterations in these processes can be linked to downstream changes in inflammation, autophagy, and altered bactericidal activity.

INTRODUCTIONDown syndrome (DS) is associated with elevated risk for Alzheimer’s disease (AD) due to beta amyloid (Aβ) lifelong accumulation. We hypothesized that the spatial distribution of brain Aβ predicts future dementia conversion in individuals with DS.METHODSWe acquired 18F-Florbetapir PET scans from 19 nondemented individuals with DS at baseline and monitored them for four years, with five individuals transitioning to dementia. Machine learning classification determined features on 18F-Florbetapir standardized uptake value ratio (SUVR) maps that predicted transition.RESULTSIn addition to “AD signature” regions including the inferior parietal cortex, temporal lobes, and the cingulum, we found that Aβ cortical binding in the prefrontal and superior frontal cortices distinguished subjects who transitioned to dementia. Classification did well in predicting transitioners.DISCUSSIONOur study suggests that specific regional profiles of brain amyloid in older adults with DS may predict cognitive decline and are informative in evaluating the risk for dementia.HighlightsRegional [18F]-Florbetapir PET predicts future transition to dementia in Downs Syndrome.Increased amyloid in prefrontal, inferior parietal, superior frontal, rostral middle frontal, and posterior cingulate cortices detect transitioiners, with prefrontal and superior frontal being best overall.Amyloid PET-based classification able to discriminate between transitioners and non-transitioners.

Ultraviolet radiation (UVR) is a consistent part of the environment that has both beneficial and harmful effects on human health. UVR filters in the form of commercial sunscreens have been widely used to reduce the negative health effects of UVR exposure. Despite their benefit, literature suggests that some filters can penetrate skin and have off-target biological effects. We noted that many organic filters are hydrophobic and contain aromatic rings, making them potential modulators of Aryl hydrocarbon Receptor (AhR) signaling. We hypothesized that some filters may be able to act as agonists or antagonists on the AhR. Using a luciferase reporter cell line, we observed that the UVR filter octinoxate potentiated the ability of the known AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), to activate the AhR. Cotreatments of keratinocytes with octinoxate and FICZ lead to increased levels of cytochrome P4501A1 (CYP1A1) and P4501B1 (CYP1B1) mRNA transcripts, in an AhR-dependent fashion. Mechanistic studies revealed that octinoxate is an inhibitor of CYP1A1 and CYP1B1, with IC50 values at approximately 1 µM and 586 nM, respectively. In vivo topical application of octinoxate and FICZ also elevated CYP1A1 and CYP1B1 mRNA levels in mouse skin. Our results show that octinoxate is able to indirectly modulate AhR signaling by inhibiting CYP1A1 and CYP1B1 enzyme function, which may have important downstream consequences for the metabolism of various compounds and skin integrity. It is important to continue studying the off-target effects of octinoxate and other UVR filters, because they are used on skin on a daily basis world-wide.

Tuberculosis (TB) is the leading infectious killer in the world. Mycobacterium tuberculosis (Mtb), the bacteria that causes the disease, is phagocytosed by alveolar macrophages (AM) and infiltrating monocyte-derived macrophages (MDM) in the lung. Infected macrophages then upregulate effector functions through epigenetic modifications to make DNA accessible for transcription. The metabolic switch to glycolysis and the production of proinflammatory cytokines are key effector functions, governed by epigenetic changes, that are integral to the ability of the macrophage to mount an effective immune response against Mtb. We hypothesised that suberanilohydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor (HDACi), can modulate epigenetic changes upstream of the metabolic switch and support immune responses during Mtb infection. The rate of glycolysis in human MDM, infected with Mtb and treated with SAHA, was tracked in real time on the Seahorse XFe24 Analyzer. SAHA promoted glycolysis early in the response to Mtb. This was associated with significantly increased production of IL-1β and significantly reduced IL-10 in human MDM and AM. Since innate immune function directs downstream adaptive immune responses, we used SAHA-treated Mtb-infected AM or MDM in a co-culture system to stimulate T cells. Mtb-infected macrophages that had previously been treated with SAHA promoted IFN-γ, GM-CSF, and TNF co-production in responding T helper cells but did not affect cytotoxic T cells. These results indicate that SAHA promoted the early switch to glycolysis, increased IL-1β, and reduced IL-10 production in human macrophages infected with Mtb. Moreover, the elevated proinflammatory function of SAHA-treated macrophages resulted in enhanced T helper cell cytokine polyfunctionality. These data provide an in vitro proof-of-concept for the use of HDACi to modulate human immunometabolic processes in macrophages to promote innate and subsequent adaptive proinflammatory responses.

Tuberculosis is the single biggest infectious killer in the world and presents a major global health challenge. Antimicrobial therapy requires many months of multiple drugs and incidences of drug resistant tuberculosis continues to rise. Consequently, research is now focused on the development of therapies to support the function of infected immune cells. HIF1α-mediated induction of aerobic glycolysis is integral to the host macrophage response during infection with Mtb, as this promotes bacillary clearance. Some iron chelators have been shown to modulate cellular metabolism through the regulation of HIF1α. We examined if the iron chelator, desferrioxamine (DFX), could support the function of primary human macrophages infected with Mtb. Using RT-PCR, we found that DFX promoted the expression of key glycolytic enzymes in Mtb-infected primary human MDMs and human alveolar macrophages. Using Seahorse technology, we demonstrate that DFX enhances glycolytic metabolism in Mtb-stimulated human MDMs, while helping to enhance glycolysis during mitochondrial distress. Furthermore, the effect of DFX on glycolysis was not limited to Mtb infection as DFX also boosted glycolytic metabolism in uninfected and LPS-stimulated cells. DFX also supports innate immune function by inducing IL1β production in human macrophages during early infection with Mtb and upon stimulation with LPS. Moreover, using hypoxia, Western blot and ChIP-qPCR analyses, we show that DFX modulates IL1β levels in these cells in a HIF1α-mediated manner. Collectively, our data suggests that DFX exhibits potential to enhance immunometabolic responses and augment host immune function during early Mtb infection, in selected clinical settings.

Emerging evidence indicates that the predictability of signals early in life may influence the developing brain. This study examines links between a novel indicator of maternal mood dysregulation, mood entropy, and child neurodevelopmental outcomes. Associations between prenatal maternal mood entropy and child neurodevelopment were assessed in 2 longitudinal cohorts. Maternal mood was measured several times over pregnancy beginning as early as 15 weeks' gestation. Shannon's mood entropy was applied to distributions of mothers' responses on mood questionnaires. Child cognitive and language development were evaluated at 2 and 6-9 years of age. Higher prenatal maternal mood entropy was associated with lower cognitive development scores at 2 years of age and lower expressive language scores at 6-9 years of age. These associations persisted after adjusting for maternal pre and postnatal mood levels and for other relevant sociodemographic factors. Our findings identify maternal mood entropy as a novel predictor of child neurodevelopment. Characterizing components of maternal mood in addition to level of severity or valence may further our understanding of specific processes by which maternal mood shapes child development. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Current European surveillance regulations for scrapie, a naturally occurring transmissible spongiform encephalopathy (TSE) or prion disease in sheep and goats, require testing of fallen stock or healthy slaughter animals, and outline measures in the case of confirmation of disease. An outbreak of classical scrapie in a herd with 2500 goats led to the culling of the whole herd, providing the opportunity to examine a subset of goats, take samples, and examine them for the presence of disease-associated prion protein (PrPSc) to provide further information on scrapie test sensitivity, pathology, and association with prion protein genotype. Goats were examined clinically prior to cull, and the brains examined post mortem by Bio-Rad ELISA, a rapid screening test used for active surveillance in sheep and goats, and two confirmatory tests, Western blot and immunohistochemistry. Furthermore, up to 10 lymphoid tissues were examined by immunohistochemistry. Of 151 goats examined, three (2.0%) tested positive for scrapie by ELISA on brain, confirmed by confirmatory tests, and a further five (3.3%) were negative by ELISA but positive by at least one of the confirmatory tests. Only two of these, both positive by ELISA, displayed evident signs of scrapie. In addition, 10 (6.6%) goats, which also included two clinical suspects, were negative on brain examination but had detectable PrPSc in lymphoid tissue. PrPSc was detected most frequently in the medial retropharyngeal lymph node (LN; 94.4% of all 18 cases) and palatine tonsil (88.9%). Abnormal behavior and circling or loss of balance when blindfolded were the best clinical discriminators for scrapie status. None of the goats that carried a single allele in the prion protein gene associated with increased resistance to scrapie (Q211, K222, S146) were scrapie-positive, and the percentage of goats with these alleles was greater than expected from previous surveys. Significantly more goats that were scrapie-positive were isoleucine homozygous at codon 142 (II142). The results indicate that the sensitivity of the applied screening test is poor in goats compared to the confirmatory tests as gold standard, particularly for asymptomatic animals. Sensitivity of surveillance could be improved by testing retropharyngeal LN or palatine tonsil in addition to brain.

Objective The aim of this study is to examine the effect of postoperative chemotherapy on survival in patients with stage II or III rectal adenocarcinoma who undergo neoadjuvant chemoradiation (CRT) and surgical resection. Methods A retrospective review of the National Cancer Database (NCDB) from 2006 to 2013 was performed. Cases were analyzed based on pathologic complete response (pCR) status and use of adjuvant therapy. The Kaplan-Meier method was used to estimate overall survival probabilities. Results 23,045 cases were identified, of which 5832 (25.31%) achieved pCR. In the pCR group, 1513 (25.9%) received adjuvant chemotherapy, and in the non-pCR group, 5966 (34.7%) received adjuvant therapy. In the pCR group, five-year survival probability was 87% (95% CI 84%–89%) with adjuvant therapy and 81% (95% CI 79%–82%) without adjuvant therapy. In the non-pCR group, five-year survival probability was 78% (95% CI 76%–79%) with adjuvant therapy and 70% (95% CI 69%–71%) without adjuvant therapy. In the non-pCR and node-negative subgroup (ypN-), five-year survival probability was 86% (95% CI 84%–88%) with adjuvant therapy and 76% (95% CI 74%–77%) without adjuvant therapy. In the non-pCR and node-positive subgroup (ypN+), five-year survival probability was 67% (95% CI 65%–70%) with adjuvant therapy and 60% (95% CI 58%–63%) without adjuvant therapy. Conclusions Adjuvant chemotherapy in stage II or III rectal adenocarcinoma is associated with increased five-year survival probability regardless of pCR status. We observed similar survival outcomes among non-pCR ypN- treated with adjuvant chemotherapy compared with patients achieving pCR treated with adjuvant chemotherapy.

Background The American Academy of Pediatrics (AAP) recommends shared reading beginning as soon as possible after birth to promote healthy development. Shared reading quality can strongly influence outcomes, especially in children from low-SES households. Dialogic reading is a method developed to enhance verbal interactivity and engagement through book sharing, advocated by the AAP and clinic-based programs such as Reach Out and Read. There is no brief, validated, caregiver report measure of dialogic reading or shared reading quality currently available. Methods This cross-sectional study involved 49 healthy mother-child dyads (mean child age 4.5 yrs., SD = 0.6 yrs.) from 2 separate MRI-based studies. The DialogPR was administered by trained research coordinators following MRI, along with the READ subscale of the validated StimQ-P measure of home cognitive environment. The DialogPR consists of eight items developed in consultation with experts in early literacy, based on the PEER/CROWD dialogic reading conceptual model. Estimated reading level is 6th grade. Descriptive statistics were computed at both the item and scale levels. Modern theory Rasch methods were used to analyze all eight DialogPR items along with preliminary estimates of reliability and validity. Results Our combined sample involved 15 boys and 34 girls, and was diverse in terms of age, household income, and maternal education. DialogPR administration time was less than 2 min, with no problems reported. The DialogPR demonstrated strong internal consistency and reliability (Cronbach’s alpha = 0.82), and criterion-related validity with the StimQ-P READ (Spearman’s rho coefficient = 0.53). Rasch analysis revealed strong psychometric properties in terms of reliability, variability in item difficulty, and inter-item and item-measure correlations. Conclusions Preliminary evidence suggests that the DialogPR may be an efficient means to assess shared reading quality and dialogic reading via caregiver report for clinical and research purposes, warranting further investigation.

A persistent semidiurnal internal tidal bore feature occurs at the head of the Monterey Bay Submarine Canyon and drives regular intrusions of cold, subthermocline waters onto the adjacent shelf. In this study, we examine the influence of this internal tidal bore feature on the larval fish community using over a year of periodic larval fish samples collected coincidently with physical measurements. Larval samples were categorized into one of two water mass periods: a “warm period” representative of shallow coastal shelf waters and a “cold period” characteristics of colder waters present during internal bore forcing. Using multivariate statistical methods, we show warm and cold periods, along with seasonality, are the primary drivers of larval fish community composition. A significantly different community composition was observed between warm and cold water mass periods. This difference was primarily due to decreased abundance in most taxa during the cold periods, and did not indicate an obvious shift in the assemblage of the taxa. However, our data do indicate that some taxa may show higher abundance during cold periods compared to warm periods, but further studies are warranted. Along with seasonality, the presence/absence of subthermocline waters driven by internal bores appears to be a key control on nearshore larval fish community composition at this location.

Pollution remediation decisions in developing communities are often made with limited technical data and stakeholder engagement. Local knowledge of contamination is oftentimes neglected, resulting in efforts that fail to align with community objectives. In this work, we propose a new approach for incorporating local knowledge on contamination into remediation efforts, resulting in a community-informed conceptual site model framework for pollution remediation. This framework uses qualitative and quantitative social science methods to develop a holistic view of contamination as defined by the community, pairing social knowledge with existing technical information about a site. An example of the application of this framework is provided from a field study conducted in a mercury-contaminated artisanal and small-scale gold mining community in Andes, Colombia. We conducted qualitative unstructured and semi-structured interviews and surveys to elicit local knowledge on mercury contamination. We combined this stakeholder input with limited scientific published literature on mercury contamination in artisanal mining communities to develop different conceptual site models that vary based on the level and type of stakeholder input. Our findings demonstrate how local knowledge on contamination varies due to contextual factors within the community, revealed through the engagement. This work also demonstrates how the new framework can be utilized by environmental practitioners to define the needs, wants, and priorities of stakeholder groups throughout a remediation project, ensuring maximum participation in solution development.

We expect the incomes of physicians to remain high in the next decades. Using the latest published physician income data (2015) we calculated the weighted median income of U.S. physicians and the net present value (NPV) of an investment in physician education. We estimated the NPV assuming that the physicians training began in 2007 and their practice would commence in 2015. We estimated the NPV of the lifetime earnings of a physician based on the median income of all physicians in the sample to be between $7.1 and $7.3 million. This finding of high NPV’s is consistent with almost all earlier studies of this kind. Physicians continue to experience relatively high incomes and very slow increases in the number of new graduates. We expect an excess demand for positions in medical colleges to continue. Our findings with respect to the incomes of non-primary physicians (surgeons, radiologist and cardiologists), indicate will continue to be much higher than those of primary physicians. There are strong evidence suggesting this is because of blockages in physician residency openings in these non-primary fields of medicine., peer-reviewed

We extend the task-based empirical framework used in the job polarization literature to analyze the susceptibility of low-wage employment to technological substitution. We nd that increases in the cost of low-wage labor (via minimum wage hikes) lead to relative employment declines at cognitively routine occupations but not manuallyroutine or non-routine low-wage occupations. This suggests that low-wage routine cognitive tasks are susceptible to technological substitution. While the short-run em