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Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.

IntroductionThe understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic.MethodsTo examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection.ResultsUsing quantitative microscopy targeting markers for neurodegeneration and neuroinflammation, as well as fluid and imaging biomarkers, we detailed the progression of misfolded tau spreading and the consequential inflammatory response induced by glial cells.DiscussionBy combining the analysis of several in vivo biomarkers with extensive brain microscopy analysis, we described the initial steps of misfolded tau spreading and neuroinflammation in a monkey model highly translatable to AD patients.HighlightsDual tau mutation delivery in the entorhinal cortex induces progressive tau pathology in rhesus macaques. Exogenous human 4R-tau coaptates monkey 3R-tau during transneuronal spread, in a prion-like manner. Neuroinflammatory response is coordinated by microglia and astrocytes in response to tau pathology, with microglia targeting early tau pathology, while astrocytes engaged later in the progression, coincident with neuronal death. Monthly collection of CSF and plasma revealed a profile of changes in several AD core biomarkers, reflective of neurodegeneration and neuroinflammation as early as 1 month after injection.

After the challenges of the COVID-19 pandemic, the NEU (2021) report states that one in three teachers plan to leave the profession in the next 5 years. As previous studies published by the DfE focusing on workload have not affected the wastage rate of the profession, there is something deeper at work which needs to be explored. A critical theory, mixed-methods approach is used to gain a breadth and depth of understanding of the attitudes of 55 respondents to a survey and 17 participants in semi-structured interviews. All data collection was carried out in secondary schools in Lincolnshire, where teacher pay is good in comparison with the county average of workforce pay. These methods aim to test the assumption that concerns about workload and pay are causing teachers' discontent. The findings reveal that teacher attitudes towards their working lives are complex owing to individuals trying to internalise the values of both traditional and new professionalisms. Owing to this, teachers can appear contradictory in their demands and tolerance of the demands of the profession and themselves. The characteristics of neoliberal management including transactional leadership, competition and ambivalence to processes in favour of outcomes, do not match traditional professional values of dedication, expertise and working for the greater good.

Microglial neuroinflammation appears to be neuroprotective in the early pathological stage, yet neurotoxic, which often precedes neurodegeneration in Alzheimer's disease (AD). However, it remains unclear how the microglial activities transit to the neurotoxic state during AD progression, due to complex neuron-glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini-brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid-beta (Aβ)-overexpressing neurons and reactive astrocytes produce interferon-gamma (IFNγ) and excessive oxidative stress. IFNγ results in the downregulation of mitogen-activated protein kinase (MAPK) and the upregulation of Kelch-like ECH-associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid-2-related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NFκB)-axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated-tau accumulation, and discernable neuronal loss. Interestingly, recovering Nrf2 in the microglia prevents the activation of proinflammatory microglia and significantly blocks the tauopathy in AD minibrains. Taken together, it is envisioned that IFNγ-driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.

For many cancer patients, immune checkpoint inhibitors (ICIs) can be life-saving. However, the immune-related adverse events (irAEs) from ICIs can be debilitating and can quickly become severe or even be fatal. Often, irAEs will precipitate visits to the emergency department (ED). Therefore, early recognition and the decision to admit, observe, or discharge these patients from the ED can be key to a cancer patients morbidity and mortality. ED clinicians typically make their decision for disposition (admit, observe, or discharge) within 2-6 h from their patients ED presentation. However, irAEs are particularly challenging in the ED because of atypical presentations, the absence of classic symptoms, the delayed availability of diagnostic tests during the ED encounter, and the fast pace in the ED setting. At present, there is no single sufficiently large ED data source with clinical, biological, laboratory, and imaging data that will allow for the development of a tool that will guide early recognition and appropriate ED disposition of patients with potential irAEs. We describe an ongoing federally funded project that aims to develop an immune-related emergency disposition index (IrEDi). The project capitalizes on a multi-site collaboration among 4 members of the Comprehensive Oncologic Emergency Research Network (CONCERN): MD Anderson Cancer Center, Ohio State University, Northwestern University, and University of California San Diego. If the aims are achieved, the IrEDi will be the first risk stratification tool derived from a large racial/ethnically and geographically diverse population of cancer patients. The future goal is to validate irEDi in general EDs to improve emergency care of cancer patients on ICIs.

BACKGROUND: Shigella is a leading cause of diarrhea and dysentery in children in low-resource settings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine would be to reduce mortality and morbidity associated with Shigella diarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery. The aim of the study was to quantify the reduction in Shigella attributable diarrhea, all diarrhea, and antibiotic use in the first 2 years of life that could be prevented by a Shigella vaccine. METHODS AND FINDINGS: We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, a birth cohort study that followed 1,715 children with twice weekly surveillance for enteric infections, illnesses, and antibiotic use for the first 2 years of life from November 2009 to February 2014 at 8 sites. We estimated the impact of 2 one-dose (6 or 9 months) and 3 two-dose (6 and 9 months, 9 and 12 months, and 12 and 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. We used Monte Carlo simulations to estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use comparing each vaccination scenario to no vaccination. We analyzed 9,392 diarrhea episodes and 15,697 antibiotic courses among 1,715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100 child-years. A Shigella vaccine with a mean vaccine efficacy of 60% against severe disease given at 9 and 12 months prevented 10.6 (95% CI [9.5, 11.5]) Shigella diarrhea episodes of any severity per 100 child-years (relative 34.5% reduction), 3.0 (95% CI [2.5, 3.5]) F/M courses for Shigella treatment per 100 child-years (relative 35.8% reduction), and 5.6 (95% CI [5.0, 6.3]) antibiotic courses of any drug class for Shigella treatment per 100 child-years (relative 34.5% reduction). This translated to a relative 3.8% reduction in all diarrhea, a relative 2.8% reduction in all F/M courses, a relative 3.1% reduction in F/M exposures to bystander pathogens, and a relative 0.9% reduction in all antibiotic courses. These results reflect Shigella incidence and antibiotic use patterns at the 8 MAL-ED sites and may not be generalizable to all low-resource settings. CONCLUSIONS: Our simulation results suggest that a Shigella vaccine meeting WHO targets for efficacy could prevent about a third of Shigella diarrhea episodes, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use are expected to be modest (

Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors. Single-cell RNA sequencing and flow cytometry revealed exercise modulated the number and phenotype of tumor-infiltrating CD8+ T cells and myeloid cells. Specifically, exercise caused a phenotypic shift in the tumor-associated macrophage population and increased the expression of MHC class II transcripts. We further demonstrated that ERK5 S496A knock-in mice, which are phosphorylation deficient at the S496 residue, mimicked the exercise effect when unexercised, yet when exercised, these mice displayed a reversal in the effect of exercise on tumor growth and macrophage polarization compared with wild-type mice. Taken together, our results reveal tumor-specific differences in the immune response to exercise and show that ERK5 signaling via the S496 residue plays a crucial role in exercise-induced tumor microenvironment changes. See related Spotlight by Betof Warner, p. 1158.

Cancer immunotherapy—including immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT)—has become a standard, potentially curative treatment for a subset of advanced solid and liquid tumors. However, most patients with cancer do not benefit from the rapidly evolving improvements in the understanding of principal mechanisms determining cancer immune responsiveness (CIR); including patient-specific genetically determined and acquired factors, as well as intrinsic cancer cell biology. Though CIR is multifactorial, fundamental concepts are emerging that should be considered for the design of novel therapeutic strategies and related clinical studies. Recent advancements as well as novel approaches to address the limitations of current treatments are discussed here, with a specific focus on ICI and ACT.

Introduction: Inflammation is associated with tumor initiation, and existing tumors are associated with immune suppression locally and systemically. Cancer treatment is also associated with immune suppression. This review evaluates evidence related to the use of acupuncture for modulation of inflammation and the immune system in cancer patients. Methods: Nine databases were searched for prospective, randomized, controlled trials evaluating the use of acupuncture for modulation of the immune system in cancer patients through March 2024. Only studies involving needle insertion into acupuncture points were included. No language limitations were applied. Studies were assessed for risk of bias (ROB) according to Cochrane criteria. The primary outcomes were levels of immune and inflammatory markers. Results: Of 3607 articles identified, 1526 duplicates were omitted, and 2261 articles were screened. Sixty-four (58 Chinese, 6 English) publications met all inclusion criteria and were evaluated for ROB. Forty-seven studies were rated as unclear ROB, and nine studies were rated as high ROB. However, when the blinding and allocation concealment criteria were removed, 12 studies had low ROB. Fifty-six studies were included in the meta-analysis, which found that acupuncture significantly increased interferon gamma (IFN-γ; P

Background and purpose: As patients with advanced melanoma live longer in the context of systemic therapy advancements, better strategies for durable control of bulky tumors are needed. In this study, we evaluated if dose-escalated hypofractionated radiation therapy (HFRT) can provide durable local control and improve tumor-associated symptoms in patients with unresectable or bulky metastatic melanoma for whom stereotactic ablative radiotherapy (RT) approaches are not feasible due to tumor size or location. Materials and methods: We retrospectively reviewed 49 patients with unresectable or bulky metastatic melanoma who were treated to a total of 53 tumor targets with 12–17 fractions HFRT at our institution between 2015–2022. Clinical scenarios included: unresectable, locoregional only disease (26 %); oligometastatic disease (5 known sites of disease or with at least 3 sites progressing, 40 %). Results: Of the 53 HFRT targets, 91 % (n = 48) had radiographic evidence of response as defined by either stabilization (6 %, n = 3), decreased size (74 %, n = 39), or decreased FDG avidity (11 %, n = 6). Of the 43 symptomatic patients, 98 % (n = 42) had symptomatic improvement. One −year local control was 79 %, with 2-year progression-free and overall survival of 33 % and 39 % respectively. The most common acute toxicities were radiation dermatitis (16 %, n = 8) or a pain flare (14 %, n = 7). Late toxicities were uncommon and typically grade 1. Conclusion: HFRT provides favorable local control and symptomatic relief with limited toxicity in tumors not amenable to surgical resection or stereotactic ablative RT.

While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G4C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.

Children in low-resource settings carry enteric pathogens asymptomatically and are frequently treated with antibiotics, resulting in opportunities for pathogens to be exposed to antibiotics when not the target of treatment (i.e., bystander exposure). We quantified the frequency of bystander antibiotic exposures for enteric pathogens and estimated associations with resistance among children in eight low-resource settings. We analyzed 15,697 antibiotic courses from 1,715 children aged 0 to 2 y from the MAL-ED birth cohort. We calculated the incidence of bystander exposures and attributed exposures to respiratory and diarrheal illnesses. We associated bystander exposure with phenotypic susceptibility of E. coli isolates in the 30 d following exposure and at the level of the study site. There were 744.1 subclinical pathogen exposures to antibiotics per 100 child-years. Enteroaggregative Escherichia coli was the most frequently exposed pathogen, with 229.6 exposures per 100 child-years. Almost all antibiotic exposures for Campylobacter (98.8%), enterotoxigenic E. coli (95.6%), and typical enteropathogenic E. coli (99.4%), and the majority for Shigella (77.6%), occurred when the pathogens were not the target of treatment. Respiratory infections accounted for half (49.9%) and diarrheal illnesses accounted for one-fourth (24.6%) of subclinical enteric bacteria exposures to antibiotics. Bystander exposure of E. coli to class-specific antibiotics was associated with the prevalence of phenotypic resistance at the community level. Antimicrobial stewardship and illness-prevention interventions among children in low-resource settings would have a large ancillary benefit of reducing bystander selection that may contribute to antimicrobial resistance.

We analyzed samples obtained at baseline and 24 months in a mass azithromycin administration trial in Niger using quantitative polymerase chain reaction. In villages randomized to azithromycin, Shigella was the only pathogen reduced at 24 months (prevalence ratio, 0.36 [95% confidence interval: .17-.79]; difference in log quantity, -.42 [-.75 to -.10]).

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.

Abstract Background As the population ages, older people account for a larger proportion of the health and social care budget. A significant body of evidence suggests that arts and creativity interventions can improve the physical, mental and social wellbeing of older adults, however the value and/or cost-effectiveness of such interventions remains unclear. Methods We systematically reviewed the economic evidence relating to such interventions, reporting our findings according to PRISMA guidelines. We searched bibliographic databases (MEDLINE, EMBASE, Econlit and Web of Science and NHSEED), trial registries and grey literature. No language or temporal restrictions were applied. Two screening rounds were conducted independently by health economists experienced in systematic literature review. Methodological quality was assessed, and key information extracted and tabulated to provide an overview of the published literature. A narrative synthesis without meta-analysis was conducted. Results Only six studies were identified which provided evidence relating to the value or cost-effectiveness of arts and creativity interventions to improve health and wellbeing in older adults. The evidence which was identified was encouraging, with five out of the six studies reporting an acceptable probability of cost-effectiveness or positive return on investment (ranging from £1.20 to over £8 for every £1 of expenditure). However, considerable heterogeneity was observed with respect to study participants, design, and outcomes assessed. Of particular concern were potential biases inherent in social value analyses. Conclusions Despite many studies reporting positive health and wellbeing benefits of arts and creativity interventions in this population, we found meagre evidence on their value or cost-effectiveness. Such evidence is costly and time-consuming to generate, but essential if innovative non-pharmacological interventions are to be introduced to minimise the burden of illness in this population and ensure efficient use of public funds. The findings from this review suggests that capturing data on the value and/or cost-effectiveness of such interventions should be prioritised; furthermore, research effort should be directed to developing evaluative methods which move beyond the confines of current health technology assessment frameworks, to capture a broader picture of ‘value’ more applicable to arts and creativity interventions and public health interventions more generally. PROSPERO registration CRD42021267944 (14/07/2021).

ObjectiveTo quantify the frequency of antibiotic treatments attributable to specific enteric pathogens due to the treatment of diarrhoea among children in the first 2 years of life in low-resource settings.DesignSecondary analysis of a longitudinal birth cohort study, Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED).SettingThis study was conducted at eight sites in Bangladesh, Brazil, India, Nepal, Peru, Pakistan, South Africa and Tanzania.ParticipantsWe analysed 9392 reported diarrhoea episodes, including 6677 with molecular diagnostic test results, as well as 31 408 non-diarrhoeal stools from 1715 children aged 0-2 years with 2 years of complete follow-up data.Primary and secondary outcome measuresWe estimated incidence rates and the proportions of antibiotic use for diarrhoea and for all indications attributable to the top 10 aetiologies of diarrhoea. We estimated associations between specific aetiologies and antibiotic treatment, and assessed whether clinical characteristics of the diarrhoea episodes mediated these relationships.ResultsShigella and rotavirus were the leading causes of antibiotic treatment, responsible for 11.7% and 8.6% of diarrhoea treatments and 14.8 and 10.9 courses per 100 child-years, respectively. Shigella and rotavirus-attributable diarrhoea episodes were 46% (RR: 1.46; 95% CI: 1.33 to 1.60), and 19% (RR: 1.19; 95% CI: 1.09 to 1.31) more likely to be treated with antibiotics, respectively, compared with other aetiologies. Considering antibiotic uses for all indications, these two pathogens accounted for 5.6% of all antibiotic courses, 19.3% of all fluoroquinolone courses and 9.5% of all macrolide courses. Among indicated treatments for dysentery, Shigella and Campylobacter jenjui/Campylobacter coli were responsible for 27.5% and 8.5% of treated episodes, respectively.ConclusionsThe evidence that Shigella and rotavirus were disproportionately responsible for antibiotic use due to their high burden and severity further strengthens the value of interventions targeted to these pathogens. Interventions against Campylobacter could further prevent a large burden of indicated antibiotic treatment for dysentery, which could not be averted by antibiotic stewardship interventions.