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Neuroinflammation is characterized by the elevation of cytokines and adenosine triphosphate (ATP), which in turn activates microglia. These immunoregulatory molecules typically form gradients in vivo, which significantly influence microglial behaviors such as increasing calcium signaling, migration, phagocytosis, and cytokine secretion. Quantifying microglial calcium signaling in the context of inflammation holds the potential for developing precise therapeutic strategies for neurological diseases. However, the current calcium imaging systems are technically challenging to operate, necessitate large volumes of expensive reagents and cells, and model immunoregulatory molecules as uniform concentrations, failing to accurately replicate the in vivo microenvironment. In this study, we introduce a novel calcium monitoring micro-total analysis system (CAM-μTAS) designed to quantify calcium dynamics in microglia (BV2 cells) within defined cytokine gradients. Leveraging programmable pneumatically actuated lifting gate microvalve arrays and a Quake valve, CAM-μTAS delivers cytokine gradients to microglia, mimicking neuroinflammation. Our device automates sample handling and cell culture, enabling rapid media changes in just 1.5 s, thus streamlining the experimental workflow. By analyzing BV2 calcium transient latency to peak, we demonstrate location-dependent microglial activation patterns based on cytokine and ATP gradients, offering insights contrasting those of non-gradient-based perfusion systems. By harnessing advancements in microsystem technology to quantify calcium dynamics, we can construct simplified human models of neurological disorders, unravel the intricate mechanisms of cell-cell signaling, and conduct robust evaluations of novel therapeutics. [ABSTRACT FROM AUTHOR]

AbstractAn increasing focus of recent research is on the role of technology in support of teaching, learning and renewal or revitalization of endangered languages. The potential roles of a given piece of technology logically depend, at least to some extent, on the features built into the technology at design stage. Since most language revitalization and renewal efforts are local, community-based initiatives, the preferences and insights of community members are critical to build into the design, to maximize the relevance and appeal of the technology to those who might use it to maintain and increase knowledge and skills in their language. Recognizing this, the project reported on here incorporated co-design into the development of a mobile app, Warrma Mangarrayi (“Listen to Mangarrayi”). The app design also drew on a model of language revitalization, which offers a conceptualization of how technology can be a resource for a language revitalization team whose goals include everyday phrase-based communication in the endangered language. In this article we discuss the iterative user-centered co-design process adopted for the research and the improvements resulting from community user feedback on different versions and how the resulting resource, Warrma Mangarrayi, responded to community needs and aspirations. [ABSTRACT FROM AUTHOR]

The article focuses on the elevated risk of early maternal death among women whose children have been removed from their care, drawing on observational data from Pause, a UK-based charity. It highlights the critical health and social vulnerabilities faced by these mothers, including mental health issues, domestic abuse, and substance misuse, which are inadequately addressed by current child-focused services.

This literature review systematically analyses publications and articles up to mid-2023 related to the COVID-19 pandemic in the field of HE, specifically identifying pressures that students are experiencing. The aim of the review was to identify insights into the tensions faced by students in HE following their experiences of educational interruptions due to COVID-19. Additionally, this review explored the literature relating to the personal, professional, academic and societal pressures experienced by HE students. Student engagement, sense of belonging, alienation and resilience in a post-pandemic context was also examined. Results suggest that the effects of COVID-19 have increased pressure on HE students in multifaceted and interconnecting ways. Post-pandemic, students' mental health and wellbeing is significantly reducing resilience. Issues facing the cohort of students currently at school will filter on into HE if not actioned. Therefore, Government and HEIs need to address the macro, meso and micro after effects of the COVID-19 pandemic. To do this, further focussed research is needed into post-pandemic HEI support systems and practical pedagogical strategies. HEIs could examine the effects of stress and anxiety resulting from the COVID-19 pandemic and could apply conceptual tools and educational theories to influence future strategies to increase students' resilience, engagement, sense of belonging and thus academic resilience. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To better understand the detrimental effects of domestic violence and abuse on children and young people • To acknowledge the importance of having independent domestic violence advocates in children’s hospitals • To reflect on how you can enhance your practice with regard to domestic violence and abuse. Domestic violence and abuse (DVA) has detrimental effects on the health and well-being of children and young people exposed to it, whether they witness or experience it. The introduction of independent domestic violence advocates in UK hospitals has enhanced the safety of victims of DVA. In 2020-2021 an independent domestic violence advocate post was piloted at a children’s hospital for one year, the advocate’s role being to train hospital staff and support women who had experienced DVA. A service evaluation showed that the training and support provided by the independent domestic violence advocate had benefits for women, children and staff. It also confirmed that the commissioning of services for children exposed to DVA is often underfunded and overshadowed by the provision of support to adults. [ABSTRACT FROM AUTHOR]

Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition of neutrophil chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, the mechanisms by which neutrophils promote tumor progression in humans, as well as how CXCR2 inhibition could potentially serve as a cancer therapy, remain elusive. In this study, we developed a human cell-based microphysiological system to quantify neutrophil-tumor spheroid interactions in both "separated" and "contact" scenarios. We found that neutrophils promote the invasion of tumor spheroids through the secretion of soluble factors and direct contact with cancer cells. However, they promote the proliferation of tumor spheroids solely through direct contact. Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils. [ABSTRACT FROM AUTHOR]

Understanding the factors which control endothelial cell (EC) function and angiogenesis is crucial for developing the horse as a disease model, but equine ECs remain poorly studied. In this study, we have optimised methods for the isolation and culture of equine aortic endothelial cells (EAoECs) and characterised their angiogenic functions in vitro. Mechanical dissociation, followed by magnetic purification using an anti-VE-cadherin antibody, resulted in EC-enriched cultures suitable for further study. Fibroblast growth factor 2 (FGF2) increased the EAoEC proliferation rate and stimulated scratch wound closure and tube formation by EAoECs on the extracellular matrix. Pharmacological inhibitors of FGF receptor 1 (FGFR1) (SU5402) or mitogen-activated protein kinase (MEK) (PD184352) blocked FGF2-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and functional responses, suggesting that these are dependent on FGFR1/MEK-ERK signalling. In marked contrast, vascular endothelial growth factor-A (VEGF-A) had no effect on EAoEC proliferation, migration, or tubulogenesis and did not promote ERK1/2 phosphorylation, indicating a lack of sensitivity to this classical pro-angiogenic growth factor. Gene expression analysis showed that unlike human ECs, FGFR1 is expressed by EAoECs at a much higher level than both VEGF receptor (VEGFR)1 and VEGFR2. These results suggest a predominant role for FGF2 versus VEGF-A in controlling the angiogenic functions of equine ECs. Collectively, our novel data provide a sound basis for studying angiogenic processes in horses and lay the foundations for comparative studies of EC biology in horses versus humans. [ABSTRACT FROM AUTHOR]

Objectives: To map organisational interventions for workplace suicide prevention, identifying the effects, mechanisms, moderators, implementation and economic costs, and how interventions are evaluated. Background: Suicide is a devastating event that can have a profound and lasting impact on the individuals and families affected, with the highest rates found among adults of work age. Employers have a legal and ethical responsibility to provide a safe working environment for their employees, which includes addressing the issue of suicide and promoting mental health and well-being. Methods: A realist perspective was taken, to identify within organisational suicide prevention interventions, what works, for whom and in what circumstances. Published and unpublished studies in six databases were searched. To extract and map data on the interventions the Effect, Mechanism, Moderator, Implementation, Economic (EMMIE) framework was used. Mechanisms were deductively analysed against Bronfenbrenner's socio-ecological model. Results: From 3187 records screened, 46 papers describing 36 interventions within the military, healthcare, the construction industry, emergency services, office workers, veterinary surgeons, the energy sector and higher education. Most mechanisms were aimed at the individual's immediate environment, with the most common being education or training on recognising signs of stress, suicidality or mental illness in oneself. Studies examined the effectiveness of interventions in terms of suicide rates, suicidality or symptoms of mental illness, and changes in perceptions, attitudes or beliefs, with most reporting positive results. Few studies reported economic costs but those that did suggested that the interventions are cost-effective. Conclusions: It seems likely that organisational suicide prevention programmes can have a positive impact on attitudes and beliefs towards suicide as well reducing the risk of suicide. Education, to support individuals to recognise the signs and symptoms of stress, mental ill health and suicidality in both themselves and others, is likely to be an effective starting point for successful interventions. [ABSTRACT FROM AUTHOR]

Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One of the disease-specific features of TDP-43 inclusions is the aberrant phosphorylation of TDP-43 at serines 409/410 (pS409/410). Here, we developed rabbit monoclonal antibodies (mAbs) that specifically detect pS409/410-TDP-43 in multiple model systems and FTD/ALS patient samples. Specifically, we identified three mAbs (26H10, 2E9 and 23A1) from spleen B cell clones that exhibit high specificity and sensitivity to pS409/410-TDP-43 peptides in an ELISA assay. Biochemical analyses revealed that pS409/410 of recombinant TDP-43 and of exogenous 25 kDa TDP-43 C-terminal fragments in cultured HEK293T cells are detected by all three mAbs. Moreover, the mAbs detect pS409/410-positive TDP-43 inclusions in the brains of FTD/ALS patients and mouse models of TDP-43 proteinopathy by immunohistochemistry. Our findings indicate that these mAbs are a valuable resource for investigating TDP-43 pathology both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Purpose of Review: Acute lymphoblastic leukemia (ALL) is a rare hematologic neoplasm in adults, with most cases defined by pathology related to abnormal B cell proliferation known as B-cell ALL. The course is challenging, with less-than-optimal survival outcomes, even with aggressive multiagent chemotherapy and consideration for stem cell transplantation. Novel therapies focused on targetable pathways are being investigated to improve outcomes while simultaneously decreasing toxicity. In our review, we aim to evaluate the utilization of blinatumomab in B-cell ALL and provide insight on how this guides our management. Recent Findings: Blinatumomab is a bispecific T-cell engager (BiTE) immunotherapy that neutralizes malignant cells by instigating CD3-positive T cells to target CD19-positive B cells. However, this therapy targets both malignant and non-malignant lymphocytes with potentially severe side effects such as cytokine release syndrome or neurotoxicity. Evidence evaluating utilization in the relapsed or refractory setting has been most supported; however, newer trials have also indicated improved survival in the frontline treatment of B-cell ALL. Summary: As this therapy is relatively new, the treatment team may include members who are less experienced with the typical treatment course and drug mechanics. This review synthesized available data investigating the effectiveness of blinatumomab effectiveness and its adverse events in addition to providing guidance on safe administration methods utilizing a multidisciplinary healthcare team. When care is coordinated in these settings, serious side effects can be recognized early, allowing for necessary intervention leading to improved quality of life and overall survival. Future research will continue to evaluate blinatumomab in different lines of therapy and expand its way into community settings. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to identify original insights into the educational social mobility conundrum in the UK via examination of the current body of empirical and existing literature associated with disadvantaged secondary school students. The lens of the 'psychosocial and academic trust alienation theory' (PATA) has been applied to explore themes of educational social mobility disadvantage, disengagement and alienation and trauma and trust. This systematic literature review followed PRISMA guidelines, with the SPIDER model adopted to demonstrate the search strategy employed which identified N = 58 publications for inclusion. The contribution of this research to the field of children, young people and society is three‐fold: Firstly, findings provide evidence of the additional educational psychological theory. Secondly, secondary education is identified as a pivotal milestone, where efforts to drive change for educational progress contributing to social mobility progress for disadvantaged students could be focused. Thirdly, the synthesis of current research and literature, identified that there is currently no existing literature related to the PATA theory positioned within the disadvantaged secondary school student context aligned to educational social mobility. This analysis shows that the issues experienced in the education system by disadvantaged students in secondary education correlate with the layered elements of the PATA theory, providing justification for further empirical research. Additionally, the insights reported here could be of interest to the children and young people sector, educational psychology community, educational policy‐makers and international groups who share similar social policy, social mobility demographics and educational systems. [ABSTRACT FROM AUTHOR]

Women with cerebral palsy have the same sexual and reproductive healthcare (SRH) needs and rights as non-disabled women across the life course. Multi-level barriers prevent their SRH needs from being met in a timely way. Grouped according to Bronfenbrenner's socio-ecological model, these include physical and psychosocial determinants. The aim of this scoping review was to collate global literature of access to, and utilisation of, SRH for women with cerebral palsy across the life course. We screened five databases for international empirical studies published in English between 2000–2019. Twelve studies met the inclusion criteria. The review highlights that women with cerebral palsy face challenges to receiving good quality healthcare, including limited practitioner knowledge and training on the effects of cerebral palsy in adulthood and how it interacts with women's SRH needs. Much more research is needed to inform the provision of appropriate SRH treatment for women with cerebral palsy across the life course. This article blends together the findings of 12 international studies on healthcare of girls and adult women with cerebral palsy, particularly focusing on sexual and reproductive health and healthcare. The review indicates a significant gap in evidence about the experiences of healthcare transitions for women with cerebral palsy as they move from childhood to adulthood and children's to adult healthcare The review highlights large gaps in the global literature, in relation to sexual and reproductive healthcare across the lifecourse of disabled women in general, but women with cerebral palsy in particular. The studies found that General Practitioners (GPs) (family doctors) did not consider how prescribed contraceptives relate to impairment effects for girls and women with cerebral palsy. Barriers to good quality sexual and reproductive healthcare for women with cerebral palsy include: inaccessible physical environment and procedures (cervical smear and breast scans), and limited practitioner knowledge about the effects of cerebral palsy in adulthood for women and its interaction with sexual and reproductive health needs. [ABSTRACT FROM AUTHOR]

Post-separation for domestic violence (DV) survivors is known to be a period of heightened risk of domestic homicide. Evidence points to increased rates of DV during the Covid-19 pandemic, with specific challenges in help-seeking from DV services, yet studies that capture this qualitatively are still emerging. This UK study investigated the experiences of 21 separated DV survivors (all women) during the Covid-19 pandemic. Inductive, thematic analysis highlighted participants' psychological distress, isolation, fear of Covid-19 transmission, and detachment from support networks. The findings reflect the interconnected nature of adversities experienced by DV survivors and the exacerbation of these due to the insidious, multifaceted, and synergistic impacts of DV and the pandemic. [ABSTRACT FROM AUTHOR]

The specialist voluntary sector plays a crucial role in supporting survivors of sexual violence. However, in England, short-term funding underpins the sector's financial stability. This article examines sector leaders' ways of coping, resisting and being affected by funding practices. Using the concept of edgework, we show how funding and commissioning dynamics push individuals to the edge of service sustainability, job satisfaction, and emotional well-being. We examine how these edges are "worked," for example, by circumventing and remolding the edge. We offer an original way to theorize participants, make visible the emotional toll of service precarity and offer suggestions for support. [ABSTRACT FROM AUTHOR]

Healthcare workers are exposed to various factors in the workplace that may put them at an increased risk of suicide, but there is a lack of evidence reviewing interventions put in place by employers that may modify this risk. The authors undertook a systematic review to identify and assess organisational interventions aimed at preventing suicide in the healthcare workforce. Databases were systematically searched between January 2022 and August 2022. Eligibility for inclusion in the review was determined using a population, intervention, comparison, outcome framework, and 12 studies met the inclusion criteria. Studies were summarised using narrative synthesis and interventions included education, screening, modification of the workplace, referrals for support and/or therapy and peer support. Outcomes included: uptake, satisfaction, pre-training and post-training knowledge, symptoms, risk of suicide and economic costs. It was identified that various suicide prevention interventions are feasible in healthcare organisations and likely to have positive effects for staff. However, there is a lack of robust evaluation of these interventions, so further research is warranted., Competing Interests: None declared, (© 2024 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.)

Objectives: Most people who have experienced sexual violence (SV) will disclose the event(s) to someone. Key recipients of disclosure are those working in healthcare. Telling someone in healthcare about experiences of SV can be an important step in accessing necessary medical care and being signposted to other services. While recognising healthcare settings are a key place for people to seek support, evidence is lacking about how best to create a safe environment for disclosure to take place, how services can make changes to better facilitate this experience and what changes matter most., Design: This study used a realist approach to identify mechanisms that facilitate safe and supported disclosure. Data were generated through three focus groups with Sexual and Reproductive Health Services healthcare professionals in the UK, and one-to-one interviews with survivors of SV who attended healthcare settings (n=18)., Results: The analysis found that service users needed to feel empowered and recognised as appropriate candidates for care in the material used to promote sexual healthcare services after SV. This promotional material needs to address rape myths, stereotypes and silence surrounding SV, to ensure that all individuals and especially those from diverse groups are empowered to access care. Three fundamental mechanisms for safe and supported disclosure were identified: being listened to, being validated and having choice. Trauma-informed care was identified as being essential for implementing these mechanisms. Healthcare professionals who were confident and competent regarding enquiry about SV and response to disclosures of SV were key., Conclusions: The development of services that are conducive to the disclosure of SV is needed to provide better support for those who have experienced SV and are ready to seek support. Use of appropriate promotional material, specific staff training and a trauma-informed approach are key elements to improve services., Competing Interests: Competing interests: JDR reports personal fees from GSK Pharma, Hologic Diagnostics, Mycovia and Janssen Pharma, as well as ownership of shares in GSK Pharma and AstraZeneca Pharma; is author of the UK and European Guidelines on Pelvic Inflammatory Disease; is a member of the European Sexually Transmitted Infections Guidelines Editorial Board; and is a member of the National Institute for Health Research (NIHR) Funding Committee (Health Technology Assessment Programme). He is an NIHR journals editor and associate editor of Sexually Transmitted Infections journal. He is an officer of the International Union against Sexually Transmitted Infections (treasurer) and a charity trustee of the Sexually Transmitted Infections Research Foundation., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Oxycodone abuse begins with prescription oral oxycodone, yet vulnerability factors determining abuse are largely undefined. We evaluated genetic vulnerability in a rat model of oral oxycodone self-administration (SA): increasing oxycodone concentration/session (0.025-0.1mg/ml; 1,4,16-h) followed by extinction and reinstatement. Active licks and oxycodone intake were greater in females than males during 4-h and 16-h sessions (p< 0.001). Each sex increased intake during 16-h vs 4-h sessions (p<2e-16), but a subset of strains dramatically augmented intake at 16-h (p=0.0005). Heritability ( h 2 ) of active licks/4-h at increasing oxycodone dose ranged from 0.30-0.53. Under a progressive ratio schedule, breakpoints were strain-dependent (p<2e-16). Cued reinstatement was greater in females (p<0.001). Naive rats were assessed by elevated plus maze (EPM), open field (OF) and novel object interaction (NOI). We correlated these behaviors with 28 parameters of oxycodone SA. Anxiety-defining EPM traits were most associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Sex and heredity are major determinants of motivation to take and seek oxycodone; intake augments dramatically during extended access in specific strains; and pleiotropic genes affect anxiety and multiple SA parameters., Competing Interests: Conflict of Interest Statement The authors declare that this study was supported exclusively by funds available from the National Institutes of Health (USA). No commercial funds were utilized and there were no competing interests.

Background:  Manual data entry is time-consuming, inefficient, and error prone. In contrast, leveraging two-dimensional (2D) barcodes and barcode scanning tools is a rapid and effective practice for automatically entering vaccine data accurately and completely. CDC pilots documented clinical and public health impacts of 2D barcode scanning practices on data quality and completeness, time savings, workflow efficiencies, and staff experience., Objectives:  Data entry practices and entered records from routine and mass vaccination settings were analyzed. Data quality improvement opportunities were identified., Methods:  A sample of 50 million emergency use authorization (EUA) coronavirus disease 2019 (COVID-19) vaccine records were analyzed for accuracy and completeness across three data fields: lot number, expiration date, and National Drug Code (NDC). The EUA COVID-19 vaccines lacked a 2D barcode containing these data fields, which necessitated manual data entry at administration. A CDC pilot at clinic compared scanned and manually entered data for routine vaccines across these same data fields., Results:  Analysis of 50 million manually entered EUA COVID-19 vaccine administration records indicated significant gaps in data accuracy and completeness across three data fields. Over half of the analyzed EUA vaccine NDCs (53%) and one-third of the expiration dates (35%) had missing or inaccurate data recorded. Pilot data also showed many errors when manually entered. However, when the pilot's routine vaccines were scanned (out of 71,969 records), nearly all entries were complete and accurate across all three data fields (ranging from 99.7% to 99.999% accurate)., Conclusion:  Vaccine 2D barcode scanning practices increased data accuracy and completeness (up to 99.999% accurate) across data fields assessed. When used consistently, vaccine 2D barcode scanning can resolve issues demonstrated in manually entered data. To realize these benefits, the immunization community should widely use scanning practices. To increase use, CDC developed a Vaccine 2D Barcode National Adoption Strategy and implementation resources., Competing Interests: None declared., (Thieme. All rights reserved.)