Explantation with Lateral Pedicle Mastopexy.

BACKGROUND: While breast explantation combined with mastopexy is an increasingly common procedure, it does present certain technical difficulties. We present a technique of explantation mastopexy with the use of an extended lateral pedicle for auto-augmentation. METHODS: A consecutive series of 40 cases was retrospectively reviewed, with patient reported outcome questionnaire and photography at 3 and 12 months. RESULTS: The mean age was 57 years (range 40 - 70 years), and mean duration of implantation was 20.4 years (range 7 - 42 years). 12 women had undergone previous mastopexy (30%). Minor wound complications requiring simple dressings were seen in 7 cases (17.5%). Major infected wound problems occurred in 1 case, who was a smoker and had other co-morbidities. All except 1 case reported being satisfied or very satisfied with the outcome, with a mean patient reported satisfaction score of 4.9/5. When the photographs were independently assessed by a cosmetic practitioner, all cases were rated as average, good or very good, with a mean score of 4.1/5. CONCLUSIONS: The procedure is associated with low risk of post-operative complications, good cosmetic outcomes, and a high degree of patient satisfaction. We feel this technique provides a logical, reproducible method for combined explantation and mastopexy.

A Systematic Online Living Evidence Summary of experimental Alzheimer's disease research.

BACKGROUND: Despite extensive investment, the development of effective treatments for Alzheimer's disease (AD) has been largely unsuccessful. To improve translation, it is crucial to ensure the quality and reproducibility of foundational evidence generated from laboratory models. Systematic reviews play a key role in providing an unbiased overview of the evidence, assessing rigour and reporting, and identifying factors that influence reproducibility. However, the sheer pace of evidence generation is prohibitive to evidence synthesis and assessment. NEW METHOD: To address these challenges, we have developed AD-SOLES, an integrated workflow of automated tools that collect, curate, and visualise the totality of evidence from in vivo experiments. RESULTS: AD-SOLES is a publicly accessible interactive dashboard aiming to surface and expose data from in vivo experiments. It summarises the latest evidence, tracks reporting quality and transparency, and allows research users to easily locate evidence relevant to their specific research question. COMPARISON WITH EXISTING METHODS: Using automated screening methodologies within AD-SOLES, systematic reviews can begin at an accelerated starting point compared to traditional approaches. Furthermore, through text-mining approaches within the full-text of publications, users can identify research of interest using specific models, outcomes, or interventions without relying on details in the title and/or abstract. CONCLUSIONS: By automating the collection, curation, and visualisation of evidence from in vivo experiments, AD-SOLES addresses the challenges posed by the rapid pace of evidence generation. AD-SOLES aims to offer guidance for research improvement, reduce research waste, highlight knowledge gaps, and support informed decision making for researchers, funders, patients, and the public.

'There was nothing, just absolute darkness': Understanding the needs of those caring for children and young people with complex neurodisability in a diverse UK context: A qualitative exploration in the ENCOMPASS study.

BACKGROUND: Children and young people (CYP) with complex neurodisability experience multiple physical, communication, educational and social challenges, which require complex packages of multidisciplinary care. Part of the holistic care required includes supporting the families and parents/caregivers. The aim of the wider study was to introduce a new programme ('Ubuntu') to parents/caregivers and healthcare professionals (HCPs) in order to test the feasibility and acceptability of the concept and content, with the goal of potential adaptation for the UK in mind. Data collection and analysis uncovered rich data on caregiving journeys, navigation of health services, and perceived service gaps. This paper focuses solely on these topics. Further papers will report on the feasibility and adaptation data. METHODS: Two rounds of semi-structured interviews were conducted with 12 caregivers of CYP with complex neurodisability and six HCPs from a variety of disciplines, recruited from a community child health service in London Borough of Newham, UK in 2020. The interviews included open-ended questions to explore caregiving journeys, experiences of navigating health services and perceived service gaps. Transcripts were analysed using a data-driven inductive thematic analysis. RESULTS: Three themes were identified that related to the aim of understanding caregivers' experiences and unmet needs relating to current service provision. These were (1) Caregiver Mental Health, (2) The Information Gap and (3) The Need for Holistic Support. Mental health difficulties were reported, particularly around the period of diagnosis. Priority needs included the provision of clear information about the diagnosis and services offered, opportunities to forge peer support networks and for services across the community to collaborate. CONCLUSIONS: The delivery of health services for CYP with neurodisability should encompass the broad needs of the family as well as meeting the clinical needs of the CYP.

The impact of the first phase of the COVID-19 pandemic on referral patterns and therapeutic service provision for children and young people's psychosocial distress in a Low-or Middle-Income Country: A service evaluation of routinely collected data from a non-government organisation operating in schools in the Western Cape, South Africa.

INTRODUCTION: In low- and middle-income countries (LMICs), including South Africa, there is a paucity of psychosocial support services. Therefore, services are often provided in schools by non-government organisations like Community Keepers (CK). The COVID-19 pandemic and resultant restrictions meant that children and young people's (CYP) lives changed, negatively affecting their mental health. Further, organisations like CK had to change their working processes. METHOD: This project compared routinely collected data from CK from 2019 (pre-pandemic) to 2020 (pandemic) to describe the changes that occurred in referral patterns to, and service provision by, CK. RESULTS: Both pre-pandemic and during the pandemic, most referrals of CYP were for emotional/psychological support and behavioural difficulties. In 2020, referrals for general guidance increased, whilst referrals for peer group issues and sexuality decreased. Further, CK completed more brief check-ins, provided wellbeing workshops to increased numbers of teachers, parents and CYP, and had more consultation sessions with other service providers during the pandemic. DISCUSSION: Routinely collected data from this community-based service in a LMIC context shows differences in the way that support was provided, and to whom, during the COVID-19 pandemic. Clinical implications, including the importance of increasing access to psychosocial support via technology, are included.

The COVID-19 pandemic disproportionately impacted children, young people and families who are most vulnerable, including those in low- and middle-income countries (LMICs). Within LMICs, the lack of trained psychological professionals and investment in mental healthcare interventions means access to help is limited. School-based provision, which may increase access to mental health support was curtailed during school closures when face-to face service provision was prohibited. It is well-documented that the COVID-19 pandemic impacted CYP's mental and emotional well-being. However, it is less well understood how the need and service provision of third sector non-government organisations changed during this time. Thus, we partnered with a non-government organisation, Community Keepers (CK) who are based in Western Cape, South Africa to understand how referral patterns changed from 2019 (pre-pandemic) to 2020 (peri-pandemic) and explore the specific adaptations that CK made to service provision. CK aims to provide free mental health care services to CYP, their parents (legal guardians / primary caregivers; henceforth referred to as parents) and teachers, on-site at schools (www.communitykeepers.org). Results suggest that both pre-pandemic and during the pandemic, most referrals of CYP were for emotional/psychological support and behavioural difficulties. In 2020, referrals for general guidance and chronic/serious illness increased, whilst referrals for peer group issues and sexuality decreased. Further, CK completed wellbeing workshops to increased numbers of teachers, parents and CYP, and had more consultation sessions with other service providers during the pandemic. In addition, COVID-19 restrictions necessitated a reduction in face-to-face sessions and a move towards more systemic support as well as telephonic and/or online support to individuals. This paper demonstrates that should another global crisis like the Covid-19 pandemic occur, necessitating school closures and/or restrictions to in-person interaction, it will be important for organisations working in schools, particularly with CYP who are particularly vulnerable, to pivot their provision to enable continued support. Further, specific recommendations for CK were given regarding data collection, that can be used to support growth and understanding service provision patterns across similar settings.

Immobilized NRG1 Accelerates Neural Crest like Cell Differentiation Toward Functional Schwann Cells Through Sustained Erk1/2 Activation and YAP/TAZ Nuclear Translocation.

Neural Crest cells (NC) are a multipotent cell population that give rise to a multitude of cell types including Schwann cells (SC) in the peripheral nervous system (PNS). Immature SC interact with neuronal axons via the neuregulin 1 (NRG1) ligand present on the neuronal surface and ultimately form the myelin sheath. Multiple attempts to derive functional SC from pluripotent stem cells have met challenges with respect to expression of mature markers and axonal sorting. Here, they hypothesized that sustained signaling from immobilized NRG1 (iNRG1) might enhance the differentiation of NC derived from glabrous neonatal epidermis towards a SC phenotype. Using this strategy, NC derived SC expressed mature markers to similar levels as compared to explanted rat sciatic SC. Signaling studies revealed that sustained NRG1 signaling led to yes-associated protein 1 (YAP) activation and nuclear translocation. Furthermore, NC derived SC on iNRG1 exhibited mature SC function as they aligned with rat dorsal root ganglia (DRG) neurons in an in vitro coculture model; and most notably, aligned on neuronal axons upon implantation in a chick embryo model in vivo. Taken together their work demonstrated the importance of signaling dynamics in SC differentiation, aiming towards development of drug testing platforms for de-myelinating disorders.

Health net-outcome objectives and approaches for spatial planning and development: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to review the body of knowledge on net gain and no net loss (net-outcome) objectives and approaches applicable to health in spatial planning and development policies and practice. INTRODUCTION: There is an established body of academic and gray literature addressing environmental net-outcome objectives, such as biodiversity net gain, in spatial planning policies and practice. A "health net gain" objective has recently been proposed as a driver for health protection and the realization of health. Such an objective and approach are yet to be scoped and defined. INCLUSION CRITERIA: This review will consider sources in the scientific and gray literature that describe health net-outcome objectives that can be implemented in spatial planning and development policies and practice. Source contexts will not be limited to specific countries, geographical areas, or settings. All types of evidence will be considered. METHODS: This review will follow the JBI methodology for scoping reviews. Databases to be searched include PsycINFO (APA), Embase, HMIC Health Management Information Consortium, MEDLINE (Ovid), Scopus, and selected databases from the ProQuest Social Science Premium Collection. Sources of gray literature to be searched include ProQuest Dissertations and Theses, TRIP Pro, and BASE. No language or date restrictions will be applied. Two independent reviewers will retrieve and review full-text studies and extract data. The results will be presented in tabular or diagrammatic format with a narrative summary. REVIEW REGISTRATION: Open Science Framework https://osf.io/4dbcm.

An in-depth exploration of the multifaceted roles of EVs in the context of pathogenic single-cell microorganisms.

SUMMARYExtracellular vesicles (EVs) have been recognized throughout scientific communities as potential vehicles of intercellular communication in both eukaryotes and prokaryotes, thereby influencing various physiological and pathological functions of both parent and recipient cells. This review provides an in-depth exploration of the multifaceted roles of EVs in the context of bacteria and protozoan parasite EVs, shedding light on their contributions to physiological processes and disease pathogenesis. These studies highlight EVs as a conserved mechanism of cellular communication, which may lead us to important breakthroughs in our understanding of infection, mechanisms of pathogenesis, and as indicators of disease. Furthermore, EVs are involved in host-microbe interactions, offering insights into the strategies employed by bacteria and protozoan parasites to modulate host responses, evade the immune system, and establish infections.

Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination.

Schwann cells are critical for the proper development and function of the peripheral nervous system, where they form a mutually beneficial relationship with axons. Past studies have highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this work, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2) in vivo results in early and severe defects in peripheral nerve development. Using a proteomic approach in vitro, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on the presence of axonal signals. Furthermore, we show in vivo that loss of Phb2 in mouse Schwann cells causes ineffective proliferation and dysregulation of transcription factors EGR2 (KROX20), POU3F1 (OCT6) and POU3F2 (BRN2) that are necessary for proper Schwann cell maturation. Schwann cell-specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the development defect seen in mice lacking Schwann cell Phb2. This work develops our understanding of Schwann cell biology, revealing that Phb2 may directly or indirectly modulate the timely expression of transcription factors necessary for proper peripheral nervous system development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.

Genome-wide CRISPR/Cas9 screen shows that loss of GET4 increases mitochondria-endoplasmic reticulum contact sites and is neuroprotective.

Organelles form membrane contact sites between each other, allowing for the transfer of molecules and signals. Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are cellular subdomains characterized by close apposition of mitochondria and ER membranes. They have been implicated in many diseases, including neurodegenerative, metabolic, and cardiac diseases. Although MERCS have been extensively studied, much remains to be explored. To uncover novel regulators of MERCS, we conducted a genome-wide, flow cytometry-based screen using an engineered MERCS reporter cell line. We found 410 genes whose downregulation promotes MERCS and 230 genes whose downregulation decreases MERCS. From these, 29 genes were selected from each population for arrayed screening and 25 were validated from the high population and 13 from the low population. GET4 and BAG6 were highlighted as the top 2 genes that upon suppression increased MERCS from both the pooled and arrayed screens, and these were subjected to further investigation. Multiple microscopy analyses confirmed that loss of GET4 or BAG6 increased MERCS. GET4 and BAG6 were also observed to interact with the known MERCS proteins, inositol 1,4,5-trisphosphate receptors (IP3R) and glucose-regulated protein 75 (GRP75). In addition, we found that loss of GET4 increased mitochondrial calcium uptake upon ER-Ca2+ release and mitochondrial respiration. Finally, we show that loss of GET4 rescues motor ability, improves lifespan and prevents neurodegeneration in a Drosophila model of Alzheimer's disease (Aß42Arc). Together, these results suggest that GET4 is involved in decreasing MERCS and that its loss is neuroprotective.

Harnessing preexisting influenza virus-specific immunity increases antibody responses against SARS-CoV-2.

In pandemic scenarios involving novel human pathogenic viruses, it is highly desirable that vaccines induce strong neutralizing antibodies as quickly as possible. However, current vaccine strategies require multiple immunization doses to produce high titers of neutralizing antibodies and are poorly protective after a single vaccination. We therefore wished to design a vaccine candidate that would induce increased protective immune responses following the first vaccine dose. We hypothesized that antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein could be increased by drawing upon immunity to a previous infection. We generated a fusion protein containing the influenza H1N1 PR8 virus nucleoprotein (NP) and the SARS-CoV-2 spike RBD. Mice with or without preexisting immunity to PR8 were then vaccinated with NP/RBD. We observed significantly increased SARS-CoV-2 neutralizing antibodies in mice with PR8 immunity compared to mice without preexisting PR8 immunity. Vaccination with NP/RBD protected mice from SARS-CoV-2-induced morbidity and mortality after a single dose. Additionally, we compared SARS-CoV-2 virus titers in the lungs and nasal turbinates 4 days post-challenge of mice vaccinated with NP/RBD. SARS-CoV-2 virus was detectable in the lungs and nasal turbinate of mice without preexisting PR8 immunity, while SARS-CoV-2 virus was completely undetectable in mice with preexisting PR8 immunity. We also found that CD4-positive T cells in mice with preexisting immunity to PR8 play an essential role in producing the increased antibody response against RBD. This vaccine strategy potentially can be modified to target other pathogens of concern and offers extra value in future pandemic scenarios.IMPORTANCEIncreased globalization and changes in human interactions with wild animals has increased the likelihood of the emergence of novel viruses with pandemic potential. Vaccines can be effective in preventing severe disease caused by pandemic viruses. However, it takes time to develop protective immunity via prime-boost vaccination. More effective vaccine designs should quickly induce protective immunity. We propose leveraging preexisting immunity to a different pathogen to boost protection against emerging viruses. We targeted SARS-CoV-2 as a representative pandemic virus and generated a fusion protein vaccine that combines the nucleoprotein from influenza A virus and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Our vaccine design significantly increased the production of RBD-specific antibodies in mice that had previously been exposed to influenza virus, compared to those without previous exposure. This enhanced immunity reduced SARS-CoV-2 replication in mice. Our results offer a vaccine design that could be valuable in a future pandemic setting.

Development and Implementation of Digital Diagnostic Algorithms for Neonatal Units in Zimbabwe and Malawi: Development and Usability Study.

BACKGROUND: Despite an increase in hospital-based deliveries, neonatal mortality remains high in low-resource settings. Due to limited laboratory diagnostics, there is significant reliance on clinical findings to inform diagnoses. Accurate, evidence-based identification and management of neonatal conditions could improve outcomes by standardizing care. This could be achieved through digital clinical decision support (CDS) tools. Neotree is a digital, quality improvement platform that incorporates CDS, aiming to improve neonatal care in low-resource health care facilities. Before this study, first-phase CDS development included developing and implementing neonatal resuscitation algorithms, creating initial versions of CDS to address a range of neonatal conditions, and a Delphi study to review key algorithms. OBJECTIVE: This second-phase study aims to codevelop and implement neonatal digital CDS algorithms in Malawi and Zimbabwe. METHODS: Overall, 11 diagnosis-specific web-based workshops with Zimbabwean, Malawian, and UK neonatal experts were conducted (August 2021 to April 2022) encompassing the following: (1) review of available evidence, (2) review of country-specific guidelines (Essential Medicines List and Standard Treatment Guidelinesfor Zimbabwe and Care of the Infant and Newborn, Malawi), and (3) identification of uncertainties within the literature for future studies. After agreement of clinical content, the algorithms were programmed into a test script, tested with the respective hospital's health care professionals (HCPs), and refined according to their feedback. Once finalized, the algorithms were programmed into the Neotree software and implemented at the tertiary-level implementation sites: Sally Mugabe Central Hospital in Zimbabwe and Kamuzu Central Hospital in Malawi, in December 2021 and May 2022, respectively. In Zimbabwe, usability was evaluated through 2 usability workshops and usability questionnaires: Post-Study System Usability Questionnaire (PSSUQ) and System Usability Scale (SUS). RESULTS: Overall, 11 evidence-based diagnostic and management algorithms were tailored to local resource availability. These refined algorithms were then integrated into Neotree. Where national management guidelines differed, country-specific guidelines were created. In total, 9 HCPs attended the usability workshops and completed the SUS, among whom 8 (89%) completed the PSSUQ. Both usability scores (SUS mean score 75.8 out of 100 [higher score is better]; PSSUQ overall score 2.28 out of 7 [lower score is better]) demonstrated high usability of the CDS function but highlighted issues around technical complexity, which continue to be addressed iteratively. CONCLUSIONS: This study describes the successful development and implementation of the only known neonatal CDS system, incorporated within a bedside data capture system with the ability to deliver up-to-date management guidelines, tailored to local resource availability. This study highlighted the importance of collaborative participatory design. Further implementation evaluation is planned to guide and inform the development of health system and program strategies to support newborn HCPs, with the ultimate goal of reducing preventable neonatal morbidity and mortality in low-resource settings.

Development and Pilot Implementation of Neotree, a Digital Quality Improvement Tool Designed to Improve Newborn Care and Survival in 3 Hospitals in Malawi and Zimbabwe: Cost Analysis Study.

Background: Two-thirds of the 2.4 million newborn deaths that occurred in 2020 within the first 28 days of life might have been avoided by implementing existing low-cost evidence-based interventions for all sick and small newborns. An open-source digital quality improvement tool (Neotree) combining data capture with education and clinical decision support is a promising solution for this implementation gap. Objective: We present results from a cost analysis of a pilot implementation of Neotree in 3 hospitals in Malawi and Zimbabwe. Methods: We combined activity-based costing and expenditure approaches to estimate the development and implementation cost of a Neotree pilot in 1 hospital in Malawi, Kamuzu Central Hospital (KCH), and 2 hospitals in Zimbabwe, Sally Mugabe Central Hospital (SMCH) and Chinhoyi Provincial Hospital (CPH). We estimated the costs from a provider perspective over 12 months. Data were collected through expenditure reports, monthly staff time-use surveys, and project staff interviews. Sensitivity and scenario analyses were conducted to assess the impact of uncertainties on the results or estimate potential costs at scale. A pilot time-motion survey was conducted at KCH and a comparable hospital where Neotree was not implemented. Results: Total cost of pilot implementation of Neotree at KCH, SMCH, and CPH was US $37,748, US $52,331, and US $41,764, respectively. Average monthly cost per admitted child was US $15, US $15, and US $58, respectively. Staff costs were the main cost component (average 73% of total costs, ranging from 63% to 79%). The results from the sensitivity analysis showed that uncertainty around the number of admissions had a significant impact on the costs in all hospitals. In Malawi, replacing monthly web hosting with a server also had a significant impact on the costs. Under routine (nonresearch) conditions and at scale, total costs are estimated to fall substantially, up to 76%, reducing cost per admitted child to as low as US $5 in KCH, US $4 in SMCH, and US $14 in CPH. Median time to admit a baby was 27 (IQR 20-40) minutes using Neotree (n=250) compared to 26 (IQR 21-30) minutes using paper-based systems (n=34), and the median time to discharge a baby was 9 (IQR 7-13) minutes for Neotree (n=246) compared to 3 (IQR 2-4) minutes for paper-based systems (n=50). Conclusions: Neotree is a time- and cost-efficient tool, comparable with the results from limited similar mHealth decision-support tools in low- and middle-income countries. Implementation costs of Neotree varied substantially between the hospitals, mainly due to hospital size. The implementation costs could be substantially reduced at scale due to economies of scale because of integration to the health systems and reductions in cost items such as staff and overhead. More studies assessing the impact and cost-effectiveness of large-scale mHealth decision-support tools are needed.

Perceptions and Experiences of Undergraduate Students Regarding Social Media as a Tool for Government COVID-19-Related Messages: A Qualitative Study in Nottingham, UK.

The rise of social media has given way to its use as a form of public health communication. Previous research has shown social media-based interventions to be effective, particularly for university students. Social media was used as a tool for public health messaging during the COVID-19 pandemic; however, there is a lack of information regarding the experiences and perceptions of such messaging and its effectiveness among UK university students. A qualitative study was conducted to explore the perceptions and experiences of public health messaging on social media during the pandemic, as well as the effects of such messaging. Fourteen semi-structured interviews with undergraduate students at the University of Nottingham, UK, were conducted. Five main themes were identified: effects of COVID-19 on university students, use of social media by university students, COVID-19 messaging on social media, effects of public health messaging on social media in compliance with COVID-19 guidelines, and improving public health messaging for the future. This study provides a novel insight into the experiences and perceptions of undergraduate students at a UK university regarding public health messaging on social media during the COVID-19 pandemic.

Adaptive Filter Model of Cerebellum for Biological Muscle Control With Spike Train Inputs.

Prior applications of the cerebellar adaptive filter model have included a range of tasks within simulated and robotic systems. However, this has been limited to systems driven by continuous signals. Here, the adaptive filter model of the cerebellum is applied to the control of a system driven by spiking inputs by considering the problem of controlling muscle force. The performance of the standard adaptive filter algorithm is compared with the algorithm with a modified learning rule that minimizes inputs and a simple proportional-integral-derivative (PID) controller. Control performance is evaluated in terms of the number of spikes, the accuracy of spike input locations, and the accuracy of muscle force output. Results show that the cerebellar adaptive filter model can be applied without change to the control of systems driven by spiking inputs. The cerebellar algorithm results in good agreement between input spikes and force outputs and significantly improves on a PID controller. Input minimization can be used to reduce the number of spike inputs, but at the expense of a decrease in accuracy of spike input location and force output. This work extends the applications of the cerebellar algorithm and demonstrates the potential of the adaptive filter model to be used to improve functional electrical stimulation muscle control.

Breast cancer surgical decision-making. Experiences of Non-Caucasian women globally. A qualitative systematic review.

OBJECTIVES: To perform a qualitative systematic review exploring the influencing factors within the surgical decision-making (SDM) processes following a breast cancer diagnosis in non-caucasian women globally. STUDY DESIGN: Qualitative systemic review following PRISMA guidelines. METHODS: A comprehensive search strategy was applied to four databases. 5243 papers were screened using a composed inclusion and exclusion criteria resulting in 10 total papers to be included. These papers underwent JBI quality assessment and ConQual assessment to ensure strength in validation, reliability, and quality. RESULTS: Six main overarching themes relating to SDM were determined: fear, information, patient-doctor relationship, wellbeing, external influences, and culture. All ethnicities experienced fear in one way. Misinformation was widely experienced in concordance with either a lack of education (Iranian and Ghanian women) or language barriers (immigrant populations). Trust was overarching in all patient-doctor relationships, some being overshadowed by an authoritative dynamic in Ghanian and Iranian women. Well-being, both psychological and body image was noted in all but the Ghanian and Iranian women. Every ethnicity experienced external influences involving either others, time or cost. Lastly, cultural expectations and beliefs of the doctor was present in all native or immigrant Asian communities. CONCLUSIONS: The study identified several factors which were common between ethnicities, notably multifactorial fear, well-being factors, opinions and trust of others, and timing. Conversely, information availability and the nature of patient-doctor relationships varied widely between ethnicities. The study has identified some realistic and achievable focus areas for practice improvement, but also notes the challenges of changing long-established cultural norms.

An ex vivo model of Toxoplasma recrudescence reveals developmental plasticity of the bradyzoite stage.

IMPORTANCE: The classical depiction of the Toxoplasma lifecycle is bradyzoite excystation conversion to tachyzoites, cell lysis, and immune control, followed by the reestablishment of bradyzoites and cysts. In contrast, we show that tachyzoite growth slows independent of the host immune response at a predictable time point following excystation. Furthermore, we demonstrate a host cell-dependent pathway of continuous amplification of the cyst-forming bradyzoite population. The developmental plasticity of the excysted bradyzoites further underlines the critical role the cyst plays in the flexibility of the lifecycle of this ubiquitous parasite. This revised model of Toxoplasma recrudescence uncovers previously unknown complexity in the clinically important bradyzoite stage of the parasite, which opens the door to further study these novel developmental features of the Toxoplasma intermediate life cycle.

Human neutrophil-like cells demonstrate antimicrobial responses to the chronic cyst form of Toxoplasma gondii.

The protozoan parasite Toxoplasma gondii infects approximately 2.5 billion people worldwide. Infection induces a rapid dissemination of parasites throughout the body followed by the formation of lifelong cysts within neurons of the host brain. Both stages require a dynamic immune response comprised of both innate and adaptive cells. Neutrophils are a primary responding cell to acute infection and have been observed in the brain during murine chronic infection. Previous studies investigating human neutrophils found that invasion by Toxoplasma tachyzoites inhibits apoptosis of neutrophils, prolonging their survival under inflammatory conditions. Here, we demonstrate the differentiation of two distinct subsets following exposure of human neutrophil-like-cells (HNLC) to Toxoplasma cysts. In vitro stimulation and imaging studies show cyst-specific induction of cytokines and cyst clearance by HNLCs. Further testing demonstrates that aged HNLCs perform less phagocytosis of cysts compared to non-aged HNLCs. In conclusion, this study identifies a novel response of HNLCs to Toxoplasma cysts and may indicate a role for neutrophils in the clearance of cysts during human infection with Toxoplasma.

The development and validation of the Discrimination and Stigma Scale Ultra Short for People Living with Dementia (DISCUS-Dementia).

BACKGROUND: The recent World Health Organization (WHO) blueprint for dementia research and Lancet Commission on ending stigma and discrimination in mental health has identified a gap around dementia-related measures of stigma and discrimination that can be used in different cultural, language and regional contexts. AIMS: We aimed to characterise experiences of discrimination, and report initial psychometric properties of a new tool to capture these experiences, among a global sample of people living with dementia. METHOD: We analysed data from 704 people living with dementia who took part in a global survey from 33 different countries and territories. Psychometric properties were examined, including internal consistency and construct validity. RESULTS: A total of 83% of participants reported discrimination in one or more areas of life, and this was similar across WHO Regions. The exploratory factor analysis factor loadings and scree plot supported a unidimensional structure for the Discrimination and Stigma Scale Ultra Short for People Living with Dementia (DISCUS-Dementia). The instrument demonstrated excellent internal consistency, with most of the construct validity hypotheses being confirmed and qualitative responses demonstrating face validity. CONCLUSIONS: Our analyses suggest that the DISCUS-Dementia performs well with a global sample of people living with dementia. This scale can be integrated into large-scale studies to understand factors associated with stigma and discrimination. It can also provide an opportunity for a structured discussion around stigma and discrimination experiences important to people living with dementia, as well as planning psychosocial services and initiatives to reduce stigma and discrimination.

Group 1 metabotropic glutamate receptor expression defines a T cell memory population during chronic Toxoplasma infection that enhances IFN-gamma and perforin production in the CNS.

Within the brain, a pro-inflammatory response is essential to prevent clinical disease due to Toxoplasma gondii reactivation. Infection in the immunocompromised leads to lethal Toxoplasmic encephalitis while in the immunocompetent, there is persistent low-grade inflammation which is devoid of clinical symptoms. This signifies that there is a well-balanced and regulated inflammatory response to T. gondii in the brain. T cells are the dominant immune cells that prevent clinical disease, and this is mediated through the secretion of effector molecules such as perforins and IFN-γ. The presence of cognate antigen, the expression of survival cytokines, and the alteration of the epigenetic landscape drive the development of memory T cells. However, specific extrinsic signals that promote the formation and maintenance of memory T cells within tissue are poorly understood. During chronic infection, there is an increase in extracellular glutamate that, due to its function as an excitatory neurotransmitter, is normally tightly controlled in the CNS. Here we demonstrate that CD8+ T cells from the T. gondii-infected brain parenchyma are enriched for metabotropic glutamate receptors (mGluR's). Characterization studies determined that mGluR+ expression by CD8+ T cells defines a distinct memory population at the transcriptional and protein level. Finally, using receptor antagonists and agonists we demonstrate mGluR signaling is required for optimal CD8+ T cell production of the effector cytokine IFNγ. This work suggests that glutamate is an important environmental signal of inflammation that promotes T cell function. Understanding glutamate's influence on T cells in the brain can provide insights into the mechanisms that govern protective immunity against CNS-infiltrating pathogens and neuroinflammation.