Potential drug repurposing of ruxolitinib to inhibit the JAK/STAT pathway for the treatment of patients with epithelial ovarian cancer.

AIM: This review aimed to describe the potential for therapeutic targeting of the JAK/STAT signaling pathway by repurposing the clinically-approved JAK inhibitor ruxolitinib in the patients with epithelial ovarian cancer (OC) setting. METHODS: We reviewed publications that focus on the inhibition of the JAK/STAT pathway in hematological and solid malignancies including OC. RESULTS: Preclinical studies showed that ruxolitinib effectively reduces OC cell viability and metastasis and enhances the anti-tumor activity of chemotherapy drugs. There are a number of recent clinical trials exploring the role of JAK/STAT inhibition in solid cancers including OC. Early results have not adequately supported efficacy in solid tumors. However, there are preclinical data and clinical studies supporting the use of ruxolitinib in combination with both chemotherapy and other targeted drugs in OC setting. CONCLUSION: Inflammatory conditions and persistent activation of the JAK/STAT pathway are associated with tumourigenesis and chemoresistance, and therapeutic blockade of this pathway shows promising results. For women with OC, clinical investigation exploring the role of ruxolitinib in combination with chemotherapy agents or other targeted therapeutics is warranted.

Characterisation of the immune microenvironment of cutaneous squamous cell carcinoma in immunosuppression.

Cutaneous squamous cell carcinoma (cSCC) is a common cancer. Systemic immunosuppression with drugs such as Prednisone results in more aggressive disease. We hypothesise that more aggressive disease in immunosuppression is the result of immune changes in the tumor microenvironment. We characterised T cell, phagocytic and antigen presenting cell subsets in cSCC and determined if these infiltrates were altered by immunosuppressive therapy. We found a dominant "CD8 profile" in the centre of cSCC lesions, with CD8 cells correlating with Tbet, FoxP3, OX40 and "M2-like" macrophages, whereas a "Tbet and granulocyte profile" with associated inflammation predominated at the margin of the tumor. Individuals on systemic immunosuppressive therapy had lesions that were comparable in size, stage and number of vessels to immune competent individuals; however, the number of CD11c positive cells in the lesion centre was significantly reduced. We conclude that cSCC lesions are immunologically heterogeneous across the lesion and that systemically immunosuppressed individuals have reduced CD11c positive cells in the centre of the lesion. The role and detailed phenotype of CD11c positive cells in cSCC lesions warrant further investigation.

Functional effects of immune complexes formed between pembrolizumab and patient-generated anti-drug antibodies.

The PD-1-targeting IgG4 antibody pembrolizumab has significant anti-tumor activity in a proportion of stage IV melanoma patients. A subset of patients develop anti-drug antibodies (ADA) which can form immune complexes (IC) with pembrolizumab. Although IC can induce powerful, Fc-mediated, immune-regulatory effects, their functional impact during pembrolizumab treatment is unclear. The functional effects of IC generated in vitro using pembrolizumab and patient-derived ADA was, therefore, investigated. Screening identified a patient whose trough serum samples from three treatment cycles contained both ADA with neutralizing activity and low levels of pembrolizumab. This patient responded well to therapy over 2 years and had ongoing, infusion-related, hypersensitivity reactions despite the later absence of detectable ADA. The components of IC were mimicked by forming a complex of pembrolizumab by absorption onto a solid phase with or without subsequent exposure to the ADA+ patient sera. Complexes comprised of pembrolizumab alone significantly inhibited TLR4 (LPS)-driven IL-10 production by PBMC and stimulated the generation of reactive oxygen species by granulocytes. In contrast, soluble and solid-phase F(ab´)2 fragments of pembrolizumab had no effect demonstrating the requirement for cross-linked Fc regions. IC containing pembrolizumab and ADA could additionally induce complement and NK activation. The results of this study demonstrate that, when oligomerized, the Fc region of pembrolizumab alone can provide immuno-regulatory signals. Furthermore, IC containing both pembrolizumab and patient-generated ADA can induce additional signals. These Fc-mediated signals may modulate both hypersensitivity reactions and anti-tumor responses associated with pembrolizumab therapy.

Quantifying BRCA1 and BRCA2 mRNA Isoform Expression Levels in Single Cells.

BRCA1 and BRCA2 spliceogenic variants are often associated with an elevated risk of breast and ovarian cancers. Analyses of BRCA1 and BRCA2 splicing patterns have traditionally used technologies that sample a population of cells but do not account for the variation that may be present between individual cells. This novel proof of concept study utilises RNA in situ hybridisation to measure the absolute expression of BRCA1 and BRCA2 mRNA splicing events in single lymphoblastoid cells containing known spliceogenic variants (BRCA1c.671-2 A>G or BRCA2c.7988 A>T). We observed a large proportion of cells (>42%) in each sample that did not express mRNA for the targeted gene. Increased levels (average mRNA molecules per cell) of BRCA2 ∆17_18 were observed in the cells containing the known spliceogenic variant BRCA2c.7988 A>T, but cells containing BRCA1c.671-2 A>G were not found to express significantly increased levels of BRCA1 ∆11, as had been shown previously. Instead, we show for each variant carrier sample that a higher proportion of cells expressed the targeted splicing event compared to control cells. These results indicate that BRCA1/2 mRNA is expressed stochastically, suggesting that previously reported results using RT-PCR may have been influenced by the number of cells with BRCA1/2 mRNA expression and may not represent an elevation of constitutive mRNA expression. Detection of mRNA expression in single cells allows for a more comprehensive understanding of how spliceogenic variants influence the expression of mRNA isoforms. However, further research is required to assess the utility of this technology to measure the expression of predicted spliceogenic BRCA1 and BRCA2 variants in a diagnostic setting.

Vitamin C and immune cell function in inflammation and cancer.

Vitamin C (ascorbate) is maintained at high levels in most immune cells and can affect many aspects of the immune response. Intracellular levels generally respond to variations in plasma ascorbate availability, and a combination of inadequate intake and increased turnover during severe stress can result in low plasma ascorbate status. Intracellular ascorbate supports essential functions and, in particular, acts as an enzyme cofactor for Fe- or Cu-containing oxygenases. Newly discovered enzymes in this family regulate cell metabolism and epigenetics, and dysregulation of their activity can affect cell phenotype, growth and survival pathways, and stem cell phenotype. This brief overview details some of the recent advances in our understanding of how ascorbate availability can affect the hydroxylases controlling the hypoxic response and the DNA and histone demethylases. These processes play important roles in the regulation of the immune system, altering cell survival pathways, metabolism and functions.

Attitudes towards the use and acceptance of eHealth technologies: a case study of older adults living with chronic pain and implications for rural healthcare.

BACKGROUND: Providing health services to an ageing population is challenging, and in rural areas even more so. It is expensive to provide high quality services to small populations who are widely dispersed; staff and patients are often required to travel considerable distances to access services, and the economic downturn has created a climate where delivery costs are under constant review. There is potential for technology to overcome some of these problems by decreasing or ceasing the need for patients and health professionals to travel to attend/deliver in-person appointments. A variety of eHealth initiatives (for example Pathways through Pain an online course aimed to aid self-help amongst those living with persistent pain) have been launched across the UK, but roll out remains at an early stage. METHODS: This mixed-methods study of older adults with chronic pain examines attitudes towards, current use of and acceptance of the use of technology in healthcare. A survey (n = 168, 40% response rate) captured broad experiences of the use of technology in health and social care. Semi-structured interviews (four with technology and seven without technology participants) elicited attitudes towards technology in healthcare and explored attributes of personal and social interaction during home visits. RESULTS: People suffering from chronic pain access healthcare in a variety of ways. eHealth technology use was most common amongst older adults who lived alone. There was broad acceptance of eHealth being used in future care of people with chronic pain, but older adults wanted eHealth to be delivered alongside existing in-person visits from health and social care professionals. CONCLUSIONS: eHealth has the potential to overcome some traditional challenges of providing rural healthcare, however roll out needs to be gradual and begin by supplementing, not substituting, existing care and should be mindful of individual's circumstances, capability and preferences. Acceptance of technology may relate to existing levels of personal and social contact, and may be greater where technological help is not perceived to be replacing in-person care.

A Nature-Based Intervention for Promoting Physical Activity in Older Adults: A Qualitative Study Using the COM-B Model.

Physical inactivity contributes to over 800,000 deaths annually. Numerous non-pharmacological interventions provide a route to address this behavioural risk factor linked to the growth of non-communicable diseases. Here, we consider a nature-based intervention, specifically group outdoor health walks (GOHW), as a non-pharmacological intervention to increase physical activity and contribute to health and quality of life amongst older adults. We used the theoretically grounded Capability, Opportunity, Motivation, and Behaviour (COM-B) model as a lens to examine interviews with participants in a GOHW with an activity tracker and signposted by health clinics in Scotland, UK. Analysis identified capabilities, opportunities, and motivations, their impact on behaviour, and perceived physical and mental health. The application of the COM-B model to intervention evaluation allowed us to examine two separate behaviours, that of (i) engaging with the intervention itself, and (ii) incorporating the behaviour into one's life that the intervention targets. Analysis identified emerging capabilities, opportunities, and motivations that supported additional health-promoting behaviours, including increased time outdoors in nature and leadership to self-organise continued group walks. We offer insight into the design of nature-based interventions to effectively engage older adults with chronic health conditions and foster personal behaviour change for health and well-being.

Development of a long term, ex vivo, patient-derived explant model of endometrial cancer.

Incidence of endometrial cancer (EC) is rising in the developed world. The current standard of care, hysterectomy, is often infeasible for younger patients and those with high body mass index. There are limited non-surgical treatment options and a lack of biologically relevant research models to investigate novel alternatives to surgery for EC. The aim of the present study was to develop a long-term, patient-derived explant (PDE) model of early-stage EC and demonstrate its use for investigating predictive biomarkers for a current non-surgical treatment option, the levonorgestrel intra-uterine system (LNG-IUS). Fresh tumour specimens were obtained from patients with early-stage endometrioid EC. Tumours were cut into explants, cultured on media-soaked gelatin sponges for up to 21 days and treated with LNG. Formalin-fixed, paraffin embedded (FFPE) blocks were generated for each explant after 21 days in culture. Tumour architecture and integrity were assessed by haematoxylin and eosin (H&E) and immunohistochemistry (IHC). IHC was additionally performed for the expression of five candidate biomarkers of LNG resistance. The developed ex vivo PDE model is capable of culturing explants from early-stage EC tumours long-term (21 Days). This model can complement existing models and may serve as a tool to validate results obtained in higher-throughput in vitro studies. Our study provides the foundation to validate the extent to which EC PDEs reflect patient response in future research.

Blood Vitamin C Levels of Patients Receiving Immunotherapy and Relationship to Monocyte Subtype and Epigenetic Modification.

The treatment of metastatic melanoma has been revolutionised by immunotherapy, yet a significant number of patients do not respond, and many experience autoimmune adverse events. Associations have been reported between patient outcome and monocyte subsets, whereas vitamin C (ascorbate) has been shown to mediate changes in cancer-stimulated monocytes in vitro. We therefore investigated the relationship of ascorbate with monocyte subsets and epigenetic modifications in patients with metastatic melanoma receiving immunotherapy. Patients receiving immunotherapy were compared to other cancer cohorts and age-matched healthy controls. Ascorbate levels in plasma and peripheral blood-derived mononuclear cells (PBMCs), monocyte subtype and epigenetic markers were measured, and adverse events, tumour response and survival were recorded. A quarter of the immunotherapy cohort had hypovitaminosis C, with plasma and PBMC ascorbate levels significantly lower than those from other cancer patients or healthy controls. PBMCs from the immunotherapy cohort contained similar frequencies of non-classical and classical monocytes. DNA methylation markers and intracellular ascorbate concentration were correlated with monocyte subset frequency in healthy controls, but correlation was lost in immunotherapy patients. No associations between ascorbate status and immune-related adverse events or tumour response or overall survival were apparent.

Digital life as a cabaret, old chum: A dramaturgical analysis of older digitalised home residents and their wider caring networks.

The use of smart and assistive devices for remote healthcare monitoring is becoming increasingly popular for older people in their homes. However, the lived and long-term experiences of such technology, for the older residents and their wider caring networks remains unclear. Using in-depth qualitative data collected between June 2019 and January 2020 from older people living in their own homes in rural Scotland, we highlight that although such monitoring could improve the experiences of older people and their wider caring networks, this may create additional care and surveillance. We employ the concept of dramaturgy, which understands society to be a stage on which actors perform, allowing us to explore how different residents and their networks make sense of their experiences with domestic healthcare monitoring. We found that some digitalised devices may reduce the degree to which older people and their wider caring networks can live authentic and truly independent lifestyles.

Toku Oranga: the subjective wellbeing and psychological functioning of postgraduate and medical students in Otautahi Christchurch.

AIMS: Postgraduate and medical students are at risk of psychological distress and burnout, which can cause significant functional and occupational impairment. We aimed to report subjective wellbeing, psychological distress and burnout in postgraduate and medical students in Otautahi Christchurch, Aotearoa (New Zealand), and identify any associations between participant and course information and outcome measures including exposure to major earthquakes in 2010/2011 and the 2019 terrorist attack. METHODS: A self-report online survey was completed by 140 students between November 2019 and March 2020. Life satisfaction, psychological distress and burnout were primary outcomes. Data were analysed using univariate and multivariable analysis. RESULTS: High levels of psychological distress were present in both student groups. Burnout was reported by 78% of respondents. There were no significant associations found between exposure to the Christchurch earthquakes or terrorist attack with primary outcomes. Personality factors, resilience and perceived support and success were weakly associated with wellbeing, distress and burnout. CONCLUSIONS: Postgraduates and medical students reported high levels of psychological distress and burnout. The earthquakes and terrorist attack do not appear to be associated with negative effects in these cohorts. Personality and resilience characteristics may assist in predicting students at risk of morbidity and evaluating potentially relevant interventions.

Adipose derived stem cell extracellular vesicles modulate primary human macrophages to an anti-inflammatory phenotype in vitro.

EVs released by adipose derived stem cells (ADSCs) have shown promise as a therapeutic for tissue repair because of their purported immune-regulatory properties. Extracellular vesicles (EVs) from ADSCs could be beneficial in improving graft retention rates for autologous fat grafting (AFG) post-mastectomy as, currently, grafted tissue rates are variable. Enriching grafted tissue with ADSC-EVs may improve retention rates by modulating macrophages resident within both the breast and lipoaspirate. We aimed to identify key macrophage phenotypes that are modulated by ADSC-EVs in vitro. ADSCs were isolated from lipoaspirates of women undergoing AFG and characterised by flow cytometry and differentiation potential. ADSC-EVs were isolated from culture media and characterised by tuneable resistive pulse sensing, transmission electron microscopy and Western blot. Primary monocyte-derived macrophages were polarized to an M1-like (GM-CSF, IFNγ), M2-like phenotype (M-CSF, IL-4) or maintained (M0-like; M-CSF) and ADSC-EVs were co-cultured with macrophages for 48 h. Flow cytometry and high-dimensional analysis clustered macrophages post co-culture. A manual gating strategy was generated to recapitulate these clusters and was applied to a repeat experimental run. Both runs were analysed to examine the prevalence of each cluster, representing a unique macrophage phenotype, with and without ADSC-EVs. Following the addition of ADSC-EVs, M0-like macrophages demonstrated a reciprocal shift of cell distribution from a cluster with a 'high inflammatory profile' (CD36+++CD206+++CD86+++; 16.5 ± 7.0%; p < 0.0001) to a cluster with a 'lower inflammatory profile' (CD36+CD206+CD86+; 35  ± 21.5%; p < 0.05). M1-like macrophages shifted from a cluster with a 'high inflammatory profile' (CD206++CD11b++CD36++CD163++; 26.1 ± 9.4%; p = 0.0024) to a 'lower inflammatory profile' (CD206+CD11b+CD36+CD163+; 72.8  ± 8.7%; p = 0.0007). There was no shift in M2-like clusters following ADSC-EV treatment. ADSC-EVs are complex regulators of macrophage phenotype that can shift macrophages away from a heightened pro-inflammatory state.

The Contribution of Environmental Science to Mental Health Research: A Scoping Review.

Mental health is influenced by multiple complex and interacting genetic, psychological, social, and environmental factors. As such, developing state-of-the-art mental health knowledge requires collaboration across academic disciplines, including environmental science. To assess the current contribution of environmental science to this field, a scoping review of the literature on environmental influences on mental health (including conditions of cognitive development and decline) was conducted. The review protocol was developed in consultation with experts working across mental health and environmental science. The scoping review included 202 English-language papers, published between 2010 and 2020 (prior to the COVID-19 pandemic), on environmental themes that had not already been the subject of recent systematic reviews; 26 reviews on climate change, flooding, air pollution, and urban green space were additionally considered. Studies largely focused on populations in the USA, China, or Europe and involved limited environmental science input. Environmental science research methods are primarily focused on quantitative approaches utilising secondary datasets or field data. Mental health measurement was dominated by the use of self-report psychometric scales. Measures of environmental states or exposures were often lacking in specificity (e.g., limited to the presence or absence of an environmental state). Based on the scoping review findings and our synthesis of the recent reviews, a research agenda for environmental science's future contribution to mental health scholarship is set out. This includes recommendations to expand the geographical scope and broaden the representation of different environmental science areas, improve measurement of environmental exposure, prioritise experimental and longitudinal research designs, and giving greater consideration to variation between and within communities and the mediating pathways by which environment influences mental health. There is also considerable opportunity to increase interdisciplinarity within the field via the integration of conceptual models, the inclusion of mixed methods and qualitative approaches, as well as further consideration of the socio-political context and the environmental states that can help support good mental health. The findings were used to propose a conceptual model to parse contributions and connections between environmental science and mental health to inform future studies.

Characterisation of enzyme prodrug gene therapy combinations in coated spheroids and vascular networks in vitro.

BACKGROUND: Enzyme prodrug gene therapy is designed as a targeted cancer treatment, destroying gene-modified and bystander cells via exogenous enzyme-generated cytotoxins. Targeting of tumour blood vessels using gene therapy is attractive, although optimal enzyme prodrug combinations have yet to be identified. METHODS: Seven enzyme prodrug combinations were ranked in two endothelial (HUVEC, HMEC-1) and one tumour cell line (T24) for their ability to reduce proliferation and viability. The ability to destroy bystander cells in two dimensions (2D) and three dimensions (3D), mode of cell kill, and the ability to disrupt vascular networks were measured. RESULTS: Endothelial cell proliferation (bromodeoxyuridine uptake) was reduced most effectively by Herpes simplex virus thymidine kinase (TK) with ganciclovir (GCV), followed by Escherichia coli nitroreductase NfsB (NTR) with CB1954; viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] was reduced most efficiently by NTR/CB1954 followed by TK/GCV. Of the seven combinations, only NTR/CB1954 displayed measurable bystander effects in 2D monolayers, and none demonstrated bystander killing in coated spheroids, a 3D spatially distinct model with tissue-like cell density. NTR-expressing endothelial cells displayed increased apoptosis, necrosis and caspase-3 activity after CB1954 treatment. Despite good antiproliferative activity, TK/GCV was ineffective at disrupting vascular network-like structures of endothelial cells, whereas NTR/CB1954 was efficient. NTR/metronidazole and the vascular disrupting agent, combretastatin A-4 phosphate, were the only other effective agents. CONCLUSIONS: Collectively, these data demonstrate that cytotoxic rather than cytostatic activity is necessary for efficient vascular disruption in vitro, and bystander killing is not essential. We identify NTR/CB1954 and NTR/metronidazole as candidates for in vivo investigation of vascular-targeted gene therapy.

Renal transplant recipients have elevated frequencies of circulating myeloid-derived suppressor cells.

BACKGROUND: Cancer, particularly cutaneous squamous cell carcinoma (SCC), is a major cause of mortality in renal transplant recipients (RTRs). Myeloid-derived suppressor cells (MDSC) play a central role in suppressing cancer immunosurveillance but their potential mobilisation in RTRs and levels relative to those of other immunoregulatory dendritic cell (DC) populations have not been analysed. METHODS: The circulating frequencies of MDSC and DC were analysed by multicolour flow cytometry in immunocompetent patients without (n = 13) or with (ICI-SCC(Pos), n = 14) current SCC, normal donors (NDs, n = 34), chronic kidney disease patients (CKD patients, n = 22) and RTRs (n = 31). RESULTS: Compared to NDs, RTRs had significantly elevated levels of both CD14(Neg) and CD14(Pos) MDSC subsets (P < 0.001), while CKD patients and ICI-SCC(Pos) had significantly elevated levels of only the CD14(Neg)-MDSC subset. DC frequencies were significantly decreased in RTRs and CKD patients but were at normal levels in ICI-SCC(Pos). The MDSC/DC ratio was significantly elevated (P < 0.05) in RTRs (median = 5.7), CKD patients (median = 3.2) and ICI-SCC(Pos) (median = 3.5) relative to NDs (median = 0.7). The use of immunosuppressive drugs in CKD patients and past/current occurrence of SCC in RTRs was associated with significantly increased CD14(Neg)-MDSC frequencies. MDSC enriched from RTRs, when co-cultured with activated NDs T cells significantly suppressed extracellular IL-10 levels and can, when activated with formyl-methionyl-leucyl-phenylalanine, inhibit T-cell proliferation. CONCLUSIONS: RTRs, CKD patients and ICI-SCC(Pos) have increased MDSC frequencies and MDSC/DC ratios. These changes may impact on cancer immunosurveillance. Therefore, MDSC represent both a potential therapeutic target and prognostic marker in these patients, with respect to the development of SCC and other malignancies.

Exercise in People With Cancer: A Spotlight on Energy Regulation and Cachexia.

Exercise is increasingly becoming a standard of cancer care, with well-documented benefits for patients including improved mental wellbeing and reduced treatment-related side effects. However, important gaps in knowledge remain about how to optimise exercise prescription for people with cancer. Importantly, it remains unclear how exercise affects the progression of cancer cachexia (a wasting disease stemming from energy imbalance, and a common manifestation of advanced malignant disease), particularly once the condition has already developed. It was recently suggested that the anti-tumour effect of exercise might come from improved energetic capacity. Here, we highlight the possible effect of exercise on energetic capacity and energy regulation in the context of cancer, and how this might affect the progression of cancer cachexia. We suggest that due to the additional energy demand caused by the tumour and associated systemic inflammation, overreaching may occur more easily in people with cancer. Importantly, this could result in impaired anti-tumour immunity and/or the exacerbation of cancer cachexia. This highlights the importance of individualised exercise programs for people with cancer, with special consideration for the regulation of energy balance, ongoing monitoring and possible nutritional supplementation to support the increased energy demand caused by exercise.

Social Isolation in Older Adults: A Qualitative Study on the Social Dimensions of Group Outdoor Health Walks.

Physical distancing practices during the COVID-19 global pandemic contributed to a high degree of social isolation among older adults. To reduce loneliness and other ill effects of social isolation, public health experts recommended outdoor social gathering, with physical distancing. Adopting a case study approach, we explored how social aspects of group outdoor health walks (GOHWs) mitigate social isolation for older adults and improve individual social wellbeing. We used semi-structured interviews to understand the experiences of social isolation and social relationships in nine older (50-80 s) adults participating in a GOHW in Scotland, United Kingdom (UK). Verbatim transcripts were analysed through an iterative process of thematic analysis carried out by an interdisciplinary team of qualitative researchers from environmental psychology, medicine, and geography. Themes provide insight into the social dimensions of GOHWs, the mediating effects of social experiences, and the contribution these make to individual social wellbeing. GOHWs provide opportunities to be part of a group and attend to the needs of inexperienced or physically challenged individuals. Being part of the group walk fosters casual interpersonal interactions through spontaneous mixing during and after the walk. This programmatic structure counters loneliness, engenders pleasurable anticipation of regular contact with others, supports physical activity, and fosters group cohesion. These in turn contribute to individual social wellbeing, including expanding social networks, meaningful relationships, a sense of belonging, and acting on empathy for others. GOWHs may be beneficial for mitigation of social isolation as we emerge from the COVID-19 pandemic. Findings were used to propose a conceptual model to parse social constructs and inform selection or development of quantitative social measures for future studies of nature-based interventions such as GOHWs.

Importance of the endometrial immune environment in endometrial cancer and associated therapies.

Endometrial cancer is rising in prevalence. The standard treatment modality of hysterectomy is becoming increasingly inadequate due primarily to the direct link between endometrial cancer and high BMI which increases surgical risks. This is an immunogenic cancer, with unique molecular subtypes associated with differential immune infiltration. Despite the immunogenicity of endometrial cancer, there is limited pre-clinical and clinical evidence of the function of immune cells in both the normal and cancerous endometrium. Immune checkpoint inhibitors for endometrial cancer are the most well studied type of immune therapy but these are not currently used as standard-of-care and importantly, they represent only one method of immune manipulation. There is limited evidence regarding the use of other immunotherapies as surgical adjuvants or alternatives. Levonorgestrel-loaded intra-uterine systems can also be effective for early-stage disease, but with varying success. There is currently no known reason as to what predisposes some patients to respond while others do not. As hormones can directly influence immune cell function, it is worth investigating the immune compartment in this context. This review assesses the immunological components of the endometrium and describes how the immune microenvironment changes with hormones, obesity, and in progression to malignancy. It also describes the importance of investigating novel pathways for immunotherapy.

Responding to Cardiac Arrest in the Community in the Digital Age.

Sudden cardiac arrest (SCA) is a common event, affecting almost 400,000 individuals annually in North America. Initiation of cardiopulmonary resuscitation (CPR) and early defibrillation using an automated external defibrillator (AED) are critical for survival, yet many bystanders are reluctant to intervene. Digital technologies, including mobile devices, social media, and crowdsourcing might help play a role to improve survival from SCA. In this article we review the current digital tools and strategies available to increase rates of bystander recognition of SCA, prompt immediate activation of emergency medical services (EMS), initiate high-quality CPR, and to locate, retrieve, and operate AEDs. Smartphones can help to educate and connect bystanders with EMS dispatchers, through text messaging or video calling, to encourage the initiation of CPR and retrieval of the closest AED. Wearable devices and household smart speakers could play a future role in continuous vital signs monitoring in individuals at risk of lethal arrhythmias and send an alert to either chosen contacts or EMS. Machine learning algorithms and mathematical modelling might aid EMS dispatchers with better recognition of SCA as well as policymakers with where to best place AEDs for optimal accessibility. There are challenges with the use of digital tech, including the need for government regulation and issues with data ownership, accessibility, and interoperability. Future research will include smart cities, e-linkages, new technologies, and using social media for mass education. Together or in combination, these emerging digital technologies might represent the next leap forward in SCA survival.

Urban-Rural Differences in Cardiac Arrest Outcomes: A Retrospective Population-Based Cohort Study.

Background: Approximately 10% of people who suffer an out-of-hospital cardiac arrest (OHCA) treated by paramedics survive to hospital discharge. Survival differs by up to 19.2% between urban centres and rural areas. Our goal was to investigate the differences in OHCA survival between urban centres and rural areas. Methods: This was a retrospective cohort study of OHCA patients treated by Nova Scotia Emergency Medical Services (EMS) in 2017. Cases of traumatic, expected, and noncardiac OHCA were excluded. Data were collected from the Emergency Health Service electronic patient care record system and the discharge abstract database. Geographic information system analysis classified cases as being in urban centres (population > 1000 people) or rural areas, using 2016 Canadian Census boundaries. The primary outcome was survival to hospital discharge. Multivariable logistic regression covariates were age, sex, bystander resuscitation, whether the arrest was witnessed, public location, and preceding symptoms. Results: A total of 510 OHCAs treated by Nova Scotia Emergency Medical Services were included for analysis. A total of 12% (n = 62) survived to discharge. Patients with OHCAs in urban centres were 107% more likely to survive than those with OHCAs in rural areas (adjusted odds ratio = 2.1; 95% confidence interval = 1.1 to 3.8; P = 0.028). OHCAs in urban centres had a significantly shorter mean time to defibrillation of shockable rhythm (11.2 minutes ± 6.2) vs those in rural areas (17.5 minutes ± 17.3). Conclusions: Nova Scotia has an urban vs rural disparity in OHCA care that is also seen in densely populated OHCA centres. Survival is improved in urban centres. Further improvements in overall survival, especially in rural areas, may arise from community engagement in OHCA recognition and optimized healthcare delivery.

Contexte: Environ 10 % des personnes qui subissent un arrêt cardiaque en milieu extrahospitalier (ACEH), traité par des intervenants paramédicaux, survivent jusqu'à leur congé de l'hôpital. Le taux de survie peut différer de 19,2 % entre les centres urbains et les régions rurales. Notre étude visait à étudier les différences en matière de survie après un ACEH entre les centres urbains et les régions rurales. Méthodologie: Il s'agissait d'une étude de cohorte rétrospective portant sur des patients ayant subi un ACEH traité par les services médicaux d'urgence de la Nouvelle-Écosse en 2017. Les cas d'ACEH traumatique, prévu et non cardiaque ont été exclus. Les données ont été recueillies à partir du système de dossiers électroniques de soins aux patients des services médicaux d'urgence et de la Base de données sur les congés des patients. L'analyse du système d'information géographique a classé les cas selon qu'ils sont survenus dans un centre urbain (population de plus de 1 000 personnes) ou dans une région rurale, en utilisant les limites du recensement canadien de 2016. Le principal paramètre d'évaluation était la survie à la sortie de l'hôpital. Les covariables utilisées dans la régression logistique multivariée étaient l'âge, le sexe, la réanimation effectuée par des témoins si présents lors de l'arrêt cardiaque, l'emplacement public et les symptômes précédents. Résultats: Au total, 510 ACEH traités par les services médicaux d'urgence de la Nouvelle-Écosse ont été inclus aux fins de l'analyse. En tout, 12 % (n = 62) des sujets ont survécu jusqu'à leur congé hospitalier. Les patients ayant subi un ACEH dans un centre urbain étaient 107 % plus susceptibles de survivre que ceux ayant subi un ACEH dans une région rurale (rapport de cotes ajusté : 2,1; intervalle de confiance à 95 % : 1,1 ­ 3,8; p = 0,028). Le temps moyen de délivrance d'un choc lors d'un ACEH avec rythme défibrillable est significativement plus court (11,2 ± 6,2 minutes) dans un centre urbain que dans une région rurale (17,5 ± 17,3 minutes). Conclusions: La Nouvelle-Écosse fait état d'une disparité dans les soins de l'ACEH entre les régions urbaines et les régions rurales, que l'on observe également dans les villes densément peuplées. La survie est plus longue dans les centres urbains. Il est possible de prolonger davantage la survie globale, en particulier dans les régions rurales, en sensibilisant la communauté à l'ACEH et en optimisant la prestation des soins de santé.