Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity.

Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor immunity. Numerous STING pathway agonists are now being tested in clinical trials, but the effectiveness of this approach is not yet clear and a better understanding of the relative importance of this pathway in various tumor settings is needed. We have evaluated syngeneic tumor models with different baseline inflammatory states to determine the contributions of STING activity in both tumor and non-tumor cellular compartments to anti-tumor immune responses. We find that productive anti-tumor immune responses in the poorly immunogenic B16F10 model show a strong dependence on STING expression in non-tumor cells. In the immunogenic MC38 model, constitutive STING activation in tumor cells can partially bypass the requirement for STING-dependent activity from immune cells. Our findings reveal multiple, context-dependent roles for STING activity in the regulation of anti-tumor immunity and the response to immunotherapy. In preclinical models where STING is basally active, checkpoint inhibition is more likely to have a therapeutic effect and removal of STING signaling from either the tumor or the non-tumor compartment has a minimal effect. Removal of STING signaling in both, however, diminishes the efficacy derived from checkpoint therapy. Further work is needed to understand the heterogeneity of STING signaling in patients, both in tumor cells and the tumor microenvironment, and the best means of harnessing this pathway to generate anti-tumor immunity and improve therapeutic outcomes.

The lockdown experience scale for students (LESS).

BACKGROUND: The Covid-19 pandemic has resulted in many student populations learning online in lockdown. While the mental health consequences of lockdown are increasingly understood, the core features of 'cabin fever' - the experience of lockdown - are poorly described. METHODS: We conducted a questionnaire survey of 649 undergraduate medicine and health sciences students. Item content was developed based on current literature and input from student representatives. RESULTS: Mokken scaling identified seven questions that together formed a strongly unidimensional scale which comprised two domains: social isolation/cabin fever and demotivation / demoralisation. Scale scores were significantly associated with depression, self-rated mental health, impaired study efficacy and doomscrolling. CONCLUSIONS: The adverse effects of lockdown on student wellbeing appear to be driven to an important extent by an experience of isolation and demotivation that corresponds to narrative descriptions of cabin fever. In the foreseeable event of future pandemics, these experiences are a promising target for health promotion in students studying in lockdown.

Measuring Emergency Department Staff Perceptions of Causes and Management of Violence.

BACKGROUND: Half of all reported violent incidents in health care settings occur in the emergency department (ED) placing all staff members at risk. However, research typically does not include all ED work groups or validated measures beyond nurses and physicians. OBJECTIVE: The aims of this study were to (a) validate an established instrument measuring perceptions of causes of violence and attitudes toward managing violence within an inclusive workforce sample; and (b) explore variation in perceptions, attitudes, and incidence of violence and safety to inform a violence prevention program. METHODS: This is an investigator-initiated single-site cross-sectional survey design assessing the psychometric properties of the Management of Aggression and Violence Attitude Scale (MAVAS) within a convenience sample (n = 134). Construct validity was assessed using exploratory factor analysis and reliability was evaluated by the Cronbach's α estimation. Descriptive, correlational, and inferential estimates explored differences in perceptions, attitudes, and incidence of violence and safety. RESULTS: Exploratory factor analysis indicated validity of the MAVAS with a seven-factor model. Its internal consistency was satisfactory overall (Cronbach's α= 0.87) and across all subscales (Cronbach's α values = 0.52-0.80). Significant variation in incidence of physical assault, perceptions of safety, and causes of violence was found between work groups. CONCLUSIONS: The MAVAS is a valid and reliable tool to measure ED staff members' perceptions of causes of violence and attitudes toward managing violence. In addition, it can inform training according to differences in work group learner needs.

Improving access and provision of preventive oral health care for very young, poor, and low-income children through a new interdisciplinary partnership.

OBJECTIVES: We provided oral health care services at 2 sites using a nurse practitioner-dietitian team to increase dental workforce capacity and improve access to care for low-income preschool children. METHODS: Our team provided oral health assessments and education, fluoride varnish application, and dentist referrals. The primary endpoint was participants' access to oral health care. Secondary endpoints included increasing the practice scope of registered dietitians through training programs for oral health assessment and the application of fluoride varnishes for children. The oral health and hygiene and dietary habits of the participants were also determined. RESULTS: From 2010 to 2013, 4360 children received fluoride varnishes in 7195 total visits. Although the proportion of children with dental caries at the first visit was greater at the urban site, both sites were similar by visits 2 and 3. The number of caries declined with increased program visits, which coincided with an increase in the proportion of participants visiting a dentist. CONCLUSIONS: Progress toward eliminating dental health disparities requires addressing barriers to dental care access. We showed that expanding access to oral health services through nurse practitioner-dietitian cooperation improved access to preventive fluoride varnishing use in low-income children.

Resource Deployment in Response to Trauma Patients.

Background Variance in the deployment of the trauma team to the emergency department (ED) can result in patient treatment delays and excess burden on ED personnel. Characteristics of trauma patients, including mechanism of injury, injury type, and age, have been associated with differences in trauma resource deployment. Therefore, this retrospective, single-site study aimed to examine the deployment patterns of trauma resources, the characteristics of the trauma patients associated with levels of trauma resource deployment, and the deployment impact on ED workforce utilization and non-trauma ED patients. Methodology This was an investigator-initiated, single-institution, retrospective cohort study of all patients designated as a trauma response and admitted to a community hospital's ED from July 01, 2019, through July 01, 2022. Results Resource deployment for trauma patients varied by mechanism of injury (p < 0.001), injury type (p < 0.001), and patient age groups (p < 0.001). Specifically, there was a lower average trauma activation for geriatric trauma patients with a fall as a mechanism of injury compared to all younger patient groups with any mechanism of injury (F(5) = 234.49, p < 0.001). In the subsample, there was an average of 3.35 ED registered nurses (RNs) allocated to each trauma patient. Additionally, the ED RNs were temporarily reallocated from an average of 4.09 non-trauma patients to respond to trauma patients, despite over a third of the trauma patients in the subsample being the trauma patients being discharged home from the ED. Conclusions Trauma activation responses need to be standardized with a specific plan for geriatric fall patients to ensure efficient use of trauma and ED personnel resources.

Autonomous IL-36R signaling in neutrophils activates potent antitumor effector functions.

While the rapid advancement of immunotherapies has revolutionized cancer treatment, only a small fraction of patients derive clinical benefit. Eradication of large, established tumors appears to depend on engaging and activating both innate and adaptive immune system components to mount a rigorous and comprehensive immune response. Identifying such agents is a high unmet medical need, because they are sparse in the therapeutic landscape of cancer treatment. Here, we report that IL-36 cytokine can engage both innate and adaptive immunity to remodel an immune-suppressive tumor microenvironment (TME) and mediate potent antitumor immune responses via signaling in host hematopoietic cells. Mechanistically, IL-36 signaling modulates neutrophils in a cell-intrinsic manner to greatly enhance not only their ability to directly kill tumor cells but also promote T and NK cell responses. Thus, while poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the pleiotropic effects of IL-36 and its therapeutic potential to modify tumor-infiltrating neutrophils into potent effector cells and engage both the innate and adaptive immune system to achieve durable antitumor responses in solid tumors.

Variation of prescription drug prices in community pharmacies: A national cross-sectional study.

Background; There is evidence of significant variation of prescription drug prices in community pharmacies in several countries. Prescription drugs are a major source of expenditure for patients. High prices can lead to cost-related non-adherence and adverse health outcomes. Objective; This study's aim was to establish the variation and availability of prescription drug prices in community pharmacies in Ireland. Methods; Using a cross-sectional design, prices were sought in community pharmacies using phone, email and website enquiries. A purposive sample of 12 prescription drugs was included. The prescription drugs were selected from the top 100 medications by dispensing frequency in 2017 on Ireland's main state drug scheme. For each pharmacy, the price was checked for three drugs only. Researchers sought to contact 1,500 pharmacies by phone and 320 by email, as well as consult the website of 370 pharmacies. Results; In total, 1,529 pharmacies responded to queries, 1,362 by telephone and 167 by email. Overall, 88.5% (N = 1,353) of pharmacies who answered queries, provided prices. For each drug, the average price quoted to researchers was higher than the price paid by the state for patients who can access subsidised medicines. The ratio of 90th to 10th percentile prices ranged from 1.3 to 2.0 for the twelve drugs. A Welch's t-test found that for nine of the 12 drugs, the price was significantly higher (p < .05) for chain pharmacies compared to independent pharmacies. Conclusions; Evidence was found of significant price variation in community pharmacies. There was also evidence that some community pharmacies were not following regulatory guidance on drug pricing transparency. Policy measures such as mandated price transparency, or fixed prescription drug prices could help address these price issues.

Non-specific symptoms-based pathways for diagnosing less common cancers in primary care: a service evaluation.

BACKGROUND: Although less common cancers account for almost half of all cancer diagnoses in England, their relative scarcity and complex presentation, often with non-specific symptoms, means that patients often experience multiple primary care consultations, long times to diagnosis, and poor clinical outcomes. An urgent referral pathway for non-specific symptoms, the Multidisciplinary Diagnostic Centre (MDC), may address this problem. AIM: To examine the less common cancers identified during the MDC pilots and consider whether such an approach improves the diagnosis of these cancers. DESIGN AND SETTING: A service evaluation of five MDC pilot projects in England from December 2016 to March 2019. METHOD: Data items were collected by pilot sites in near-real time, based mainly on the English cancer outcomes and services dataset, with additional project-specific items. Simple descriptive and comparative statistics were used, including χ2 tests for proportions and t-tests for means where appropriate. RESULTS: From 5134 referrals, 378 cancers were diagnosed, of which 218 (58%) were less common. More than 30 different less common tumour types were diagnosed in this cohort. Of the MDC patients with less common cancers, 23% (n = 50) had ≥3 GP consultations before referral and, at programme level, a median time of 57 days was recorded from GP urgent referral to treatment for these tumour types. CONCLUSION: A non-specific symptomatic referral route diagnoses a broad range of less common cancers, and can support primary care case management for patients with symptoms of possible cancer that do not qualify for a site-specific urgent referral.

A patient-specific numerical model of the ankle joint for the analysis of contact pressure distribution.

A patient-specific numerical model of the ankle joint has been developed using open-source software with realistic material properties that mimics the physiological movement of the foot during the stance phase of the gait cycle. The patient-specific ankle geometry has been segmented as a castellated surface using 3DSlicer from the computed tomography image scans of a subject with no congenital or acquired pathology; subsequently, the bones are smoothed, and cartilage is included as a uniform thickness extruded layer. A high-resolution Cartesian mesh has been generated using cfMesh. The material properties are assigned in the model based on the CT image Hounsfield intensities and compared to a sandwich-based material model. Gait data of the same subject was obtained and used to relatively position the tibia, talus, and calcaneus bones in the model. The stance phase of the gait cycle is simulated using a cell-centred finite-volume method implemented in open-source software OpenFOAM. The predicted peak contact pressures occur in the range of 4.85-5.53 MPa with average pressures in the range of 1.56-1.95 MPa, and the contact area ranges between 429 and 707.8 mm2 for the entire stance phase with the mid-stance phase predicting the maximum contact area. These predictions are in agreement with results from the literature. The effect of arthritis on the contact characteristics of the ankle joint has also been examined. A concentrated increase in pressure was predicted that could be manifested as pain, thereby leading to reduced motion in the ankle. The model, with continued development, has the capability to understand the effect of joint degradation and furthermore, could help provide a tool to predict the efficiency of therapeutic surgical procedures as well as guide the development of next generation ankle prostheses. The work would be made available in the University College Dublin depository (https://github.com/laxmimurali/anklejoint) as well as research gate once the article has been published.

Cross-sectional study using primary care and cancer registration data to investigate patients with cancer presenting with non-specific symptoms.

INTRODUCTION: Patients presenting to primary care with site-specific alarm symptoms can be referred onto urgent suspected cancer pathways, whereas those with non-specific symptoms currently have no dedicated referral routes leading to delays in cancer diagnosis and poorer outcomes. Pilot Multidisciplinary Diagnostic Centres (MDCs) provide a referral route for such patients in England. OBJECTIVES: This work aimed to use linked primary care and cancer registration data to describe diagnostic pathways for patients similar to those being referred into MDCs and compare them to patients presenting with more specific symptoms. METHODS: This cross-sectional study linked primary care data from the National Cancer Diagnosis Audit (NCDA) to national cancer registration and Route to Diagnosis records. Patient symptoms recorded in the NCDA were used to allocate patients to one of two groups - those presenting with symptoms mirroring referral criteria of MDCs (non-specific but concerning symptoms (NSCS)) and those with at least one site-specific alarm symptom (non-NSCS). Descriptive analyses compared the two groups and regression analysis by group investigated associations with long primary care intervals (PCIs). RESULTS: Patients with NSCS were more likely to be diagnosed at later stage (32% stage 4, compared with 21% in non-NSCS) and via an emergency presentation (34% vs 16%). These patients also had more multiple pre-referral general practitioner consultations (59% vs 43%) and primary care-led diagnostics (blood tests: 57% vs 35%). Patients with NSCS had higher odds of having longer PCIs (adjusted OR: 1.24 (1.11 to 1.36)). Patients with lung and urological cancers also had higher odds of longer PCIs overall and in both groups. CONCLUSIONS: Differences in the diagnostic pathway show that patients with symptoms mirroring the MDC referral criteria could benefit from a new referral pathway.

Creating the conditions for change: an NHS perspective.

PURPOSE: Improving early diagnosis of cancer through system change initiatives is endemic in England's NHS cancer services. These initiatives, however, often fail to gain traction due to the complexities of health system structures. The purpose of this paper is to explore whether using a change framework grounded in systems thinking could be of help to system leaders. DESIGN/METHODOLOGY/APPROACH: A portfolio of geographically independent projects, all implementing cancer service changes as part of the Accelerate, Coordinate, Evaluate Programme, was used for the study. Eight projects were purposively selected to give a varied case-mix. Two semi-structured interviews were conducted with each project. Analysis of interviews was carried out using the Framework Method. FINDINGS: Processes working for (growth processes) and against (limiting processes) change were evident in and common across all eight projects. Projects commonly encountered challenges of relevance, time and bounded thinking. Having a network of committed people was vital for both initiating and sustaining change. Furthermore, understanding stakeholders' emotional responses to change helped mitigate emergent challenges. PRACTICAL IMPLICATIONS: Leaders should pay constant attention to the dynamics of change, taking time to anticipate and diffuse challenges whilst simultaneously working to create the conditions that help change flourish. A change framework rooted in complex systems theory can help leaders understand the contradictory and non-linear processes inherent in transformational change. ORIGINALITY/VALUE: Few studies seek to understand change dynamics by comparing the experiences of separate change initiatives implemented contemporaneously. The findings offer leaders practical insights on how to implement transformation.

Evaluation of a health service adopting proactive approach to reduce high risk of lung cancer: The Liverpool Healthy Lung Programme.

OBJECTIVES: This Liverpool Healthy Lung Programme is a response to high rates of lung cancer and respiratory diseases locally and aims to diagnose lung cancer at an earlier stage by proactive approach to those at high risk of lung cancer. The objective of this study is to evaluate the programme in terms of its likely effect on mortality from lung cancer and its delivery to deprived populations. METHODS: Persons aged 58-75 years, with a history of smoking or a diagnosis of chronic obstructive pulmonary disease (COPD)2 according to general practice records were invited for lung health check in a community health hub setting. A detailed risk assessment and spirometry were performed in eligible patients. Those with a 5% or greater five-year risk of lung cancer were referred for a low dose CT3 scan. RESULTS: A total of 4 566 subjects attended the appointment for risk assessment and 3 591 (79%) consented to data sharing. More than 80% of the patients were in the most deprived quintile of the index of multiple deprivation. Of those attending, 63% underwent spirometry and 43% were recommended for a CT scan. A total of 25 cancers were diagnosed, of which 16 (64%) were stage I. Comparison with the national stage distribution implied that the programme was reducing lung cancer mortality by 22%. CONCLUSIONS: Community based proactive approaches to early diagnosis of lung cancer in health deprived regions are likely to be effective in early detection of lung cancer.

Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade.

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy.Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190-202. ©2017 AACR.

Venous thromboembolism: An overview.

Venous thromboembolism (VTE) is a disease that includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). It is a common, lethal disorder that affects both hospitalized and nonhospitalized patients. PE and DVT are 2 clinical presentations of VTE and share the same predisposing factors. In most cases, PE is a consequence of DVT. This article discusses the predisposing factors, prevalence, and individuals who are at risk of developing this often life-threatening disease.