Regulation and modulation of antitumor immunity in pancreatic cancer.

Pancreatic ductal adenocarcinoma carries a dismal prognosis, and outcomes have improved little with modern therapeutics. Checkpoint-based immunotherapy has failed to elicit responses in the vast majority of patients with pancreatic cancer. Alongside tumor cell-intrinsic mechanisms associated with oncogenic KRAS-induced inflammation, the tolerogenic myeloid cell infiltrate has emerged as a critical impediment to adaptive antitumor immune responses. Furthermore, the discovery of an intratumoral microbiome and the elucidation of host-microbe interactions that curtail antitumor immunity also present opportunities for intervention. Here we review the mechanisms of immunotherapy resistance in pancreatic ductal adenocarcinoma and discuss strategies to directly augment T cell responses in parallel with myeloid cell- and microbiome-targeted approaches that may enable immune-mediated control of this malignancy.

PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.

γδ T Cells Support Pancreatic Oncogenesis by Restraining αß T Cell Activation.

Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αßT cells. Although αßT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL.

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA)1. However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species-but not species in the genera Candida, Saccharomyces or Aspergillus-accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment-or knockdown of C3aR in tumour cells-were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl- (also known as Mbl2) or C3-deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.

The Current Status and Challenges of Prehospital Trauma Care in Low- and Middle-Income Countries: A Systematic Review.

BACKGROUND: This review aims to understand the present circumstances on the provision of prehospital trauma care in low- and middle-income countries (LMICs), particularly scoping the challenges experienced by LMICs in this regard. The objective is to systematically evaluate the currently available evidence on this topic. Based on the themes and challenges identified in the provision of prehospital trauma care in LMICs, we provide a series of recommendations and a knowledge base for future research in the field. METHODS: A systematic database search was conducted of original articles that explored and reported on prehospital trauma care in LMIC in EMBASE, MEDLINE, Cochrane database, and Google Scholar, from inception to March 2022. All original articles reporting on prehospital trauma care from 2010 to 2022 in LMICs were assessed, excluding case reports, small case series, editorials, abstracts, and pre-clinical studies; those with data inconsistencies that impede data extraction; and those with study populations fewer than ten. RESULTS: The literature search identified 2,128 articles, of which 29 were included in this review, featuring 27,848 participants from LMICs countries. Four main areas of focus within the studies were identified: (1) exploring emergency service systems, frameworks, and interconnected networks within the context of prehospital trauma care; (2) transportation of patients from the response site to hospital care; (3) medical education and the effects of first responder training in LMICs; and (4) cultural and social factors influencing prehospital trauma care-seeking behaviors. Due to overarching gaps in social and health care systems, significant barriers exist at various stages of providing prehospital trauma care in LMICs, particularly in injury identification, seeking treatment, transportation to hospital, and receiving timely treatment and post-intervention support. CONCLUSION: The provision of prehospital trauma care in LMICs faces significant barriers at multiple levels, largely dependent on wider social, geographic, economic, and political factors impeding the development of such higher functioning systems within health care. However, there have been numerous breakthroughs within certain LMICs in different aspects of prehospital trauma care, supported to varying degrees by international initiatives, that serve as case studies for widespread implementation and targets. Such experiential learning is essential due to the heterogenous landscapes that comprise LMICs.

Delivering medical leadership training through the Healthcare Leadership Academy: a four year analysis.

BACKGROUND: Formal leadership training is typically targeted at senior health professionals. The Healthcare Leadership Academy (HLA) was formed in 2016 to provide a leadership programme for students and early-career health professionals. This study analyses the effectiveness of the HLA scholarship programme as an intervention for improving interest in and preparing scholars for future leadership roles. METHODS: Survey data was used to assess the effectiveness of the HLA Scholarship program in cultivating leadership development. Questions required either multiple-choice, free text, ranking or Likert scale ('strongly agree', 'agree', 'neither agree nor disagree', 'disagree', 'strongly disagree) responses. Participants spanned six regions (London, Newcastle, Bristol, Belfast, Edinburgh, and Amsterdam) in four countries (England, Scotland, Northern Ireland, and the Netherlands). Descriptive statistical analyses were conducted, and insights were drawn from the open-ended survey questions using a leadership framework. RESULTS: Seventy participants who underwent the course between 2016 and 2020 completed the questionnaire. Nearly all (99%) found that the training provided on the programme had equipped them to be more effective leaders, with 86% of respondents stating that they were more likely to take on leadership roles. Nearly all (97.1%) found the course to be either of good or very good quality. Nineteen insights were identified from free text responses that fitted under one of the four themes of the leadership framework: "optimising", "resolving uncertainty", "enhancing adaptability", and "promulgating a vision". CONCLUSIONS: Healthcare leadership is a non-negotiable component of healthcare delivery in the 21st Century. As healthcare professionals, it is our duty to be effective leaders confident and competent in navigating the increasingly complex systems within which we operate for the benefit of ourselves, colleagues, and patients. By accounting for known shortcomings and developing ameliorative measures, the HLA Scholarship programme addresses unmet needs in a structured manner to support effective long-term healthcare leadership development.

Getting off tract: contributions of intraorgan microbiota to cancer in extraintestinal organs.

The gastrointestinal ecosystem has received the most attention when examining the contributions of the human microbiome to health and disease. This concentration of effort is logical due to the overwhelming abundance of microbes in the gut coupled with the relative ease of sampling compared with other organs. However, the intestines are intimately connected to multiple extraintestinal organs, providing an opportunity for homeostatic microbial colonisation and pathogenesis in organs traditionally thought to be sterile or only transiently harbouring microbiota. These habitats are challenging to sample, and their low microbial biomass among large amounts of host tissue can make study challenging. Nevertheless, recent findings have shown that many extraintestinal organs that are intimately linked to the gut harbour stable microbiomes, which are colonised from the gut in selective manners and have highlighted not just the influence of the bacteriome but that of the mycobiome and virome on oncogenesis and health.

Progressive shingles in a toddler due to reactivation of Varicella Zoster vaccine virus four days after infection with SARS-CoV-2; a case report.

BACKGROUND: Herpes zoster (HZ) is the clinical syndrome associated with reactivation of latent varicella-zoster virus (VZV). Several factors have been implicated to promote VZV reactivation; these include immunosuppression, older age, mechanical trauma, physiologic stress, lymphopenia, and more recently, infection with severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2). Recent reports suggest an increase in the number of HZ cases in the general population during the global COVID-19 pandemic. However, it is unknown what proportion of HZ during the pandemic is due to reactivation of wild-type or vaccine-strain VZV. CASE: Here we report the first known case of HZ concomitant with SARS-CoV2 infection in a 20-month-old female who was treated with a single dose of dexamethasone, due to reactivation of the vaccine-type strain of VZV after presenting with a worsening vesicular rash. CONCLUSION: In this case, we were able to show vaccine-strain VZV reactivation in the context of a mild acute symptomatic COVID-19 infection in a toddler. Being able to recognize HZ quickly and effectively in a pediatric patient can help stave off the significant morbidity and mortality associated with disease process.

Visualisation Approaches in Technology-Enhanced Medical Simulation Learning: Current Evidence and Future Directions.

Technology-enhanced learning (TEL) has been proposed as an approach to minimise the healthcare workforce shortage preventing universal healthcare coverage. Simulation-based medical education is a well-established teaching method. Little is known about effective strategies to translate in-person medical simulation teaching into a virtual world. This work aimed to review the literature on approaches to visualisation in technology-enhanced medical simulation. A systematic search strategy was optimised using three databases: Embase, MEDLINE, and APA PsycInfo. Additional papers were identified through cross-referencing. The last date of this search was 3 January 2022. The articles were analysed qualitatively. The risk of bias was assessed using ROBINS-I and RoB 2 tools. The search yielded 656 results with 9 additional papers identified through cross-referencing. Following deduplication and exclusions, 23 articles were included in a qualitative synthesis of evidence. Offline and online computer-based modules with virtual patient cases or practical skills simulations were identified as the most prevalent clinical simulation teaching modalities. Visualisation approaches included text, images, animations, videos, and 3D environments. Significant heterogeneity of study designs with a moderate risk of bias was established. Based on the current data, the virtual patient scenarios should use natural language input interfaces enriched with video and voice recordings, 3D animations, and short text descriptions to make the patient management experience more lifelike and increase knowledge retention. However, there is no agreed framework for assessing the pedagogical value of these innovations. High-quality randomised controlled trials of TEL-based clinical simulation are essential to advance the field.

Leading Transformation in Medical Education Through Extended Reality.

Extended reality (XR) has exponentially developed over the past decades to incorporate technology whereby users can visualise, explore, and interact with 3-dimensional-generated computer environments, and superimpose virtual reality (VR) onto real-world environments, thus displaying information and data on various levels of the reality-virtuality continuum. In the context of medicine, VR tools allow for anatomical assessment and diagnosis, surgical training through lifelike procedural simulations, planning of surgeries and biopsies, intraprocedural guidance, and medical education. The following chapter aims to provide an overview of the currently available evidence and perspectives on the application of XR within medical education. It will focus on undergraduate and postgraduate teaching, medical education within Low-Middle Income Countries, key practical steps in implementing a successful XR programme, and the limitations and future of extended reality within medical education.

Present and future of machine learning in breast surgery: systematic review.

BACKGROUND: Machine learning is a set of models and methods that can automatically detect patterns in vast amounts of data, extract information, and use it to perform decision-making under uncertain conditions. The potential of machine learning is significant, and breast surgeons must strive to be informed with up-to-date knowledge and its applications. METHODS: A systematic database search of Embase, MEDLINE, the Cochrane database, and Google Scholar, from inception to December 2021, was conducted of original articles that explored the use of machine learning and/or artificial intelligence in breast surgery in EMBASE, MEDLINE, Cochrane database and Google Scholar. RESULTS: The search yielded 477 articles, of which 14 studies were included in this review, featuring 73 847 patients. Four main areas of machine learning application were identified: predictive modelling of surgical outcomes; breast imaging-based context; screening and triaging of patients with breast cancer; and as network utility for detection. There is evident value of machine learning in preoperative planning and in providing information for surgery both in a cancer and an aesthetic context. Machine learning outperformed traditional statistical modelling in all studies for predicting mortality, morbidity, and quality of life outcomes. Machine learning patterns and associations could support planning, anatomical visualization, and surgical navigation. CONCLUSION: Machine learning demonstrated promising applications for improving breast surgery outcomes and patient-centred care. Neveretheless, there remain important limitations and ethical concerns relating to implementing artificial intelligence into everyday surgical practices.

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

A cost-utility analysis comparing endovascular coiling to neurosurgical clipping in the treatment of aneurysmal subarachnoid haemorrhage.

Endovascular coiling (EC) has been identified in systematic reviews and meta-analyses to produce more favourable clinical outcomes in comparison to neurosurgical clipping (NC) when surgically treating a subarachnoid haemorrhage from a ruptured aneurysm. Cost-effectiveness analyses between both interventions have been done, but no cost-utility analysis has yet been published. This systematic review aims to perform an economic analysis of the relative utility outcomes and costs from both treatments in the UK. A cost-utility analysis was performed from the perspective of the National Health Service (NHS), over a 1-year analytic horizon. Outcomes were obtained from the randomised International Subarachnoid Aneurysm Trial (ISAT) and measured in terms of the patient's modified Rankin scale (mRS) grade, a 6-point disability scale that aims to quantify a patient's functional outcome following a stroke. The mRS score was weighted against the Euro-QoL 5-dimension (EQ-5D), with each state assigned a weighted utility value which was then converted into quality-adjusted life years (QALYs). A sensitivity analysis using different utility dimensions was performed to identify any variation in incremental cost-effectiveness ratio (ICER) if different input variables were used. Costs were measured in pounds sterling (£) and discounted by 3.5% to 2020/2021 prices. The cost-utility analysis showed an ICER of - £144,004 incurred for every QALY gained when EC was utilised over NC. At NICE's upper willingness-to-pay (WTP) threshold of £30,000, EC offered a monetary net benefit (MNB) of £7934.63 and health net benefit (HNB) of 0.264 higher than NC. At NICE's lower WTP threshold of £20,000, EC offered an MNB of £7478.63 and HNB of 0.374 higher than NC. EC was found to be more 'cost-effective' than NC, with an ICER in the bottom right quadrant of the cost-effectiveness plane-indicating that it offers greater benefits at lower costs. This is supported by the ICER being below the NICE's threshold of £20,000-£30,000 per QALY, and both MNB and HNB having positive values (> 0).

Mitral valve surgery assisted by virtual and augmented reality: Cardiac surgery at the front of innovation.

BACKGROUND: Given the variety in mitral valve (MV) pathology and associated surgical techniques, extended reality (XR) holds great potential to assist MV surgeons. This review aims to systematically evaluate the currently available evidence investigating the use of XR and associated technologies in MV surgery. METHODS: A systematic database search was conducted of original articles and case reports that explored the use of XR and MV surgery in EMBASE, MEDLINE, Cochrane database and Google Scholar, from inception to February 2022. RESULTS: Our search yielded 171 articles, of which 15 studies were included in this review, featuring 328 patients. Two main areas of application were identified: (i) pre-operative planning and (ii) predicting post-operative outcomes. The articles reporting outcomes relating to pre-operative planning were further categorised as exploring themes relevant to (i) mitral annular assessment; (ii) training; (iii) evaluation of surgical technique; (iv) surgical approach or plan and (v) selecting ring size or type. Preoperatively, XR has been shown to evaluate mitral annular pathology more accurately than echocardiography, informing the surgeon about the optimal surgical technique, approach and plan for a particular patient's MV pathology. Furthermore, XR could simulate and aid ring size/type selection for MV annuloplasty, creating a personalized surgical plan. Additionally, XR could estimate the postoperative MV biomechanical and physiological characteristics, predicting and pre-empting post-operative complications. CONCLUSION: XR demonstrated promising applications for assisting MV surgery, enhancing outcomes and patient-centred care, nevertheless, there remain the need for randomized studies to ascertain its feasibility, safety, and validity in clinical practice.

Fungi, host immune response, and tumorigenesis.

Advances in -omics analyses have tremendously enhanced our understanding of the role of the microbiome in human health and disease. Most research is focused on the bacteriome, but scientists have now realized the significance of the virome and microbial dysbiosis as well, particularly in noninfectious diseases such as cancer. In this review, we summarize the role of mycobiome in tumorigenesis, with a dismal prognosis, and attention to pancreatic ductal adenocarcinoma (PDAC). We also discuss bacterial and mycobial interactions to the host's immune response that is prevalently responsible for resistance to cancer therapy, including immunotherapy. We reported that the Malassezia species associated with scalp and skin infections, colonize in human PDAC tumors and accelerate tumorigenesis via activating the C3 complement-mannose-binding lectin (MBL) pathway. PDAC tumors thrive in an immunosuppressive microenvironment with desmoplastic stroma and a dysbiotic microbiome. Host-microbiome interactions in the tumor milieu pose a significant threat in driving the indolent immune behavior of the tumor. Microbial intervention in multimodal cancer therapy is a promising novel approach to modify an immunotolerant ("cold") tumor microenvironment to an immunocompetent ("hot") milieu that is effective in eliminating tumorigenesis.

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming.

BACKGROUND AND AIMS: The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). APPROACH AND RESULTS: We found that in SH, γδT cells are recruited to the liver by C-C chemokine receptor (CCR) 2, CCR5, and nucleotide-binding oligomerization domain-containing protein 2 signaling and are skewed toward an interleukin (IL)-17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand-dependent manner. γδT cells exhibit a distinct Vγ4+ , PD1+ , Ly6C+ CD44+ phenotype in SH. Moreover, γδT cells up-regulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced SH and accelerates disease resolution. CONCLUSIONS: We demonstrate that hepatic γδT cells exacerbate SH, independent of IL-17 expression, by mitigating conventional CD4+ T-cell expansion and modulating their inflammatory program by CD1d-dependent vascular endothelial growth factor expression.

Open access availability of anatomy papers presented at meetings of the American and British Associations of Clinical Anatomists.

INTRODUCTION: Dissemination of research depends on published work being accessible. In many disciplines open access (OA) research is more frequently cited, although this has never before been demonstrated amongst anatomy publications. The objective of this study was to assess a selection of published anatomy papers to determine the effect of gold and bronze OA availability on citation rates. MATERIALS AND METHODS: Taken together, 625 peer-reviewed publications were identified from 2927 abstracts presented at meetings of AACA (2003-2010) and BACA (2000-2015). RESULTS: In total 18.75% (69 of 368) of papers presented at BACA and 21.79% (56 of 257) of those presented at AACA reached OA publication.  Citation rates are significantly higher amongst OA papers as compared to non-OA papers presented at these two anatomy conferences (OA 18.95, Non-OA 15.14 p = 0.047). OA papers were most commonly themed around education and pure anatomy. CONCLUSIONS: The average OA publication rate of 20.0% in anatomical research arising from these conferences is significantly lower than the average rate for scientific research. Citation rates are significantly higher amongst OA anatomy papers presented at these two conferences.