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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.
BACKGROUND: Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021. METHODS: We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. FINDINGS: In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6-7·8] deaths; 10·7% [9·8-11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8-171·6] DALYs; 5·6% [5·0-6·1] of all DALYs). In 2021, there were 93·8 million (89·0-99·3) prevalent and 11·9 million (10·7-13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4-67·7), intracerebral haemorrhage constituted 28·8% (28·3-28·8), and subarachnoid haemorrhage constituted 5·8% (5·7-6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4-117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7-38·1]), diet high in sugar-sweetened beverages (23·4% [12·7-35·7]), low physical activity (11·3% [1·8-34·9]), high systolic blood pressure (6·7% [2·5-11·6]), lead exposure (6·5% [4·5-11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5-10·5]). INTERPRETATION: Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden. FUNDING: Bill & Melinda Gates Foundation.
Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole-genome sequencing with histopathological features.
BACKGROUND: Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification. METHODS: We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of > 19,000 copy number corrected single nucleotide variants. RESULTS: In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees. CONCLUSIONS: Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread.
Analysis of 3D pathology samples using weakly supervised AI.
Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.
Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity.
Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
The calcium-sensing receptor as a nutrient sensor.
Critical to cell fate in many cell types is the ability to sense and respond to acute changes in free ionized extracellular calcium concentration ([Ca(2+)](o)). Such tight control is mediated by the activation of a protein known as the extracellular-calcium-sensing receptor (CaR). CaR belongs to the 'family C' of G-protein-coupled receptors and was the first G-protein-coupled receptor to be identified to have an inorganic cation, calcium, as its ligand. While calcium is the physiological agonist of the receptor, several other polyvalent cations and polycations can also modulate CaR function as do certain L-aromatic amino acids, polyamines, salinity and pH. This feature renders the CaR uniquely capable of generating cell- and tissue-specific responses, and of integrating inputs deriving from changes in the Ca(2+)(o) concentration with signals deriving from the local metabolic environment. Here we address the role of the CaR in physiology and disease, the range of CaR modulators and the potential roles of the CaR as a metabolic sensor in a variety of physiological (and pathological) scenarios.
Enriched HLA-E and CD94/NKG2A Interaction Limits Antitumor CD8+ Tumor-Infiltrating T Lymphocyte Responses.
Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor-specific T cells impairs IL2 receptor-dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.
Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.
We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.
Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 Genomes Project.
PURPOSE: Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS. METHODS: We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples. RESULTS: We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 °C or 65 °C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs). CONCLUSION: We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.
IFITM3-specific antibody reveals IFN preferences and slow IFN induction of the antiviral factor IFITM3 in humans.
Using a specific antibody, we found that expression of the viral restriction factor IFITM3 differs across cell types within the immune compartment with higher expression in myeloid rather than lymphoid cells. IFITM3 expression was increased following IFN stimulation, mostly type I, in immune cells, with the exception of T cells.
Tea trolley teaching in critical care: Integrating evidence-based practice with library services.
Tea trolley teaching is a tried and tested method of providing bedside education to hospital staff. This project aimed to integrate the tea trolley teaching model, already established in our local critical care unit, with library services. The goal was to equip clinical staff with the necessary training to retrieve literature and support evidence-based practice. Our evaluation highlights the value of this combined intervention of teaching research skills to upskill staff working in our intensive care units. This paper describes a scalable model of critical care bedside education that integrates library-focused teaching to upskill nurses in some of the prerequisite skills needed for evidence-based practice (EBP).
Matched pair analysis of wide versus narrow focus during shockwave lithotripsy for urolithiasis.
PURPOSE: To compare stone clearance and complications between a 'wide' (9 × 50 mm) and 'narrow' shockwave focus (6 × 28 mm) when undertaking shockwave lithotripsy (SWL) in patients with renal or ureteric stones. METHODS: Data from patients undergoing SWL using the dual focus Storz Modulith SLX-F2 lithotripter at a single centre were prospectively collected between February 2018 and September 2020. Patients were matched by stone size, location, and number of treatments. Stone clearance, re-presentation within 31 days, symptoms, complications, and need for post SWL-interventions were compared using McNemar's test. RESULTS: Patients receiving wide focus SWL (WF-SWL, n = 152) were matched with patients receiving narrow focus SWL (NF-SWL, n = 152). Median stone size was 6 mm; energy delivered to WF-SWL and NF-SWL groups was comparable. Complete stone clearance was achieved in 55% of WF-SWL patients (n = 84) and 41% (n = 63) of NF-SWL patients (p = 0.04). Treatment was considered successful in 74% (n = 113) of WF-SWL cases and 66% (n = 100) of NF-SWL (p = 0.20). No difference in rates of readmission, post-procedural pain, haematuria, urinary tract infections, analgesia or antibiotic requirements were identified. CONCLUSION: This service evaluation demonstrates no differences in rates of overall treatment success nor complications on comparing WF-SWL and NF-SWL.
Induction of macrophage efferocytosis in pancreatic cancer via PI3Kγ inhibition and radiotherapy promotes tumour control.
BACKGROUND: The immune suppression mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unknown, but preclinical studies have implicated macrophage-mediated immune tolerance. Hence, pathways that regulate macrophage phenotype are of strategic interest, with reprogramming strategies focusing on inhibitors of phosphoinositide 3-kinase-gamma (PI3Kγ) due to restricted immune cell expression. Inhibition of PI3Kγ alone is ineffective in PDAC, despite increased infiltration of CD8+ T cells. OBJECTIVE: We hypothesised that the immune stimulatory effects of radiation, and its ability to boost tumour antigen availability could synergise with PI3Kγ inhibition to augment antitumour immunity. DESIGN: We used orthoptic and genetically engineered mouse models of pancreatic cancer (LSL-KrasG12D/+;Trp53R172H/+;Pdx1-Cre). Stereotactic radiotherapy was delivered using contrast CT imaging, and PI3Kγ inhibitors by oral administration. Changes in the tumour microenvironment were quantified by flow cytometry, multiplex immunohistochemistry and RNA sequencing. Tumour-educated macrophages were used to investigate efferocytosis, antigen presentation and CD8+ T cell activation. Single-cell RNA sequencing data and fresh tumour samples with autologous macrophages to validate our findings. RESULTS: Tumour-associated macrophages that employ efferocytosis to eradicate apoptotic cells can be redirected to present tumour antigens, stimulate CD8+ T cell responses and increase local tumour control. Specifically, we demonstrate how PI3Kγ signalling restricts inflammatory macrophages and that inhibition supports MERTK-dependent efferocytosis. We further find that the combination of PI3Kγ inhibition with targeted radiotherapy stimulates inflammatory macrophages to invoke a pathogen-induced like efferocytosis that switches from immune tolerant to antigen presenting. CONCLUSIONS: Our data supports a new immunotherapeutic approach and a translational rationale to improve survival in PDAC.
Clonal phylogenies inferred from bulk, single cell, and spatial transcriptomic analysis of epithelial cancers.
Epithelial cancers are typically heterogeneous with primary prostate cancer being a typical example of histological and genomic variation. Prior studies of primary prostate cancer tumour genetics revealed extensive inter and intra-patient genomic tumour heterogeneity. Recent advances in machine learning have enabled the inference of ground-truth genomic single-nucleotide and copy number variant status from transcript data. While these inferred SNV and CNV states can be used to resolve clonal phylogenies, however, it is still unknown how faithfully transcript-based tumour phylogenies reconstruct ground truth DNA-based tumour phylogenies. We sought to study the accuracy of inferred-transcript to recapitulate DNA-based tumour phylogenies. We first performed in-silico comparisons of inferred and directly resolved SNV and CNV status, from single cancer cells, from three different cell lines. We found that inferred SNV phylogenies accurately recapitulate DNA phylogenies (entanglement = 0.097). We observed similar results in iCNV and CNV based phylogenies (entanglement = 0.11). Analysis of published prostate cancer DNA phylogenies and inferred CNV, SNV and transcript based phylogenies demonstrated phylogenetic concordance. Finally, a comparison of pseudo-bulked spatial transcriptomic data to adjacent sections with WGS data also demonstrated recapitulation of ground truth (entanglement = 0.35). These results suggest that transcript-based inferred phylogenies recapitulate conventional genomic phylogenies. Further work will need to be done to increase accuracy, genomic, and spatial resolution.