Comparing Automated Subcortical Volume Estimation Methods; Amygdala Volumes Estimated by FSL and FreeSurfer Have Poor Consistency.

Subcortical volumes are a promising source of biomarkers and features in biosignatures, and automated methods facilitate extracting them in large, phenotypically rich datasets. However, while extensive research has verified that the automated methods produce volumes that are similar to those generated by expert annotation, the consistency of methods with each other is understudied. Using data from the UK Biobank, we compare the estimates of subcortical volumes produced by two popular software suites: FSL and FreeSurfer. Although most subcortical volumes exhibit good to excellent consistency across the methods, the tools produce diverging estimates of amygdalar volume. Through simulation, we show that this poor consistency can lead to conflicting results, where one but not the other tool suggests statistical significance, or where both tools suggest a significant relationship but in opposite directions. Considering these issues, we discuss several ways in which care should be taken when reporting on relationships involving amygdalar volume.

Ikaros sets the threshold for negative B-cell selection by regulation of the signaling strength of the AKT pathway.

Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection.

The Human Neonatal Skin Fibroblast, an Available Cell Source for Tissue Production and Transplantation, Exhibits Low Risk of Immunogenicity In Vitro.

The immunogenicity of allogeneic skin fibroblasts in transplantation has been controversial. Whether this controversy comes from a natural heterogeneity among fibroblast subsets or species-specific differences between human and mouse remains to be addressed. In this study, we sought to investigate whether fibroblasts derived from either adult or neonatal human skin tissues could induce different immune responses toward phagocytosis and T cell activation using in vitro co-culture models. Our results indicate that both phagocytosis and T cell proliferation are reduced in the presence of neonatal skin fibroblasts compared to adult skin fibroblasts. We also show that neonatal skin fibroblasts secrete paracrine factors that are responsible for reduced T cell proliferation. In addition, we show that neonatal skin fibroblasts express less class II human leukocyte antigen (HLA) molecules than adult skin fibroblasts after interferon gamma priming, which might also contribute to reduced T cell proliferation. In conclusion, this study supports the use of allogeneic neonatal skin fibroblasts as a readily available cell source for tissue production and transplantation to treat patients with severe injuries.

The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis in C. elegans.

The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified the Caenorhabditis elegans F-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations in fbxl-5 partially suppress the vitellogenesis defects observed in the heterochronic mutants lin-4 and lin-29, both of which ectopically express fbxl-5 at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest that fbxl-5 functions in concert with cul-6, a cullin gene, and the Skp1-related gene skr-3 to regulate vitellogenesis. Additionally, fbxl-5 acts genetically upstream of rict-1, which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.

Polyamine Catabolism Revisited: Acetylpolyamine Oxidase Plays a Minor Role due to Low Expression.

Biogenic polyamines are ubiquitous compounds. Dysregulation of their metabolism is associated with the development of various pathologies, including cancer, hyperproliferative diseases, and infections. The canonical pathway of polyamine catabolism includes acetylation of spermine and spermidine and subsequent acetylpolyamine oxidase (PAOX)-mediated oxidation of acetylpolyamines (back-conversion) or their direct efflux from the cell. PAOX is considered to catalyze a non-rate-limiting catabolic step. Here, we show that PAOX transcription levels are extremely low in various tumor- and non-tumor cell lines and, in most cases, do not change in response to altered polyamine metabolism. Its enzymatic activity is undetectable in the majority of cell lines except for neuroblastoma and low passage glioblastoma cell lines. Treatment of A549 cells with N1,N11-diethylnorspermine leads to PAOX induction, but its contribution to polyamine catabolism remains moderate. We also describe two alternative enzyme isoforms and show that isoform 4 has diminished oxidase activity and isoform 2 is inactive. PAOX overexpression correlates with the resistance of cancer cells to genotoxic antitumor drugs, indicating that PAOX may be a useful therapeutic target. Finally, PAOX is dispensable for the replication of various viruses. These data suggest that a decrease in polyamine levels is achieved predominantly by the secretion of acetylated spermine and spermidine rather than by back-conversion.

Modulating the fidelity and spatial extent of electrotactile stimulation to elicit the embodiment of a virtual hand.

Restoring tactile feedback in virtual reality can improve user experience and facilitate the feeling of embodiment. Electrotactile stimulation can be an attractive technology in this context as it is compact and allows for high-resolution spatially distributed stimulation. In the present study, a 32-channel tactile glove worn on the fingertips was used to provide tactile sensations during a virtual version of a rubber hand illusion experiment. To assess the benefits of multichannel stimulation, we modulated the spatial extent of feedback and its fidelity. Thirty-six participants performed the experiment in two conditions, in which stimulation was delivered to a single finger or all fingers, and three tactile stimulation types within each condition: no tactile feedback, simple single-point stimulation, and complex sliding stimulation mimicking the movements of the brush. Following each trial, the participants answered a multi-item embodiment questionnaire and reported the proprioceptive drift. The results confirmed that modulating the spatial extent of stimulation, from a single finger to all fingers, was indeed a successful strategy. When stimulating all fingers, tactile stimulation significantly improved all subjective measures compared to receiving no tactile stimulation. However, unexpectedly, the second strategy, that of modulating the fidelity of feedback, was not successful since there was no difference between the simple and complex tactile feedback in any of the measures. The results, therefore, imply that the effects of tactile feedback are better expressed in a more dynamic scenario (i.e., making/breaking contact and delivering stimulation to different body locations), while it still needs to be investigated if further improvements of the complex feedback can make it more effective compared to the simple approach.

Assessing focal spot alignment in clinical linear accelerators: a comprehensive evaluation with triplet phantoms.

A fundamental parameter to evaluate the beam delivery precision and stability on a clinical linear accelerator (linac) is the focal spot position (FSP) measured relative to the collimator axis of the radiation head. The aims of this work were to evaluate comprehensive data on FSP acquired on linacs in clinical use and to establish the ability of alternative phantoms to detect effects on patient plan delivery related to FSP. FSP measurements were conducted using a rigid phantom holding two ball-bearings at two different distances from the radiation source. Images of these ball-bearings were acquired using the electronic portal imaging device (EPID) integrated with each linac. Machine QA was assessed using a radiation head-mounted PTW STARCHECK phantom. Patient plan QA was investigated using the SNC ArcCHECK phantom positioned on the treatment couch, irradiated with VMAT plans across a complete 360° gantry rotation and three X-ray energies. This study covered eight Elekta linacs, including those with 6 MV, 18 MV, and 6 MV flattening-filter-free (FFF) beams. The largest range in the FSP was found for 6 MV FFF. The FSP of one linac, retrofitted with 6 MV FFF, displayed substantial differences in FSP compared to 6 MV FFF beams on other linacs, which all had FSP ranges less than 0.50 mm and 0.25 mm in the lateral and longitudinal directions, respectively. The PTW STARCHECK phantom proved effective in characterising the FSP, while the SNC ArcCHECK measurements could not discern FSP-related features. Minor variations in FSP may be attributed to adjustments in linac parameters, component replacements necessary for beam delivery, and the wear and tear of various linac components, including the magnetron and gun filament. Consideration should be given to the ability of any particular phantom to detect a subsequent impact on the accuracy of patient plan delivery.

The Impact of Perilesional Heatsink Structures on Ablation Volumes in Laser Interstitial Thermal Therapy for Brain Metastases.

BACKGROUND AND OBJECTIVES: Laser interstitial thermal therapy (LITT) has demonstrated promise in surgical neuro-oncology because of its effectiveness in delivering precise thermal energy to lesions. The extent of ablation (EOA) is a prognostic factor in improving patient outcomes but is often affected by perilesional heatsink structures, which can lead to asymmetric ablations. The purpose of this study was to quantitatively evaluate the impact of various perilesional heatsink structures on the EOA in LITT for brain metastases. METHODS: Twenty-seven procedures for 22 unique patients with brain metastases fit the inclusion criteria. Intracranial heatsink structures were identified: sulci, meninges, cerebrospinal fluid (CSF) spaces, and vasculature. Asymmetric ablation was determined by measuring 3 pairs of orthogonal distances from the proximal, midpoint, and distal locations along the laser catheter to the farthest edge of the ablation zone bilaterally. Distances from the same points on the laser catheter to the nearest heatsink were also recorded. The Heatsink Effect Index was created to serve as a proxy for asymmetric ablation. Pearson correlations, t-tests, and analysis of variance were the statistical analyses performed. RESULTS: From the midpoint of the catheter, the 27 heatsinks were meninges (40.7%), sulci (22.2%), vasculature (22.2%), and CSF spaces (14.8%). Across all points along the catheter track, there was a significant generalized heatsink effect on asymmetric ablations (P < .0001). There was a negative correlation observed between asymmetric ablations and EOA from the midpoint of the laser catheter (r = -0.445, P = .020). Compared with sulci, CSF spaces trended toward a greater effect on asymmetric ablation volumes (P = .069). CONCLUSION: This novel quantitative analysis shows that perilesional heatsinks contribute to asymmetric ablations. CSF spaces trended toward higher degrees of asymmetric ablations. Importantly, neurosurgeons may anticipate asymmetric ablations preoperatively if heatsinks are located within 13.3 mm of the laser probe midpoint. These preliminary results may guide surgical decision-making in LITT for metastatic brain lesions.

Heart Failure With Improved Ejection Fraction: Prevalence, Predictors, and Guideline-Directed Medical Therapy.

Recently, a new category of heart failure with improved ejection fraction (HFimpEF) has emerged in the classification system. This is defined as the subgroup of patients with heart failure with reduced ejection fraction (HFrEF) whose left ventricular ejection fraction has recovered partially or completely, with no specific cut-off values established yet in the guidelines. In our review, we aim to provide an overview of prevalence, predictors, mechanism of remodeling, and management strategies regarding HFimpEF. These patients constitute a sizeable cohort among patients with reduced ejection fraction. Certain patient characteristics including younger age and female gender, absence of comorbid conditions, low levels of biomarkers, and non-ischemic etiology were identified as positive predictors. The heart undergoes significant maladaptive changes post failure leading to adverse remodeling influenced etiology and duration. Goal-directed medical therapy including beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs) have notably improved cardiac function by inducing reverse remodeling. Despite a more favorable prognosis compared to HFrEF, patients with improved ejection fraction (EF) still face clinical events and reduced quality of life, and remain at risk of adverse outcomes. Although the evidence is scarce, it is advisable to continue treatment modalities despite improvement in EF, including device therapies, to prevent relapse and clinical deterioration. It is imperative to conduct further research to understand the mechanism leading to EF amelioration and establish guidelines to identify and direct management strategies.

Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials.

Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture (MMV), we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GP) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence and NaV1.8 patch clamp assays, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration-response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile.

Assessing the interplay between off-target promiscuity, cytotoxicity, and tolerability in rodents to improve the safety profile of novel anti-malarial plasmepsin X inhibitors.

Within drug development, high off-target promiscuity as well as potent cytotoxicity, are associated with a high attrition rate. We investigated the safety profile of novel plasmepsin X (PMX) inhibitors for the treatment of malaria. In our screening cascade, a total of 249 PMX compounds were profiled in a panel of in vitro secondary pharmacology assays containing 44 targets (SafetyScreen44™ panel) and in a cytotoxicity assay in HepG2 cells using ATP as an endpoint. Six of the lead compounds were subsequently tested in a 7-day rat toxicology study, and/or in a cardiovascular study in guinea pigs. Overall, compounds with high cytotoxicity in HepG2 cells correlated with high promiscuity (off-target hit rate >20%) in the SafetyScreen44™ panel and were associated with poor tolerability in vivo (decedents, morbidity, adverse clinical signs, or severe cardiovascular effects). Some side effects observed in rats or guinea pigs could putatively be linked with hits in the secondary pharmacological profiling, such as the M1 or M2 muscarinic acetylcholine receptor, opioid µ and/or κreceptors or hERG/CaV1.2/Na+ channels, which were common to > 50% the compounds tested in vivo. In summary, compounds showing high cytotoxicity and high promiscuity are likely to be poorly tolerated in vivo. However, such associations do not necessarily imply a causal relationship. Identifying the targets that cause these undesirable effects is key for early safety risk assessment. A tiered approach, based on a set of in vitro assays, helps selecting the compounds with highest likelihood of success to proceed to in vivo toxicology studies.

A multimodal fMRI dataset unifying naturalistic processes with a rich array of experimental tasks.

Cognitive neuroscience has advanced significantly due to the availability of openly shared datasets. Large sample sizes, large amounts of data per person, and diversity in tasks and data types are all desirable, but are difficult to achieve in a single dataset. Here, we present an open dataset with N = 101 participants and 6 hours of scanning per participant, with 6 multifaceted cognitive tasks including 2 hours of naturalistic movie viewing. This datasets' combination of ample sample size, extensive data per participant, more than 600 hours worth of data, and a wide range of experimental conditions - including cognitive, affective, social, and somatic/interoceptive tasks - positions it uniquely for probing important questions in cognitive neuroscience.

Association of endothelial function and lower extremity perfusion in peripheral artery disease.

Background: The current study aims to investigate the association between endothelial function and lower extremity perfusion in patients with peripheral artery disease (PAD). Patients and methods: In total 229 patients with PAD (Rutherford stage 0-3) were enrolled in the current study. Endothelial function was assessed by measuring flow-mediated dilation (FMD) and endothelial cell proliferation capacity (ECPC). Lower extremity perfusion was assessed by measuring oscillometry-based ankle brachial index (oABI) and pulse wave index (PWI). In addition, carotid intima-media-thickness (cIMT) was also measured as a surrogate marker for atherosclerosis. Correlations between FMD, ECPC, oABI, PWI, and cIMT were analysed using Pearson correlation coefficient. The relationship between the above variables and the severity of PAD was investigated using ordinal logistic regression analysis. Results: Correlation analysis showed that FMD negatively associated with PWI (r = -0.183, p = 0.005), ECPC positively associated with oABI (r = 0.162, p = 0.014), and oABI negatively associated with PWI (r = -0.264, p < 0.001). Ordinal logistic regression analysis showed that ECPC (ß = -0.009, p = 0.048), oABI (ß = -5.290, p < 0.001), and age (ß = -0.058, p = 0.002) negatively associated with the PAD Rutherford stages. In addition, PWI (ß = 0.006, p < 0.001), cIMT (ß = 18.363, p = 0.043) positively associated with the PAD Rutherford stages. Conclusions: Endothelial function significantly associates with lower extremity perfusion in patients with PAD, and both are related to the severity of PAD.

Measuring and increasing rates of self-isolation in the context of COVID-19: a systematic review with narrative synthesis.

OBJECTIVES: This study aimed to investigate (1) definitions of self-isolation used during the COVID-19 pandemic; (2) measures used to quantify adherence and their reliability, validity, and acceptability; (3) rates of self-isolation adherence; and (4) factors associated with adherence. STUDY DESIGN: This was a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Synthesis Without Meta-analysis (PRISMA) guidelines (PROSPERO record CRD42022377820). METHODS: MEDLINE, PsycINFO, Embase, Web of Science, PsyArXiv, medRxiv, and grey literature sources were searched (1 January 2020 to 13 December 2022) using terms related to COVID-19, isolation, and adherence. Studies were included if they contained original, quantitative data of self-isolation adherence during the COVID-19 pandemic. We extracted definitions of self-isolation, measures used to quantify adherence, adherence rates, and factors associated with adherence. RESULTS: We included 45 studies. Self-isolation was inconsistently defined. Four studies did not use self-report measures. Of 41 studies using self-report, one reported reliability; another gave indirect evidence for the lack of validity of the measure. Rates of adherence to self-isolation for studies with only some concerns of bias were 51%-86% for COVID-19 cases, 78%-94% for contacts, and 16% for people with COVID-19-like symptoms. There was little evidence that self-isolation adherence was associated with sociodemographic or psychological factors. CONCLUSIONS: There was no consensus in defining, operationalising, or measuring self-isolation, resulting in significant risk of bias in included studies. Future definitions of self-isolation should state behaviours to be enacted and duration. People recommended to self-isolate should be given support. Public health campaigns should aim to increase perceived effectiveness of self-isolation and promote accurate information about susceptibility to infection.

Variability in COVID-19 Symptom Presentation During Pregnancy and its Impact on Maternal and Infant Outcomes Across the Pandemic.

BACKGROUND: With the dominance of different SARS-CoV-2 variants, the severity of COVID-19 has evolved. We aimed to investigate the difference in symptom prevalence and the association between symptoms and adverse pregnancy outcomes during the dominance of Wild-type/Alpha, Delta, and Omicron. METHODS: COVID-19 related symptom prevalence, maternal and specific neonatal outcomes of 5431 pregnant women registered in this prospective study were compared considering the dominant virus variant. Logistic regression models analyzed the association between specific symptoms and intensive care unit (ICU) admission or preterm birth. RESULTS: Infection with the Delta variant led to an increase in the symptom burden compared to the Wild-type/Alpha variant and the highest risk for respiratory tract symptoms, feeling of sickness, headache, and dizziness/drowsiness. An infection with the Omicron variant was associated with the lowest risk of dyspnea and changes in smell/taste but the highest risk for nasal obstruction, expectoration, headaches, myalgia, and fatigue compared to the Wild-type/Alpha and Delta variant dominant periods. With the progression of the Wild-type/Alpha to the Delta variant neonatal outcomes worsened. Dyspnea and fever were strong predictors for maternal ICU admission and preterm birth independent of vaccination status or trimester of infection onset. CONCLUSION: The symptom burden increased during the Delta period and was associated with worse pregnancy outcomes than in the Wild-type/Alpha area. During the Omicron dominance there still was a high prevalence of less severe symptoms. Dyspnea and fever can predict a severe maternal illness.

Trends and Factors Associated With Peripheral Vascular Interventions for the Treatment of Claudication From 2011 to 2022: A National Medicare Cohort Study.

BACKGROUND: Previous cross-sectional studies have identified wide practice pattern variations in the use of peripheral vascular interventions (PVIs) for the treatment of claudication. However, there are limited data on longitudinal practice patterns. We aimed to describe the temporal trends and charges associated with PVI use for claudication over the past 12 years in the United States. METHODS AND RESULTS: We conducted a retrospective analysis using 100% Medicare fee-for-service claims data to identify all patients who underwent a PVI for claudication between January 2011 and December 2022. We evaluated the trends in utilization and Medicare-allowed charges of PVI according to anatomic level, procedure type, and intervention settings using generalized linear models. Multinomial logistic regressions were used to evaluate factors associated with different levels and types of PVI. We identified 599 197 PVIs performed for claudication. The proportional use of tibial PVI increased 1.0% per year, and atherectomy increased by 1.6% per year over the study period. The proportion of PVIs performed in ambulatory surgical centers/office-based laboratories grew at 4% per year from 12.4% in 2011 to 55.7% in 2022. Total Medicare-allowed charges increased by $11 980 035 USD/year. Multinomial logistic regression identified significant associations between race and ethnicity and treatment setting with use of both atherectomy and tibial PVI. CONCLUSIONS: The use of tibial PVI and atherectomy for the treatment of claudication has increased dramatically in in ambulatory surgical center/office-based laboratory settings, non-White patients, and resulting in a significant increase in health care charges. There is a critical need to improve the delivery of value-based care for the treatment of claudication.

Stereotactic Magnetic Resonance-Guided Daily Adaptive SABR (SMART) for Localised Non-Metastatic Pancreatic Cancer: First Reported Clinical Outcomes From the UK.

AIMS: Prognosis of locally advanced pancreatic cancer (LAPC) remains poor with limited therapeutic options. Radiation therapy in pancreatic cancer has been restricted by the disease's proximity to radiosensitive organs at risk (OAR). However, stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) has demonstrated promise in delivering ablative doses safely. We sought to report clinical outcomes from a UK-based Compassionate Access Programme that provided access to SMART to patients with LAPC. MATERIALS AND METHODS: This was a registry retrospective study conducted at a single centre with access to SMART. Patients with LAPC were treated with prescription dose of 40 Gy in 5 fractions. The planning objective was that 98% of PTV received ≥95% of the prescribed dose, prioritising duodenal, stomach and bowel UK SABR consortium constraints. Daily online adaptation was performed using magnetic resonance guidance and on-table re-optimisation. 0-3 months and > 3-month post-treatment-related toxicities, local progression-free survival, metastatic-free survival and overall survival were evaluated. RESULTS: 55 patients were treated with SMART at our institution from 2020 to 2022. Median follow-up from date of diagnosis was 17 months (range 5-37 months). Median age was 69.87% of patients underwent induction chemotherapy. 71% of patients reported 0-1 grade acute toxicity only. No grade >3 acute toxicity was reported. 5 patients (9%) reported a grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal stricture). No grade >3 toxicity after 3 months was reported. 6 (10%) of patients had grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal haemorrhage). Median local PFS post diagnosis was 17 months (95% CI 15.3-18.7). Median OS post diagnosis was 19 months (95% CI 15.9-22.1). One-year local control post SMART was 65%. CONCLUSION: This is the first UK-reported experience of MR-guided daily adaptive pancreatic SABR. SMART shows promise in delivering ablative doses with acceptable toxicity rates and good clinical outcomes.