3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

Psychometric Properties of the Attitudes Toward Polyamory Scale (ATP) in the Spanish Context.

Given the potential discrimination faced by individuals in polyamorous relationships, understanding attitudes toward polyamory in society is crucial. To this end, instruments to measure attitudes toward polyamory with adequate psychometric properties are necessary. The aim of this study was to adapt the Attitudes Toward Polyamory Scale (ATP) to the Spanish context and analyze its psychometric properties in a sample of young adults. The sample comprised 1,162 individuals aged 18 to 35 years. Participants responded to sociodemographic questions and completed the Revised Sexual Opinion Survey (SOS) and the ATP. The findings indicate: (1) adequate reliability coefficients, (2) good fit statistics for the one-factor confirmatory model that verify results of exploratory factor analysis, (3) that homosexual and bisexual people have more favorable attitudes toward polyamory than heterosexual, (4) positive correlations between ATP scores, SOS scores, and political orientation (individuals with higher levels of erotophilia and a more left-leaning political orientation tend to hold more favorable attitudes toward polyamory), and (5) association between ATP scores and religion, with non-religious individuals showing more favorable attitudes toward polyamory than Catholics. In conclusion, the ATP demonstrates adequate psychometric properties in Spanish young adults.

Transcultural adaptation to Spain of the CDPQOL questionnaire specific for coeliac children.

This study aimed to translate, cross-culturally adapt, and validate the CDPQOL questionnaire, a coeliac disease (CD)-specific paediatric health-related quality of life (HRQoL) instrument (CDPQOL), in Spanish children with CD. The CDPQOL questionnaire has two versions for children aged 8-12 and 13-18. Translation and linguistic validation were performed following an international consensus process. Internal consistency was calculated using Cronbach's alpha and McDonald's omega coefficients, and convergent validity was assessed with average variance extracted (AVE). Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA), when necessary, were carried out to assess the construct validity. A total of 235 children were included. In the 8-12 age group, a change in the distribution of items to a new structure of three dimensions (negative emotions, food feelings and social interaction) was required. In this new model, CFA supported the fit of the model (χ2/gl = 1.79, RMSEA = 0.077 (IC 95% 0.05-0.100), CFI = 0.969, TLI 0.960, SRMR = 0.081) and Cronbach's alpha and McDonald's omega coefficients were > 0.7 in all three dimensions. In the 13-18 age group, CFA showed that all fit indexes were acceptable (χ2/gl = 1.702, RMSEA = 0.102 (IC 95% 0.077-0.127), p < 0.001, CFI = 0.956, TLI = 0.947, SRMR = 0.103) and Cronbach's alpha and McDonald's omega coefficients were > 0.7 in all three dimensions, except for uncertainty dimension. Conclusions: The Spanish version of the CDPQOL questionnaire is a useful instrument to assess quality of life in coeliac children whose native language was Spanish spoken in Spain, with changes in item distribution in the younger age group questionnaire. What is Known: • The first specific questionnaire for coeliac children, Dutch Coeliac Disease Questionnaire (CDDUX), which focuses on diet, was translated into Spanish and validated allowing to evaluate the HRQoL of Spanish coeliac children. • Spanish Children and parents feel the disease had no substantial negative impacts on patient HRQoL using this questionnaire, similar to that observed with other countries. What is New: • The age specific for CD children (CDPQOL) was elaborated in the USA and focuses on other aspects not evaluated by CDDUX such as emotional and social issues related to living with CD. • The CDPQOL was translated into Spanish and validated allowing it to be used to assess Spanish coeliac children's QoL.

Clinical Implications of Temporomandibular Condyle Agenesis in a Toddler.

Agenesis of the temporomandibular condyle is a congenital/developmental disorder that can present with the absence of the condyle and an incomplete development of the articular fossa and eminence, resulting in facial asymmetry as well as masticatory dysfunction. The purpose of this report is to present the case of a three-year-old girl with absence of the left temporomandibular condyle. The patient presented with pain and dysfunction in the left masseter muscle, pre-auricular area and ear as well as mild chin deviation to the left. The most common treatment modality is to wait and treat this condition with surgical intervention once the patient is grown. However, oral orthopedic appliances can be considered to promote bone formation prior to surgery. Prompt recognition and early treatment is advisable to take advantage of the child's growth and avoid further facial asymmetry, pain and dysfunction.

Anti-cancer bioactivity of sweet basil leaf derived extracellular vesicles on pancreatic cancer cells.

Most living organisms secrete tiny lipid bilayer particles encapsulating various biomolecular entities, including nucleic acids and proteins. These secreted extracellular vesicles (EVs) are shown to aid in communication between cells and their environment. EVs are mainly involved in the signalling and manipulation of physiological processes. Plant EVs display similar functional activity as seen in mammalian EVs. Medicinal plants have many bioactive constituents with potential applications in cancer treatment. Particularly, Basil (Ocimum basilicum), has wide therapeutic properties including anti-inflammatory, anti-cancer, and anti-infection, among others. In this study, we focused on using EVs purified from Apoplast Washing Fluid (AWF) of Basil plant leaves as a biological therapeutic agent against cancer. Characterization of Basil EVs revealed a size range of 100-250 nm, which were later assessed for their cell uptake and apoptosis inducing abilities in pancreatic cancer cells. Basil plant EVs (BasEVs) showed a significant cytotoxic effect on pancreatic cancer cell line MIA PaCa-2 at a concentration of 80 and 160 µg/mL in cell viability, as well as clonogenic assays. Similarly, RT-PCR and western blot analysis has shown up regulation in apoptotic gene and protein expression of Bax, respectively, in BasEV treatment groups compared to untreated controls of MIA PaCa-2. Overall, our results suggest that EVs from basil plants have potent anti-cancer effects in pancreatic cancer cells and can serve as a drug delivery system, demanding an investigation into the therapeutic potential of other medicinal plant EVs.

A consortium of different Saccharomyces species enhances the content of bioactive tryptophan-derived compounds in wine fermentations.

In recent years, the presence of molecules derived from aromatic amino acids in wines has been increasingly demonstrated to have a significant influence on wine quality and stability. In addition, interactions between different yeast species have been observed to influence these final properties. In this study, a screening of 81 yeast strains from different environments was carried out to establish a consortium that would promote the improvement of indolic compound levels in wine. Two strains, Saccharomyces uvarum and Saccharomyces eubayanus, with robust fermentative capacity were selected to be combined with a Saccharomyces cerevisiae strain with a predisposition towards the production of indolic compounds. Fermentation dynamics were studied in pure cultures, co-inoculations and sequential inoculations, analysing strain interactions and end-of-fermentation characteristics. Fermentations showing significant interactions were further analyzed for the resulting indolic compounds and aroma profile, with the aim of observing potential interactions and synergies resulting from the combination of different strains in the final wine. Sequential inoculation of S. cerevisiae after S. uvarum or S. eubayanus was observed to increase indolic compound levels, particularly serotonin and 3-indoleacetic acid. This study is the first to demonstrate how the formation of microbial consortia can serve as a useful strategy to enhance compounds with interesting properties in wine, paving the way for future studies and combinations.

Performance Evaluation of QT-RR Adaptation Time Lag Estimation in Exercise Stress Testing.

BACKGROUND: Slower adaptation of the QT interval to sudden changes in heart rate has been identified as a risk marker of ventricular arrhythmia. The gradual changes observed in exercise stress testing facilitates the estimation of the QT-RR adaptation time lag. METHODS: The time lag estimation is based on the delay between the observed QT intervals and the QT intervals derived from the observed RR intervals using a memoryless transformation. Assuming that the two types of QT interval are corrupted with either Gaussian or Laplacian noise, the respective maximum likelihood time lag estimators are derived. Estimation performance is evaluated using an ECG simulator which models change in RR and QT intervals with a known time lag, muscle noise level, respiratory rate, and more. The accuracy of T-wave end delineation and the influence of the learning window positioning for model parameter estimation are also investigated. RESULTS: Using simulated datasets, the results show that the proposed approach to estimation can be applied to any changes in heart rate trend as long as the frequency content of the trend is below a certain frequency. Moreover, using a proper position of the learning window for exercise so that data compensation reduces the effect of nonstationarity, a lower mean estimation error results for a wide range of time lags. Using a clinical dataset, the Laplacian-based estimator shows a better discrimination between patients grouped according to the risk of suffering from coronary artery disease. CONCLUSIONS: Using simulated ECGs, the performance evaluation of the proposed method shows that the estimated time lag agrees well with the true time lag.

Drivers of the In-Mouth Interaction between Lupin Protein Isolate and Selected Aroma Compounds: A Proton Transfer Reaction-Mass Spectrometry and Dynamic Time Intensity Analysis.

Plant proteins often carry off-notes, necessitating customized aroma addition. In vitro studies revealed protein-aroma binding, limiting release during consumption. This study employs in vivo nose space proton transfer reaction-time-of-flight-mass spectrometry and dynamic sensory evaluation (time intensity) to explore in-mouth interactions. In a lupin protein-based aqueous system, a sensory evaluation of a trained "green" attribute was conducted simultaneously with aroma release of hexanal, nonanal, and 2-nonanone during consumption. Results demonstrated that enlarging aldehyde chains and relocating the keto group reduced maximum perceived intensity (Imax_R) by 71.92 and 72.25%. Protein addition decreased Imax_R by 30.91, 36.84, and 72.41%, indicating protein-aroma interactions. Sensory findings revealed a perceived intensity that was lower upon protein addition. Aroma lingering correlated with aroma compounds' volatility and hydrophobicity, with nonanal exhibiting the longest persistence. In vitro mucin addition increased aroma binding four to 12-fold. Combining PTR-ToF-MS and time intensity elucidated crucial food behavior, i.e., protein-aroma interactions, that are pivotal for food design.

Impact of Direct Transport to Thrombectomy-Capable Center vs. Nearby/Distant Local Stroke Centers on Stroke Outcome in Patients Undergoing Thrombectomy: A Real-Life Study.

Our aim was to compare the stroke outcomes of a direct transfer (DT) to a thrombectomy-capable center vs. initial care at two local stroke centers: a nearby hospital (NH, 36 km) and a distant hospital (DH, 113 km). Patients who underwent a mechanical thrombectomy were analyzed (February 2017-October 2021), and the outcome was considered favorable if the modified Rankin scale (mRS) score was ≤ 2 at three months. A total of 300 patients were included, 55 of which were transferred from the NH and 58 from the DH. There was a difference in the median (IQR) transfer time of 39 min between the hospitals (149 min for the NH vs. 188 min for the DH, p = 0.003). After adjusting for confounding variables, a secondary transfer from the DH, compared to a DT, was associated with a lower functional independence: mRS score ≤ 2 (OR = 0.37, 95% CI = 0.14-0.97, p = 0.043), without significant differences in the mortality between the groups. These differences were not observed in patients from the NH. Conclusions: A secondary transfer from a distant hospital was associated with a poorer functional outcome at 3 months. This unfavorable outcome was not observed among patients transferred from a nearby hospital. These findings highlight the importance of categorizing the suitability of one transfer model over another based on the proximity of hospitals to the thrombectomy center, but also in accordance with organizational and geographic characteristics that vary within each health region.

Ending Trans Fat-The First-Ever Global Elimination Program for a Noncommunicable Disease Risk Factor: JACC International.

Industrially produced trans fat (iTFA) is a harmful compound created as a substitute for animal and saturated fats. Estimated to cause up to 500,000 deaths per year, it is replaceable. In 2018, Resolve to Save Lives, the World Health Organization (WHO), Global Health Advocacy Incubator, and NCD Alliance partnered to achieve global trans fat elimination. The WHO Director-General called for the elimination of trans fat by 2023 through best practice policies outlined in the WHO REPLACE package. Since the accelerated global efforts in 2018, 43 countries have adopted best practice regulations protecting an additional 3.2 billion people and building momentum toward global elimination. Current coverage will prevent 66% of deaths estimated to be caused each year by trans fat in foods. Despite producing and selling iTFA-free products in many countries, companies continue to sell iTFA-containing products in unregulated markets. Global incentives, accountability mechanisms, and regional policies will help achieve the elimination goal.

Performance of self-etching adhesives on caries-affected primary dentin treated with glutaraldehyde or silver diamine fluoride.

OBJECTIVES: to evaluate the quality and stability of adhesive interfaces established by self-etching adhesives on caries-affected primary dentin (CAD) treated with glutaraldehyde (GA) or silver diamine fluoride (SDF). METHODS: 42 primary molars were exposed to a microbiological caries-inducing protocol and divided into 6 groups according to the adhesive system (Clearfil SE - CL or FL Bond II - FL) and pretreatment (water, GA or SDF) applied on CAD. One tooth from each group was analyzed for surface modification using infrared spectroscopy. Crowns were restored with resin composite (n = 36) and cut into beams and slices. The beams were subjected to microtensile testing, Raman spectroscopy and SEM after 24 h and 6 months of storage. The slices were analyzed using Micro-Raman spectroscopy to determine the diffusion zone thickness (DZ) in each period. Data were analyzed by ANOVA and Tukey or Kruskal-Wallis and Dunn tests (α = 0.05%). RESULTS: SDF reduced the immediate bond strength for both adhesives. The control groups showed a decrease in BS after 6 months in artificial saliva. GA increased immediate DZ for FL, while SDF had the opposite effect on CL. GA decreased the DZ for FL at 6 months. There was a predominance of adhesive failures with areas of cohesive dentin fractures within control groups. SIGNIFICANCE: Modifications caused by dentin surface treatments may directly affect the performance of adhesive systems and the quality and stability of adhesive restorations.

Regional differences in infective endocarditis epidemiology and outcomes in Spain. A contemporary population-based study.

INTRODUCTION AND OBJECTIVES: Our aim was to describe the contemporary epidemiological profile of infective endocarditis (IE) in Spain, and to evaluate variations in IE incidence, characteristics, and outcomes among the different Spanish regions (autonomous communities [AC]). METHODS: We conducted a retrospective, population-based study, using data obtained from national in-patient hospital activity of all patients discharged with a diagnosis of IE from hospitals included in the Spanish National Health System, from January 2016 to December 2019. Differences in the IE profile between the 17 Spanish AC were analyzed. RESULTS: A total of 9008 hospitalization episodes were identified during the study period. Standardized incidence of IE was 5.77 (95%CI, 5.12-6.41) cases per 100 000 population. Regarding predisposing conditions, 26.8% of episodes occurred in prosthetic valve carriers, 36.8% had some kind of valve heart disease, and 10.6% had a cardiac implantable electronic device. Significant differences were found between AC in terms of incidence, predisposing conditions, and microbiological profile. Cardiac surgery was performed in 19.3% of episodes in the total cohort, and in 33.4% of the episodes treated in high-volume referral centers, with wide variations among AC. Overall in-hospital mortality was 27.2%. Risk-adjusted mortality rates also varied significantly among regions. CONCLUSIONS: We found wide heterogeneity among Spanish AC in terms of incidence rates and the clinical and microbiological characteristics of IE episodes. The proportion of patients undergoing surgery was low and in-hospital mortality rates were high, with wide differences among regions. The development of regional networks with referral centers for IE could facilitate early surgery and improve outcomes.

Respiratory Complications Are the Main Predictors of 1-Year Mortality in Patients with Hip Fractures: The Results from the Alzira Retrospective Cohort Study.

Introduction: Hip fractures pose a significant challenge for older individuals given their high incidence and one-year mortality rate. The objective of this study was to identify the primary predictors of one-year mortality in older adults hospitalized for hip fractures. Methods: We conducted a retrospective cohort study involving adults aged 70 years or older who were admitted to the hospital for fragility hip fractures between 1 January 2014 and 31 December 2021. A total of 3229 patients were recruited, with 846 (26.2%) experiencing one-year mortality. Results: Respiratory complications (HR 2.42, 95%CI 1.42-4.14; p = 0.001) were the most significant predictors of one-year mortality, followed by hospital readmission (HR 1.96, 95%CI 1.66-2.32; p < 0.001), the male sex (HR 1.88, 95%CI 1.46-2.32; p < 0.001), cardiac complications (HR 1.88, 95%CI 1.46-2.32; p < 0.001), and a diagnosis of dementia at admission (HR 1.37, 95%CI 1.13-1.66; p = 0.001). The Charlson Index and the American Society of Anesthesiologists physical status classification system also significantly increased the mortality risk. Conversely, higher hemoglobin levels at admission and elevated albumin at discharge significantly reduced the mortality risk. Conclusions: The one-year mortality rate is substantial in older adults with hip fractures who are admitted to an orthogeriatric unit. The appropriate management of anemia, nutritional disorders, and comorbidity at admission and during the follow-up could potentially mitigate long-term mortality after hip fractures.

Prevalence and perceptions of flavour capsule cigarettes among adults who smoke in Brazil, Japan, Republic of Korea, Malaysia and Mexico: findings from the ITC surveys.

INTRODUCTION: The global market of flavour capsule cigarettes (FCCs) has grown significantly over the past decade; however, prevalence data exist for only a few countries. This study examined prevalence and perceptions of FCCs among adults who smoke across five countries. METHODS: Cross-sectional data among adults who smoked cigarettes came from the International Tobacco Control Policy Evaluation Project Surveys-Brazil (2016/2017), Japan (2021), Republic of Korea (2021), Malaysia (2020) and Mexico (2021). FCCs use was measured based on reporting one's usual/current brand or favourite variety has flavour capsule(s). Perceptions of the harmfulness of one's usual brand versus other brands were compared between those who used capsules versus no capsules. Adjusted logistic regression models examined correlates of FCC use. RESULTS: There were substantial differences in the prevalence of FCC use among adults who smoke across the five countries: Mexico (50.3% in 2021), Republic of Korea (31.8% in 2021), Malaysia (26.5% in 2020), Japan (21.6% in 2021) and Brazil (6.7% in 2016/2017). Correlates of FCC use varied across countries. Capsule use was positively associated with being female in Japan and Mexico, younger age in Japan, Republic of Korea and Malaysia, high education in Brazil, Japan and Mexico, non-daily smoking in Republic of Korea, and having plans to quit in Japan and Republic of Korea. There was no consistent pattern of consumer perceptions of brand harmfulness. CONCLUSION: Our study documented the high prevalence of FCCs in some countries, pointing to the need to develop and implement regulatory strategies to control these attractive products.

Pre-exposure prophylaxis program in the Community of Madrid: Two years of experience.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) against the human immunodeficiency virus (HIV) is an effective and safe preventive measure. However, it has not reached all target users who could benefit from it. The study aimed to understand the sociodemographic, clinical and behavioral baseline characteristics of PrEP users. As a secondary objective, the use of concomitant medication and drug consumption were described. METHODOLOGY: Observational, retrospective and descriptive study of the sociodemographic, clinical and behavioral characteristics of the users who were included in the PrEP program of the Community of Madrid during the first two years of experience. RESULTS: Two thousand two hundred fifty-six PrEP users were included, 99.0% men, with a mean age of 36.9 years (SD 8.68). 33.1% presented a sexually transmitted infection (STI) on the first visit, highlighting chlamydiasis and rectal gonococci. 70.4% reported using drugs associated with sex, and 42.4% participated in chemsex sessions in the last 3 months. A high percentage of users with concomitant medication was observed (37.6%), highlighting drugs related to mental health and alopecia. CONCLUSIONS: A multidisciplinary approach is required to cover all the needs of PrEP users, including mental health evaluation measures and addiction treatment with the clinical approach.

Do patients with inflammatory bowel disease really know what other immune-mediated inflammatory diseases they are diagnosed with?

BACKGROUND AND AIMS: The association of inflammatory bowel disease (IBD) with other immune-mediated inflammatory diseases (IMIDs) in the same patient is well known. We aimed to evaluate the degree of knowledge that patients with IBD have regarding the coexistence of other IMIDs and to analyze the factors associated with the concordance between self-reported and confirmed medical information. METHODS: Patients with IBD at a tertiary hospital answered a questionnaire on the presence of 54 IMIDs (self-reported diagnosis), and their IMID diagnosis was confirmed in their medical records (reference diagnosis). Agreement between the self-reported IMID and the IMID according to medical records was evaluated. The association between concordance and different predictors was evaluated using logistic regression models. RESULTS: A total of 1,620 patients were included. Six hundred and twenty-six (39%) patients were diagnosed with at least one IMID, and 177 (11%) with two or more. Overall agreement between patients´ self-report and medical records was k:0.61. When we grouped IMIDs according to affected organs or systems, agreement on rheumatic IMIDs was moderate (k:0.58), whereas agreement on cutaneous (k:0.66), endocrine (k: 0.74) and ocular (k:0.73) IMIDs was substantial. Among patients who had IMIDs, the factor associated with greater concordance was female gender, while lower concordance was associated with a lower educational level and the fact that the IMID had been diagnosed at the same time or later than IBD. CONCLUSION: The knowledge that patients with IBD have regarding the coexistence of other IMIDs is poor, especially in rheumatic IMIDs.

Gender differences in clinical features and outcomes of patients over 75 years presenting with acute heart failure. Results of a nationwide study (2016-2019).

BACKGROUND: Heart failure (HF) is a major health problem in Western countries, and a leading cause of hospitalizations and death. There is a scarcity of data on the influence of sex on HF outcomes in elderly patients. The aim of the present study was to analyze differences between men and women in clinical characteristics, in-hospital mortality, 30-day HF readmission rates, cardiovascular mortality and HF readmission rates at 1 year after discharge in patients older than 75 years hospitalized for HF in Spain. METHODS: Retrospective analysis of patients discharged with a main diagnosis of HF from all Spanish public hospitals between 2016 and 2019. Patients aged 75 years or older were selected, and a comparison was made between male and female patients. RESULTS: From 2016 to 2019, a total of 354,786 episodes of HF in this age subgroup were identified, 59.2% being women. The overall mean age was 85.2 ± 5.4 years, being higher in women (85.9 ± 5.5 vs. 84.2 ± 5.3 years, p < 0.001). Risk-adjusted in-hospital mortality was lower in women (odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.92-0.97; p < 0.001). Female sex also showed a protective effect for 30-day readmissions, with an OR of 1.06 (95% CI: 1.04-1.09; p < 0.001). One-year cardiovascular mortality (24.1% vs. 25.0%; p < 0.001) and one-year HF readmission rates (30.8% vs. 31.6%; p = 0.001) were lower in women. CONCLUSIONS: Almost 60% of hospital admissions for HF in people aged 75 years or older between 2016 and 2019 in Spain were female patients. Female sex seems to play a protective role on in-hospital mortality and the rate of admissions and mortality at 1 year after discharge.

3D histology reveals that immune response to pancreatic precancers is heterogeneous and depends on global pancreas structure.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, in part due to its unique stromal and immune microenvironment. Pancreatic intraepithelial neoplasia, or PanIN, is the main precursor lesion to PDAC. Recently it was discovered that PanINs are remarkably abundant in the grossly normal pancreas, suggesting that the vast majority will never progress to cancer. Here, through construction of 48 samples of cm3-sized human pancreas tissue, we profiled the immune microenvironment of 1,476 PanINs in 3D and at single-cell resolution to better understand the early evolution of the pancreatic tumor microenvironment and to determine how inflammation may play a role in cancer progression. We found that bulk pancreatic inflammation strongly correlates to PanIN cell fraction. We found that the immune response around PanINs is highly heterogeneous, with distinct immune hotspots and cold spots that appear and disappear in a span of tens of microns. Immune hotspots generally mark locations of higher grade of dysplasia or locations near acinar atrophy. The immune composition at these hotspots is dominated by naïve, cytotoxic, and regulatory T cells, cancer associated fibroblasts, and tumor associated macrophages, with little similarity to the immune composition around less-inflamed PanINs. By mapping FOXP3+ cells in 3D, we found that regulatory T cells are present at higher density in larger PanIN lesions compared to smaller PanINs, suggesting that the early initiation of PanINs may not exhibit an immunosuppressive response. This analysis demonstrates that while PanINs are common in the pancreases of most individuals, inflammation may play a pivotal role, both at the bulk and the microscopic scale, in demarcating regions of significance in cancer progression.