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At least 145 records · Page 8

Comparative Analysis of Report-Back of Research Results Strategies for Personal Chemical Exposure Data

Background. Report-back of research results (RBRR) is ethically supported and highly requested by participants yet lacks broadly transferable guidelines for RBRR. Effective RBRR must be responsive to target audience needs and may not be addressed by a ‘one-size-fits-all’ approach. Objective. Within a subset of our 19 studies on RBRR, we had the unique opportunity to carry out a comparative analysis of RBRR strategies across cohorts with similar development and evaluation methods, yet distinct in life stage, geography, number and type of chemicals assessed, and community contexts. Methods. We highlight key outcomes from three environmental health studies: an ongoing New York, NY cohort (Fair Start; n=486) and a Detroit, MI cohort (CLEAR; n=34) assessing exposure to ambient urban pollution during pregnancy, and a longitudinal cohort in Houston, TX (Houston-3H) following Hurricane Harvey (n=312). Focus group and survey data were analyzed to identify lessons learned and explore how RBRR supports understanding of environmental health. Results. Commonalities emerged in RBRR development, design, organization, and data visualization, as well as in how RBRR can contribute to an understanding of health-environment connections. Differences included preferences for individual versus community level findings, as well as distinguishable contextual considerations. For pregnancy cohorts, messaging was framed with cultural sensitivity, and to avoid unintended consequences of parental guilt due to prenatal exposures. In the post-disaster Houston-3H study, participants requested additional transparency regarding sampling design and study rationale. Significance. All RBRR case studies reported chemicals without known regulatory or health guidelines, so results were contextualized within the study population. Participants across cohorts requested multi-study comparisons to better understand their results beyond their communities. While foundational RBRR elements (e.g. plain language, graphic organizers) may supersede cohort-specific differences, RBRR should be personalized to encompass perceptions of health across different life-stage, cultural, and environmental contexts.

Vogel, Taylor J.↗

Mortality among workers at the Rocky Flats Plant, 1951–2017

The Rocky Flats (RFs) Plant operated from 1951–1989 as part of the U.S. Department of Energy (DOE) nuclear complex. Its primary mission was weapons component fabrication, whereby workers were potentially exposed to radioactive and non-radioactive hazards. RF worker mortality was compared to the general population, and dose-response relationships between mortality and radiation organ doses were examined. RF workers first employed between 1951 and 1979 for ⩾30 d were identified (n = 9397). Vital status was determined using national and state death records up to 2017. Organ doses from external photons and neutrons irritation and internalised plutonium (Pu), americium (Am), and uranium (U) were modelled as cumulative lagged total doses per year. Beryllium exposure was evaluated as an effect modifier using data from the DOE Nationwide Beryllium Medical Program. Statistical analyses included standardised mortality ratios (SMRs), Cox proportional hazard models, and excess relative risk (ERR) models. Approximately 53.2% of workers were deceased by the end of the study. Nearly 90% were monitored for radiation exposure, with a mean weighted absorbed dose of 59.0 mGy for the lungs. Nearly 45% of workers had intakes of alpha-particle emitting radionuclides, and 46.7% were monitored for neutrons. Leading causes of death included ischemic heart disease (n = 999) and lung cancer (n = 361). The highest SMRs were observed for berylliosis (SMR: 176.9; 95% CI: 76.2, 348.7; n < 10) and asbestosis (SMR: 4.65; 95% CI: 2.23, 8.55; n = 10). Dose-response analyses showed no statistical increase in risk from low-dose radiation including lung cancer (ERR per 100 mGy: −0.02; 95% CI: −0.11, 0.08; n = 361) and Parkinson’s disease (ERR per 100 mGy: 0.13; 95% CI: −0.26, 0.31; n = 57). Approximately 45% of workers were monitored for beryllium, with a weak non-significant indication of effect modification for lung cancer risk. The RF cohort showed no evidence of a statistically significant increase in mortality from occupational radiation exposure. However, this study was limited by low statistical power, which inhibits the ability to detect effects. Future pooling of Million Person Study (MPS) cohorts will provide further insights, particularly regarding Pu as a carcinogen.

61 RADIATION PROTECTION AND DOSIMETRY↗

Multi-modal characterisation of early-stage, subclinical cardiac deterioration in patients with type 2 diabetes

Abstract Background Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure with preserved ejection fraction and cardiac arrhythmias. Precursors of these complications, such as diabetic cardiomyopathy, remain incompletely understood and underdiagnosed. Detection of early signs of cardiac deterioration in T2DM patients is critical for prevention. Our goal is to quantify T2DM-driven abnormalities in ECG and cardiac imaging biomarkers leading to cardiovascular disease. Methods We quantified ECG and cardiac magnetic resonance imaging biomarkers in two matched cohorts of 1781 UK Biobank participants, with and without T2DM, and no diagnosed cardiovascular disease at the time of assessment. We performed a pair-matched cross-sectional study to compare cardiac biomarkers in both cohorts, and examined the association between T2DM and these biomarkers. We built multivariate multiple linear regression models sequentially adjusted for socio-demographic, lifestyle, and clinical covariates. Results Participants with T2DM had a higher resting heart rate (66 vs. 61 beats per minute,p < 0.001), longer QTc interval (424 vs. 420ms,p < 0.001), reduced T wave amplitude (0.33 vs. 0.37mV,p < 0.001), lower stroke volume (72 vs. 78ml,p < 0.001) and thicker left ventricular wall (6.1 vs. 5.9mm,p < 0.001) despite a decreased Sokolow-Lyon index (19.1 vs. 20.2mm,p < 0.001). T2DM was independently associated with higher heart rate (beta = 3.11, 95% CI = [2.11,4.10],p < 0.001), lower stroke volume (beta = −4.11, 95% CI = [−6.03, −2.19],p < 0.001) and higher left ventricular wall thickness (beta = 0.133, 95% CI = [0.081,0.186],p < 0.001). Trends were consistent in subgroups of different sex, age and body mass index. Fewer significant differences were observed in participants of non-white ethnic background. QRS duration and Sokolow-Lyon index showed a positive association with the development of cardiovascular disease in cohorts with and without T2DM, respectively. A higher left ventricular mass and wall thickness were associated with cardiovascular outcomes in both groups. Conclusion T2DM prior to cardiovascular disease was linked with a higher heart rate, QTc prolongation, T wave amplitude reduction, as well as lower stroke volume and increased left ventricular wall thickness. Increased QRS duration and left ventricular wall thickness and mass were most strongly associated with future cardiovascular disease. Although subclinical, these changes may indicate the presence of autonomic dysfunction and diabetic cardiomyopathy. Graphical Abstract

Cardiovascular System & Cardiology↗

The relationship between urinary selenium levels and risk of gestational diabetes mellitus: A nested case–control study

Background Selenium (Se) is an essential trace element for the human body. Serum Se and urinary Se are also biomarkers to assess Se exposure status. However, studies focusing on the association between urinary Se and the risk of gestational diabetes mellitus (GDM) are rare. Objective To investigate the association between urinary Se and the risk of GDM. Methods A nested case–control study based on a prospective birth cohort in Wuhan, China, which focuses on the effects of prenatal environmental factors exposure on pregnant women and children’s health was conducted. Two hundred and twenty-six cases and 452 controls were included. Maternal urine samples were collected before GDM diagnosis, and the urinary Se levels were determined. We assessed the association of urinary Se with GDM by conditional logistic regression with maternal urinary Se level as a categorical variable, and estimated the association between Se and glucose levels by multiple linear regression. The potential modifier roles of maternal age and fetal sex have also been assessed. Results Lower urinary level of Se was significantly associated with a higher risk of GDM (OR = 2.35 for the tertile 1, 95% CI:1.36-4.06; adjusted OR = 1.79 for the tertile 2, 95%CI:1.09-2.95; p for trend = 0.01). Fetal sex had an interaction with Se in the association with GDM. The association was more pronounced among pregnant women with female fetuses than with male fetuses. Discussion Our study suggested a significant negative association between urinary Se and the risk of GDM, and this association may vary depending on the fetal sex.

Liu, Yuanxia↗

Patterns of Care, Tolerability, and Safety of the First Cohort of Patients Treated on a Novel High-Field MR-Linac Within the MOMENTUM Study: Initial Results From a Prospective Multi-Institutional Registry

High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Stochastic parametric skeletal dosimetry model for humans: General approach and application to active marrow exposure from bone-seeking beta-particle emitters

The objective of this study is to develop a skeleton model for assessing active marrow dose from bone-seeking beta-emitting radionuclides. This article explains the modeling methodology which accounts for individual variability of the macro- and microstructure of bone tissue. Bone sites with active hematopoiesis are assessed by dividing them into small segments described by simple geometric shapes. Spongiosa, which fills the segments, is modeled as an isotropic three-dimensional grid (framework) of rod-like trabeculae that “run through” the bone marrow. Randomized multiple framework deformations are simulated by changing the positions of the grid nodes and the thickness of the rods. Model grid parameters are selected in accordance with the parameters of spongiosa microstructures taken from the published papers. Stochastic modeling of radiation transport in heterogeneous media simulating the distribution of bone tissue and marrow in each of the segments is performed by Monte Carlo methods. Model output for the human femur at different ages is provided as an example. The uncertainty of dosimetric characteristics associated with individual variability of bone structure was evaluated. An advantage of this methodology for the calculation of doses absorbed in the marrow from bone-seeking radionuclides is that it does not require additional studies of autopsy material. The biokinetic model results will be used in the future to calculate individual doses to members of a cohort exposed to 89,90 Sr from liquid radioactive waste discharged to the Techa River by the Mayak Production Association in 1949–1956. Further study of these unique cohorts provides an opportunity to gain more in-depth knowledge about the effects of chronic radiation on the hematopoietic system. In addition, the proposed model can be used to assess the doses to active marrow under any other scenarios of 90 Sr and 89 Sr intake to humans.

59 BASIC BIOLOGICAL SCIENCES↗

Validation of a Proteomic Signature of Lung Cancer Risk from Bronchial Specimens of Risk-Stratified Individuals

A major challenge in lung cancer prevention and cure hinges on identifying the at-risk population that ultimately develops lung cancer. Previously, we reported proteomic alterations in the cytologically normal bronchial epithelial cells collected from the bronchial brushings of individuals at risk for lung cancer. The purpose of this study is to validate, in an independent cohort, a selected list of 55 candidate proteins associated with risk for lung cancer with sensitive targeted proteomics using selected reaction monitoring (SRM). Bronchial brushings collected from individuals at low and high risk for developing lung cancer as well as patients with lung cancer, from both a subset of the original cohort (batch 1: n = 10 per group) and an independent cohort of 149 individuals (batch 2: low risk (n = 32), high risk (n = 34), and lung cancer (n = 83)), were analyzed using multiplexed SRM assays. ALDH3A1 and AKR1B10 were found to be consistently overexpressed in the high-risk group in both batch 1 and batch 2 brushing specimens as well as in the biopsies of batch 1. Validation of highly discriminatory proteins and metabolic enzymes by SRM in a larger independent cohort supported their use to identify patients at high risk for developing lung cancer.

60 APPLIED LIFE SCIENCES↗

Sociodemographic effects on pandemic fatigue are multifaceted and context-specific: A longitudinal analysis of physical distancing adherence

Pandemic fatigue emerged early during the COVID-19 pandemic and remains a concern as new variants emerge and ongoing public health measures are needed to control them. A wide range of factors can affect pandemic fatigue, but empiric research indicating which may be most important to adherence in specific populations is lacking. We conducted a longitudinal study of changes in physical distancing in two cohorts: adults living with children <18 years and adults ≥50 years old. Six types of non-work, non-household contacts were ascertained at six times from April to October 2020. We used generalized estimating equations Poisson regression to estimate the one-week change in contact rate and how this differed based on sociodemographic characteristics. The rate of all contact types increased during the middle of the study period and decreased toward the end. Changes in contact rates over time differed according to several sociodemographic characteristics, including age, gender, race/ethnicity, education, household composition, and access to transportation. Furthermore, the factors influencing the rate of change in contact rates differed by the type or setting of the contact, for example contacts as a result of visiting another person’s home versus during a retail outing. These results provide evidence for potential mechanisms by which pandemic fatigue has resulted in lower physical distancing adherence.

60 APPLIED LIFE SCIENCES↗

The POINTER Imaging baseline cohort: Associations between multimodal neuroimaging biomarkers, cardiovascular health, and cognition

Abstract INTRODUCTION The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. METHODS Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta‐amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. RESULTS A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ−, Aβ+ (29%) participants were older, had higher apolipoprotein E (APOE) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. DISCUSSION In this heterogenous, at‐risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non‐AD (Alzheimer's disease) pathway to brain injury and cognitive decline. Highlights The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle POINTER Imaging collected multimodal neuroimaging data in this unique, at‐risk cohort Amyloid burden was related to age, apolipoprotein E (APOE) ε4 carriage, and measures of disease progression Associations between amyloid and tau, and tau and cognition, were relatively weak CVD risk and tau pathology were independently related to memory

Neurosciences & Neurology↗

Organochlorine pesticides and risk of papillary thyroid cancer in U.S. military personnel: a nested case-control study

Background: The effects of organochlorine pesticide (OCP) exposure on the development of human papillary thyroid cancer (PTC) are not well understood. A nested case-control study was conducted with data from the U.S. Department of Defense Serum Repository (DoDSR) cohort between 2000 and 2013 to assess associations of individual OCPs serum concentrations with PTC risk. Methods: This study included 742 histologically confirmed PTC cases (341 females, 401 males) and 742 individually-matched controls with pre-diagnostic serum samples selected from the DoDSR. Associations between categories of lipid-corrected serum concentrations of seven OCPs and PTC risk were evaluated for classical PTC and follicular PTC using conditional logistic regression, adjusted for body mass index category and military branch to compute odds ratios (OR) and 95% confidence intervals (CIs). Effect modification by sex, birth cohort, and race was examined. Results: There was no evidence of associations between most of the OCPs and PTC, overall or stratified by histological subtype. Overall, there was no evidence of an association between hexachlorobenzene (HCB) and PTC, but stratified by histological subtype HCB was associated with significantly increased risk of classical PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 1.61, 95% CI, 1.09, 2.38; p for trend = 0.05) and significantly decreased risk of follicular variant PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 0.38, 95% CI, 0.16, 0.91; p for trend = 0.04). Further stratified by sex, risk of classical PTC was higher for females (third tertile above LOD vs. <LOD, OR = 2.23, 95% CI: 1.23, 4.06; p-trend = 0.02) than for males (OR = 1.22, 95%CI: 0.72–2.08; p-trend = 0.56), though the test for interaction by sex was not statistically significant (p-interaction = 0.30). Similarly, β-hexachlorocyclohexane (β-HCCH) was associated with a higher risk for classical PTC for women with concentrations ≥LOD versus <LOD (OR = 1.76, 95% CI: 1.07, 2.89), while the effects were null for men. There were no consistent trends when stratified by race or birth year. Conclusions: The U.S. Environmental Protection Agency has classified HCB and other OCPs we studied here as probable human carcinogens. Our findings of increased risks for classical PTC associated with increased concentrations of HCB and β-HCCH, which were stronger among females, should be replicated in future studies of other populations.

60 APPLIED LIFE SCIENCES↗

Dose reconstruction for plutonium-239 intakes at the Rocky Flats Plant

Purpose: The Rocky Flats (RF) Plant was a weapons manufacturing facility that operated from the early 1950s to 1989. Its primary missions were the production of plutonium (Pu) pits for thermonuclear weapons and the processing of retired weapons for Pu recovery. The purpose of this study was to estimate radiation doses to a cohort of 4499 RF workers from an intake of 239 Pu, the primary plutonium isotope handled at the site. Materials and methods: The latest biokinetic models of the International Commission on Radiological Protection, or site-specific variations of those models, were used to estimate 239 Pu intakes for each worker based on model fits to bioassay data often coupled with lung measurements. Results: Urinary excretion and lung retention data for most 239 Pu intakes could be fit reasonably well by a mixture of Pu dioxide and moderately soluble material. For some workers, better fits were obtained by application of other absorption types including Type S, 239 Pu nitrate, or pure 239 Pu dioxide, or by assuming intake via a wound. The lungs typically received the highest tissue doses, with fifty-year committed equivalent doses in the range of 0.5–1 Sv for 275 workers, 1–5 Sv for 115 workers, and greater than 5 Sv for 12 workers. Conclusions: RF was a unique site regarding a large number of lung measurements available for determining the appropriate absorption types for inhaled material. Further, this provided higher confidence in reconstructed 239 Pu doses than is generally gained from urinary data alone.

61 RADIATION PROTECTION AND DOSIMETRY↗

PET Imaging of Leg Arteries for Determining the Input Function in PET/MRI Brain Studies Using a Compact, MRI-Compatible PET System

In this work, we used a compact, high-resolution, and magnetic resonance imaging (MRI)-compatible positron emission tomography (PET) camera (VersaPET) to assess the feasibility of measuring the image-derived input function (IDIF) from arteries in the leg with the ultimate goal of enabling fully quantitative PET brain imaging without blood sampling. We used this approach in five 18 F-FDG PET/MRI brain studies in which the input function was also acquired using the gold standard of serial arterial blood sampling. After accounting for partial volume, dispersion, and calibration effects, we compared the metabolic rates of glucose (MRglu) quantified from VersaPET IDIFs in 80 brain regions to those using the gold standard and achieved a bias and variability of <5% which is within the range of reported test-retest values for this type of study. We also achieved a strong linear relationship (R 2 >0.97) against the gold standard across regions. The results of this preliminary study are promising and support further studies to optimize methods, validate in a larger cohort, and extend to the modeling of other radiotracers.

47 OTHER INSTRUMENTATION↗

A framework for inferring and analyzing pharmacotherapy treatment patterns

Background: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied to real-world data. Methods: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy fills, dispensed inpatient antidepressant medications, emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse. Results: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39 mg. Additionally, we found associations between outcomes and dosage change. Conclusions: For 252,179 Veterans who served in Iraq and Afghanistan with subsequent MDD noted in their electronic medical records, we documented and described the major pharmacotherapy prescription patterns implemented by Veterans Health Administration providers. Ten patterns accounted for almost 70% of the data. Associations between antidepressant usage and outcomes in observational data may be confounded. The low numbers of adverse events, especially those associated with all-cause mortality, make our calculations imprecise. Furthermore, our outcomes are also indications for both disease and treatment. Despite these limitations, we demonstrate the usefulness of our framework in providing operational insight into clinical practice, and our results underscore the need for increased monitoring during critical points of treatment.

60 APPLIED LIFE SCIENCES↗

Positron emission tomography harmonization in the Alzheimer's Disease Neuroimaging Initiative: A scalable and rigorous approach to multisite amyloid and tau quantification

Abstract INTRODUCTION A key goal of the Alzheimer's Disease NeuroImaging Initiative (ADNI) positron emission tomography (PET) Core is to harmonize quantification of β‐amyloid (Aβ) and tau PET image data across multiple scanners and tracers. METHODS We developed an analysis pipeline (Berkeley PET Imaging Pipeline, B‐PIP) for ADNI Aβ and tau PET images and applied it to PET data from other multisite studies. Steps include image pre‐processing, refacing, magnetic resonance imaging (MRI)/PET co‐registration, visual quality control (QC), quantification of tracer uptake, and standardization of Aβ and tau standardized uptake value ratios (SUVrs) across tracers. RESULTS Measurements from 10,105 cross‐sectional and longitudinal Aβ and tau PET scans acquired in several studies between 2010 and 2024 can be processed, harmonized, and directly merged across tracers and cohorts. DISCUSSION The B‐PIP developed in ADNI is a scalable image harmonization approach used in several observational studies and clinical trials that facilitates rigorous Aβ and tau PET quantification and data sharing. Highlights Quantitative results from ADNI Aβ and tau PET data are generated using a rigorous, scalable image processing pipeline This pipeline has been applied to PET data from several other large, multisite studies and trials Quantitative outcomes are harmonizable across studies and are shared with the scientific community

Neurosciences & Neurology↗

The effect of protein mutations on drug binding suggests ensuing personalised drug selection

The advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in the state of Qatar. From Sanger sequencing, we identified several new deleterious mutations in the estrogen receptor 1 gene (ESR1). The effect of these mutations on drug treatment in the protein target encoded by ESR1, namely the estrogen receptor, was achieved via rapid and accurate protein–ligand binding affinity interaction studies which were performed for the selected drugs and the natural ligand estrogen. Four nonsynonymous mutations in the ligand-binding domain were subjected to molecular dynamics simulation using absolute and relative binding free energy methods, leading to the ranking of the efficacy of six selected drugs for patients with the mutations. Our study shows that a personalised clinical decision system can be created by integrating an individual patient’s genomic data at the molecular level within a computational pipeline which ranks the efficacy of binding of particular drugs to variant proteins.

59 BASIC BIOLOGICAL SCIENCES↗

Clean Energy Cybersecurity Accelerator Cohort 1: Authentication and Authorization

In the 2023 National Cybersecurity Strategy, the Biden-Harris Administration defines the need for a "defensible, resilient digital ecosystem where it is costlier to attack systems than defend them." The strategy cites the Clean Energy Cybersecurity Accelerator (CECA) as an exemplary effort to bolster the security and resilience of clean energy generation. These efforts help "secure the clean energy grid of the future and [generate] security best practices that extend to other critical infrastructure sectors" and promise broad and far-reaching impacts to bridge the capabilities of private industry and the needs of energy production. Cohort 1 of CECA launched in the fall of 2022 with a focus on solutions that provide strong authentication and authorization for industrial control systems to mitigate attacks on the energy grid. Authentication and authorization verify that the identity (authentication) and permissions (authorization) of a user or device are aligned with their assigned roles. Weaknesses in either can have serious repercussions. To assess the strength of Cohort 1's solutions, CECA devised threat scenarios grounded in historical precedents: the CECA team reviewed exploits from real-world case studies of state-sponsored actors to match the assessment's attack paths and targets. Cohort 1 results provided the energy industry, product vendors, and related agencies valuable insights into the efficacy and applicability of solutions in common system configurations under realistic threat scenarios. The results of the assessment highlight points for interrogation and improvement in subsequent technology iterations. CECA's evaluations are part of an ongoing conversation and collaboration to bolster U.S. cyber resilience against adversaries today and in the future.

24 POWER TRANSMISSION AND DISTRIBUTION↗