Population Level Research Articles

Brain Asymmetry, Individual-Level and Population-Level Asymmetry as Minimization of Energy and Free Energy

Asymmetries in the organization of the nervous system have been observed in many animals of different species, from the nematode C. elegans to humans, attracting considerable attention and stimulating studies and the formulation of hypotheses aimed at understanding the existence and behavioral consequences of brain asymmetries at both the individual and population levels. We show that these asymmetries and the various phenomenological aspects of brain asymmetry, for example, sparing of neural tissue, control of motor responses and, at the population level, evolutionarily stable strategies in mathematical game theory arise as consequence of the general principles of minimization of energy and free energy, characterizing the lowest energy state. The resulting model covers all the different aspects of current models. At the individual level, the antisymmetric configuration realizes the lowest energy state of the system. At the population level, the minimization of free energy induces the emergence of directional asymmetry and collective properties of the population. For a large number of components, the population is felt by each of them as a whole collective agent rather than as a collection of individuals.

Economic evaluation of work productivity gains associated with ribociclib (RIB) in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) early breast cancer (EBC) in the United States.

e23117 Background: Despite treatment with standard-of-care adjuvant endocrine therapy, many patients with HR+/HER2− EBC continue to experience recurrences, most of which are distant. Recurrences can lead to extensive costs, including indirect costs associated with the loss of income due to reduction or complete loss in the ability to work. The cyclin-dependent kinase 4/6 inhibitor RIB + an aromatase inhibitor (AI) was FDA-approved in Sept 2024 to reduce risk of recurrence among patients with HR+/HER2− disease (stage II and III at high risk of recurrence). At a 44.2 mo median follow-up of NATALEE, with all patients off RIB, RIB + a nonsteroidal AI (NSAI) vs NSAI significantly improved invasive disease-free survival (iDFS; HR, 0.715 [0.609-0.840]) with a 4y landmark Δ of 4.9%. This analysis assessed long-term work productivity gains of treating patients with HR+/HER2− EBC with RIB+NSAI vs NSAI from a US societal perspective. Methods: A Markov model was developed to estimate the distribution of being in 4 health states (invasive disease-free [IDF], locoregional recurrence [LR], distant recurrence [DR], and death) for patients with HR+/HER2− EBC treated with RIB+NSAI vs NSAI over a lifetime horizon. Efficacy data were modeled using patient-level iDFS data from the NATALEE trial up to 4.5y (median follow up: 44.2 mo) using Kaplan Meier (KM) method and parametric extrapolation of the KM curves afterward. Other clinical data were obtained from literature. Data on age- and gender-adjusted employment rates, wages, and number of workdays lost in each health state were obtained from published literature and applied to the distribution of patients across each health state. Work productivity-related indirect cost across health states was estimated until the cohort reached 65y, retirement age assumed for the base-case. All cost inputs were in 2024 USD. Work productivity was estimated at individual pt and US population levels. Scenario analyses to test alternative assumptions were conducted. Results: Patients receiving RIB+NSAI on average spent more time in IDF and less time in LR and DR states vs those receiving NSAI alone. A pt receiving RIB+NSAI was estimated to have more lifetime earnings ($494,317) vs those receiving NSAI ($482,581), with the work-related productivity gain from the addition of RIB estimated at $11,736 per patient. At the US population level, the total lifetime work productivity gains for the estimated 54,257 patients receiving the addition of RIB to NSAI in 2024 were projected to be $637.7 million. Conclusions: The addition of RIB to NSAI in the adjuvant treatment of HR+/HER2− EBC not only improves iDFS but can also yield substantial work productivity gains for individual patients with HR+/HER2− EBC and for society as a whole.

Association between walking speed and multimorbidity patterns in community-dwelling older adults with diabetes and/or hypertension: a latent class analysis.

Diabetes (DM) plus hypertension (HTN) is a prevalent multimorbidity pattern. However, it is unclear which other diseases frequently coexist with DM and HTN and their impact on walking speed. Therefore, we identified multimorbidity patterns in community-dwelling older adults with: i) DM, ii) HTN and iii) DM + HTN and we examined the association between multimorbidity patterns and walking speed. This was a cross-sectional study. We included 5090 community-dwelling older adults, from the National Health and Aging Trends Study, a population-based study of older adults (≥ 65years) in the U.S. We performed latent class analysis to identify multimorbidity patterns and then performed ANCOVA to examine the association between these multimorbidity patterns and walking speed. We identified 10 unique multimorbidity patterns: low multimorbidity, joint multimorbidity, cardiovascular-joint multimorbidity, psychological-joint multimorbidity, cardiovascular multimorbidity, cardiovascular-joint-respiratory multimorbidity, Metabolic-bone-joint multimorbidity, metabolic-cardiovascular-joint multimorbidity, metabolic-psychological-joint multimorbidity, metabolic-cardiovascular-joint-respiratory multimorbidity and metabolic-joint multimorbidity. Multimorbidity patterns with larger numbers of diseases and those that included psychological conditions (depression or anxiety) were associated with slower walking speeds compared to multimorbidity patterns with somatic conditions alone (e.g., arthritis). At a population level, these multimorbidity patterns may help to identify subgroups of older adults with slower walking speed who may benefit from targeted assessment and management to improve their walking speed. The online version contains supplementary material available at 10.1007/s40200-025-01598-5.

APOE4 and prevalence of degenerative cervical myelopathy: A genetic case-control study in the UK Biobank cohort.

APOE4 and prevalence of degenerative cervical myelopathy: A genetic case-control study in the UK Biobank cohort.

Plasma epigenomic profiling to reveal molecular correlates of response and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC).

5074 Background: The PSMA-directed radioligand therapy, 177Lu-PSMA-617, is the most recent FDA approved therapy in mCRPC. Despite prolonging progression-free survival (PFS) and overall survival (OS) at a population level, response to therapy is heterogeneous and resistance remains poorly understood. Benchmarking molecular correlates of clinical outcomes following 177Lu-PSMA-617 could provide critical insights into predicting response and resistance to therapy. We applied a multimodal epigenomic liquid biopsy platform to plasma samples from mCRPC patients treated with 177Lu-PSMA-617 to characterize molecular features associated with treatment response. Methods: Baseline plasma samples were collected from patients with mCRPC at the time of PSMA PET imaging and initiation of 177Lu-PSMA-617 therapy. Epigenomic profiling of genome-wide signals from promoters, enhancers, and DNA methylation was performed on 1 mL of plasma (N=85, ctDNA ≥ 0.5%). Plasma epigenomic signals were analyzed to evaluate pathway activity, their association with treatment response using Cox proportional hazards model and neuroendocrine transformation. Response to 177Lu-PSMA-617 was determined by investigator-assessed clinical-radiographic (CR)-PFS. Results: We observed a significant association between predicted PSMA PET SUV mean from plasma epigenomic signals (using a previously derived model) and response to 177Lu-PSMA-617 (hazard ratio [HR] = 0.27, P<0.05). Further, unbiased analysis of plasma epigenomic signal across the genome identified FOLH1 (the gene encoding PSMA) as being significantly associated with CR-PFS (P<0.05). Low circulating tumor fraction was also independently associated with favorable CR-PFS (HR = 0.42, P<0.05). Pathway analysis identified activation of estrogen signalling and cellular plasticity to be associated with shorter CR-PFS, and immune signalling gene signatures to be associated with longer CR-PFS (all FDR<0.1). A subset of patients (n=4) exhibited increased plasma epigenomic signal at neuroendocrine genes, such as CHGA , DLL3 and SEZ6 . While too small to draw statistical conclusions, elevated neuroendocrine gene activity in plasma was associated with numerically shorter OS. Conclusions: Epigenomic profiling of plasma cfDNA enabled minimally-invasive characterization of molecular correlates of response and resistance, identifying genes and pathways associated with favorable and poor outcomes to 177Lu-PSMA-617 in mCRPC. By providing real-time insights into tumor biology and therapeutic efficacy, this platform supports precision medicine approaches for optimizing outcomes in PSMA-targeted therapies.

The effect of enrolment policies on patient affiliation to a family physician: A quasi-experimental evaluation in Canada.

The effect of enrolment policies on patient affiliation to a family physician: A quasi-experimental evaluation in Canada.

Restrictive and permissive alcohol policies during the COVID-19 pandemic and their association with alcohol consumption in the United States.

Restrictive and permissive alcohol policies during the COVID-19 pandemic and their association with alcohol consumption in the United States.

Relationship Between Maternal Height with Children Under Two Years Old Stunting Occurrence

ABSTRACT The prevalence of stunting is often used as a marker of child malnutrition at the population level. The height of the mother reflects the previous nutritional and socio-economic status of the mother. This research aims to determine the relationship between maternal height and the incidence of stunting in children under two years old. An analytical study with a case-control study design was conducted based on medical records of mothers and their infants born in 2022 at a health center in Ngawi. This study identified 32 children with stunting were taken as cases and 32 other children with normal nutritional status as control. Maternal height had no association with the incidence of stunting (p=0.210). Adult height varies across countries, the extent to which the prevalence of stunting reflects parental height is also likely to vary. From a policy perspective, it is helpful to distinguish between the prevalence of child stunting attributable to the current environment and that attributable to parental height. Keywords: Maternal Height; Nutritional Status; Stunting

A Population-based Analysis of Gender Differences in Survival Outcomes for Gastric Gastrointestinal Stromal Tumors.

A Population-based Analysis of Gender Differences in Survival Outcomes for Gastric Gastrointestinal Stromal Tumors.

Survival outcomes for ovarian cancer patients in the post–poly ADP-ribose polymerase inhibitor (PARPi) era in the US.

5586 Background: PARPi introduction in clinical practice has led to major changes in the therapeutic landscape for ovarian cancer (OC) 1 . Olaparib is approved alone or in combination with bevacizumab for the first line maintenance therapy of BRCA-mutated or homologous repair deficient (HRD) OC. We hypothesize that the introduction of PARPi in routine clinical practice for maintenance therapy in OC has resulted in improvements in survival outcomes among OC patients (pts) treated in the real world. Methods: Pts with a diagnosis of stage III/IV epithelial OC age ≥18 years between 2000-2021 were obtained from the Surveillance, Epidemiology, and End Results (SEER) Database. A cutoff on 2017 was made based on the initial approval of PARPi for maintenance therapy. Statistical analyses were conducted with SPSS. Pts characteristics were reported in frequencies and compared with the Chi-squared test. The Kaplan-Meier method was used to estimate median OS. Cox Regression was used identify independent prognostic factors of survival. P-value ≤0.05 was considered statistically significant. Results: 59,913 pts were included with median age 63 years, 60.9% non-hispanic white, and 55.8% with serous histology. 44,873 pts were diagnosed in the pre-PARPi cohort and 15,040 in the post-PARPi cohort. 76.3% and 76.1% of pts received any chemotherapy and surgery, respectively. Similar distribution in analyzed variables was found when comparing among eras. The median OS for pre-PARPi pts was 37 months (95%CI: 36.4-37.6) and post-PARPi pts was 38 months (36.6-39.4), p=0.023. In multivariate analysis, pts diagnosed in the post-PARPi era had improved OS compared with pts in pre-PARPi era (HR=0.93, 95%CI:0.91-0.96, p<0.001). Conclusions: To the extent of our knowledge, this study is the first real world analysis of survival outcomes in OC pts after the introduction of PARPi at a population level in the US. The introduction of PARPi maintenance therapy has resulted in a modest improvement in OS in the overall OC population unselected for BRCA or HRD status. 1. Tew WP et al. J Clin Oncol. 2020 Oct 20;38(30):3468-93.

Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats.

Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats.

Nanocellulose dysregulated glucose homeostasis in female mice on a Western diet: The role of gut microbiome.

Nanocellulose dysregulated glucose homeostasis in female mice on a Western diet: The role of gut microbiome.

Disparities in guideline-concordant treatment receipt for localized prostate cancer (PCa): A SEER-based analysis.

e17155 Background: Localized PCa is classified into six NCCN risk categories, each with specific treatment recommendations. However, treatment concordance across these categories and its variation by race in clinical practice remain unexplored. Therefore, we aim to describe patterns of guideline-concordant treatment receipt for localized PCa across risk groups and race. Methods: Surveillance, Epidemiology, and End Results (SEER) database (2018–2020) was queried to identify patients with localized PCa from 17 registries. Data regarding clinical T stage, Gleason patterns, PSA level, biopsy cores and initial treatment received (radiation, radical prostatectomy, systemic therapy) was obtained. Each patient was then stratified into one of six NCCN-based risk categories using a rule-based algorithm. Using the stratified risk category of each patient, treatment recommendations were obtained from the NCCN guidelines. Concordance was assessed by comparing the received treatment and guideline-recommended treatment. A focused bi-variate logistic regression analysis was performed adjusting for risk groups, and race. Odds ratio (OR) with 95% confidence intervals (CI) were computed to quantify the magnitude of guideline-discordant treatment receipt. Results: This analysis included 69,584 patients with localized PCa (White: 53,875 [77.4%]; Black: 11,265 [16.2%]; Asian/Pacific Islander: 4,133 [5.9%]; American Indian/Alaska Native: 311 0.5%]). In terms of risk groups, patients in higher risk categories had increased odds of discordance compared to the lower risk groups (Table). In terms of race, Black men had significantly higher odds of receiving guideline-discordant therapy (OR:1.67, 95% CI:1.58–1.76), while no statistically significant difference was observed with American Indian/Alaska Native men (OR:1.21, 95% CI: 0.92–1.61) and Asian/Pacific Islander men (OR:1.05, 95% CI:0.97–1.14) compared to White men. Conclusions: Population level data, based on limited sample size in some groups, suggests that treatment concordance with NCCN guidelines varies by risk group and race in localized PCa. Black patients, and those with higher risk groups were more likely to receive guideline-discordant therapy. These findings highlight the need for strategies and prospective studies at individual patient level to evaluate and enhance guideline adherence to promote personalized care for these patients. Variable Discordant Treatment (%) OR (95% CI) White 22168 (41.1) REF Black 5653 (47.5) 1.67 (1.58-1.76) * Asian/Pacific Islander 1822 (44.1) 1.05 (0.97-1.14) American Indian/Alaska Native 191 (61.4) 1.22 (0.92- 1.61) Very Low Risk 770 (9) REF Low Risk 146 (2) 0.16 (0.13-0.19) * Favorable Risk 35 (0.4) 0.03 (0.02-0.04) * Unfavorable Risk 15125 (83.2) 36.30 (33.72-39.25) * High/Very High Risk 13441 (50) 7.32 (6.83-7.86) * * p <0.05.

Assessment of smartwatch-based electrocardiogram (ECG) abnormality detection among childhood cancer survivors.

10069 Background: Childhood cancer survivors (CCS), exposed to cardiotoxic cancer therapies, are at lifelong risk for premature cardiovascular disease. However, adherence to guideline recommended screening is low later in life, long after cancer treatment. Novel wearable technologies offer a potential low-cost, easy screening method for arrythmias in CCS, including AF, bradycardia, and tachycardia. However, their utility in population level screening for CCS is unknown. Methods: We collected paired single lead smartwatch with FDA cleared ECG functionality and 12-lead 10 second ECGs from adult participants in the St. Jude Lifetime Cohort Study (SJLIFE) who were treated for their primary cancer 1962-2012 and survived ≥5 years. Participants completed an in-person comprehensive examination including a standard 10 second 12-lead ECG recording as well as single lead rhythms were collected using a smartwatch. The smartwatch provided automated annotations including sinus rhythm, AF, bradycardia (HR<60 bpm), tachycardia (HR>100 bpm), and inconclusive rhythm. We compared the smartwatch generated statements to reference diagnostic statements generated by GE MUSE system. Results: There were 598 same day ECG pairs in 580 participants (83% White, 14% Black, 50% male, and mean age(SD) 37(10) years). The mean(SD) times between smartwatch and reference ECG recordings were 32(50) minutes. The heart rate from reference ECG and smartwatch ECG had a Pearson Correlation of r=0.85 (p<0.001). The smartwatch ECGs presented statistically significantly (p<0.001) higher heart rates compared to reference ECGs with mean heart rate difference (95% confidence interval) of 1.2 (0.5-1.8) beats per minute. Standard 12-lead ECGs processed by GE MUSE annotations included 478 (80%) sinus rhythm and 120 (20%) as ‘no sinus rhythm’ with 1 (0.2%) AF, 57 (9.5%) sinus bradycardia, 18 (3.2%) sinus tachycardia and 28 (6.4%) other rhythms. The smartwatch assigned sinus rhythm to 590 (98.7%) of these ECGs. The detailed rhythm annotations between reference ECG and smartwatch ECGs are summarized in Table 1. The smartwatch detected only 3.5% (2 of 57) of reference bradycardia, none of the 18 reference tachycardia and 1 AF event. Overall, among 120 ECGs labelled as ‘no sinus rhythm’ by the reference device, only 3 (2.6%) of them were also labeled as ‘no sinus rhythm’ by the smartwatch. Conclusions: The smartwatch considered in this study produces heart rate that is not clinically different than heart rate calculated by a reference 12-lead ECG. However, the ECG abnormalities identified by reference ECGs were typically missed by the smartwatch. Comparison of GE MUSE and smartwatch ECG statements. Smartwatch Statements Sinus Rhythm Atrial Fibrillation Low Heart Rate High Heart Rate Inconclusive/Poor GE MUSE Statements Sinus Rhythm 478 0 3 0 2 483 Atrial Fibrillation 1 0 0 0 0 1 Bradycardia 55 0 2 0 0 57 Tachycardia 18 0 0 0 1 19 Other Rhythm 38 0 0 0 0 38 Total 590 0 6 0 3 598

Separating the signal from the noise: how mortality rate associated with hip fracture changes over time after accounting for population level mortality rates.

Separating the signal from the noise: how mortality rate associated with hip fracture changes over time after accounting for population level mortality rates.

Towards a shared understanding of the concept of cure in early-stage treatment of solid tumors.

e13866 Background: Advancement in early-stage solid tumor treatments, notably with potentially curative therapies in (neo)adjuvant settings, underscores the need of establishing common terminology around the concept of cure incorporating different perspectives and audiences. This study explores how various terminologies can enhance communication between stakeholders. Methods: A systematic literature review was conducted in MEDLINE and Embase databases for global English language publications (January 2014 to July 2024) using a PICOTS framework to identify explicit and implicit definitions of cure, clinical criteria for determining cure, and modeling approaches. The focus was on specific solid tumors, including melanoma, non-small cell lung cancer, renal cell carcinoma, triple-negative breast cancer, bladder cancer, and head and neck cancer, where early-stage (neo)adjuvant drug therapies have been approved. This was supplemented with conference abstract searches. Results: Across the 62 articles identified, cure was most discussed in breast, melanoma and lung cancer but there was no consistency in defining cure for (neo)adjuvant therapies. Definitions varied but centered around three concepts alone or in combination: absence of disease progression/recurrence (27%), eradication of cancerous cells (15%), and survival (79%). The different applications, driven by stakeholder perspectives, resulted in heterogeneity and inconsistency. Publications focusing on cure metrics and survival adopted a population-level perspective familiar to payers and public health professionals. Established approaches to modeling cure exist in the economic literature but differences were observed in application influencing payer views on cure. Only one global publication categorized cancer types based on cure metric estimations. Definitions emphasizing absence of disease progression and eradication of cancer cells aligned more with a "medical cure" perspective, resonating with clinicians who prefer describing patients as long-term survivors rather than being cured. Historical population-level evidence on cure may not align with an individual patient’s perspective. Various factors affecting cure assessment were identified, including the audience, patient characteristics (e.g., gender) and disease-related factors (e.g., tumor profiles). Conclusions: There is no clear convergence of opinion on describing cure in early-stage treatment of solid tumors. Stakeholders differ in their perspectives and description of cure, often balancing patient and disease specific considerations with population level evidence. Ensuring standardized terminology and appropriate language to describe potential curative value in early-stage interventions for solid tumors will support more effective communication between stakeholders.

Survival outcomes for patients with extensive stage small cell lung cancer (ES-SCLC) treated with consolidative thoracic radiation therapy (cTRT) and chemoimmunotherapy (CIT): A population level study.

e20126 Background: CIT has been adopted as the first-line treatment for ES-SCLC, supported by clinical trials which showed significant survival benefits. A synergistic effect of cTRT + CIT is theorized to enhance survival outcomes, but real-world data supporting the routine use of cTRT + CIT is limited. This study aims to investigate the safety and effectiveness of patients with ES-SCLC treated with CIT + cTRT in routine clinical practice. Methods: We identified a cohort of ES-SCLC patients treated with CIT + cTRT, with treatment initiated from Sept 2019 to Nov 2023, using Glans-Look Research Database, a province wide lung cancer registry, from which baseline demographic, diagnostic, treatment, and outcome information were derived. The last day of follow up was Dec 10, 2024. Descriptive statistics and survival analyses were generated. Results: 50 patients were identified, median age at diagnosis was 68. At CIT initiation, 34 (68%) patients had ECOG ≤ 1 and 38 (76%) had baseline brain metastasis. 35 (70%) patients received durvalumab, 11 (22%) atezolizumab, and 4 (8%) alternate immune checkpoint inhibitors (ICI). All CIT used ICI with platinum-based chemotherapy and etoposide. The median time from CIT initiation to cTRT was 4.7 months. The total dose of cTRT varied, with most patients (n= 23) receiving 30Gy in 10 fractions. 4 patients received doses above 30Gy (40-60 Gy in 8-20 fractions) and 23 received doses below 30Gy (22.5-25 Gy in 5-10 fractions). The incidence of post-cTRT pneumonitis was n=9 (18%), induced by radiation (n=4), ICI (n=3) or mixed etiology (n=2); the majority were low grade (n=8; grade 1-2) and managed with outpatient steroids, but 1 incidence of grade 3 pneumonitis required hospitalization. 20 (40%) patients experienced clinically significant CIT-induced adverse events (AEs) requiring treatment modification/interruption. Serious AE (≥ grade 3) included myelosuppression (n=6), cardiac (n=1), gastrointestinal toxicity (n=5), sepsis (n=1), and paraparesis (n=1). The median overall survival (OS) and progression-free survival (PFS) post-CIT initiation were 21.3 and 11.7 months, respectively. The presence of baseline brain metastasis was associated with both worse OS (HR = 3.0, 95% CI 1.2-7.2, p = 0.015) and PFS (HR = 2.9, 95% CI 1.3-6.4, p = 0.008). The type of ICI, atezolizumab vs durvalumab, did not significantly impact OS (HR = 0.85, 95% CI 0.36-2, p = 0.7) or PFS (HR = 0.95, 95% CI 0.44-2.1, p = 0.9). Conclusions: Our study observed a high incidence of pneumonitis (18%) in this largest North American cohort of real-life ES-SCLC patients receiving CIT + cTRT. Pivotal trials of CIT did not permit cTRT and had reported pneumonitis rates of < 2 %. Most of our pneumonitis cases were low-grade and did not require hospitalization. Overall, CIT + cTRT appears to be well tolerated in this cohort of real world patients.

Pulmonary rehabilitation utilization in patients with chronic respiratory diseases: 2014-2019.

Pulmonary rehabilitation utilization in patients with chronic respiratory diseases: 2014-2019.

Will Indonesia's Forests Survive Development Pressure? Machine Learning Predictions for Energy-Critical Tropical Watersheds

Land Use and Land Cover (LULC) changes play an important role in influencing the hydrological conditions of a watershed. The conversion of land such as forests, shrubs and grasslands into agricultural land can disrupt the hydrological balance of the watershed. The availability of information related to LULC dynamics in the future is needed to assist sustainable watershed management planning. Machine learning technology, such as Cellular Automata, can provide accurate predicting. The objective of this research is to simulate LULC based on machine learning in the Mamasa Sub-watershed. Two model combinations were employed to simulate LULC: Artificial Neural Network-Cellular Automata (ANN-CA) and Logistic Regression-Cellular Automata (LR-CA). The research results found that the ANN-CA model achieved percent of correctness and overall kappa of 83.6745 and 0.75412, respectively, which were higher than those of the LR-CA model (82.3498 and 0.73361). The prediction results of both model combinations still fall below the actual LULC values, especially in the case of large LULC classes such as forests, range-shrub, rice, and pasture. Conversely, higher accuracy is observed for smaller classes such as wetlands-forested, orchard, residential, and oak. However, it should be noted that this research did not include several socio-economic variables, such as population and income level, which are considered to influence changes in LULC. Future research is expected to analyse the influence of each variable and include some socio-economic variables that may have a significant influence on LULC change.

Cellular morphodynamics as quantifiers for functional states of resident tissue macrophages in vivo

Resident tissue macrophages (RTMs) are essential for tissue homeostasis. Their diverse functions, from monitoring interstitial fluids to clearing cellular debris, are accompanied by characteristic morphological changes that reflect their functional status. While current knowledge of macrophage behaviour comes primarily from in vitro studies, their dynamic behavior in vivo is fundamentally different, necessitating a more physiologically relevant approach to their understanding. In this study, we employed intravital imaging to generate dynamic data from peritoneal RTMs in mice under various conditions and developed a comprehensive image processing pipeline to quantify RTM morphodynamics over time, defining human-interpretable cell size and shape features. These features allowed for the quantitative and qualitative differentiation of cell populations in various functional states, including pro- and anti-inflammatory activation and endosomal dysfunction. The study revealed that under steady-state conditions, RTMs exhibit a wide range of morphodynamical phenotypes, constituting a naïve morphospace of behavioral motifs. Upon challenge, morphodynamic patterns changed uniformly at the population level but predominantly within the constraints of this naïve morphospace. Notably, aged animals displayed a markedly shifted naïve morphospace, indicating drastically different behavioral patterns compared to their young counterparts. The developed method also proved valuable in optimizing explanted tissue setups, bringing RTM behavior closer to the physiological native state. Our versatile approach thus provides novel insights into the dynamic behavior of bona fide macrophages in vivo, enabling the distinction between physiological and pathological cell states and the assessment of functional tissue age on a population level.