Emergency medicine (EM) residency programs are required to teach quality improvement (QI), yet few adopt a sustainability lens to QI despite broad recognition of the importance of climate sustainability in healthcare. To address this gap, some programs have piloted innovative approaches such as sustainability QI electives or projects, although evidence of their effectiveness remains limited. We designed and implemented a sustainability QI initiative to recycle used instruments from three bedside procedure kits (laceration repair, incision and drainage, chest tube placement) commonly used in the emergency department to reduce waste. Our goal was to describe the effectiveness of a financial intervention on instrument recycling by comparing the differences in recycling rates between the baseline and incentive periods using a quasi-Poisson regression analysis. At the end of the first year of instrument recycling, the recycling rate was 9%. Providing a financial incentive to residents over a two-year period significantly increased the recycling rate to a mean of 24% (standard deviation 13), with a rate ratio of 3.03 (95% CI 1.57-5.85), P < .001. While the residents did not meet their recycling target of 50% to receive the incentive payment, their overall recycling rate increased. Providing a financial incentive to residents for recycling efforts was modestly successful in encouraging residents to participate in an instrument recycling initiative. Motivating busy clinicians to engage in sustainable practice is challenging; projects that prioritize systems-level changes may be more effective than those that require changes in individual clinical practices.
Stem cell-derived neuron-glia models provide a robust platform for studying brain physiology, developing therapeutics, and exploring biocomputation. Extracellular vesicles (EVs) containing neurotrophic factors, also derived from stem cells, have the capacity to facilitate the formation of neural networks within these systems. However, their bioactivity is often compromised by the propagation of oxidative stress between cells during their manufacture, limiting reproducibility. Here, the Cellular Redox Spreading Shield (CROSS) is introduced as a droplet microfluidic-assembled antioxidant crystal-loaded microgel that sustains antioxidant activity for up to 6-7 days in stem cell cultures. In mesenchymal stromal cell (MSC) cultures, CROSS mitigates oxidation propagation and preserves potent neurotrophic EV production. These EVs, specifically enriched with neurotrophic microRNAs, enhance neural stem cell differentiation into neuron-glia networks, characterized by increased synaptic density and functional connectivity, as determined by calcium transient imaging combined with graph theory. In contrast, EVs from untreated, oxidatively stressed MSCs impair neural stem cell differentiation and network formation. This work highlights the importance of CROSS in stabilizing cellular production of neurotrophic EVs, with broad implications for neural tissue regeneration and biohybrid technologies.
West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease, and no specific prophylaxis or treatment exists for infections by WNV and most related orthoflaviviruses. Here, we isolated and characterized antibodies from WNV convalescent individuals and report that neutralizing autoantibodies against type I interferons did not impair antiviral antibody development. Among the monoclonal antibodies with potent neutralizing activity against WNV that were identified, W010 targeted a distinct epitope within the envelope protein domain III (EDIII) and conferred both pre- and post-exposure protection in a murine WNV model, even when interferon signaling was impaired. A second protective antibody, W014, exhibited broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.
Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesized that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility of human cells to cell death. We found that large cells are more resistant to ferroptosis caused by system xc- inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase, the iron-chelating protein ferritin, and the lysosomal protease cathepsin B, which can catabolize cysteine-rich extracellular proteins to produce additional cystine for fueling the synthesis of glutathione. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
Modulation of T cell receptor (TCR) sensitivity during positive selection is critical to avoid negative selection and direct thymocytes into their appropriate lineage. Thymocytes just prior to positive selection (preselection) are highly responsive to low affinity self-ligands and are also actively rearranging their TCRα locus as they await a positive selection signal. Preselection double-positive thymocytes were thought to be relatively homogeneous, and TCR modulation during this stage had not been previously described. Here, we provide evidence for progressive gene expression changes within the preselection double-positive thymocyte population that correlates with a gradual reduction in TCR responsiveness and reduced upregulation of TCR target genes associated with the CD4 fate. We relate these observations to the link between positive selection and T cell lineage commitment.
Doxycycline postexposure prophylaxis (doxyPEP) must reach people at high risk for bacterial STIs to reduce STI rates and inequities. PrEP-to-Need Ratios (PNR) identified inequities in PrEP by measuring PrEP prescriptions relative to HIV rates. We evaluated a novel application of the PNR framework to doxyPEP for STIs to identify inequities in doxyPEP by race/ethnicity. Using cross-sectional clinical and surveillance datasets, we compared doxyPEP use relative to STI diagnoses, a measure of need, among patients eligible for a doxyPEP prescription seen at San Francisco City Clinic in the three years following release of citywide doxyPEP guidelines (October 2022). "Use" was defined as having received a prescription for or self-reporting taking doxyPEP. "Need" was the number of unique patients diagnosed with at least one chlamydia, gonorrhea, or early syphilis infection. The doxyPEP-to-Need Ratio (dPNR) was calculated as the ratio of "use" to "need" and was compared by race/ethnicity and year. By the end of the evaluation period (September 2025), doxyPEP use was highest among eligible Latine patients (76%), then Asian (71%) and White (67%) patients, and lowest among Black patients (59%). However, because Latine and Black patients had similarly higher rates of doxyPEP-preventable infections compared to Asian and White patients, dPNR was consistently higher for Asian and White patients compared to Latine and Black patients. Latine and Black patients experienced persistently lower doxyPEP use relative to need compared to White patients. dPNR is a novel and useful metric for identifying actionable inequities in doxyPEP access for STI prevention.
Student navigation through a PhD Program is marked by intellectual challenges, emotional fluctuations, and personal growth. Students develop excellence by absorbing and adjusting, recovering, and improving in response to challenges. The ability to bounce back is termed elasticity, an engineering principle where systems are designed to withstand stress, recover from disruptions, and maintain functionality. Students can proceed from elasticity (resilience) to then develop antifragility, the ability to become better from an experience. It occurred to the first author (a PhD graduate student in biomedical sciences) that developing antifragility is conceptually easier to understand by applying basic engineering concepts. We examine five thematic categories that connect engineering concepts with practical realities of graduate study: (1) load and stress management; (2) redundancy and backup systems; (3) setback modes and recovery; (4) adaptive capacity and flexibility; and (5) sustainability and long-term performance. By understanding how to gain antifragility, one can navigate demands more effectively.
Detained youth are disproportionately affected by sociostructural determinants of health and consequently experience substantially higher rates of behavioral health (i.e., mental health and substance use) concerns than their similarly aged peers. Although the juvenile legal system is purportedly grounded in a rehabilitative model, gaps in access to timely behavioral health services during incarceration are common and undermine this goal, highlighting confinement itself as an additional sociostructural determinant of health. Brief, intensive, and concentrated (BIC) interventions have been proposed as a promising approach for addressing behavioral health needs among detained youth; however, empirical evaluations of such approaches are limited in correctional settings. One type of BIC intervention, single-session interventions (SSIs), holds significant potential for short-term youth detention settings but must be contextually adapted to support ethical, feasible, and effective implementation. In this commentary, we outline key ethical, cultural, and implementation considerations for SSI delivery and identify strategic points across the detention trajectory where SSIs may address unmet behavioral health needs (e.g., entry into detention, following disciplinary incidents, before and after court hearings, and before reentry). We conclude by discussing implications for future research aimed at expanding access to developmentally responsive behavioral health supports for detained youth.
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TB meningitis (TBM) has up to 50% mortality in people living with HIV. We investigated differences in cerebrospinal fluid (CSF) host immune responses associated with short-term mortality. We enrolled a prospective cohort of adults with definite, probable and possible HIV-related TBM in Kampala, Uganda. Metagenomic next-generation sequencing (mNGS) of bulk CSF RNA was used to detect co-infecting or alternate CNS pathogens and refine cohort diagnosis. Host transcriptomic profiles from the refined cohort were then compared between 14-day survivors and non-survivors. CSF mNGS reclassified or excluded 14% of participants based on pathogen detection, yielding 110 participants for transcriptomic analysis, of whom 23% (n=25) died within 14 days. More than 2000 genes were differentially expressed in the CSF based on 14-day mortality (adjusted p-value <0.05). Survivors upregulated T-cell receptor signaling (LCK, FYN, LAT), T-cell survival and differentiation (IL7, CD27, IL12RB1), B-cell receptor signaling (CD81, PLCG2, TNFRSF13C), cytotoxic lymphocyte and NK cell genes (KLRD1, ULBP1), TNF signaling, and class I MHC antigen processing pathways, while downregulating neutrophil chemoattractant CXCL1 and classical complement genes C4A and C4B. Unsupervised clustering identified a hypoinflammatory subgroup with significantly elevated mortality. Short-term TBM survival was associated with upregulation of adaptive immunity - including T-cell, B-cell, NK cell, and cytotoxic lymphocyte signaling - alongside TNF signaling and IFN-γ-driven class I MHC antigen processing pathways, with concurrent restraint of complement and neutrophil pathways. This supports investigation of targeted immunomodulatory agents that preserve protective responses while selectively dampening injurious innate pathways, rather than broad immunosuppression with corticosteroids.
The key advantage of spatial transcriptomics (ST) technologies lies in the spatial domain: these techniques not only offer an unprecedented opportunity to interrogate intact biological samples in a spatially informed manner, but also set the stage for integration with other imaging-based modalities. However, how to most effectively exploit spatial context and integrate ST with imaging-based modalities that capture morphological insight remains an open and heavily investigated question. To address this, particularly under real-world experimental constraints such as limited dataset size, class imbalance, and bounding-box-based segmentation, we used a publicly available murine ileum Multiplexed Error-Robust Fluorescence In Situ Hybridisation (MERFISH) dataset to evaluate whether a minimally tuned variational autoencoder (VAE) could extract informative low-dimensional representations from cell crops of spot counts, nuclear stain, membrane stain, or a combination thereof. We assessed the resulting embeddings through PERMANOVA, cross-validated classification, and unsupervised clustering, and compared them to classical image-based feature vectors extracted via CellProfiler. While transcript counts (TC) generally outperformed other feature spaces, the VAE-derived latent spaces (LSs) captured meaningful biological variation and enabled improved label recovery for specific cell types. LS2, in particular, trained solely on morphological input, also exhibited moderate predictive power for a handful of genes in a ridge regression model. Notably, combining TC with LSs improved clustering outcomes in a strategy-dependent manner, yielding gains in either cluster homogeneity or label recovery under graph- or factor-based clustering approaches, respectively. In contrast, CellProfiler-derived features provided little benefit, highlighting the advantage of learned representations over handcrafted features. Collectively, these findings demonstrate that even under constrained conditions, VAEs can extract biologically meaningful signals from imaging data and constitute a promising strategy for multi-modal integration.
Staphylococcus aureus is a leading cause of life-threatening infections worldwide. The diagnosis and treatment of S. aureus infections are further complicated by the global rise of antimicrobial resistance. Therefore, rapid detection of active S. aureus remains a critical unmet need to provide effective infection management. In this study, we identified 2-deoxy-2-[18F]-fluorosakebiose ([18F]FSK) as an optimal radiotracer to detect active S. aureus and established its efficient chemoenzymatic radiosynthesis to facilitate clinical translation. Methods: Several [18F]FDG-derived disaccharides were obtained via reverse phosphorolysis: [18F]FSK (α-1,3-linked), 2-deoxy-[18F]-fluoromaltose (α-1,4-linked), 2-deoxy-2-[18F]-fluorolaminaribiose (β-1,3-linked), and 2-deoxy-2-[18F]-fluorocellobiose (β-1,4-linked). These tracers were screened in vitro in multiple S. aureus isolates to identify bacterial incorporation. The lead candidate, [18F]FSK, was further characterized via biodistribution and dosimetry analyses and evaluated in a S. aureus myositis model to assess antimicrobial treatment response. Finally, to promote the clinical translation of [18F]FSK, 2 different radiosynthetic strategies were investigated: reverse phosphorolysis of [18F]FDG using maltose phosphorylase and using newly identified nigerose (also called sakebiose) phosphorylases. Results: Nigerose phosphorylase-derived [18F]FSK was selected as the optimal radiotracer for detecting S. aureus because of its consistent and robust uptake in multiple S. aureus isolates. [18F]FSK demonstrated favorable distribution and elimination over time, with minimal nonspecific signals in uninfected organs. The estimated human effective doses indicated an effective dose comparable to that of [18F]FDG. The radiosynthesis of [18F]FSK, initially obtained as an accidental byproduct of maltose phosphorylase catalysis, was further improved using a nigerose phosphorylase originating from thermostable Spirochaeta thermophila, enabling nearly quantitative conversion of [18F]FDG to [18F]FSK (up to 97%). Conclusion: We demonstrated that [18F]FSK is a potent and robust PET radiotracer for the detection of active S. aureus in vivo and aids in the selection of an appropriate antimicrobial treatment. These findings highlight the potential use of [18F]FSK in promoting the effective management of S. aureus infections in clinical settings.
Sinonasal malignancies frequently present with symptoms overlapping chronic inflammatory conditions, complicating early detection and delaying treatment. A fast, non-invasive approach capable of resolving cell states across inflammatory and malignant disease from routine nasal swabs could substantially improve clinical screening. Using the REM-I platform, we generated a reference atlas of deep learning-enabled single-cell morpholomic features from >641K immune cell brightfield images. This reference atlas was integrated with >2.5 M images obtained from nasal swabs spanning health, chronic rhinosinusitis (CRS), and sinonasal carcinoma to perform differential feature testing and comparative feature enrichment across disease states. Sinonasal carcinoma samples exhibited distinct immune remodeling, including increased myeloid-enriched cell abundance and elevated small dark pixel intensity consistent with enhanced granulocyte activity. Basophil/NK-enriched clusters and epithelial clusters contained tumor-associated cells with deep learning-derived morphologic signatures not observed in CRS or healthy samples. These findings support the potential use of nasal swabs in early point-of-care diagnostics.
Transcriptional reprogramming has an important role in kidney glomerular disease. Using in vivo murine models of podocyte injury, we studied the roles of the FOXC2 and WT1 transcription factors (TFs) in podocyte injury. Podocytes are a crucial cell type of glomeruli, the filtration units of each nephron. Podocyte injury is often the incipient event leading to chronic kidney disease. It is well established that the TFs FOXC2 and WT1 are required in podocytes to maintain the glomerular filtration barrier. Their role in the response to injury is less well understood. Here, we tested the hypothesis that FOXC2 and WT1 act together to mediate transcriptional reprogramming in response to podocyte injury. Similarly to that of WT1, genome-wide FOXC2 binding to target genes is dynamic during the course of injury, initially increasing, but late in injury there is a dramatic decrease in FOXC2 expression and in its binding to target genes. Podocyte-specific inactivation of FoxC2 or Wt1 in adult mice limits the transcriptional response to injury. Correlating FOXC2 and WT1 ChIP-seq analyses demonstrated that they co-bind many genes expressed in podocytes. Thus, reprogramming the transcriptome involves dynamic changes in the binding of FOXC2 and WT1 to their target genes during a reparative injury response.
Treatment-resistant wounds driven by polymicrobial biofilms are a major clinical challenge, affecting millions globally and leading to chronic inflammation, persistent pain, and poor healing outcomes. These wounds are characterized by mature biofilms reinforced by dense extracellular polymeric substances, which confer strong tolerance to conventional treatments. Despite emerging technologies, such as nanoparticles, bacteriophages, and engineered enzymes, effective clearance of established biofilms remains challenging. Here, we develop a microblasting wound dressing (µBLAST) that delivers spatially confined mechano-chemical disruption at the tissue-biofilm interface to remove viscoelastic biofilm matrices and promote tissue regeneration. The µBLAST is assembled by embedding MnO2-doped diatom biosilica beneath an H2O2-releasing cellulose mesh, enabling localized catalytic microbubble generation within biofilm matrices. Confined expansion and rupture of oxygen bubbles produce localized mechanical stress sufficient to dislodge mature, antibiotic-resistant polymicrobial biofilms, while sustained H2O2 release prolongs particle activity. In a murine wound model infected with mature P. aeruginosa and methicillin-resistant S. aureus biofilms, µBLAST treatment significantly reduces biofilm burden, accelerates re-epithelialization, promotes hair regrowth, and mitigates inflammation. Moreover, µBLAST enhances antibiotic efficacy, suppressing biofilm regrowth even at ten-fold reduced drug doses. These findings highlight confined mechano-chemical biofilm disruption as a therapeutic strategy for treating mature, antibiotic-resistant biofilm infections and promoting tissue regeneration.
Patient-reported symptoms following COVID-19 exposure have been understudied in cirrhosis. This study evaluated type, severity, and persistence of symptoms along with impact on quality of life (QOL) post-SARS-CoV-2 infection in a cohort with and without alcohol-related cirrhosis. Patients with cirrhosis receiving care in hepatology clinics at three institutions were surveyed for symptoms and liver disease QOL (LDQOL) using standardized instruments following SARS-CoV-2 infection. Acute (<30 days), post-acute (≥30 days since onset), and Long COVID (≥3 months) symptoms were compared by cirrhosis etiology and decompensated status. Associations between severe COVID-19 symptoms and LDQOL were examined using multivariable models. 156 patients with prior COVID-19 exposure had a median age of 66.5 years; 18% were female; 43% had alcohol-related liver disease (ALD); and 42% decompensated cirrhosis. Among 208 surveys conducted, the median (Q1, Q3) number of symptoms reported was 6 (3, 10), with 66% reporting at least one severe/very severe symptom and 21% had Long COVID. There were no significant differences in symptoms by cirrhosis etiology or decompensation except those with ALD had higher post-acute symptoms compared to non-ALD (RR 2.17, P = .04). Moreover, the total number of severe symptoms was inversely associated with LDQOL. For each additional severe symptom reported, LDQOL decreased by 1.12 points after adjusting for age, sex, ALD, decompensated cirrhosis, and MELD-Na score (95% CI -1.70 to -0.53, P = .001). Assessing severity and persistence of post-COVID-19 exposure symptoms can help clinicians address patient-reported QOL concerns, optimize cirrhosis management, and inform integrated care for ALD and AUD.
Biological AI models (BAIMs) are advancing rapidly and hold substantial promise. Yet, these models raise dual-use concerns, particularly regarding capabilities that could enhance pathogens with pandemic potential. Current risk mitigation discussions for BAIMs are concentrated in the post-development stage, focusing on evaluations and safeguards, after a model has been trained. We argue that upstream, pre-development risk-benefit review (RBR) is a necessary, missing component of effective BAIM governance. The broad range of models, their capabilities, and purpose-built applications, as well as a majority-academic developer community, make this approach feasible and realistic. We propose a review framework with the following five components and discuss key characteristics of each component: (1) review trigger criteria that determine whether a model should undergo an RBR. The review trigger criteria are (A) a model is reasonably anticipated to possess capabilities of concern or (B) it will be trained on sensitive pathogen data classified under the Biosecurity Data Levels (BDL) system; structured risk (2) and benefit (3) reviews using qualitative and quantitative criteria; (4) integration of risk and benefit scores into a composite assessment; and (5) proportionate risk mitigation recommendations. We expect that such reviews (2 through 5) would apply to only a small fraction of BAIMs and would benefit responsible developers by establishing clear expectations at the outset of model development. We discuss how such a framework could be implemented broadly across academic institutions, commercial developers, and federal, philanthropic, and private funding bodies, and address limitations such as the subjectivity of risk assessments. RBR for BAIMs remains nascent and will require expert-driven working groups to define capabilities of concern, establish clear review criteria, and assess risk mitigation efficacy. RBRs are a promising conceptual approach for BAIM risk management and should be pioneered, refined, and vetted through real-world application with model developers.
Annexin A6 (AnxA6) is a predominantly intracellular calcium-dependent membrane-binding multifunctional protein that is also detected extracellularly and in small extracellular vesicles (exosomes). We previously demonstrated that lapatinib resistance in triple-negative breast cancer (TNBC) cells is associated with AnxA6 upregulation and accumulation of cholesterol in late endosomes. Here, we investigated the fate of AnxA6 and cholesterol in lapatinib-resistant (LAP-R) cells and whether extracellular AnxA6 influences TNBC cell survival. We demonstrate that reduced expression of AnxA6 in LAP-R cells decreased the secretion of MCP-1/CCL2, CCL8/IL-8, DKK1, TSP-1, and OPN by antibody arrays. The secretion of exosomes was also markedly reduced in AnxA6-depleted LAP-R cells, while AnxA6 upregulation stimulated the release of MCP-1 and exosomes. Compared to the respective controls, exosome-associated AnxA6, Rab7, and cholesterol levels were increased in exosomes isolated from AnxA6-expressing LAP-R cells. Mechanistically, we demonstrated by co-immunoprecipitation, GST pulldown, and proximity ligation assays that AnxA6 interacts with SNAP23, a component of the membrane fusion machinery. Finally, blocking extracellular AnxA6 with neutralizing antibodies reduced the viability of AnxA6-low TNBC cells but had little effect on AnxA6-high cells. These findings suggest that extracellular AnxA6 is critical for the survival of highly proliferative AnxA6-low basal-like breast cancer cells and that AnxA6 influences TNBC progression by facilitating the secretion of pro-inflammatory cytokines and cholesterol-enriched exosomes.
Short-chain fatty acids (SCFAs) are immunometabolites produced by the gut microbiome. In animal models, SCFAs affect traumatic brain injury (TBI) severity by modulating the immune response and serving as an energy source. The goal of this study was to assess whether SCFAs are associated with functional outcome in adult patients with moderate-to-severe TBI (msTBI). Prospective cohort study. Urban Trauma Center. Adults (age ≥ 15 yr) who had TBI with Glasgow Coma Scale 3-12, intracranial hemorrhage on head CT scan, and at least one reactive pupil. Blood samples had to be collected within 3 hours of trauma. None. Univariate and multivariate analyses demonstrated that plasma SCFAs were associated with better functional outcomes at discharge and 6 months, an association driven primarily by differences in plasma acetate and propionate. K-means clustering of acetate and propionate levels identified two patient clusters with distinct discharge and 6-month functional outcomes but similar clinical, biomarker, and radiographic injury severity. Cluster 1 (n = 47) had higher SCFA levels compared with cluster 2 (n = 76) and cluster 1 had more favorable outcomes at discharge (Glasgow Outcome Scale 4-5: 83% vs. 55%; p = 0.003) and 6 months (Extended Glasgow Outcome Scale 4-8: 78% vs. 45%; p = 0.005). Multivariable logistic regression adjusting for the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)lab model identified an independent association between the SCFA cluster and functional outcome at discharge (p = 0.001) and 6 months (p = 0.03). Adding the SCFA cluster to the IMPACTlab model improved the area under the receiver operating characteristic curve for the prediction model for a favorable outcome. Our study suggests that SCFA levels are associated with functional outcome after msTBI. Future studies will focus on identifying mechanisms through which SCFAs may improve msTBI outcomes and what drives interpatient variation in their levels, which could position SCFAs as prognostic biomarkers and therapeutic targets in TBI.
Purpose: We investigated the association between age and retinal microvasculature parameters as measured by optical coherence tomography angiography (OCTA) and the modifying effect of diabetes status on this association. Methods: In this serial, cross-sectional study, 3 × 3 mm2 macular OCTA images were obtained from healthy adults and adults with diabetes mellitus (DM) with no diabetic retinopathy (DR) or with mild non-proliferative DR (NPDR). The parameters analyzed included foveal avascular zone (FAZ) area and perimeter, vessel density (VD), vessel length density (VLD), and flow index (FI) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP). The associations between OCTA parameters and age were explored using multivariable linear regression models. Results: For the included 1855 patients (1855 eyes) (49% male; mean age: 55 years), the results were as follows: no diabetes (N = 217), DM no DR (N = 1352), and mild NPDR (N = 286). Increasing age was significantly associated with decreased SCP and DCP VD and VLD in the diabetic and non-diabetic groups. The slope of association between SCP and DCP FI and age in the diabetic patients was significantly different than that in the control patients. Conclusions: The strength of the association between aging and OCTA parameters differed significantly between the controls and those with early retinopathy, pointing to a potentially altered retinal vascular homeostasis secondary to diabetic pathophysiology. This finding offers insight into the early pathological biomarkers of DR and may guide early DR management for patients based on personalized risk scores.