Timing decisions as the next frontier for collective intelligence.

The past decade has witnessed a growing interest in collective decision making, particularly the idea that groups can make more accurate decisions compared with individuals. However, nearly all research to date has focused on spatial decisions (e.g., food patches). Here, we highlight the equally important, but severely understudied, realm of temporal collective decision making (i.e., decisions about when to perform an action). We illustrate differences between temporal and spatial decisions, including the irreversibility of time, cost asymmetries, the speed-accuracy tradeoff, and game theoretic dynamics. Given these fundamental differences, temporal collective decision making likely requires different mechanisms to generate collective intelligence. Research focused on temporal decisions should lead to an expanded understanding of the adaptiveness and constraints of living in groups.

Andalusian Public Eye-Banks: a decade of continuous improvement.

OBJECTIVES: To show donation data, number of keratoplasties and the changes in transplant indications and techniques that occurred in Andalusia in the period from 2013 to 2022. MATERIALS AND METHODS: The present work is a retrospective and descriptive study that included all keratoplasties performed between January 2013 and December 2022 in Andalusia, as well as the evolution of the cornea donation and transplant activity of the public and private hospitals pertaining to the waiting list management system of the Public Health System of Andalusia. Transplants performed in private centers with corneas from outside Andalusia were excluded. RESULTS: Cornea donation activity in Andalusia in the decade 2013-2022 has experienced a growth of more than 126%, while overall transplant activity has increased by 157% in public hospitals. Penetrating keratoplasty has decreased from 83% in 2013 to 43% in 2022, while lamellar techniques have increased from 17% to 57% in this same period. Since 2018, more lamellar transplants are performed than penetrating transplants. Regarding indications, endothelial conditions already represent the first cause of transplantation. In 2022 alone, the public Andalusian Eye Banks evaluated 1,054 corneas and prepared 281 endothelial grafts. CONCLUSION: In the decade from 2013 to 2022 in Andalusia there has been an increase in donation activity and the number of keratoplasties. The public Eye Banks implementation in this period has played a key role in the widespread adoption of lamellar keratoplasty techniques and has enabled the transition to perform a greater number of lamellar keratoplasties compared to penetrating keratoplasty.

Intravenous Tocilizumab versus Standard of Care in the Treatment of Severe and Critical COVID-19-related Pneumonia: A Single-center, Double-blind, Placebo-controlled, Phase 3 Trial.

Background: Severe and critical COVID-19 disease is characterized by hyperinflammation involving pro-inflammatory cytokines, particularly IL-6. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors. Objectives: This study evaluated the efficacy of tocilizumab in Filipino patients with severe to critical COVID-19 disease. Methods: This phase 3 randomized double-blind trial, included patients hospitalized for severe or critical COVID-19 in a 1:1 ratio to receive either tocilizumab plus local standard of care or placebo plus standard of care. Patients were eligible for a repeat IV infusion within 24-48 hours if they deteriorated or did not improve. Treatment success or clinical improvement was defined as at least two categories of improvement from baseline in the WHO 7-point Ordinal Scale of patient status, in an intention-to-treat manner. Results: Forty-nine (49) patients were randomized in the tocilizumab arm and 49 in the placebo arm. There was no significant difference in age, comorbidities, COVID-19 severity, need for mechanical ventilation, presence of acute respiratory distress syndrome, or biomarker levels between groups. Use of adjunctive therapy was similar between groups, with corticosteroid used in 91.8% in tocilizumab group and 81.6% in the placebo group, while remdesivir was used in 98% of participants in both groups.There was no significant difference between groups in terms of treatment success in both the intention-to-treat analysis (relative risk=1.05, 95% CI: 0.85-1.30) and per-protocol analysis (relative risk=0.98, 95% CI: 0.80 to 1.21). There was no significant difference in time to improvement of at least two categories relative to baseline on the 7-point Ordinal Scale of clinical status. Conclusion: The use of tocilizumab on top of standard of care in the management of patients with severe to critical COVID-19 did not result in significant improvement as defined by the WHO 7-point Ordinal Scale of patient status, nor in significant improvement in incidence of mechanical ventilation, incidence of ICU admission, length of ICU stay, and mortality rate.

Buffering and phenological mismatch: A change of perspective.

The potential for climate change to disrupt phenology-mediated interactions in interaction networks has attracted considerable attention in recent decades. Frequently, studies emphasize the fragility of ephemeral seasonal interactions, and the risks posed by phenological asynchrony. Here, we argue that the fitness consequences of asynchrony in phenological interactions may often be more buffered than is typically acknowledged. We identify three main forms that buffering may take: (i) mechanisms that reduce asynchrony between consumer and resource; (ii) mechanisms that reduce the costs of being asynchronous; and (iii) mechanisms that dampen interannual variance in performance across higher organizational units. Using synchrony between the hatching of winter moth caterpillars and the leafing of their host-plants as a case study, we identify a wide variety of buffers that reduce the detrimental consequences of phenological asynchrony on caterpillar individuals, populations, and meta-populations. We follow this by drawing on examples across a breadth of taxa, and demonstrate that these buffering mechanisms may be quite general. We conclude by identifying key gaps in our knowledge of the fitness and demographic consequences of buffering, in the context of phenological mismatch. Buffering has the potential to substantially alter our understanding of the biotic impacts of future climate change-a greater recognition of the contribution of these mechanisms may reveal that many trophic interactions are surprisingly resilient, and also serve to shift research emphasis to those systems with fewer buffers and towards identifying the limits of those buffers.

Phenology.

Flowers blooming, fungi fruiting, insects biting, fish spawning, geese migrating, deer calving; our consciousness is steeped in a seasonal calendar of nature's events. Phenology is the study of these recurring, seasonal life-history events, though nowadays this term is widely applied to the events themselves. From Shakespeare's sonnet 98, "From you I have been absent in the spring", to the appearance of seasonal events and migratory species in the oral traditions of Native Americans, interest in phenology is long-standing and transcends cultures. In this primer we introduce the study of phenology, trace the development of the field, and examine the prominent role phenology has played in evidencing the widespread impacts of anthropogenic climate change on life on Earth. We will consider the potential implications of climatic change for the ability of populations to persist and the stability of species interactions.

Intravenous tocilizumab versus standard of care in the treatment of severe and critical COVID-19-related pneumonia: A single center, double-blind, placebo controlled, phase 3 trial

Background@#Severe and critical COVID-19 disease is characterized by hyperinflammation involving pro-inflammatory cytokines, particularly IL-6. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors. @*Objectives@#This study evaluated the efficacy of tocilizumab in Filipino patients with severe to critical COVID-19 disease. @*Methods@#This phase 3 randomized double-blind trial, included patients hospitalized for severe or critical COVID-19 in a 1:1 ratio to receive either tocilizumab plus local standard of care or placebo plus standard of care. Patients were eligible for a repeat IV infusion within 24-48 hours if they deteriorated or did not improve. Treatment success or clinical improvement was defined as at least two categories of improvement from baseline in the WHO 7-point Ordinal Scale of patient status, in an intention-to-treat manner. @*Results@#Forty-nine (49) patients were randomized in the tocilizumab arm and 49 in the placebo arm. There was no significant difference in age, comorbidities, COVID-19 severity, need for mechanical ventilation, presence of acute respiratory distress syndrome, or biomarker levels between groups. Use of adjunctive therapy was similar between groups, with corticosteroid used in 91.8% in tocilizumab group and 81.6% in the placebo group, while remdesivir was used in 98% of participants in both groups. There was no significant difference between groups in terms of treatment success in both the intention-to-treat analysis (relative risk=1.05, 95% CI: 0.85-1.30) and per-protocol analysis (relative risk=0.98, 95% CI: 0.80 to 1.21). There was no significant difference in time to improvement of at least two categories relative to baseline on the 7-point Ordinal Scale of clinical status. @*Conclusion@#The use of tocilizumab on top of standard of care in the management of patients with severe to critical COVID-19 did not result in significant improvement as defined by the WHO 7-point Ordinal Scale of patient status, nor in significant improvement in incidence of mechanical ventilation, incidence of ICU admission, length of ICU stay, and mortality rate.

Clinical Outcomes of COVID-19 Infection among Patients with Chronic Obstructive Pulmonary Disease: Findings from the Philippine CORONA Study.

BACKGROUND: The global pandemic caused by the coronavirus disease 2019 (COVID-19) resulted in many deaths from fulminant respiratory failure. Chronic obstructive pulmonary disease (COPD) is the leading cause of morbidity and mortality worldwide. There has been great concern regarding the impact of COPD on the COVID-19 illness. METHODS: Data from the Philippine CORONA study were analyzed to determine the association of COPD and COVID-19 in terms of mortality, disease severity, respiratory failure, mechanical ventilation, and lengths of stay in the intensive care unit (ICU) and hospital. RESULTS: A total of 10,881 patients were included in this study, and 156 (1.4%) patients had been diagnosed with COPD. A majority of COVID-19 patients with COPD had other existing comorbidities: hypertension, diabetes mellitus, chronic cardiac disease, and chronic kidney disease. COPD patients were 2.0× more likely to present with severe to critical COVID-19 disease. COVID-19 patients with COPD in our study have a 1.7× increased mortality, 1.6× increased respiratory failure, and 2.0× increased risk for ICU admission. Smokers with COVID-19 were 1.8× more likely to present with more severe disease and have a 1.9× increased mortality. CONCLUSION: Our study supports the growing evidence that COPD among COVID-19 patients is a risk factor for higher mortality, more severe form of COVID-19, higher ICU admission, and higher respiratory failure needing ventilatory support.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.

Centrifugation-Assisted Three-Dimensional Printing of Devices Embedded with Fully Enclosed Microchannels.

The challenges in reliably removing the sacrificial material from fully enclosed microfluidic channels hinder the use of three-dimensional (3D) printing to create microfluidic devices with intricate geometries. With advances in printer resolution, the etching of sacrificial materials from increasingly smaller channels is poised to be a bottleneck using the existing techniques. In this study, we introduce a microfabrication approach that utilizes centrifugation to effortlessly and efficiently remove the sacrificial materials from 3D-printed microfluidic devices with densely packed microfeatures. We characterize the process by measuring the etch rate under different centrifugal forces and developed a theoretical model to estimate process parameters for a given geometry. The effect of the device layout on the centrifugal etching process is also investigated. We demonstrate the applicability of our approach on devices fabricated using inkjet 3D printing and stereolithography. Finally, the advantages of the introduced approach over commonly used injection-based etching of sacrificial material are experimentally demonstrated in direct comparisons. A robust method to postprocess additively manufactured geometries composed of intricate microfluidic channels can help utilize both the large printing volume and high spatial resolution afforded by 3D printing in creating a variety of devices ranging from scaffolds to large-scale microfluidic assays.

Opposing Responses to Scarcity Emerge from Functionally Unique Sociality Drivers.

AbstractFrom biofilms to whale pods, organisms across taxa live in groups, thereby accruing numerous diverse benefits of sociality. All social organisms, however, pay the inherent cost of increased resource competition. One expects that when resources become scarce, this cost will increase, causing group sizes to decrease. Indeed, this occurs in some species, but there are also species for which group sizes remain stable or even increase under scarcity. What accounts for these opposing responses? We present a conceptual framework, literature review, and theoretical model demonstrating that differing responses to sudden resource shifts can be explained by which sociality benefit exerts the strongest selection pressure on a particular species. We categorize resource-related benefits of sociality into six functionally distinct classes and model their effect on the survival of individuals foraging in groups under different resource conditions. We find that whether, and to what degree, the optimal group size (or correlates thereof) increases, decreases, or remains constant when resource abundance declines depends strongly on the dominant sociality mechanism. Existing data, although limited, support our model predictions. Overall, we show that across a wide diversity of taxa, differences in how group size shifts in response to resource declines can be driven by differences in the primary benefits of sociality.

Space-for-time substitutions in climate change ecology and evolution.

In an epoch of rapid environmental change, understanding and predicting how biodiversity will respond to a changing climate is an urgent challenge. Since we seldom have sufficient long-term biological data to use the past to anticipate the future, spatial climate-biotic relationships are often used as a proxy for predicting biotic responses to climate change over time. These 'space-for-time substitutions' (SFTS) have become near ubiquitous in global change biology, but with different subfields largely developing methods in isolation. We review how climate-focussed SFTS are used in four subfields of ecology and evolution, each focussed on a different type of biotic variable - population phenotypes, population genotypes, species' distributions, and ecological communities. We then examine the similarities and differences between subfields in terms of methods, limitations and opportunities. While SFTS are used for a wide range of applications, two main approaches are applied across the four subfields: spatial in situ gradient methods and transplant experiments. We find that SFTS methods share common limitations relating to (i) the causality of identified spatial climate-biotic relationships and (ii) the transferability of these relationships, i.e. whether climate-biotic relationships observed over space are equivalent to those occurring over time. Moreover, despite widespread application of SFTS in climate change research, key assumptions remain largely untested. We highlight opportunities to enhance the robustness of SFTS by addressing key assumptions and limitations, with a particular emphasis on where approaches could be shared between the four subfields.

Evaluation of reference genes for qRT-PCR studies in the colchicine producing Gloriosa superba L.

The flame lily, Gloriosa superba L., is one of the two primary sources of the anti-inflammatory drug, colchicine. Previous studies have shown that a higher level of colchicine production occurs in the rhizomes than in leaves and roots. Earlier precursor feeding and transcriptome analysis of G. superba have provided a putative pathway and candidate genes involved in colchicine biosynthesis. Comparative analysis of expression levels of candidate pathway genes in different tissues of G. superba using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) can reveal highly expressed genes in the rhizome compared to other tissues which could suggest roles of the gene products in colchicine biosynthesis. Normalization is an important step in effectively analyzing differential gene expression by qRT-PCR with broader applications. The current study selected candidate reference genes from the transcriptome datasets and analyzed them to determine the most stable genes for normalization of colchicine biosynthesis-related genes. Using RefFinder, one stable reference gene, UBC22, was selected to normalize gene expression levels of candidate methyltransferase (MT) genes in the leaves, roots, and rhizomes of G. superba. With UBC22 as reference gene, the methyltransferases, GsOMT1, GsOMT3, and GsOMT4 showed significantly higher expression levels in the rhizome of G. superba, while MT31794 was more highly expressed in the roots. In conclusion, the current results showed a viable reference gene expression analysis system that could help elucidate colchicine biosynthesis and its exploitation for increased production of the drug in G. superba. Supplementary Information: The online version contains supplementary material available at 10.1007/s11816-023-00840-x.

Establishing Quality Control Procedures for Large-Scale Plasma Proteomics Analyses.

Proteomics research has been transformed due to high-throughput liquid chromatography (LC-MS/MS) tandem mass spectrometry instruments combined with highly sophisticated automated sample preparation and multiplexing workflows. However, scaling proteomics experiments to large sample cohorts (hundreds to thousands) requires thoughtful quality control (QC) protocols. Robust QC protocols can help with reproducibility, quantitative accuracy, and provide opportunities for more decisive troubleshooting. Our laboratory conducted a plasma proteomics study of a cohort of N = 335 patient samples using tandem mass tag (TMTpro) 16-plex batches. Over the course of a 10-month data acquisition period for this cohort we collected 271 pooled QC LC-MS/MS result files obtained from MS/MS analysis of a patient-derived pooled plasma sample, representative of the entire cohort population. This sample was tagged with TMTzero or TMTpro reagents and used to inform the daily performance of the LC-MS/MS instruments and to allow within and across sample batch normalization. Analytical variability of a number of instrumental and data analysis metrics including protein and peptide identifications, peptide spectral matches (PSMs), number of obtained MS/MS spectra, average peptide abundance, percent of peptides with a Δ m/z between ±0.003 Da, percent of MS/MS spectra obtained at the maximum injection time, and the retention time of selected tracking peptides were evaluated to help inform the design of a robust LC-MS/MS QC workflow for use in future cohort studies. This study also led to general tips for using selected metrics to inform real-time troubleshooting of LC-MS/MS performance issues with daily QC checks.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and tumor microenvironment, overcoming multiple obstacles of CAR T therapy for solid tumors.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumor is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach massively reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquired early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogrammed and reversed immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells (PBMC) of healthy or metastatic breast cancer patients, induced robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a novel therapy for solid tumor.

Beyond collective intelligence: Collective adaptation.

We develop a conceptual framework for studying collective adaptation in complex socio-cognitive systems, driven by dynamic interactions of social integration strategies, social environments and problem structures. Going beyond searching for 'intelligent' collectives, we integrate research from different disciplines and outline modelling approaches that can be used to begin answering questions such as why collectives sometimes fail to reach seemingly obvious solutions, how they change their strategies and network structures in response to different problems and how we can anticipate and perhaps change future harmful societal trajectories. We discuss the importance of considering path dependence, lack of optimization and collective myopia to understand the sometimes counterintuitive outcomes of collective adaptation. We call for a transdisciplinary, quantitative and societally useful social science that can help us to understand our rapidly changing and ever more complex societies, avoid collective disasters and reach the full potential of our ability to organize in adaptive collectives.

Single Systemic Administration of a Gene Therapy Leading to Disease Treatment in Metachromatic Leukodystrophy Arsa Knock-Out Mice.

Metachromatic leukodystrophy (MLD) is a rare, inherited, demyelinating lysosomal storage disorder caused by mutations in the arylsulfatase-A gene (ARSA). In patients, levels of functional ARSA enzyme are diminished and lead to deleterious accumulation of sulfatides. Herein, we demonstrate that intravenous administration of HSC15/ARSA restored the endogenous murine biodistribution of the corresponding enzyme, and overexpression of ARSA corrected disease biomarkers and ameliorated motor deficits in Arsa KO mice of either sex. In treated Arsa KO mice, when compared with intravenously administered AAV9/ARSA, significant increases in brain ARSA activity, transcript levels, and vector genomes were observed with HSC15/ARSA Durability of transgene expression was established in neonate and adult mice out to 12 and 52 weeks, respectively. Levels and correlation between changes in biomarkers and ARSA activity required to achieve functional motor benefit was also defined. Finally, we demonstrated blood-nerve, blood-spinal and blood-brain barrier crossing as well as the presence of circulating ARSA enzyme activity in the serum of healthy nonhuman primates of either sex. Together, these findings support the use of intravenous delivery of HSC15/ARSA-mediated gene therapy for the treatment of MLD.SIGNIFICANCE STATEMENT Herein, we describe the method of gene therapy adeno-associated virus (AAV) capsid and route of administration selection leading to an efficacious gene therapy in a mouse model of metachromatic leukodystrophy. We demonstrate the therapeutic outcome of a new naturally derived clade F AAV capsid (AAVHSC15) in a disease model and the importance of triangulating multiple end points to increase the translation into higher species via ARSA enzyme activity and biodistribution profile (with a focus on the CNS) with that of a key clinically relevant biomarker.

Utility of laboratory and immune biomarkers in predicting disease progression and mortality among patients with moderate to severe COVID-19 disease at a Philippine tertiary hospital.

Purpose: This study was performed to determine the clinical biomarkers and cytokines that may be associated with disease progression and in-hospital mortality in a cohort of hospitalized patients with RT-PCR confirmed moderate to severe COVID-19 infection from October 2020 to September 2021, during the first wave of COVID-19 pandemic before the advent of vaccination. Patients and methods: Clinical profile was obtained from the medical records. Laboratory parameters (complete blood count [CBC], albumin, LDH, CRP, ferritin, D-dimer, and procalcitonin) and serum concentrations of cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-γ, IP-10, TNF-α) were measured on Days 0-3, 4-10, 11-14 and beyond Day 14 from the onset of illness. Regression analysis was done to determine the association of the clinical laboratory biomarkers and cytokines with the primary outcomes of disease progression and mortality. ROC curves were generated to determine the predictive performance of the cytokines. Results: We included 400 hospitalized patients with COVID-19 infection, 69% had severe to critical COVID-19 on admission. Disease progression occurred in 139 (35%) patients, while 18% of the total cohort died (73 out of 400). High D-dimer >1 µg/mL (RR 3.5 95%CI 1.83-6.69), elevated LDH >359.5 U/L (RR 1.85 95%CI 1.05-3.25), lymphopenia (RR 1.91 95%CI 1.14-3.19), and hypoalbuminemia (RR 2.67, 95%CI 1.05-6.78) were significantly associated with disease progression. High D-dimer (RR 3.95, 95%CI 1.62-9.61) and high LDH (RR 5.43, 95%CI 2.39-12.37) were also significantly associated with increased risk of in-hospital mortality. Nonsurvivors had significantly higher IP-10 levels at 0 to 3, 4 to 10, and 11 to 14 days from illness onset (p<0.01), IL-6 levels at 0 to 3 days of illness (p=0.03) and IL-18 levels at days 11-14 of illness (p<0.001) compared to survivors. IP-10 had the best predictive performance for disease progression at days 0-3 (AUC 0.81, 95%CI: 0.68-0.95), followed by IL-6 at 11-14 days of illness (AUC 0.67, 95%CI: 0.61-0.73). IP-10 predicted mortality at 11-14 days of illness (AUC 0.77, 95%CI: 0.70-0.84), and IL-6 beyond 14 days of illness (AUC 0.75, 95%CI: 0.68-0.82). Conclusion: Elevated D-dimer, elevated LDH, lymphopenia and hypoalbuminemia are prognostic markers of disease progression. High IP-10 and IL-6 within the 14 days of illness herald disease progression. Additionally, elevated D-dimer and LDH, high IP-10, IL-6 and IL-18 were also associated with mortality. Timely utilization of these biomarkers can guide clinical monitoring and management decisions for COVID-19 patients in the Philippines.

Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance.

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=-0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.