Non-viral precision T cell receptor replacement for personalized cell therapy.

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRß). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.

Modeling Lake Recovery Lag Times Following Influent Phosphorus Loading Reduction.

Internal feedback of nutrients may impede timely improvement in lake water quality. We describe a parsimonious, mechanistic framework for modeling lag times to recovery of phosphorus-enriched lakes, given decreases in external loading. The approach assumes first-order kinetics in a two-compartment system taking account of phosphorus storage in and loading from benthic sediments. Bayesian parameter modeling, published sediment phosphorus release rates, and a prior dynamic calibration for one lake are used to derive estimates of key parameters. Applications are developed for an example lake, as are maps displaying estimated times to attainment of a phosphorus criterion in lakes across a midwestern state, and lag time estimates for fractional water column concentration decrease averaged over HUC-8s. Mean lag times to 50 and 75% declines in water column phosphorus concentration were estimated as 13.1 and 39.0 years respectively, across more than 70,000 lentic water bodies in the continental United States.

Associating sleep problems with advanced cancer diagnosis, and immune checkpoint treatment outcomes: a pilot study.

BACKGROUND: Sleep problems (SP) are common in cancer patients but have not been previously assessed in patients receiving immune checkpoint inhibitors (ICI). METHODS: We collected questionnaire data on sleep apnea risk, insomnia, and general sleep patterns. We used an adjusted multivariate Poisson regression to calculate prevalence ratios (PRs) and associated 95% confidence intervals (CIs) for associations between these SP and metastatic versus localized cancer stage (M1 vs. M0), and adjusted logistic regression models to calculate ORs for associations between SP with the number of ICI infusions completed (6 + vs. < 6). RESULTS: Among 32 patients who received ICI treatment, the prevalence of low, intermediate, and high-risk OSA risk was 36%, 42%, and 21%, respectively. Overall, 58% of participants reported clinically significant insomnia. We did not find a significant association between intermediate or high risk OSA (vs. low risk) and metastatic cancer status (PR = 1.01 (95% CI: 0.28, 3.67)). Patients in the cohort who reported taking > 15 min to fall asleep were 3.6 times more likely to be diagnosed with metastatic cancer compared to those reporting shorter sleep latency (95% CI (1.74, 7.35)). We did not find a significant association between SP and number of ICI infusions completed. CONCLUSION: Our data associating sleep apnea risk, insomnia, and sleep patterns with more advanced cancer encourages further exploration in larger-scale observational studies and suggests interventional clinical trials focused on sleep quality improvement that could result in better outcomes for these patients.

A web-based tool for assessing the condition of benthic diatom assemblages in streams and rivers of the conterminous United States.

Benthic diatom assemblages are known to be indicative of water quality but have yet to be widely adopted in biological assessments in the United States due to several limitations. Our goal was to address some of these limitations by developing regional multi-metric indices (MMIs) that are robust to inter-laboratory taxonomic inconsistency, adjusted for natural covariates, and sensitive to a wide range of anthropogenic stressors. We aggregated bioassessment data from two national-scale federal programs and used a data-driven analysis in which all-possible combinations of 2-7 metrics were compared for three measures of performance. After ranking the best-performing MMIs, we selected the final MMIs by evaluating stress-response relations in independent regional datasets of diatom samples paired with measures of several water-quality stressors, including herbicides and streamflow flashiness. Each regional MMI performed well at calibration sites and represented diverse aspects of the structure and function of diatom communities. Most metrics included in the best MMIs were modeled to account for natural variation including climate, topography, soil characteristics, lithology, and groundwater influence on streamflow. MMI performance improved with higher numbers of component metrics, but this effect diminished beyond six metrics. Component metrics of MMIs were associated with a broad suite of measured stressors in every region, including salinity, nutrients, herbicides, and streamflow flashiness. We provide a web-based software application that allows users in the conterminous United States to apply our MMIs to their own datasets and compare MMI scores from their sites to a broader regional context.

Diatoms.org: supporting taxonomists, connecting communities.

Consistent identification of diatoms is a prerequisite for studying their ecology, biogeography, and successful application as environmental indicators. However, taxonomic consistency among observers has been difficult to achieve, because taxonomic information is scattered across numerous literature sources, presenting challenges to the diatomist. First, literature is often inaccessible because of cost, or its location in journals that are not widely circulated. Second, taxonomic revisions of diatoms are taking place faster than floras can be updated. Finally, taxonomic information is often contradictory across literature sources. These issues can be addressed by developing a content creation community dedicated to making taxonomic, ecological, and image-based data freely available for diatom researchers. Diatoms.org represents such a content curation community, providing open, online access to a vast amount of recent and historical information on North American diatom taxonomy and ecology. The content curation community aggregates existing taxonomic information, creates new content, and provides feedback in the form of corrections and notice of literature with nomenclatural changes. The website not only addresses the needs of experienced diatom scientists for consistent identification, but is also designed to meet users at their level of expertise, including engaging the lay public in the importance of diatom science. The website now contains over 1000 species pages contributed by over 100 content contributors, from students to established scientists. The project began with the intent to provide accurate information on diatom identification, ecology, and distribution using an approach that incorporates engaging design, user feedback, and advanced data access technology. In retrospect, the project that began as an "extended electronic book" has emerged not only as a means to support taxonomists, but for practitioners to communicate and collaborate, expanding the size of and benefits to the content curation community. In this paper, we outline the development of diatoms.org, document key elements of the project, examine ongoing challenges, and consider the unexpected emergent properties, including the value of diatoms.org as a source of data. Ultimately, if the field of diatom taxonomy, ecology, and biodiversity is to be relevant, a new generation of taxonomists needs to be trained and employed using new tools. We propose that diatoms.org is in a key position to serve as a hub of training and continuity for the study of diatom biodiversity and aquatic conditions.

Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary.

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.

Immunotherapy Approaches Beyond PD-1 Inhibition: the Future of Cellular Therapy for Head and Neck Squamous Cell Carcinoma.

OPINION STATEMENT: In a span of a few years, the surprising early successes of programmed cell death 1 (PD-1) inhibitors across a vast range of tumor types have transformed our understanding of cancer immunogenicity and provided proof of principle that T cells, if manipulated, can mediate meaningful tumor regression. In head and neck cancer, only a minority of patients respond to PD-1 therapy, but these small outcomes have fueled the enthusiasm for the next generation of immunotherapy-adoptive cell therapy-which employs recent advances in genetic engineering and cell culturing methods to generate T cells with enhanced anti-tumor efficacy for infusion back into the patient. Head and neck cancer is comprised of biologically distinct cancers, HPV-positive and HPV-negative, and the clinical responses to PD-1 inhibitors in both HPV-positive and HPV-negative head and neck patients have showcased better than any other cancer type that there are distinct pathways to immunogenicity that may lend themselves to different therapeutic approaches. Thus, head and neck cancer is uniquely poised to benefit from the personalized approach of adoptive cell therapy as well as provide a valuable platform to explore contrasting T cell modalities. In this article, we will review the growing portfolio of trials of adoptive cell therapies in head and neck cancer and discuss the future directions of this emerging new field.

Use of an amikacin-infused collagen sponge concurrent with implant removal for treatment of tibial plateau leveling osteotomy surgical site infection in 31 cases.

OBJECTIVE: To report the use and long-term outcome of dogs with surgical site infection (SSI) after tibial plateau leveling osteotomy (TPO), treated with an amikacin-infused collagen sponge and implant removal. STUDY DESIGN: Retrospective study. ANIMALS: Thirty-one client-owned dogs. METHODS: Medical records were reviewed for dogs with SSI after a TPLO that were treated with surgical implant removal and concurrent implantation of an amikacin-infused collagen sponge. Relevant clinical and surgical data were recorded. The TPLO implants were routinely removed; the surgical site was swabbed for culture. The sponge was aseptically infused with amikacin prior to implantation. Postprocedure examinations consisted of visual inspection of the incision by the surgeon and lameness scoring. RESULTS: Thirty-one dogs met all inclusion criteria. Median follow-up time was 687 days. Short-term examination after implant removal and sponge implantation revealed uneventful incisional healing in 24 dogs. Six (19.4%) dogs exhibited inflamed incision sites a median of 4 days (range, 3-9) postoperatively that resolved without additional treatment. One (3.2%) dog required empirical antibiotic treatment 7 days postoperatively but was lost to long-term follow-up. Long-term follow-up examination revealed no clinical evidence of SSI recurrence and no lameness in the remaining 30 cases. CONCLUSION: Surgical implant removal and implantation of an absorbable collagen sponge infused with amikacin alone was an effective treatment for postoperative TPLO SSI. CLINICAL SIGNIFICANCE: This procedure had a 96.8% long-term resolution of SSI. It should be considered as a treatment option for TPLO SSI.

Taxonomic harmonization may reveal a stronger association between diatom assemblages and total phosphorus in large datasets.

Diatom data have been collected in large-scale biological assessments in the United States, such as the U.S. Environmental Protection Agency's National Rivers and Streams Assessment (NRSA). However, the effectiveness of diatoms as indicators may suffer if inconsistent taxon identifications across different analysts obscure the relationships between assemblage composition and environmental variables. To reduce these inconsistencies, we harmonized the 2008-2009 NRSA data from nine analysts by updating names to current synonyms and by statistically identifying taxa with high analyst signal (taxa with more variation in relative abundance explained by the analyst factor, relative to environmental variables). We then screened a subset of samples with QA/QC data and combined taxa with mismatching identifications by the primary and secondary analysts. When these combined "slash groups" did not reduce analyst signal, we elevated taxa to the genus level or omitted taxa in difficult species complexes. We examined the variation explained by analyst in the original and revised datasets. Further, we examined how revising the datasets to reduce analyst signal can reduce inconsistency, thereby uncovering the variation in assemblage composition explained by total phosphorus (TP), an environmental variable of high priority for water managers. To produce a revised dataset with the greatest taxonomic consistency, we ultimately made 124 slash groups, omitted 7 taxa in the small naviculoid (e.g., Sellaphora atomoides) species complex, and elevated Nitzschia, Diploneis, and Tryblionella taxa to the genus level. Relative to the original dataset, the revised dataset had more overlap among samples grouped by analyst in ordination space, less variation explained by the analyst factor, and more than double the variation in assemblage composition explained by TP. Elevating all taxa to the genus level did not eliminate analyst signal completely, and analyst remained the most important predictor for the genera Sellaphora, Mayamaea, and Psammodictyon, indicating that these taxa present the greatest obstacle to consistent identification in this dataset. Although our process did not completely remove analyst signal, this work provides a method to minimize analyst signal and improve detection of diatom association with TP in large datasets involving multiple analysts. Examination of variation in assemblage data explained by analyst and taxonomic harmonization may be necessary steps for improving data quality and the utility of diatoms as indicators of environmental variables.

Racial disparity in oncologic and quality-of-life outcomes in patients with locally advanced head and neck squamous cell carcinomas enrolled in a randomized phase 2 trial.

BACKGROUND: To better understand patient-reported quality of life (PRQOL) for patients with head and neck cancer, PRQOL scores were collected in a clinical trial. METHODS: Patients were randomized to arm A (70 Gy of radiation with cisplatin) or arm B (70 Gy of radiation with cisplatin plus erlotinib at 150 mg daily). PRQOL scores were measured on days -7 (arm B only), 0, 30, and 180 with the University of Washington Quality of Life Questionnaire. Associations with clinical factors and outcomes were explored with linear mixed, logistic, and Cox regression models. RESULTS: One hundred eighty-nine patients (97 in arm A and 92 in arm B) consented to PRQOL collection. Patients were balanced apart from more females in arm A (20 [21%] vs 8 [9%]; P = .02). There were 17 black patients (18%) in arm A and 12 (13%) in arm B (P = .39). There was no change in the mean scores in arm B from day -7 to day 0 (P = .36). Scores were lower in both arms at day 30 (P for both < .0001), with no difference by arm (P = .10). Scores on day 180 remained lower for arm A (-6.79; 95% confidence interval [CI], -12.6 to -1.0; P = .02). In arm B, this difference was not significant, and this suggested that the scores had returned to the baseline by day 180 (P = .73). After adjustments for potential confounders, black race was an independent predictor for inferior scores (-11.4; 95% CI, -16.84 to -5.94; P < .0001), complete response rates (odds ratio, 0.34; 95% CI, 0.12-0.91; P = .03), and overall survival (hazard ratio, 3.71; 95% CI, 1.63-8.47; P < .01). CONCLUSIONS: PRQOL scores predictably worsened during and improved after chemoradiation. Black patients had inferior PRQOL and overall survival. Cancer 2018;124:2841-2849. © 2018 American Cancer Society.

Substratum-Associated Microbiota.

This review briefly highlights findings from a survey of 2017 literature on substratum-associated microbiota from a variety of aquatic environments, but primarily freshwaters. Centered on algae, cyanobacteria, and bacteria, topics covered include those of relevance to the Water Environment Federation, along with those of recent and emerging interest such as new or updated methods, new and interesting taxa, general ecology, trophic interactions, biogeochemical cycling, aquatic pollutants like herbicides and heavy metals, and nuisance, bloom-forming, or harmful algae. Additional coverage includes studies on bioremediation, bioassessment, biomonitoring and quantification of benthic microbiota.

Substratum-Associated Microbiota.

This survey of literature on substratumassociated microbiota from 2016 includes highlights of research findings associated with algae, cyanobacteria, and bacteria from a variety of aquatic environments, but primarily freshwaters. It covers topics of relevance to the Water Environment Federation along with those of emerging or recent interest such as nuisance, bloom forming and harmful algae, fossil fuel related contamination, and other environmental pollutants like nanoparticles. Additional interesting findings reported on include general ecology, method development, multistressor interactions, nutrient cycling, taxonomy and systematics, trophic interactions, and biomonitoring, bioassessment, and bioremediation.

The Effect of Community-Based Prevention and Care on Ebola Transmission in Sierra Leone.

OBJECTIVES: To examine the acceptability, use, effects on early isolation, and contribution to Ebola virus disease (EVD) transmission of Community Care Centers (CCCs), which were rapidly deployed in Sierra Leone during an accelerated phase of the 2014-2015 EVD epidemic. METHODS: Focus group discussions, triads, and key informant interviews assessed acceptability of the CCCs. Facility registers, structured questionnaires, and laboratory records documented use, admission, and case identification. We estimated transmission effects by comparing time between symptom onset and isolation at CCCs relative to other facilities with the national Viral Hemorrhagic Fever data set. RESULTS: Between November 2014 and January 2015, 46 CCCs were operational. Over 13 epidemic weeks, 6129 patients were triaged identifying 719 (12%) EVD suspects. Community acceptance was high despite initial mistrust. Nearly all patients presented to CCCs outside the national alert system. Isolation of EVD suspects within 4 days of symptoms was higher in CCCs compared with other facilities (85% vs 49%; odds ratio = 6.0; 95% confidence interval = 4.0, 9.1), contributing to a 13% to 32% reduction in the EVD reproduction number (Ro). CONCLUSIONS: Community-based approaches to prevention and care can reduce Ebola transmission.

Occurrence and Potential Biological Effects of Amphetamine on Stream Communities.

The presence of pharmaceuticals, including illicit drugs in aquatic systems, is a topic of environmental significance because of their global occurrence and potential effects on aquatic ecosystems and human health, but few studies have examined the ecological effects of illicit drugs. We conducted a survey of several drug residues, including the potentially illicit drug amphetamine, at 6 stream sites along an urban to rural gradient in Baltimore, Maryland, U.S.A. We detected numerous drugs, including amphetamine (3 to 630 ng L(-1)), in all stream sites. We examined the fate and ecological effects of amphetamine on biofilm, seston, and aquatic insect communities in artificial streams exposed to an environmentally relevant concentration (1 µg L(-1)) of amphetamine. The amphetamine parent compound decreased in the artificial streams from less than 1 µg L(-1) on day 1 to 0.11 µg L(-1) on day 22. In artificial streams treated with amphetamine, there was up to 45% lower biofilm chlorophyll a per ash-free dry mass, 85% lower biofilm gross primary production, 24% greater seston ash-free dry mass, and 30% lower seston community respiration compared to control streams. Exposing streams to amphetamine also changed the composition of bacterial and diatom communities in biofilms at day 21 and increased cumulative dipteran emergence by 65% and 89% during the first and third weeks of the experiment, respectively. This study demonstrates that amphetamine and other biologically active drugs are present in urban streams and have the potential to affect both structure and function of stream communities.

Synthesis of gold structures by gold-binding peptide governed by concentration of gold ion and peptide.

Although biological synthesis methods for the production of gold structures by microorganisms, plant extracts, proteins, and peptide have recently been introduced, there have been few reports pertaining to controlling their size and morphology. The gold ion and peptide concentrations affected on the size and uniformity of gold plates by a gold-binding peptide Midas-11. The higher concentration of gold ions produced a larger size of gold structures reached 125.5 µm, but an increased amount of Midas-11 produced a smaller size of gold platelets and increased the yield percentage of polygonal gold particles rather than platelets. The mechanisms governing factors controlling the production of gold structures were primarily related to nucleation and growth. These results indicate that the synthesis of gold architectures can be controlled by newly isolated and substituted peptides under different reaction conditions.

Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933.

BACKGROUND: Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma. METHODS: Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded. RESULTS: Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition. CONCLUSIONS: RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.

Systemic therapy of metastatic melanoma: on the road to cure.

The 10-year survival rate for patients with metastatic melanoma has historically been less than 10%. However, recent successes with immunotherapy and BRAF-targeted therapy have ushered in a new era in systemic therapy of this disease. These therapies have been associated with significant improvements in patient outcomes in several randomized phase III trials. Not only have these breakthroughs increased the likelihood of long-term survival in patients with melanoma, but they have also spurred the investigation of a new generation of agents for treatment of melanoma. This article reviews both current options for systemic treatment of metastatic melanoma and promising investigational approaches. We also discuss important considerations in choosing among systemic therapy options, to match the unique goals of therapy for individual patients.

Lifileucel, an Autologous Tumor-infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non-small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors.

In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy.

FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines.

A single, recurrent somatic point mutation (402C→G) in FOXL2 has been described in almost all adult-type granulosa cell tumors but not other ovarian neoplasms. Histopathological features of adult-type granulosa cell tumors can be mimicked by a variety of other tumors, making diagnosis of adult-type granulosa cell tumor challenging. It has been suggested that molecular testing for FOXL2 mutation might be a useful tool in the diagnosis of adult-type granulosa cell tumors. The aim of this study was to demonstrate how testing for the FOXL2 mutation can be used in a gynecological pathology consultation service and to establish clear procedural guidelines for FOXL2 testing. Immunohistochemistry for FOXL2 was done using an anti-FOXL2 polyclonal antiserum. If immunohistochemistry was positive, FOXL2 mutation status was subsequently analyzed using a TaqMan assay. A dilution experiment was done to assess the sensitivity and minimum tumor cellularity requirements for our TaqMan assay. Twenty problematic cases were assessed, where the differential diagnosis after the initial investigations included adult-type granulosa cell tumors. Differential diagnoses included: thecoma, Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, endometrial stromal sarcoma and others. In all cases, FOXL2 immunohistochemistry was positive and in six samples the FOXL2 mutation was detected, thus confirming a diagnosis of adult-type granulosa cell tumor. The TaqMan assay was able to reliably detect the FOXL2 mutation with input DNA in the range of 2.5-20 ng, and with a minimum of 25% tumor cell nuclei. The analysis of the FOXL2 mutational status in clinical samples is a useful diagnostic tool in situations where the differential diagnosis is between adult-type granulosa cell tumor and other ovarian tumors. The TaqMan assay requires a minimum of 2.5 ng DNA, with optimal assay performance for 5 to 10 ng DNA input. Laser capture or needle-macrodissection should be undertaken to enrich samples with tumor cell content below 25%.

Protective effects of blueberries on vascular function: A narrative review of preclinical and clinical evidence.

Blueberries are rich in nutrients and (poly)phenols, popular with consumers, and a major agricultural crop with year-round availability supporting their use in food-based strategies to promote human health. Accumulating evidence indicates blueberry consumption has protective effects on cardiovascular health including vascular dysfunction (i.e., endothelial dysfunction and arterial stiffening). This narrative review synthesizes evidence on blueberries and vascular function and provides insight into underlying mechanisms with a focus on oxidative stress, inflammation, and gut microbiota. Evidence from animal studies supports beneficial impacts on vascular function. Human studies indicate acute and chronic blueberry consumption can improve endothelial function in healthy and at-risk populations and may modulate arterial stiffness, but that evidence is less certain. Results from cell, animal, and human studies suggest blueberry consumption improves vascular function through improving nitric oxide bioavailability, oxidative stress, and inflammation. Limited data in animals suggest the gut microbiome mediates beneficial effects of blueberries on vascular function; however, there is a paucity of studies evaluating the gut microbiome in humans. Translational evidence indicates anthocyanin metabolites mediate effects of blueberries on endothelial function, though this does not exclude potential synergistic and/or additive effects of other blueberry components. Further research is needed to establish the clinical efficacy of blueberries to improve vascular function in diverse human populations in a manner that provides mechanistic information. Translation of clinical research to the community/public should consider feasibility, social determinants of health, culture, community needs, assets, and desires, barriers, and drivers to consumption, among other factors to establish real-world impacts of blueberry consumption.