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Brain metastases (BM) are rare in gynecologic cancers. Overall BM confers a poor prognosis but other factors such as number of brain lesions, patient age, the presence of extracranial metastasis, the Karnofsky Performance Status (KPS) score, and the type of primary cancer also impact prognosis. Taking a patient's whole picture into perspective is crucial in deciding the appropriate management strategy. The management of BM requires an interdisciplinary approach that frequently includes oncology, neurosurgery, radiation oncology and palliative care. Treatment includes both direct targeted therapies to the lesion(s) as well as management of the neurologic side effects caused by mass effect. There is limited evidence of when screening for BM in the gynecology oncology patient is warranted but it is recommended that any cancer patient with new focal neurologic deficit or increasing headaches should be evaluated. The primary imaging modality for detection of BM is MRI, but other imaging modalities such as CT and PET scan can be used for certain scenarios. New advances in radiation techniques, improved imaging modalities, and systemic therapies are helping to discover BM earlier and provide treatments with less detrimental side effects.

Résumé Objectifs La présente étude s’est penchée sur le point de vue des enfants relativement au retour en classe après le confinement imposé par la pandémie, sur le port du masque en classe et sur la santé mentale des enfants et des parents pendant la pandémie. Méthodologie La présente étude transversale a fait partie d’un exercice de simulation scolaire de deux jours au cours duquel les élèves ont été répartis au hasard entre diverses recommandations sur le port du masque. Au moyen d’analyses régression multiple, les chercheurs ont analysé le compte rendu des parents sur la santé mentale et, après la simulation, celui des élèves sur l’anxiété liée à la COVID-19 et le port du masque. Les élèves plus âgés ont participé à des groupes de travail semi-structurés pour compléter les données du questionnaire. Résultats Sur les 190 élèves de la présente étude, 31 % ne dépassaient pas la quatrième année et 95 % avaient hâte de rentrer en classe. La plus grande anxiété des parents ou des proches (β= 0,67; p Conclusions Chez les enfants anxieux à cause de la COVID-19, l’anxiété des parents et l’information sur la COVID-19 pourraient être des cibles d’intervention. De futures recherches devraient porter sur les effets de la mise en œuvre prolongée de mesures sanitaires d’atténuation des risques sur la réussite scolaire et la santé mentale des enfants.

The purpose of this study is to assess the integrity of chondral defect repairs filled with a cartilage allograft and sealed with either allogeneic fibrin sealant or autologous fibrin sealants created with platelet-rich plasma (PRP) or platelet-poor plasma (PPP) in a cadaver model.Twenty-millimeter medial femoral condyle (MFC) chondral defects were created in five human cadaveric knees. The defects were filled with particulated cartilage allograft hydrated with PRP from human donors until slightly recessed. Sealants were applied until flush with the articular surface using PRP and autologous thrombin serum, PPP and autologous thrombin serum, or commercial allogeneic sealant. The MFC defects were cycled using a multiaxial testing system to simulate continuous passive motion undergone during rehabilitation. After testing, the repairs were assessed for integrity by quantitatively comparing defect exposure and qualitatively assessing sealant delamination.The mean defect exposures were 4.20% ± 5.02% for the PRP group, 4.60% ± 5.18% for the PPP group, and 1.80% ± 2.95% for the allogeneic sealant group. No significant differences were observed between groups (The PRP and PPP sealants were comparable to the allogeneic sealant for graft fixation when used in conjunction with an underlying PRP-hydrated particulated cartilage allograft. The autologous sealants had better delamination resistance than the allogeneic sealant.The time-zero model is critical in elucidating the retention properties of fibrin and allogenic sealants after cartilage repair and before healing processes help stabilize the repair.

Objectives This study examined children’s perspectives about returning to in-person school following lockdown due to the pandemic and about mask-wearing in class, as well as the mental health of children and parents during the pandemic. Methods This cross-sectional study was part of a 2-day school simulation exercise that randomized students to different masking recommendations. Parent-report of mental health and post-simulation child-report of COVID-19-related anxiety and mask-wearing were analyzed using descriptive and multiple regression analyses. Semi-structured focus groups were conducted with older students to supplement questionnaire data. Results Of 190 students in this study, 31% were in grade 4 or lower 95% looked forward to returning to in-person school. Greater child anxiety about COVID-19 was predicted by increased parent/caregiver anxiety (β=0.67; P Conclusions For children anxious about COVID-19, parental anxiety and education about COVID-19 may be targets for intervention. Future research should examine the impact of prolonged implementation of public health mitigation strategies in school on academic achievement and children’s mental health.

Objective: Little is known about risk factors associated with COVID-19 infection among Arab American people. We aimed to understand the predictors of receiving a positive COVID-19 test result and being admitted to the hospital for COVID-19 among Arab American adults using data from a hospital near an Arab ethnic enclave. Methods: We used electronic medical record data for Arab American adults aged ≥18 years from March 1, 2020, through January 31, 2021, at Sharp Grossmont Hospital in La Mesa, California. The primary outcomes were receiving a positive COVID-19 test result and being admitted to the hospital for COVID-19. We ran logistic regression models with individual- and population-level risk factors to determine the odds of each primary outcome. Results: A total of 2744 Arab American adults were tested for COVID-19, of whom 783 (28.5%) had a positive test result. In the fully adjusted model, women had lower odds of receiving a positive test result than men (adjusted odds ratio [aOR] = 0.77; 95% CI, 0.64-0.92), and adults living in high-poverty areas had higher odds of receiving a positive test result than adults in lower-poverty areas (aOR = 1.25; 95% CI, 1.04-1.51). Of the 783 Arab American adults with data on admission, 131 (16.7%) were admitted. For every 1-unit increase in the Charlson Comorbidity Index, the odds of admission increased by 66% (aOR = 1.66; 95% CI, 1.36-2.04). Conclusion: The risk of receiving a positive test result for COVID-19 was higher among Arab American adults living in high-poverty areas than in lower-poverty areas. The risk of admission was directly related to overall health status. Future work should aim to understand the barriers to prevention and testing in this population.

Supplementary Table 1 Figure S1A, S1B

Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti–multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro. Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide.Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti–multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions.Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341–9. ©2016 AACR.

PURPOSE This study evaluated risk factors predicting unplanned 30-day acute service utilization among adults subsequent to hospitalization for a new diagnosis of leukemia, lymphoma, or myeloma. This study explored the prevalence of medical complications (aligned with OP-35 measure specifications from the Centers for Medicare & Medicaid Services [CMS] Hospital Outpatient Quality Reporting Program) and the potential impact of psychosocial factors on unplanned acute care utilization. METHODS This study included 933 unique patients admitted to three acute care inpatient facilities within a nonprofit community-based health care system in southern California from 2012 to 2017. Integrated comprehensive data elements from electronic medical records and facility oncology registries were leveraged for univariate statistics, predictive models constructed using multivariable logistic regression, and further exploratory data mining, with predictive accuracy of the models measured with c-statistics. RESULTS The mean age of study participants was 65 years, and 55.1% were male. Specific diagnoses were lymphoma (48.7%), leukemia (35.2%), myeloma (14.0%), and mixed types (2.1%). Approximately one fifth of patients received unplanned acute care services within 30 days postdischarge, and over half of these patients presented with one or more symptoms associated with the CMS medical complication measure. The predictive models, with c-statistics ranging from 0.7 and above for each type of hematologic malignancy, indicated good predictive qualities with the impact of psychosocial functioning on the use of acute care services ( P values < .05), including lack of consult for social work during initial admission (lymphoma or myeloma), history of counseling or use of psychotropic medications (lymphoma), and past substance use (myeloma). CONCLUSION This study provides insights into patient-related factors that may inform a proactive approach to improve health outcomes, such as enhanced care transition, monitoring, and support interventions.

Background Indigenous Peoples in Canada have survived hundreds of years of colonization and systematic exploitation, including actions carried out in the pursuit of energy resources and infrastructure development in traditional Indigenous territories. Research has been a tool in this exploitation through its legacy of research ‘on’ rather than ‘with’ Indigenous Peoples. As societies grapple with reconciliation, including how to build partnerships for sustainable land and energy development, engineering and technical research must use respectful approaches that centre on Indigenous Peoples and Indigenous Knowledge Systems. Main text This preliminary review aims to be a step to address the lack of literature on respectful research with Indigenous Peoples within the context of engineering, energy, and infrastructure. To this end, we: (a) summarize three key frameworks that have been used in technical research projects for carrying out research respectfully, as defined by Indigenous and Indigenist ways of knowing and doing (Research is Ceremony, Two-Eyed Seeing, and doing research in a “Good Way”) and derive from them overarching principles; (b) identify a sample of 13 engineering, energy and infrastructure research projects that report using an Indigenous-centred approach. These relate to five technical areas, whose relevance to Indigenous communities was verified through community partners: water, energy, housing, telecommunications, and food systems; (c) assess the extent to which these 13 projects applied the principles of respectful research when working with Indigenous communities. Among the 13 projects identified, it is evident that some researchers in the fields of engineering, energy, and infrastructure are struggling and striving to engage respectfully with Indigenous communities. However, few include full details of their relationships and interactions with Indigenous communities in their published work. Conclusions These findings suggest a lack of details on respectful collaboration with Indigenous communities in technical literature. Gaps include a scarcity of evidence that Indigenous communities were involved in high-level decision-making or provided post-project feedback. Further work is needed to embed respectful research principles into the training, processes, and institutions of technical fields. This is essential to ensure ethical partnerships between technical researchers and Indigenous communities.

Enteric fermentation from livestock accounts for over a quarter of the United States' methane emissions. A potent greenhouse gas, methane has 80 times the global warming potential of carbon dioxide over a 20-year period. An emerging focus of research is the incorporation of algae (e.g., kelp, seaweed or microalgae) into livestock feed, with several studies documenting dramatic suppression of enteric methane emissions in cattle. As part of a nationwide multidisciplinary study of using algae feed supplements to reduce methane emissions and improve dairy productivity, we used focus groups and individual interviews to measure organic and conventional dairy farmer's knowledge and opinions of algae-based feed supplements. Our goals were to learn what both organic and conventional dairy farmers know about algae-based feed supplements, why they do or do not feed them to their cows and if they were interested in the methane-reducing potential of these algal-based feeds. We also sought to understand where they get valued information about animal nutrition. We found most farmers were aware of algae-based feed supplements on the market, but organic farmers were more familiar with marketing claims. Farmers reported feeding algae-based feed supplements to address herd health concerns, especially reproductive issues and pink eye, but expressed rising costs of the supplements as an obstacle. Both organic and conventional farmers expressed interest in suppressing methane emissions, but only if incentives are provided. Lastly, participants receive trusted information about feed supplements from their dairy nutritionists, who help them make decisions around feed purchasing and rations.

Meltwater drainage beneath ice sheets is a fundamental consideration for understanding ice–bed conditions and bed-modulated ice flow, with potential impacts on terminus behavior and ice-shelf mass balance. While contemporary observations reveal the presence of basal water movement in the subglacial environment and inferred styles of drainage, the geological record of former ice sheets, including sediments and landforms on land and the seafloor, aids in understanding the spatiotemporal evolution of efficient and inefficient drainage systems and their impact on ice-sheet behavior. We highlight the past decade of advances in geological studies that focus on providing process-based information on subglacial hydrology of ice sheets, how these studies inform theory, numerical models and contemporary observations, and address the needs for future research.

Cellular metabolism influences immune cell function, with mitochondrial fatty acid β-oxidation and oxidative phosphorylation required for multiple immune cell phenotypes. Carnitine palmitoyltransferase 1a (Cpt1a) is considered the rate-limiting enzyme for mitochondrial metabolism of long-chain fatty acids, and Cpt1a deficiency is associated with infant mortality and infection risk. This study was undertaken to test the hypothesis that impairment in Cpt1a-dependent fatty acid oxidation results in increased susceptibility to infection. Screening the Cpt1a gene for common variants predicted to affect protein function revealed allele rs2229738_T, which was associated with pneumonia risk in a targeted human phenome association study. Pharmacologic inhibition of Cpt1a increases mortality and impairs control of the infection in a murine model of bacterial pneumonia. Susceptibility to pneumonia is associated with blunted neutrophilic responses in mice and humans that result from impaired neutrophil trafficking to the site of infection. Chemotaxis responsible for neutrophil trafficking requires Cpt1a-dependent mitochondrial fatty acid oxidation for amplification of chemoattractant signals. These findings identify Cpt1a as a potential host determinant of infection susceptibility and demonstrate a requirement for mitochondrial fatty acid oxidation in neutrophil biology.

ImportanceWearing a face mask in school can reduce SARS-CoV-2 transmission but it may also lead to increased hand-to-face contact, which in turn could increase infection risk through self-inoculation.ObjectiveTo evaluate the effect of wearing a face mask on hand-to-face contact by children while at school.Design, Setting, and ParticipantsThis prospective randomized clinical trial randomized students from junior kindergarten to grade 12 at 2 schools in Toronto, Ontario, Canada, during August 2020 in a 1:1 ratio to either a mask or control class during a 2-day school simulation. Classes were video recorded from 4 angles to accurately capture outcomes.InterventionsParticipants in the mask arm were instructed to bring their own mask and wear it at all times. Students assigned to control classes were not required to mask at any time (grade 4 and lower) or in the classroom where physical distancing could be maintained (grade 5 and up).Main Outcomes and MeasuresThe primary outcome was the number of hand-to-face contacts per student per hour on day 2 of the simulation. Secondary outcomes included hand-to-mucosa contacts and hand-to-nonmucosa contacts. A mixed Poisson regression model was used to derive rate ratios (RRs), adjusted for age and sex with a random intercept for class with bootstrapped 95% CIs.ResultsA total of 174 students underwent randomization and 171 students (mask group, 50.6% male; control group, 52.4% male) attended school on day 2. The rate of hand-to-face contacts did not differ significantly between the mask and the control groups (88.2 vs 88.7 events per student per hour; RR, 1.00; 95% CI, 0.78-1.28; P = >.99). When compared with the control group, the rate of hand-to-mucosa contacts was significantly lower in the mask group (RR, 0.12; 95% CI, 0.07-0.21), while the rate of hand-to-nonmucosa contacts was higher (RR, 1.40; 95% CI, 1.08-1.82).Conclusions and RelevanceIn this clinical trial of simulated school attendance, hand-to-face contacts did not differ among students required to wear face masks vs students not required to wear face masks; however, hand-to-mucosa contracts were lower in the face mask group. This suggests that mask wearing is unlikely to increase infection risk through self-inoculation.Trial RegistrationClinicalTrials.gov Identifier: NCT04531254

This study investigated whether geostatistical methods can be applied to severely drought-affected pastures to assess spatial variability in sward height (SH) and dry matter yield (DMY) and change in SH and DM in response to grazing. Geo-referenced SH data were collected using a rapid, non-destructive method (rapid pasture meter) and analysed by geostatistical methodology. Eight severely drought-affected paddocks (~1.25 ha) were grazed individually by two groups of 20 Angus heifers in two 28-day phases (P1 and P2) between 2 July and 29 August 2019. Pasture DMY was estimated from calibration equations developed for P1 and P2. Ordinary kriging was used to generate estimated surface forming maps with which to visualise the spatial variability. The degree of spatial dependence (dSD) was strongest for SH during P2 post-grazing (11%) and for DMY during P2 pre-grazing (6%). For change in SH, the dSD was 50% for P1 and 0% for P2. Disappearance of DMY dSD was 56% for P1 and 47% for P2. The range of spatial dependence (distance until variability stabilised) for both SH and DMY was lowest for P1 post-grazing (11 m), indicating that intensive sampling is required. The ranges of spatial dependence for the change in both SH and DMY were similar for P1 and P2. These results confirm that intensity of grazing by cattle is not random. Incorporation of this methodology into rapid, non-destructive pasture data collection devices would assist producers and their advisers in improving grazing management decisions. Further analysis with data from non-drought affected pastures is required to determine the robustness of this method.

The National Institutes of Health (NIH) recognizes that, despite HIV scientific advances, stigma and discrimination continue to be critical barriers to the uptake of evidence-based HIV interventions. Achieving the Ending the HIV Epidemic: A Plan for America (EHE) goals will require eliminating HIV-related stigma. NIH has a significant history of supporting HIV stigma research across its Institutes, Centers, and Offices (ICOs) as a research priority. This article provides an overview of NIH HIV stigma research efforts. Each ICO articulates how their mission shapes their interest in HIV stigma research and provides a summary of ICO-relevant scientific findings. Research gaps and/or future opportunities are identified throughout, with key research themes and approaches noted. Taken together, the collective actions on the part of the NIH, in tandem with a whole of government and whole of society approach, will contribute to achieving EHE's milestones.Los Institutos de Salud Nacional (NIH, siglas en inglés) reconocen que, a pesar de los avances en la prevención y el tratamiento, el estigma y la discriminación continúan siendo barreras críticas a la adopción de la prevención y el cuido basados en la evidencia. Las metas de Logrando el Fin de la Epidemia de VIH: Plan para América (EHE, siglas en inglés) requerirán la eliminación del estigma relacionado al VIH. Los NIH tienen una historia significativa apoyando la investigación del estigma relacionado al VIH a través de sus Institutos, Centros, y Oficinas (ICOs, siglas en inglés). Esta investigación es una prioridad fundamental y entrelazada para los ICOs. En este artículo, los autores de los NIH proveen una reseña sobre la investigación del estigma relacionado al VIH a través de los ICOs selectos. Cada ICO articula como su misión y prioridad dan forma a su interés en la investigación del estigma al VIH y provee una breve reseña de los hallazgos científicos pertinentes al ICO. Lagunas en la investigación relacionada a la misión, prioridades, y/o áreas de investigación futuras se identifican a través del artículo. También se apuntan en el resumen los temas de investigación claves y sus estrategias. En conjunto, las acciones colectivas de parte de los NIH, junto a la estrategia necesaria de parte del gobierno en su totalidad y de la sociedad en su totalidad, contribuirán al logro de las metas del EHE.

The cell division cycle is a fundamental process required for proliferation of all living organisms. The eukaryotic cell cycle follows a basic template with an ordered series of events beginning with G1 (Gap1) phase, followed successively by S (Synthesis) phase, G2 (Gap 2) phase, and M-phase (Mitosis). The process is tightly regulated in response to signals from both the internal and external milieu. The budding yeast S. cerevisiae is an outstanding model for the study of the cell cycle and its regulatory process. The basic events and regulatory processes of the S. cerevisiae cell cycle are highly conserved with other eukaryotes. The organism grows rapidly in simple medium, has a sequenced annotated genome, well-established genetics, and is amenable to analysis by proteomics and microscopy. Additionally, a range of tools and techniques are available to generate cultures of S. cerevisiae that are homogenously arrested or captured at specific phases of the cell cycle and upon release from that arrest these can be used to monitor cell cycle events as the cells synchronously proceed through a division cycle. In this chapter, we describe a series of commonly used techniques that are used to generate synchronized populations of S. cerevisiae and provide an overview of methods that can be used to monitor the progression of the cells through the cell division cycle.

Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity. Experimental Design: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line–derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models. Results: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity. Conclusions: Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.

A variety of neuropsychological changes secondary to heart failure have been documented in the literature. However, what remains unclear are which neuropsychological abilities are the most impacted by heart failure and what tests have the sensitivity to measure that impact. Eight databases were searched for articles that examined the neuropsychological functioning of patients with heart failure. Some of the inclusion criteria were articles had to have a heart failure group with a demographically comparable control group and standardized neuropsychological testing. Exclusion criteria included articles with a heart failure group with any other type of major organ failure, or comparisons that were between different classes of heart failure rather than between a heart failure and non-heart failure group. A total of 33 articles met the inclusion criteria (total heart failure sample n = 8900) and provided effect size data for 20 neuropsychological domains. All observed domain-level differences between heart failure and non-heart failure groups were statistically significant, except for simple motor functioning and confrontation naming. The greatest differences in performance were in executive functioning, global cognition, complex psychomotor speed, and verbal memory. The highest effect sizes came from Trail-Making Test-Part B, CAMCOG, Symbol Digit Modality Test, and California Verbal Learning Test. The neuropsychological patterns of heart failure suggested diffuse cognitive involvement, with higher-level processes being most affected. It is important to track neurocognition in this clinical population since neuropsychological impairment is prevalent, and screening measures appear to be reliable. Such screening and further assessment would inform future medical treatment and may improve patient care management.

Fetal growth restriction (FGR) is a significant risk factor for stillbirth, neonatal complications and adulthood morbidity. Compared with those of appropriate weight for gestational age (AGA), FGR babies have smaller placentas with reduced activity of amino acid transporter systems A and L, thought to contribute to poor fetal growth. The amino acids glutamine and glutamate are essential for normal placental function and fetal development; whether transport of these is altered in FGR is unknown. We hypothesised that FGR is associated with reduced placental glutamine and glutamate transporter activity and expression, and propose the mammalian target of rapamycin (mTOR) signaling pathway as a candidate mechanism. FGR infants [individualised birth weight ratio (IBR) 14C-glutamine and 14C-glutamate (per mg placental protein) but higher expression of key transporter proteins (glutamine: LAT1, LAT2, SNAT5, glutamate: EAAT1) versus AGA [IBR 20th–80th]. In further experiments, in vitro exposure to rapamycin inhibited placental glutamine and glutamate uptake (24 h, uncomplicated pregnancies) indicating a role of mTOR in regulating placental transport of these amino acids. These data support our hypothesis and suggest that abnormal glutamine and glutamate transporter activity is part of the spectrum of placental dysfunction in FGR.

KEY POINTS Maternal hypertension is associated with increased rates of pregnancy pathologies, including fetal growth restriction, due at least in part to reductions in nitric oxide (NO) bioavailability and associated vascular dysfunction. Dietary nitrate supplementation, from beetroot juice (BRJ), has been shown to increase NO bioavailability and improve cardiovascular function in both preclinical and clinical studies. This study is the first to investigate effects of dietary nitrate supplementation in a pregnant animal model. Importantly, the effects of nitrate-containing BRJ were compared with both 'placebo' (nitrate-depleted) BRJ as well as water to control for potential nitrate-independent effects. Our data show novel, nitrate-independent effects of BRJ to lower blood pressure and improve vascular function in endothelial nitric oxide synthase knockout (eNOS-/- ) mice. These findings suggest potential beneficial effects of BRJ supplementation in pregnancy, and emphasize the importance of accounting for nitrate-independent effects of BRJ in study design and interpretation. ABSTRACT Maternal hypertension is associated with adverse pregnancy outcomes, including fetal growth restriction (FGR), due in part to reductions in nitric oxide (NO) bioavailability. We hypothesized that maternal dietary nitrate administration would increase NO bioavailability to reduce systolic blood pressure (SBP), improve vascular function and increase fetal growth in pregnant endothelial NO synthase knockout (eNOS-/- ) mice, which exhibit hypertension, endothelial dysfunction and FGR. Pregnant wildtype (WT) and eNOS-/- mice were supplemented with nitrate-containing beetroot juice (BRJ+) from gestational day (GD) 12.5. Control mice received an equivalent dose of nitrate-depleted BRJ (BRJ-) or normal drinking water. At GD17.5, maternal SBP was measured; at GD18.5, maternal nitrate/nitrite concentrations, uterine artery (UtA) blood flow and endothelial function were assessed, and pregnancy outcomes were determined. Plasma nitrate concentrations were increased in both WT and eNOS-/- mice supplemented with BRJ+ (P < 0.001), whereas nitrite concentrations were increased only in eNOS-/- mice (P < 0.001). BRJ- did not alter nitrate/nitrite concentrations. SBP was lowered and UtA endothelial function was enhanced in eNOS-/- mice supplemented with either BRJ+ or BRJ-, indicating nitrate-independent effects of BRJ. Improvements in endothelial function in eNOS-/- mice were abrogated in the presence of 25 mm KCl, implicating enhanced EDH signalling in BRJ- treated animals. At GD18.5, eNOS-/- fetuses were significantly smaller than WT animals (P < 0.001), but BRJ supplementation did not affect fetal weight. BRJ may be a beneficial intervention in pregnancies associated with hypertension, endothelial dysfunction and reduced NO bioavailability. Our data showing biological effects of non-nitrate components of BRJ have implications for both interpretation of previous findings and in the design of future clinical trials.