Monocyte immunometabolic reprogramming in human pregnancy: contribution of trophoblast cells.

Immunometabolism research is uncovering the relationship between metabolic features and immune cell functions in physiological and pathological conditions. Normal pregnancy entails a fine immune and metabolic regulation of the maternal-fetal interaction to assist the energetic demands of the fetus with immune homeostasis maintenance. Here, we determined the immunometabolic status of monocytes of pregnant women compared with nonpregnant controls and its impact on monocyte anti-inflammatory functions such as efferocytosis. Monocytes from pregnant women (16-20 wk) and nonpregnant age-matched controls were studied. Single cell-based metabolic assays using freshly isolated monocytes from both groups were carried out in parallel with functional assays ex vivo to evaluate monocyte efferocytic capacity. On the other hand, various in vitro metabolic assays with human monocytes or monocyte-derived macrophages were designed to explore the effect of trophoblast cells in the profiles observed. We found that pregnancy alters monocyte metabolism and function. An increased glucose dependency and enhanced efferocytosis were detected in monocytes from pregnant women at resting states, compared with nonpregnant controls. Furthermore, monocytes display a reduced glycolytic response when stimulated with lipopolysaccharide (LPS). The metabolic profiling of monocytes at this stage of pregnancy was comparable with the immunometabolic phenotypes of human monocytes treated in vitro with human first trimester trophoblast cell conditioned media. These findings suggest that immunometabolic mechanisms are involved in the functional shaping of monocytes during pregnancy with a contribution of trophoblast cells. Results provide new clues for future hypotheses regarding pregnancies complicated by metabolic disorders.NEW & NOTEWORTHY Immunometabolism stands as a novel perspective to understand the complex regulation of the immune response and to provide small molecule-based therapies. By applying this approach to study monocytes during pregnancy, we found that these cells have a unique activation pattern. They rely more on glycolysis and show increased efferocytosis/IL-10 production, but they do not have the typical proinflammatory responses. We also present evidence that trophoblast cells can shape monocytes into this distinct immunometabolic profile.

Porphyromonas gingivalis outer membrane vesicles shape trophoblast cell metabolism impairing functions associated to adverse pregnancy outcome.

Periodontitis is proposed as a risk factor for preterm delivery, fetal growth restriction, and preeclampsia with severe consequences for maternal and neonatal health, but the biological mechanisms involved are elusive. Porphyromonas gingivalis gain access to the placental bed and impair trophoblast cell function, as assessed in murine and human pregnancy, suggesting a pathogenic role in adverse pregnancy and neonatal outcomes. P. gingivalis releases outer membrane vesicles (P. gingivalis OMV) during growth that spread to distant tissues and are internalized in host cells as described in metabolic, neurological, and vascular systemic diseases. Here we tested the hypothesis that P. gingivalis OMV internalized in trophoblast cells disrupt their metabolism leading to trophoblast and placenta dysfunction and adverse pregnancy outcomes. An in vitro design with human trophoblast cells incubated with P. gingivalis OMV was used together with ex vivo and in vivo approaches in pregnant mice treated with P. gingivalis OMV. P. gingivalis OMV modulated human trophoblast cell metabolism by reducing glycolytic pathways and decreasing total reactive oxygen species with sustained mitochondrial activity. Metabolic changes induced by P. gingivalis OMV did not compromise cell viability; instead, it turned trophoblast cells into a metabolic resting state where central functions such as migration and invasion were reduced. The effects of P. gingivalis OMV on human trophoblast cells were corroborated ex vivo in mouse whole placenta and in vivo in pregnant mice: P. gingivalis OMV reduced glycolytic pathways in the placenta and led to lower placental and fetal weight gain in vivo with reduced placental expression of the glucose transporter GLUT1. The present results point to OMV as a key component of P. gingivalis involved in adverse pregnancy outcomes, and even more, unveil a metabolic cue in the deleterious effect of P. gingivalis OMV on trophoblast cells and mouse pregnancy, providing new clues to understand pathogenic mechanisms in pregnancy complications and other systemic diseases.

Extracellular Vesicles of Porphyromonas gingivalis Disrupt Trophoblast Cell Interaction with Vascular and Immune Cells in an In Vitro Model of Early Placentation.

Extracellular vesicles released by the primary pathogen of periodontal disease Porphyromonas gingivalis (Pg), referred to as outer membrane vesicles (OMVs), have been associated with the pathogenesis of systemic diseases like cardiovascular disease, rheumatoid arthritis, and Alzheimer's disease. A pathogenic role for Pg by disrupting placental homeostasis was proposed in the association between periodontal disease and adverse pregnancy outcomes. On the basis that trophoblast-derived factors modulate endothelial and immune cell profiles in normal pregnancy and the scarce presence of Pg in placenta, we hypothesized that OMVs from Pg affect trophoblast cell phenotype, impairing trophoblast-endothelium and trophoblast-neutrophil interactions. By means of in vitro designs with first-trimester human trophoblast cells, endothelial cells, and freshly isolated neutrophils, we showed that Pg OMVs are internalized by trophoblast cells and modulate the activity and expression of functional markers. Trophoblast cells primed with Pg OMVs enhanced neutrophil chemoattraction and lost their anti-inflammatory effect. In addition, reduced migration with enhanced adhesion of monocytes was found in endothelial cells upon incubation with the media from trophoblast cells pretreated with Pg OMVs. Taken together, the results support a pathogenic role of Pg OMVs at early stages of pregnancy and placentation through disruption of trophoblast contribution to vascular transformation and immune homeostasis maintenance.

Gingival crevicular fluid from pregnant women impairs trophoblast cell function and trophoblast-neutrophil interaction.

PROBLEM: A strong association between periodontitis and higher susceptibility to pregnancy complications like preeclampsia has been reported although the mechanisms remain elusive. Trophoblast cells modulate the recruitment and functional shaping of maternal leukocytes at early stages to sustain an antiinflammatory microenvironment and fetal growth. Neutrophil activation with reactive oxygen species (ROS) release is associated with preeclampsia. Our aim was to study the effect of the gingival crevicular fluid (GCF) from pregnant women on trophoblast cell function and trophoblast-neutrophil interaction. METHOD OF STUDY: Pregnant women at 16-20 weeks of gestation (n = 27) and non-pregnant women (n = 8) as the control group were studied for gingivoperiodontal clinical score evaluation and GCF collection. Total bacteria and common periodontal pathogens were analyzed in GCF samples. The effect of each GCF sample was tested on first trimester trophoblast-derived cells to assess cell migration, cytokine expression and glucose uptake. Also, the effect of GCF on human peripheral neutrophil chemoattraction by trophoblast cells and ROS formation was assessed. RESULTS: Gingival crevicular fluid from pregnant women reduced trophoblast cell migration, increased proinflammatory marker expression and glucose uptake. A significant correlation between gingivoperiodontal score and trophoblast dysfunction was observed. Upon conditioning of trophoblast cells with GCF, only the GCF from pregnant women stimulated neutrophil chemoattraction. Similarly, GCF from pregnant but not from non-pregnant controls stimulated ROS formation in neutrophils. CONCLUSIONS: Gingival crevicular fluid from pregnant women is deleterious for first trimester trophoblast cell function. These effects could lead to placental homeostasis disruption underlying a pathogenic mechanism of pregnancy complications associated to periodontal disease.

Home Monitoring Programs for Patients Testing Positive for SARS-CoV-2: An Integrative Literature Review.

BACKGROUND: The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic threatened to oversaturate hospitals worldwide, necessitating rapid patient discharge to preserve capacity for the most severe cases. This need, as well as the high risk of SARS-CoV-2 transmission, led many hospitals to implement remote patient monitoring (RPM) programs for SARS-CoV-2 positive patients in an effort to provide care that was safe and preserve scarce resources. OBJECTIVE: The aim of this study is to provide an integrative review of peer-reviewed literature on different RPM programs that were implemented for SARS-CoV-2 positive patients including their strengths and challenges. METHODS: A search was conducted for peer reviewed literature using PubMed, CINAHL, OVID, and Google Scholar. Peer-reviewed studies written in English or Spanish and published between 2019 and 2021 on RPM of SARS-CoV-2-positive patients were considered. Information was extracted according to a qualitative content analysis method, informed by the Comparison of Mobile Patient Monitoring Systems Framework. RESULTS: Of 57 retrieved articles, 10 publications were included. The sample sizes ranged from 75 to 48,290 and the monitoring length ranged from 7 to 30 days. Information regarding the comparison framework was summarized. Main strengths of using RPM for SARS-CoV-2 positive patients was participant acceptance, feasibility, safety, and resource conservation. Main limitations were the lack of information on patient data security measures, robust outcomes testing, and identification of the most effective biomarkers to track SARS-CoV-2 decompensation. CONCLUSION: Different RPM programs for SARS-CoV-2 were implemented, from sending home participants with a pulse oximeter and collecting readings via call to modifying existing mobile applications and sending holistic health questionnaires to participants. This review determined that RPM is beneficial to SARS-CoV-2 positive patients; however, its effectiveness can be improved by further research. Mainly, identifying what patient data are most effective at tracking SARS-CoV-2 decompensation by utilizing advanced technology already in the market.

Current Evidence for Stereotactic Body Radiotherapy in Lung Metastases.

Lung metastases are the second most common malignant neoplasms of the lung. It is estimated that 20-54% of cancer patients have lung metastases at some point during their disease course, and at least 50% of cancer-related deaths occur at this stage. Lung metastases are widely accepted to be oligometastatic when five lesions or less occur separately in up to three organs. Stereotactic body radiation therapy (SBRT) is a noninvasive, safe, and effective treatment for metastatic lung disease in carefully selected patients. There is no current consensus on the ideal dose and fractionation for SBRT in lung metastases, and it is the subject of study in ongoing clinical trials, which examines different locations in the lung (central and peripheral). This review discusses current indications, fractionations, challenges, and technical requirements for lung SBRT.

Effect of an emergency department education and empowerment intervention on uncontrolled hypertension in a predominately minority population: The AHEAD2 randomized clinical pilot trial.

OBJECTIVE: To determine whether an emergency department (ED) education and empowerment intervention coupled with early risk assessment can help improve blood pressure (BP) in a high-risk population. METHODS: A hypertension emergency department intervention aimed at decreasing disparities (AHEAD2) is a 3-arm, single-site randomized pilot trial for feasibility in an urban academic ED. A total of 150 predominantly ethnic minorities with no primary care provider and severely elevated blood pressure (BP) (≥160/100 mm Hg) were enrolled over 10 months. Participants were randomized into 1 of 3 study arms: (1) enhanced usual care (EUC), (2) ED-initiated screening, brief intervention, and referral for treatment (ED-SBIRT), or (3) ED- SBIRT plus a 48-72 hours post-acute care hypertension transition clinic (ED-SBIRT+PACHT-c). Primary outcomes were change in systolic and diastolic BP (SBP and DBP) from baseline to 9 months. Secondary outcomes were BP control (BP <140/90 mm Hg), changes in hypertension knowledge, medication adherence, and limited bedside echocardiogram (LBE) findings. RESULTS: SBP reduction from baseline to month 9 was -26.8 (95% confidence interval [CI]: -32.8, -20.7) mm Hg for ED-SBIRT, -23.4 (95% CI: -29.5, -17.3) mm Hg for ED-SBIRT+PACHT-c, and -18.9 (95% CI: -24.9, -12.9) mm Hg for EUC. DBP decreased by -12.5 (95% CI: -16.1, -9.0) mm Hg for ED-SBIRT, -11.3 (95% CI: -14.8, -7.7) mm Hg for ED-SBIRT+PACHT-c, and -8.4 (95% CI: -11.9, -4.9) mm Hg for EUC. A multicomponent intervention compared with EUC resulted in SBP decrease of -7.9 mm Hg (95% CI: -16.4, 0.6). At 9 months, hypertension was controlled for 29.3% (95% CI: 20.3, 38.3) of intervention and 23.5% (95% CI: 11.9, 35.2) of EUC participants. All groups saw improvements in hypertension knowledge, medication adherence, and LBEs, with greater improvements in intervention groups. CONCLUSIONS: The study findings suggest that a multicomponent intervention comprising of ED education and empowerment coupled with early risk assessment may help improve BP in a high-risk population.

Targeting of uncontrolled hypertension in the emergency department (TOUCHED): Design of a randomized controlled trial.

BACKGROUND: Uncontrolled or undiagnosed hypertension (HTN) is estimated to be as high as 46% in emergency departments (EDs). Uncontrolled HTN contributes significantly to cardiovascular morbidity and disproportionately affects communities of color. EDs serve high risk populations with uncontrolled conditions that are often missed by other clinical settings and effective interventions for uncontrolled HTN in the ED are critically needed. The ED is well situated to decrease the disparities in HTN control by providing a streamlined intervention to high risk populations that may use the ED as their primary care. METHODS: Targeting of UnControlled Hypertension in the Emergency Department (TOUCHED), is a two-arm single site randomized controlled trial of 770 adults aged 18-75 presenting to the ED with uncontrolled HTN comparing (1) usual care, versus (2) an Educational and Empowerment (E2) intervention that integrates a Post-Acute Care Hypertension Consultation (PACHT-c) with a mobile health BP self-monitoring kit. The primary outcome is differences in mean systolic blood pressure (SBP) at 6-months post enrollment. Secondary outcomes include differences in mean SBP and mean diastolic BP (DBP) at 3-months and mean DBP at 6-months. Additionally, improvement in cardiovascular risk score, medication adherence, primary care engagement, and HTN knowledge will also be assessed as part of this study. CONCLUSIONS: The TOUCHED trial will be instrumental in determining the effectiveness of a brief ED-based intervention that is portable to other urban EDs with high-risk populations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03749499.