Healthy food delivery for type 2 diabetes management in rural clinics' patients: A comparative effectiveness randomized controlled trial protocol.

BACKGROUND: Rural populations experience a higher prevalence of both food insecurity and type 2 diabetes mellitus (T2DM) than metropolitan populations and face many challenges in accessing resources essential to optimal T2DM self-management. This study aims to address these challenges by delivering a T2DM-appropriate food box and recipes directly to rural participants' homes. METHODS: This is a comparative effectiveness randomized controlled trial including 400 English- or Spanish-speaking rural adult participants with T2DM (HbA1c ≥6.5%) experiencing food insecurity. Participants are randomly assigned to a 3-month Healthy Food Delivery Intervention (HFDI) plus one 60-min virtual consultation with a diabetes educator or consultation only. The HFDI includes a weekly food box delivery with recipes. Data are collected at pre-intervention, 3-months (post-intervention), 9-months, and 15-months. The primary outcome is change in HbA1c, with secondary measures including diet quality (Healthy Eating Index-2015, calculated from one 24-h dietary recall at each data collection time point), cardio-metabolic risk factors (i.e., blood pressure, lipids, body mass index, glucose), and patient-centered outcomes (e.g., T2DM self-efficacy, T2DM-related distress). Process evaluation data (e.g., successful food box deliveries, diabetes educator consultation attendance, intervention satisfaction) are collected during and post-intervention (3-months). A cost-effectiveness analysis based on traditional cost per quality-adjusted life year gain thresholds will be conducted to estimate the incremental cost-effectiveness between HFDI plus consultation and consultation alone. CONCLUSION: Findings from this study will provide evidence regarding the effectiveness of an intervention that promotes participant adherence and improves access to healthy food. CLINICAL TRIAL REGISTRATION: NCT04876053.

An integrated approach to address diabetes in the context of food insecurity: Delivering health study protocol.

Background: Diabetes self-management education and support (DSMES) interventions among food insecure individuals with type 2 diabetes (T2D) have found modest improvements in nutrition and health outcomes but are limited by barriers to attendance and retention. This study applies a community-based participatory research approach, engaging community members at all levels of intervention planning, development, implementation, and dissemination, to deliver a plain-language DSMES curriculum to food insecure community members with T2D. Methods: This is a single-arm, pre-post design assessing the efficacy of a 12-week home-delivered DSMES curriculum and T2D-appropriate food box intervention to improve the nutrition and health outcomes of food insecure individuals with T2D. The intervention consists of a weekly food box delivery and handout with video links on key DSMES topics, developed and refined using community advisor feedback. Up to 100 English-, Spanish-, or Marshallese-speaking adult participants with T2D (HbA1c ≥ 7%) and food insecurity are being recruited from food pantries in northwest Arkansas. Data is collected at pre-intervention and immediately post-intervention. The primary study outcome is change in HbA1c. Secondary measures include diet quality (Healthy Eating Index-2015, calculated from 3 24-h dietary recall interviews via phone), body mass index, blood pressure, skin carotenoids, food security, T2D self-management behaviors, T2D self-efficacy, and T2D-related distress. Results: Recruitment began in August 2021 and enrollment is anticipated to be complete in March 2023. Conclusion: Findings from this study will provide a rich understanding of diabetes-related health outcomes and dietary patterns of individuals with food insecurity and T2D and inform future food-focused DSMES interventions in this setting.

Comparison of the Immunogenicity of Cell Culture-Based and Recombinant Quadrivalent Influenza Vaccines to Conventional Egg-Based Quadrivalent Influenza Vaccines Among Healthcare Personnel Aged 18-64 Years: A Randomized Open-Label Trial.

BACKGROUND: RIV4 and cell-culture based inactivated influenza vaccine (ccIIV4) have not been compared to egg-based IIV4 in healthcare personnel, a population with frequent influenza vaccination that may blunt vaccine immune responses over time. We conducted a randomized trial among healthcare personnel (HCP) aged 18-64 years to compare humoral immune responses to ccIIV4 and RIV4 to IIV4. METHODS: During the 2018-2019 season, participants were randomized to receive ccIIV4, RIV4, or IIV4 and had serum samples collected prevaccination, 1 and 6 months postvaccination. Serum samples were tested by hemagglutination inhibition (HI) for influenza A/H1N1, B/Yamagata, and B/Victoria and microneutralization (MN) for A/H3N2 against cell-grown vaccine reference viruses. Primary outcomes at 1 month were seroconversion rate (SCR), geometric mean titers (GMT), GMT ratio, and mean fold rise (MFR) in the intention-to-treat population. RESULTS: In total, 727 participants were included (283 ccIIV4, 202 RIV4, and 242 IIV4). At 1 month, responses to ccIIV4 were similar to IIV4 by SCR, GMT, GMT ratio, and MFR. RIV4 induced higher SCRs, GMTs, and MFRs than IIV4 against A/H1N1, A/H3N2, and B/Yamagata. The GMT ratio of RIV4 to egg-based vaccines was 1.5 (95% confidence interval [CI] 1.2-1.9) for A/H1N1, 3.0 (95% CI: 2.4-3.7) for A/H3N2, 1.1 (95% CI: .9-1.4) for B/Yamagata, and 1.1 (95% CI: .9-1.3) for B/Victoria. At 6 months, ccIIV4 recipients had similar GMTs to IIV4, whereas RIV4 recipients had higher GMTs against A/H3N2 and B/Yamagata. CONCLUSIONS: RIV4 resulted in improved antibody responses by HI and MN compared to egg-based vaccines against 3 of 4 cell-grown vaccine strains 1 month postvaccination, suggesting a possible additional benefit from RIV4. CLINICAL TRIALS REGISTRATION: NCT03722589.

Both maternal and placental toll-like receptor activation are necessary for the full development of proteinuric hypertension in mice.

OBJECTIVE: Innate immune system activation and excessive inflammation contributes to hypertension during pregnancy (HTN-preg). Activation of Toll-like receptors (TLRs), the primary innate immune system sensor, is evident in women with HTN-preg and is sufficient to induce pregnancy-dependent, proteinuric hypertension in animals. However, whether HTN-preg is a maternal disease, a placental disease, or both is unclear. We hypothesized that activation of TLR3, the double-stranded RNA sensor, in both maternal systemic and placental cells would be necessary for the full development of HTN-preg in mice. STUDY DESIGN: Various mating schemes generated pregnant mice that lacked TLR3 in maternal cells, paternally-derived placental cells, and both. Mice were then injected with a TLR3 agonist on days 13, 15, and 17 of pregnancy. MAIN OUTCOME MEASURES: Blood pressure, urinary protein excretion, fetal development, maternal vascular endothelial function, and immune system activation were all assessed and compared between groups. RESULTS: Pregnant mice lacking TLR3 in maternal cells as well as pregnant mice lacking TLR3 in placental cells had significantly attenuated increases in systolic blood pressure, urinary protein excretion, fetal demise, and endothelial dysfunction compared to wild-type pregnant mice following TLR3 activation. Pregnant mice lacking TLR3 in both maternal systemic and placental cells were completely resistant to the hypertension, proteinuria, fetal demise, endothelial dysfunction, splenomegaly, and increases in pro-inflammatory immune cells induced by TLR3 activation. CONCLUSIONS: These data suggest that both maternal and placental TLR3 activation are crucial for the full development of HTN-preg and that TLR3 antagonists may be beneficial in some women with HTN-preg.

Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.

The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA.

MicroRNA-130a, a Potential Antifibrotic Target in Cardiac Fibrosis.

BACKGROUND: Cardiac fibrosis occurs because of disruption of the extracellular matrix network leading to myocardial dysfunction. Angiotensin II has been implicated in the development of cardiac fibrosis. Recently, microRNAs have been identified as an attractive target for therapeutic intervention in cardiac pathologies; however, the underlying mechanism of microRNAs in cardiac fibrosis remains unclear. MicroRNA-130a (miR-130a) has been shown to participate in angiogenesis and cardiac arrhythmia; however, its role in cardiac fibrosis is unknown. METHODS AND RESULTS: In this study, we found that miR-130a was significantly upregulated in angiotensin II-infused mice. The in vivo inhibition of miR-130a by locked nucleic acid- based anti-miR-130a in mice significantly reduced angiotensin II-induced cardiac fibrosis. Upregulation of miR-130a was confirmed in failing human hearts. Overexpressing miR-130a in cardiac fibroblasts promoted profibrotic gene expression and myofibroblasts differentiation, and the inhibition of miR-130a reversed the processes. Using the constitutive and dominant negative constructs of peroxisome proliferator-activated receptor γ 3-'untranslated region (UTR), data revealed that the protective mechanism was associated with restoration of peroxisome proliferator-activated receptor γ level leading to the inhibition of angiotensin II-induced cardiac fibrosis. CONCLUSIONS: Our findings provide evidence that miR-130a plays a critical role in cardiac fibrosis by directly targeting peroxisome proliferator-activated receptor γ. We conclude that inhibition of miR-130a would be a promising strategy for the treatment of cardiac fibrosis.

MicroRNAs: New Players in the Pathobiology of Preeclampsia.

Our understanding of how microRNAs (miRNAs) regulate gene networks and affect different molecular pathways leading to various human pathologies has significantly improved over the years. In contrary, the role of miRNAs in pregnancy-related hypertensive disorders such as preeclampsia (PE) is only beginning to emerge. Recent papers highlight that adverse pregnancy outcomes are associated with aberrant expression of several miRNAs. Presently, efforts are underway to determine the biologic function of these placental miRNAs which can shed light on their contribution to these pregnancy-related disease conditions. The discovery that miRNAs are stable in circulation coupled with the fact that the placenta is capable of releasing them to the circulation in exosomes generates a lot of enthusiasm to use them as biomarkers. In this review, we will summarize the recent findings of our understanding of miRNA regulation in relation to PE, a hypertensive disorder of pregnancy. Particular emphasis will be given to the role of key miRNA molecules such as miR-210 and miR-155 that are known to be consistently dysregulated in women with PE.

Depletion of MHC class II invariant chain peptide or γ-δ T-cells ameliorates experimental preeclampsia.

Excessive innate immune system activation and inflammation during pregnancy can lead to organ injury and dysfunction and preeclampsia (PE); however, the molecular mechanisms involved are unknown. We tested the hypothesis that Toll-like receptor (TLR) activation induces major histocompatibility complex (MHC) class II invariant chain peptide (CLIP) expression on immune cells, makes them pro-inflammatory, and are necessary to cause PE-like features in mice. Treatment with VG1177, a competitive antagonist peptide for CLIP in the groove of MHC class II, was able to both prevent and treat PE-like features in mice. We then determined that γ-δ T cells are critical for the development of PE-like features in mice since γ-δ T-cell knockout mice, like CLIP deficient mice, are resistant to developing PE-like features. Placentas from women with PE exhibit significantly increased levels of γ-δ T cells. These preclinical data demonstrate that CLIP expression and activated γ-δ T cells are responsible for the development of immunologic PE-like features and that temporarily antagonizing CLIP and/or γ-δ T cells may be a therapeutic strategy for PE.

Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice.

The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4+/FoxP3+ regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.

Human placenta-derived stromal cells decrease inflammation, placental injury and blood pressure in hypertensive pregnant mice.

Pre-eclampsia, the development of hypertension and proteinuria or end-organ damage during pregnancy, is a leading cause of both maternal and fetal morbidity and mortality, and there are no effective clinical treatments for pre-eclampsia aside from delivery. The development of pre-eclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation and endothelial dysfunction. We have reported that detection of extracellular RNA by the Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of pre-eclampsia. PLacental eXpanded (PLX-PAD) cells are human placenta-derived, mesenchymal-like, adherent stromal cells that have anti-inflammatory, proangiogenic, cytoprotective and regenerative properties, secondary to paracrine secretion of various molecules in response to environmental stimulation. We hypothesized that PLX-PAD cells would reduce the associated inflammation and tissue damage and lower blood pressure in mice with pre-eclampsia induced by TLR3 or TLR7 activation. Injection of PLX-PAD cells on gestational day 14 significantly decreased systolic blood pressure by day 17 in TLR3-induced and TLR7-induced hypertensive mice (TLR3 144-111 mmHg; TLR7 145-106 mmHg; both P<0.05), and also normalized their elevated urinary protein:creatinine ratios (TLR3 5.68-3.72; TLR7 5.57-3.84; both P<0.05). On gestational day 17, aortic endothelium-dependent relaxation responses improved significantly in TLR3-induced and TLR7-induced hypertensive mice that received PLX-PAD cells on gestational day 14 (TLR3 35-65%; TLR7 37-63%; both P<0.05). In addition, markers of systemic inflammation and placental injury, increased markedly in both groups of TLR-induced hypertensive mice, were reduced by PLX-PAD cells. Importantly, PLX-PAD cell therapy had no effects on these measures in pregnant control mice or on the fetuses. These data demonstrate that PLX-PAD cell therapy can safely reverse pre-eclampsia-like features during pregnancy and have a potential therapeutic role in pre-eclampsia treatment.

Four Pathways Involving Innate Immunity in the Pathogenesis of Preeclampsia.

The maternal innate immune system plays an important role both in normal pregnancy as well as hypertensive disorders of pregnancy including preeclampsia (PE). We propose four pathways that involve excessive innate immunity that lead to most forms of PE. Pre-existing endothelial dysfunction plus pregnancy leads to an excessive innate immune response resulting in widespread inflammation, placental and renal dysfunction, vasoconstriction, and PE. Placental dysfunction due to shallow trophoblast invasion, inadequate spiral artery remodeling, and/or low placental perfusion initiates an innate immune response leading to excessive inflammation, endothelial and renal dysfunction, and PE. A heightened innate immune system due to pre-existing or acquired infections plus the presence of a paternally derived placenta and semi-allogeneic fetus cause an excessive innate immune response which manifests as PE. Lastly, an abnormal and excessive maternal immune response to pregnancy leads to widespread inflammation, organ dysfunction, and PE. We discuss the potential role of innate immunity in each of these scenarios, as well as the overlap, and how targeting the innate immune system might lead to therapies for the treatment of PE.

Regulation of the Anti-Inflammatory Cytokines Interleukin-4 and Interleukin-10 during Pregnancy.

Inflammation mediated by both innate and adaptive immune cells is necessary for several important processes during pregnancy. Pro-inflammatory immune cell activation plays a critical role in embryo implantation, placentation, and parturition; however dysregulation of these cells can lead to detrimental pregnancy outcomes including spontaneous abortion, fetal growth restriction, maternal pathology including hypertensive disorders, or fetal and maternal death. The resolution of inflammation plays an important role throughout pregnancy and is largely mediated by immune cells that produce interleukin (IL)-4 and IL-10. The temporal and spatial aspects of reducing inflammation during pregnancy represent a complex process that if not functioning optimally can lead to persistent inflammation and pregnancy complications. In this review, we examine how immune cells that produce IL-4 and IL-10 are regulated throughout pregnancy as well as the effects that reduced IL-4 and IL-10 signaling has on fetal and maternal physiology.