Postpartum care in a cardio-obstetric clinic after preterm preeclampsia: patient and healthcare provider perspectives.

BACKGROUND: Despite the significant disruption and health implications of preterm preeclampsia with severe features for birthing people, little is known about how the system of postpartum care might be strengthened for affected families. Multidisciplinary cardio-obstetric clinics are emerging; however, there is limited research on patient and healthcare provider perspectives. OBJECTIVE: To describe patient and healthcare provider perspectives of services in a cardio-obstetric clinic following preterm preeclampsia with severe features. STUDY DESIGN: Individuals who experienced preterm preeclampsia with severe features and presented to a cardio-obstetric clinic were approached for study participation. Providers were approached if they provided postpartum care to patients with preterm preeclampsia with severe features and considered a referral to the cardio-obstetric clinic. Participants completed a remotely conducted, semistructured interview between March 2022 and April 2023. The interviews were audio-recorded, professionally transcribed, and checked for accuracy. Responses were inductively coded for content analysis around the study questions of clinical referrals, patient education, visit expectations, and care coordination in relation to ambulatory clinical services. RESULTS: Twenty participants (n=10 patients and n=10 providers) completed interviews. Healthcare system navigation was difficult, particularly in the context of postpartum needs. When patients are informed about their diagnosis, the information could both increase anxiety and be useful for long-term healthcare planning. Language concordant care did not always occur, and both patients and providers described gaps in quality services. Within the theme of responsibility, patients described needing to be vigilant, and providers recognized the gaps in referral and care coordination systems. Comprehensible patient education provided with birthing parents' companions and enhanced systems for care coordination were areas for further improvement in providing postpartum cardio-obstetric care following preterm preeclampsia. CONCLUSION: This qualitative study identified patients' struggles with a confusing postpartum healthcare system and captured providers' concerns about maintaining consistent care and improving access to long-term healthcare services to improve outcomes for patients at risk of cardiovascular disease.

The microRNA Cargo of Human Vaginal Extracellular Vesicles Differentiates Parasitic and Pathobiont Infections from Colonization by Homeostatic Bacteria.

The disturbed vaginal microbiome defined as bacterial vaginosis (BV) and the parasitic infection by Trichomonas vaginalis (TV), the most common non-viral sexually transmitted pathogen, have well-established adverse effects on reproductive outcomes and susceptibility to infection and cancer. Molecular mechanisms underlying these associations and the failure of antibiotic therapy to mitigate adverse consequences are not fully elucidated. In an in vitro human vaginal colonization model, we tested the hypothesis that responses to TV and/or BV-bacteria will disrupt the micro(mi)RNA cargo of extracellular vesicles (EV) with the potential to modify pathways associated with reproductive function, cancer, and infection. miRNAs were quantified by HTG EdgeSeq. MiRNA differential expression (DE) was established in response to TV, the BV signature pathobiont Prevotella bivia and a homeostatic Lactobacillus crispatus with adjusted p < 0.05 using R. Validated gene targets, pathways, protein-protein interaction networks, and hub genes were identified by miRWalk, STRING, Cytoscape, and CytoHubba. In contrast to L. crispatus, TV and the BV pathobiont dysregulated a massive number of EV-miRNAs, over 50% shared by both pathogens. Corresponding target pathways, protein interaction clusters and top hub genes were related to cancer, infectious disease, circadian rhythm, steroid hormone signaling, pregnancy, and reproductive tissue terms. These data support the emerging concept that bacteria and parasitic eukaryotes disturbing the human vaginal microbiome may impact reproductive health through EV-miRNA dysregulation.

Aberrant cervical innate immunity predicts onset of dysbiosis and sexually transmitted infections in women of reproductive age.

Sexually transmitted infections (STIs) and vaginal dysbiosis (disturbed resident microbiota presenting with abnormal Nugent score or candidiasis) have been associated with mucosal inflammation and risk of HIV-1 infection, cancer and poor reproductive outcomes. To date, the temporal relationships between aberrant cervical innate immunity and the clinical onset of microbial disturbance have not been studied in a large population of reproductive age women. We examined data from a longitudinal cohort of 934 Ugandan and Zimbabwean women contributing 3,274 HIV-negative visits who had complete laboratory, clinical and demographic data. Among those, 207 women later acquired HIV, and 584 women were intermittently diagnosed with C. trachomatis (CT), N. gonorrhoeae (NG), genital herpes (HSV-2), T. vaginalis (TV), candidiasis, and abnormal intermediate (4-6) or high (7-10) Nugent score, i.e. bacterial vaginosis (BV). Immune biomarker concentrations in cervical swabs were analyzed by generalized linear and mixed effect models adjusting for site, age, hormonal contraceptive use (HC), pregnancy, breastfeeding, genital practices, unprotected sex and overlapping infections. High likelihood ratios (1.5-4.9) denoted the values of cervical immune biomarkers to predict onset of abnormal Nugent score and candidiasis at the next visits. When controlling for covariates, higher levels of ß-defensin-2 were antecedent to BV, CT and HSV-2, lower anti-inflammatory ratio IL-1RA:IL-1ß-to intermediate Nugent scores and candida, lower levels of the serine protease inhibitor SLPI-to candida, lower levels of the adhesion molecule ICAM-1 -to TV, and lower levels of the oxidative stress mitigator and endothelial activation marker VEGF-to NG. Changes in innate immunity following onset of dysbiosis and infections were dependent on HC use when controlling for all other covariates. In conclusion, imminent female genital tract dysbiosis or infection can be predicted by distinct patterns of innate immunity. Future research should characterize biotic and abiotic determinants of this pre-existing innate immunity state.

Antecedents and early correlates of high and low concentrations of angiogenic proteins in extremely preterm newborns.

BACKGROUND: To identify the antecedents and very early correlates of low concentrations of angiogenic proteins in the blood of extremely preterm newborns during the first postnatal month. METHODS: Using multiplex immunoassays we measured the concentrations of vascular endothelial growth factor A (VEGF), VEGF receptor-1 (VEGFR-1), VEGF receptor-2 (VEGFR-2), placenta growth factor (PIGF), and angiopoietins 1 and 2 (Ang-1, Ang-2), as well as 21 other proteins in blood spots collected on postnatal days 1 (N=1062), 7 (N=1087), 14 (N=989), 21 (N=940) and 28 (N=880) from infants born before the 28th week of gestation. We then sought the protein-concentration correlates of concentrations in the top and bottom quartile for gestational age and day the specimen was collected. RESULTS: Children who were delivered for medical indications and those who were severely growth restricted were more likely than others to have low day-1 blood concentrations of VEGF, VEGF-R2, Ang-1, and PIGF. Systemic inflammation accompanied top quartile concentrations of every one of the 6 angiogenic proteins. CONCLUSIONS: Low day-1 concentrations of most angiogenic proteins are associated with disorders linked to placenta insufficiency/dysfunction. High concentrations, on the other hand, are associated with systemic inflammation throughout the first postnatal month.

Trichomonas vaginalis Lipophosphoglycan Exploits Binding to Galectin-1 and -3 to Modulate Epithelial Immunity.

Trichomoniasis is the most common non-viral sexually transmitted infection caused by the vaginotropic extracellular protozoan parasite Trichomonas vaginalis. The infection is recurrent, with no lasting immunity, often asymptomatic, and linked to pregnancy complications and risk of viral infection. The molecular mechanisms of immune evasion by the parasite are poorly understood. We demonstrate that galectin-1 and -3 are expressed by the human cervical and vaginal epithelial cells and act as pathogen-recognition receptors for the ceramide phosphoinositol glycan core (CPI-GC) of the dominant surface protozoan lipophosphoglycan (LPG). We used an in vitro model with siRNA galectin knockdown epithelial clones, recombinant galectins, clinical Trichomonas isolates, and mutant protozoan derivatives to dissect the function of galectin-1 and -3 in the context of Trichomonas infection. Galectin-1 suppressed chemokines that facilitate recruitment of phagocytes, which can eliminate extracellular protozoa (IL-8) or bridge innate to adaptive immunity (MIP-3α and RANTES (regulated on activation normal T cell expressed and secreted)). Silencing galectin-1 increased and adding exogenous galectin-1 suppressed chemokine responses to Trichomonas or CPI-GC/LPG. In contrast, silencing galectin-3 reduced IL-8 response to LPG. Live Trichomonas depleted the extracellular levels of galectin-3. Clinical isolates and mutant Trichomonas CPI-GC that had reduced affinity to galectin-3 but maintained affinity to galectin-1 suppressed chemokine expression. Thus via CPI-GC binding, Trichomonas is capable of regulating galectin bioavailability and function to the benefit of its parasitic survival. These findings suggest novel approaches to control trichomoniasis and warrant further studies of galectin-binding diversity among clinical isolates as a possible source for symptom disparity in parasitic infections.

Deferoxamine, Cerebrovascular Hemodynamics, and Vascular Aging: Potential Role for Hypoxia-Inducible Transcription Factor-1-Regulated Pathways.

BACKGROUND AND PURPOSE: Iron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We sought to examine the effect of iron chelation on cerebrovascular function in healthy aging and to explore whether hypoxia-inducible transcription factor-1 activation may be temporally correlated with vascular changes. METHODS: We assessed cerebrovascular function (autoregulation, vasoreactivity, and neurovascular coupling) and serum concentrations of vascular endothelial growth factor and erythropoietin, as representative measures of hypoxia-inducible transcription factor-1 activation, during 6 hours of deferoxamine infusion in 24 young and 24 older healthy volunteers in a randomized, blinded, placebo-controlled cross-over study design. Cerebrovascular function was assessed using the transcranial Doppler ultrasound. Vascular endothelial growth factor and erythropoietin serum protein assays were conducted using the Meso Scale Discovery platform. RESULTS: Deferoxamine elicited a strong age- and time-dependent increase in the plasma concentrations of erythropoietin and vascular endothelial growth factor, which persisted ≤3 hours post infusion (age effect P=0.04; treatment×time P<0.01). Deferoxamine infusion also resulted in a significant time- and age-dependent improvement in cerebral vasoreactivity (treatment×time P<0.01; age P<0.01) and cerebral autoregulation (gain: age×time×treatment P=0.04). CONCLUSIONS: Deferoxamine infusion improved cerebrovascular function, particularly in older individuals. The temporal association between improved cerebrovascular function and increased serum vascular endothelial growth factor and erythropoietin concentrations is supportive of shared hypoxia-inducible transcription factor-1-regulated pathways. Therefore, pharmacological activation of hypoxia-inducible transcription factor-1 to enhance cerebrovascular function may be a promising neuroprotective strategy in acute and chronic ischemic syndromes, especially in elderly patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT013655104.