Does source matter? Examining the effects of health experts, friends, and social media influencers on young adult perceptions of Instagram e-cigarette education messages.

PURPOSE: Young adults' e-cigarette use is a leading public health concern. Using messages from credible sources can help improve message acceptance, yet little research has examined the role of source credibility on young adults' responses to e-cigarette education messages. METHODS: We examined the impact of source on young adults' perceptions of e-cigarette education messages and e-cigarettes. In July 2022, we conducted an experimental study using an online sample of young adults (N=459, Mage=24.6) who were randomized to one of three source conditions: expert, friend, or influencer, and viewed e-cigarette education messages. We used one-way ANOVA to estimate the association between the conditions and outcomes (perceived source credibility, message trust, curiosity, use interests, perceived message effectiveness, beliefs, harm perceptions, and intentions to refrain). RESULTS: The expert condition was associated with significantly higher perceived source credibility (vs. friend, influencer; p<0.001), message trust (vs. friend, influencer; p<0.001), and curiosity (vs. influencer; p's<0.05). CONCLUSIONS: Public health campaigns may leverage health experts to deliver e-cigarette education messages targeting young adults to improve effectiveness of the messages.

Plasma from patients with vaccine-induced immune thrombotic thrombocytopenia displays increased fibrinolytic potential and enhances tissue-type plasminogen activator but not urokinase-mediated plasminogen activation.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus vector-based COVID-19 vaccines. VITT is associated with markedly raised levels of D-dimer; yet, how VITT modulates the fibrinolytic system is unknown. OBJECTIVES: We aimed to compare changes in fibrinolytic activity in plasma from patients with VITT, patients diagnosed with venous thromboembolism (VTE) after vaccination but without VITT (VTE-no VITT), and healthy vaccinated controls. METHODS: Plasma levels of plasmin-antiplasmin (PAP) complexes, plasminogen, and alpha-2-antiplasmin (α2AP) from 10 patients with VITT, 10 patients with VTE-no VITT, and 14 healthy vaccinated controls were evaluated by enzyme-linked immunosorbent assay and/or Western blotting. Fibrinolytic capacity was evaluated by quantitating PAP levels at baseline and after ex vivo plasma stimulation with 50-nM tissue-type plasminogen activator (tPA) or urokinase for 5 minutes. RESULTS: Baseline PAP complex levels in control and VTE-no VITT individuals were similar but were ∼7-fold higher in plasma from patients with VITT (P < .0001). VITT samples also revealed consumption of α2AP and fibrinogenolysis consistent with a hyperfibrinolytic state. Of interest, VITT plasma produced significantly higher PAP levels after ex vivo treatment with tPA, but not urokinase, compared to the other groups, indicative of increased fibrinolytic potential. This was not due to D-dimer as addition of D-dimer to VTE-no VITT plasma failed to potentiate tPA-induced PAP levels. CONCLUSION: A marked hyperfibrinolytic state occurs in patients with VITT, evidenced by marked elevations in PAP, α2AP consumption, and fibrinogenolysis. An unidentified plasma cofactor that selectively potentiates tPA-mediated plasminogen activation also appears to exist in the plasma of patients with VITT.

Extubation to High-Flow Nasal Cannula in Infants Following Cardiac Surgery: A Retrospective Cohort Study.

High-flow nasal cannula (HFNC) therapy is commonly used in the pediatric intensive care unit (PICU) for postextubation respiratory support. This hypothesis-generating retrospective cohort study aimed to compare postextubation PICU length of stay in infants extubated to HFNC and low flow oxygen (LF) in PICU following cardiac surgery. Of 136 infants (newborn to 1 year) who were intubated and mechanically ventilated in PICU following cardiac surgery, 72 (53%) were extubated to HFNC and 64 (47%) to LF. Compared with patients extubated to LF, those extubated to HFNC had significantly longer durations of cardiopulmonary bypass (152 vs. 109 minutes; p = 0.002), aortic cross-clamp (90 vs. 63 minutes; p = 0.003), and invasive mechanical ventilation (3.2 vs. 1.6 days; p < 0.001), although demographic and preoperative clinical variables were similar. No significant difference was observed in postextubation PICU length of stay between HFNC and LF groups in unadjusted analysis (3.3 vs. 2.6 days, respectively; p = 0.19) and after controlling for potential confounding variables (F [1,125] = 0.17, p = 0.68, R 2 = 0.16). Escalation of therapy was similar between HFNC and LF groups (8.3 vs. 14.1%; p = 0.41). HFNC was effective as rescue therapy for six patients in the LF group requiring escalation of therapy. Need for reintubation was similar between HFNC and LF groups (8.3 vs. 4.7%; p = 0.5). Although extubation to HFNC was associated with a trend toward longer postextubation PICU length of stay and was successfully used as rescue therapy for several infants extubated to LF, our results must be interpreted with caution given the limitations of our study.

A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA and adenovirus vectored vaccines.

Identifying the molecular mechanisms that promote optimal immune responses to coronavirus disease 2019 (COVID-19) vaccination is critical for future rational vaccine design. Here, we longitudinally profile innate and adaptive immune responses in 102 adults after the first, second, and third doses of mRNA or adenovirus-vectored COVID-19 vaccines. Using a multi-omics approach, we identify key differences in the immune responses induced by ChAdOx1-S and BNT162b2 that correlate with antigen-specific antibody and T cell responses or vaccine reactogenicity. Unexpectedly, we observe that vaccination with ChAdOx1-S, but not BNT162b2, induces an adenoviral vector-specific memory response after the first dose, which correlates with the expression of proteins with roles in thrombosis with potential implications for thrombosis with thrombocytopenia syndrome (TTS), a rare but serious adverse event linked to adenovirus-vectored vaccines. The COVID-19 Vaccine Immune Responses Study thus represents a major resource that can be used to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.

Improving the rate of inferior vena cava filter retrieval through multidisciplinary engagement.

Background: The placement of retrievable inferior vena cava (IVC) filters occurs commonly, but retrieval rates remain low. Consequently, there is an unmet clinical need to ensure appropriate follow-up and retrieval of these devices. Objectives: To determine the association between an IVC filter surveillance team with filter retrievals or a documented filter plan, time to retrieval, and incidence of filter complications or recurrent venous thromboembolism. Methods: Ambidirectional cohort study evaluating consecutive IVC filter insertions before and after the implementation of a multidisciplinary surveillance team (MDST). We report an odds ratio (OR) with 95% CIs, adjusted by age, sex, weight, and malignancy status. Results: Overall, 453 patients were included, with 272 individuals in the pre-MDST cohort and 181 individuals in the post-MDST cohort. The MDST was associated with a higher composite primary outcome of IVC filter retrieval or a documented filter plan from 79.4% in the pre-MDST cohort to 96.1% in the post-MDST cohort (OR, 6.44; 95% CI, 3.06-15.84). Compared with the pre-MDST cohort, IVC filter retrieval rates were higher in the post-MDST cohort (52.6%-73.5%, respectively; (OR, 2.50; 95% CI, 1.67-3.78). The MDST was associated with a shorter median time-to-filter retrieval (187-150 days, hazard ratio, 1.78; 95% CI, 1.39-2.29), but there was no significant difference when comparing symptomatic or clinically significant IVC filter complications, recurrent venous thromboembolism, or mortality. Conclusion: Our study demonstrates the importance of a structured program to ensure timely IVC filter retrieval and ultimately improve patient care.

C-reactive protein, immunothrombosis and venous thromboembolism.

C-reactive protein (CRP) is a member of the highly conserved pentraxin superfamily of proteins and is often used in clinical practice as a marker of infection and inflammation. There is now increasing evidence that CRP is not only a marker of inflammation, but also that destabilized isoforms of CRP possess pro-inflammatory and pro-thrombotic properties. CRP circulates as a functionally inert pentameric form (pCRP), which relaxes its conformation to pCRP* after binding to phosphocholine-enriched membranes and then dissociates to monomeric CRP (mCRP). with the latter two being destabilized isoforms possessing highly pro-inflammatory features. pCRP* and mCRP have significant biological effects in regulating many of the aspects central to pathogenesis of atherothrombosis and venous thromboembolism (VTE), by directly activating platelets and triggering the classical complement pathway. Importantly, it is now well appreciated that VTE is a consequence of thromboinflammation. Accordingly, acute VTE is known to be associated with classical inflammatory responses and elevations of CRP, and indeed VTE risk is elevated in conditions associated with inflammation, such as inflammatory bowel disease, COVID-19 and sepsis. Although the clinical data regarding the utility of CRP as a biomarker in predicting VTE remains modest, and in some cases conflicting, the clinical utility of CRP appears to be improved in subsets of the population such as in predicting VTE recurrence, in cancer-associated thrombosis and in those with COVID-19. Therefore, given the known biological function of CRP in amplifying inflammation and tissue damage, this raises the prospect that CRP may play a role in promoting VTE formation in the context of concurrent inflammation. However, further investigation is required to unravel whether CRP plays a direct role in the pathogenesis of VTE, the utility of which will be in developing novel prophylactic or therapeutic strategies to target thromboinflammation.

Platelets as Central Actors in Thrombosis-Reprising an Old Role and Defining a New Character.

Platelets have long been considered simple anucleate cells that rapidly adhere and aggregate at sites of vascular injury. However, recent in vivo experimental data have shed new light on the platelet response to vascular injury. These data have unexpectedly revealed that platelet thrombus formation is a highly dynamic process and yields a platelet thrombus with a distinct hierarchical structure composed of a "core" of highly activated platelets and a "shell" of platelets in a low activation state. This has given rise to the concept that therapeutic targeting of the propagating thrombus shell may hold promise as a means to target thrombosis while sparing hemostasis. While platelets have been historically considered central to arterial thrombosis, they have been traditionally viewed as minor contributors to the formation of venous thrombosis. However, this concept has recently been challenged with the emergence of a large body of evidence highlighting the important proinflammatory function of platelets. The proinflammatory function of platelets is afforded by their ability to induce neutrophil extracellular trap formation, enhance leucocyte recruitment, and secrete granular contents such as high mobility group protein B1 and polyphosphate. These proinflammatory processes trigger coagulation, via the intrinsic pathway, and are central to the formation of venous thrombosis, a condition now appreciated to be a form of sterile inflammation. These data now place platelets at the center stage in orchestrating the thromboinflammatory response underpinning venous thrombosis and have provided new hope that novel platelet-targeted therapeutics may represent a safe and effective approach to prevent venous thrombosis.

Weight-Based Enoxaparin for Venous Thromboembolism in Obesity Gives Similar Anti-Xa Levels to Patients <100 kg, with No Increase in Major Bleeding.

In trials assessing venous thromboembolism (VTE) treatment, obese patients are under-represented or excluded. The main objective of this article is to examine the safety of weight-based enoxaparin dosing in obesity, as assessed by anti-factor Xa (anti-Xa) activity, bleeding, and recurrence. A 5-year retrospective audit of patients with acute VTE, weighing > 100 kg, prescribed enoxaparin 1 mg/kg twice daily, with an anti-Xa level 2 to 6 hours post-dose. The primary outcome was anti-Xa levels, and the secondary outcomes were bleeding and recurrence. Results were compared with patients weighing < 100 kg (n = 64), and obese patients prescribed doses < 1 mg/kg (n = 28). One-hundred sixty-six patients weighing > 100 kg with VTE were identified, with 64 excluded for not fulfilling criteria. The remaining 102 patients had a median weight of 130 kg (range: 105-222 kg). The median peak anti-Xa level was 0.93 U/mL, with 56% of levels being in the proposed therapeutic range (0.5-1.0 U/mL), 40% > 1.0 U/mL, and 4% < 0.5 U/mL. The median anti-Xa levels and distribution were not significantly different between patients > 100 kg and patients < 100 kg, while obese patients prescribed < 1 mg/kg were more frequently subtherapeutic (21%). Regardless of weight, the majority of patients with moderate renal impairment (eGFR 30-59 mL/min) had an anti-Xa level > 1.0 U/mL (61%). In the obese patients, there was no major bleeding or recurrence within 30 days. In comparison, patients weighing < 100 kg, despite similar peak anti-Xa levels, had higher rates of bleeding and recurrence. This was likely due to their older age and comorbidities, particularly renal impairment and cancer. These data support weight-based dosing of enoxaparin in obesity with no maximum dose, ensuring therapeutic drug levels, with anti-Xa levels suggested in obese patients with clinical risk factors for bleeding.

MicroRNA-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension.

RATIONALE: The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. OBJECTIVE: To elucidate the transcriptional regulation of the miR-143/145 cluster and the role of miR-143 in PAH. METHODS AND RESULTS: We identified the promoter region that regulates miR-143/145 microRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signaling pathways, including estrogen receptor, liver X factor/retinoic X receptor, transforming growth factor-ß (Smads), and hypoxia (hypoxia response element), that regulated levels of all pri-miR stem loop transcription and resulting microRNA expression. We observed that miR-143-3p is selectively upregulated compared with miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMC-derived exosomes. Using assays with pulmonary arterial endothelial cells, we demonstrated a paracrine promigratory and proangiogenic effect of miR-143-3p-enriched exosomes from PASMC. Quantitative polymerase chain reaction and in situ hybridization showed elevated expression of miR-143 in calf models of PAH and in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role of miR-143 in experimental pulmonary hypertension in vivo in miR-143-/- and anti-miR-143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. CONCLUSIONS: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, whereas inhibition of miR-143-3p blocked experimental pulmonary hypertension. Taken together, these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology.

A Sex-Specific MicroRNA-96/5-Hydroxytryptamine 1B Axis Influences Development of Pulmonary Hypertension.

RATIONALE: Females are predisposed to pulmonary arterial hypertension (PAH); evidence suggests that serotonin, mutations in the bone morphogenetic protein receptor (BMPR) II gene, and estrogens influence development of PAH. The 5-hydroxytryptamine 1B receptor (5-HT1BR) mediates human pulmonary artery smooth muscle cell (hPASMC) proliferation. OBJECTIVES: We aimed to determine whether selected microRNAs (miRNAs) expressed in PASMCs are influenced by sex, BMPR-II mutations, and estrogens, and contribute to PASMC proliferation in PAH. METHODS: Expression levels of miRNAs targeting genes related to PAH, estrogen, and serotonin were determined by quantitative RT-PCR in hPASMCs and mouse PASMCs harboring a heterozygous mutation in BMPR-II (BMPR-II(R899X+/-) PASMCs). miRNA-96 targets 5-HT1BR and was selected for further investigation. miRNA target validation was confirmed by luciferase reporter assay. Precursor miRNA-96 was transfected into hPASMCs to examine effects on proliferation and 5-HT1BR expression. The effect of a miRNA-96 mimic on the development of hypoxic pulmonary hypertension in mice was also assessed. MEASUREMENTS AND MAIN RESULTS: miRNA-96 expression was reduced in BMPR-II(R899X+/-) PASMCs from female mice and hPASMCs from female patients with PAH; this was associated with increased 5-HT1BR expression and serotonin-mediated proliferation. 5-HT1BR was validated as a target for miRNA-96. Transfection of precursor miRNA-96 into hPASMCs reduced 5-HT1BR expression and inhibited serotonin-induced proliferation. Restoration of miRNA-96 expression in pulmonary arteries in vivo via administration of an miRNA-96 mimic reduced the development of hypoxia-induced pulmonary hypertension in the mouse. CONCLUSIONS: Increased 5-HT1BR expression may be a consequence of decreased miRNA-96 expression in female patient PASMCs, and this may contribute to the development of PAH.

Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis.

Pulmonary endothelial cell apoptosis is a transient, yet defining pathogenic event integral to the onset of many pulmonary vascular diseases such as pulmonary hypertension (PH). However, there is a paucity of information concerning the molecular pathway(s) that control pulmonary arterial endothelial cell apoptosis. Here, we introduce a molecular axis that when functionally active seems to induce pulmonary arterial endothelial cell apoptosis in vitro and PH in vivo. In response to apoptotic stimuli, human pulmonary arterial endothelial cells exhibited robust induction of a programmed cell death 4 (PDCD4)/caspase-3/apoptotic pathway that was reversible by direct PDCD4 silencing. Indirectly, this pathway was also repressed by delivery of a microRNA-21 mimic. In vivo, genetic deletion of microRNA-21 in mice (miR-21(-/-) mice) resulted in functional activation of the PDCD4/caspase-3 axis in the pulmonary tissues, leading to the onset of progressive PH. Conversely, microRNA-21-overexpressing mice (CAG-microRNA-21 mice) exhibited reduced PDCD4 expression in pulmonary tissues and were partially resistant to PH in response to chronic hypoxia plus SU 5416 injury. Furthermore, direct PDCD4 knockout in mice (PDCD4(-/-) mice) potently blocked pulmonary caspase-3 activation and the development of chronic hypoxia plus SU 5416 PH, confirming its importance in disease onset. Broadly, these findings support the existence of a microRNA-21-responsive PDCD4/caspase-3 pathway in the pulmonary tissues that when active serves to promote endothelial apoptosis in vitro and PH in vivo.

CTCF and Sp1 interact with the Murine gammaherpesvirus 68 internal repeat elements.

Herpesviruses maintain a dynamic balance between latency and productive infection. This is a complex process regulated by viral and cellular factors. We have developed a Murine gammaherpesvirus 68 (MHV-68) model system in which to study mechanisms underlying balance between latency and lytic infection. We have generated an epithelial cell line that carries MHV-68 in a tightly latent form by using a bacterial artificial chromosome clone of the virus genome with a mutation in the MHV-68 major lytic R transactivator gene. Complementation of this defect in trans by transfection with a plasmid encoding R transactivator initiated and restored the productive cycle. This cell line model was used to investigate transcription factor occupancy (CCCTC binding factor [CTCF] and Sp1) of the two internal repeat elements in the viral genome during latency and reactivation using chromatin immunoprecipitation. Our results show that CTCF can bind to the 40-bp and the 100-bp repeat sequences during latency, whereas binding is reduced upon reactivation. In contrast, Sp1 only bound to the 100-bp repeat after reactivation. Our results indicate that the large internal repeat sequences in MHV-68 have different functions. We hypothesise that the 40-bp repeat may be involved in regulation of gene expression during the maintenance of latency, while the 100-bp repeat domain may be involved in regulation of the lytic cycle.