Differential impact of LPG-and PG-deficient Leishmania major mutants on the immune response of human dendritic cells

<div><p>Background</p><p><i>Leishmania major</i> infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of <i>Leishmania</i> parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.</p><p>Methodology/Principal Findings</p><p>Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating <i>L</i>. <i>major</i> Friedlin V1 mutants defective in LPG alone, (FV1 <i>lpg1-</i>), or generally deficient for all PGs, (FV1 <i>lpg2-</i>). Infection with metacyclic, infective stage, <i>L</i>. <i>major</i> or purified LPG induced high levels of <i>IL12B</i> subunit gene transcripts in hDCs, which was abrogated with FV1 <i>lpg1-</i> infections. In contrast, hDC infections with FV1 <i>lpg2-</i> displayed increased <i>IL12B</i> expression, suggesting other PG-related/<i>LPG2</i> dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 <i>lpg1-</i>, FV1 <i>lpg2-</i> infections revealed that FV1 <i>lpg1-</i> mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription.</p><p>Conclusions/Significance</p><p>These data suggest that <i>L</i>. <i>major</i> LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring <i>Leishmania</i> surface glycoconjugates that result in modulation of host cellular IL12.</p></div

Novel cardioprotective and regenerative therapies in acute myocardial infarction:a review of recent and ongoing clinical trials

Following the original large-scale randomized trials of aspirin and β-blockade, there have been a number of major advances in pharmacological and mechanical treatments for acute myocardial infarction. Despite this progress, myocardial infarction remains a major global cause of mortality and morbidity, driving a quest for novel treatments in this area. As the understanding of mitochondrial dynamics and the pathophysiology of reperfusion injury has evolved, the last three decades have seen advances in ischemic conditioning, pharmacological and metabolic cardioprotection, as well as biological and stem-cell therapies. The aim of this review is to provide a synopsis of adjunctive cardioprotective and regenerative therapies currently undergoing or entering early clinical trials in the treatment of patients with acute myocardial infarction.</p

Determinants and prognostic value of echocardiographic first-phase ejection fraction in aortic stenosis

ObjectiveFirst-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis.MethodsEF1 was measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ≥2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death.ResultsTotal follow-up of the 149 participants (69.8% male, 70 (65–76) years, mean gradient 33 (21–42) mm Hg) was 238 029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (&lt;25%) despite normal ejection fraction (67% (62%–71%)). Patients with low EF1 had more severe aortic stenosis (mean gradient 39 (34–45) mm Hg vs 24 (16–35) mm Hg, p&lt;0.001) and more myocardial fibrosis (indexed extracellular volume (iECV) (24.2 (19.6–28.7) mL/m2 vs 20.6 (16.8–24.3) mL/m2, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, p&lt;0.001). Zva, iECV and infarct LGE were independent predictors of EF1. EF1 improved post-AVR (n=57 with post-AVR EF1 available, baseline 16 (12–24) vs follow-up 27% (22%–31%); p&lt;0.001). Low baseline EF1 was an independent predictor of AVR/death (HR 5.6, 95% CI 3.4 to 9.4), driven by AVR.ConclusionEF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR.</jats:sec

Contemporary outcomes after treatment of aberrant subclavian artery and Kommerell\u27s diverticulum

Objective: Aberrant subclavian artery (ASA) and Kommerell\u27s diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study is to report contemporary outcomes after invasive treatment of ASA/KD using a large international dataset. Methods: Patients who underwent treatment for ASA/KD (2000-2020) were identified through the Vascular Low Frequency Disease Consortium, a multi-institutional collaboration to investigate uncommon vascular disorders. We report the early and mid-term clinical outcomes including stroke and mortality, technical success, and other operative outcomes including reintervention rates, patency, and endoleak. Results: Overall, 285 patients were identified during the study period. The mean patient age was 57 years; 47% were female and 68% presented with symptoms. A right-sided arch was present in 23%. The mean KD diameter was 47.4 mm (range, 13.0-108.0 mm). The most common indication for treatment was symptoms (59%), followed by aneurysm size (38%). The most common symptom reported was dysphagia (44%). A ruptured KD was treated in 4.2% of cases, with a mean diameter of 43.9 mm (range, 18.0-100.0 mm). An open procedure was performed in 101 cases (36%); the most common approach was ASA ligation with subclavian transposition. An endovascular or hybrid approach was performed in 184 patients (64%); the most common approach was thoracic endograft and carotid-subclavian bypass. A staged operative strategy was employed more often than single setting repair (55% vs 45%). Compared with endovascular or hybrid approach, those in the open procedure group were more likely to be younger (49 years vs 61 years; P \u3c.0001), female (64% vs 36%; P \u3c.0001), and symptomatic (85% vs 59%; P \u3c.0001). Complete or partial symptomatic relief at 1 year after intervention was 82.6%. There was no association between modality of treatment and symptom relief (open 87.2% vs endovascular or hybrid approach 78.9%; P =.13). After the intervention, 11 subclavian occlusions (4.5%) occurred; 3 were successfully thrombectomized resulting in a primary and secondary patency of 95% and 96%, respectively, at a median follow-up of 39 months. Among the 33 reinterventions (12%), the majority were performed for endoleak (36%), and more reinterventions occurred in the endovascular or hybrid approach than open procedure group (15% vs 6%; P =.02). The overall survival rate was 87.3% at a median follow-up of 41 months. The 30-day stroke and death rates were 4.2% and 4.9%, respectively. Urgent or emergent presentation was independently associated with increased risk of 30-day mortality (odds ratio [OR], 19.8; 95% confidence interval [CI], 3.3-116.6), overall mortality (OR, 3.6; 95% CI, 1.2-11.2) and intraoperative complications (OR, 8.3; 95% CI, 2.8-25.1). Females had a higher risk of reintervention (OR, 2.6; 95% CI, 1.0-6.5). At an aneurysm size of 44.4 mm, receiver operator characteristic curve analysis suggested that 60% of patients would have symptoms. Conclusions: Treatment of ASA/KD can be performed safely with low rates of mortality, stroke and reintervention and high rates of symptomatic relief, regardless of the repair strategy. Symptomatic and urgent operations were associated with worse outcomes in general, and female gender was associated with a higher likelihood of reintervention. Given the worse overall outcomes when symptomatic and the inherent risk of rupture, consideration of repair at 40 mm is reasonable in most patients. ASA/KD can be repaired in asymptomatic patients with excellent outcomes and young healthy patients may be considered better candidates for open approaches versus endovascular or hybrid modalities, given the lower likelihood of reintervention and lower early mortality rate

International Multi-Institutional Experience with Presentation and Management of Aortic Arch Laterality in Aberrant Subclavian Artery and Kommerell\u27s Diverticulum

BACKGROUND: Aberrant subclavian artery (ASA) with or without Kommerell\u27s diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD repair in patients with a left versus right aortic arch. METHODS: Using the Vascular Low Frequency Disease Consortium methodology, a retrospective review was performed of patients ≥18 years old with surgical treatment of ASA/KD from 2000 to 2020 at 20 institutions. RESULTS: 288 patients with ASA with or without KD were identified; 222 left-sided aortic arch (LAA), and 66 right-sided aortic arch (RAA). Mean age at repair was younger in LAA 54 vs. 58 years (P = 0.06). Patients in RAA were more likely to undergo repair due to symptoms (72.7% vs. 55.9%, P = 0.01), and more likely to present with dysphagia (57.6% vs. 39.1%, P \u3c 0.01). The hybrid open/endovascular approach was the most common repair type in both groups. Rates of intraoperative complications, death within 30 days, return to the operating room, symptom relief and endoleaks were not significantly different. For patients with symptom status follow-up data, in LAA, 61.7% had complete relief, 34.0% had partial relief and 4.3% had no change. In RAA, 60.7% had complete relief, 34.4% had partial relief and 4.9% had no change. CONCLUSIONS: In patients with ASA/KD, RAA patients were less common than LAA, presented more frequently with dysphagia, had symptoms as an indication for intervention, and underwent treatment at a younger age. Open, endovascular and hybrid repair approaches appear equally effective, regardless of arch laterality

Contemporary Outcomes after Treatment of Aberrant Subclavian Artery and Kommerell\u27s Diverticulum

OBJECTIVE: Aberrant Subclavian Artery (ASA) and Kommerell\u27s Diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study is to report contemporary outcomes after invasive treatment of ASA/KD using a large international dataset. METHODS: Patients who underwent treatment for ASA/KD (2000-2020) were identified through the Vascular Low Frequency Disease Consortium (VLFDC), a multi-institutional collaboration to investigate uncommon vascular disorders. We report early and mid-term clinical outcomes including stroke and mortality, technical success, and other operative outcomes including reintervention rates, patency and endoleak. RESULTS: Overall, 285 patients were identified during the study period. The mean patient age was 57; 47% were female and 68% presented with symptoms. A right-sided arch was present in 23%. Mean KD diameter was 47.4 mm (range 13-108). The most common indication for treatment was symptoms (59%), followed by aneurysm size (38%). The most common symptom reported was dysphagia (44%). A ruptured KD was treated in 4.2% of cases, with a mean diameter of 43.9 mm (range 18-100). An open procedure (Open) was performed in 101 cases (36%); the most common approach was ASA ligation with subclavian transposition. An endovascular or hybrid approach (Endo/Hybrid) was performed in 184 (64%); the most common approach was thoracic endograft and carotid-subclavian bypass. A staged operative strategy was employed more often than single setting repair (55% vs. 45%). Compared to Endo/Hybrid, those in the Open group were more likely to be younger (49 vs. 61 years; p \u3c .0001), female (64% vs. 36%; p \u3c .0001) and symptomatic (85% vs. 59%; p \u3c .0001). Complete/partial symptomatic relief at 1 year after intervention was 82.6%. There was no association between modality of treatment and symptom relief (open 87.2% vs. endo/hybrid 78.9%; p=0.13). Post-intervention, 11 (4.5%) subclavian occlusions occurred; 3 were successfully thrombectomized resulting in a primary and secondary patency of 95% and 96% respectively, at a median follow-up of 39 months. Among the 33 (12%) reinterventions, the majority were performed for endoleak (36%), and more reinterventions occurred in the Endo/Hybrid than Open group (15% vs. 6%; p = .02). Overall survival was 87.3% at a median follow-up of 41 months. The 30-day stroke and death rates were 4.2% and 4.9%, respectively. Urgent/emergent presentation was independently associated with increased risk of 30-day mortality (OR 19.8, 95% CI 3.3-116.6), overall mortality (OR 3.6, 95% CI 1.2-11.2) and intraoperative complications (OR 8.3, 95% CI 2.8-25.1). Females had higher risk of reintervention (OR 2.6, 95% CI 1-6.5). At an aneurysm size of 44.4 mm, Receiver Operator Characteristic (ROC) curve analysis suggested that 60% of patients would have symptoms. CONCLUSIONS: Treatment of ASA/KD can be performed safely with low rates of mortality, stroke and reintervention, and high rates of symptomatic relief regardless of repair strategy. Symptomatic and urgent operations were associated with worse outcomes in general, and female gender was associated with a higher likelihood of reintervention. Given the worse overall outcomes when symptomatic and the inherent risk of rupture, consideration of repair at 40 mm is reasonable in most patients. ASA/KD can be repaired in asymptomatic patients with excellent outcomes and young healthy patients may be considered better candidates for open approaches versus endovascular/hybrid modalities, given the lower likelihood of reintervention and lower early mortality rate