Faculty Bibliography

OBJECTIVES/OBJECTIVE:The gut microbiome plays a crucial role in regulating systemic immunity and has been implicated in several chronic inflammatory diseases. Intestinal expansions of Ruminococcus gnavus (RG), a dominant gut commensal, correlate with disease flares in lupus nephritis (LN), but the underlying mechanism remains unknown. METHODS:In a Pilot cohort of patients with biopsy-proven LN, subsetted by gut microbiota community, immune status was characterised using bulk-blood RNA sequencing libraries, serum levels of representative host proteins, and levels of immunoglobulin (Ig)G antibodies to the novel lipoglycan (LG) produced by pathogenic RG strains. A Validation LN cohort was evaluated for blood transcriptomic profiles and levels of anti-LG antibodies. In murine models, mechanistic hypotheses were tested after RG gut colonisation or after intraperitoneal injection with an LG preparation, with outcomes determined by transcriptomic analyses, platelet functional readouts, and tissue histology. RESULTS:In a Pilot cohort of patients with LN, RG gut expansions were associated with high-level platelet, neutrophil, and monocyte activation. Serum levels of platelet factor 4 and release of neutrophil extracellular traps (NETs) were significantly higher in patients with high serum IgG antibody against the novel RG-specific LG, a marker of in vivo immune exposure. An LN Validation cohort confirmed these correlates and showed that anti-LG antibodies serve as a surrogate for thromboinflammatory profile in this LN-associated endotype. In mice, gut colonisation with LG-producing RG strains or a single LG injection caused megakaryocytosis and platelet activation; RG colonisation with LG-producing strains induced tubulointerstitial injury with NETosis. In vivo responses to LG toxin were Toll-like receptor 2-dependent. CONCLUSIONS:Gut expansions of the RG pathobiont may contribute to autoimmune pathogenesis through the LG toxin and cause LN flares through thromboinflammatory mechanisms in this previously unrecognised LN endotype.

BACKGROUND:Advances in pancreatic cancer surgery involve hepatotoxic chemotherapies and hepatic vasculature resections, increasing the risk of clinically relevant postpancreatectomy liver injury. The study aimed to analyze the incidence and impact of clinically relevant postpancreatectomy liver injury after pancreatectomy with hepatic vessel resection. METHODS:In this single-institutional study, patients undergoing pancreatectomy with resection of hepatic vessels (portal vein/superior mesenteric vein, celiac axis, and hepatic arteries) were analyzed. Arterial lactate, total bilirubin, alanine aminotransferase, aspartate aminotransferase, international normalized ratio, and Doppler ultrasound-derived resistive index were assessed postoperatively. Postoperative outcomes were assessed through 90 days. Clinically relevant postpancreatectomy liver injury was defined as American Association for the Study of Liver Diseases-defined liver failure and/or need for invasive treatment of liver complications. RESULTS:Among 116 patients (67% portal vein/superior mesenteric vein resection alone, 7% celiac axis/hepatic arteries alone, 26% portal vein/superior mesenteric vein + celiac axis/hepatic artery resection), 15 (13%) developed clinically relevant postpancreatectomy liver injury. Mortality was significantly higher in the clinically relevant postpancreatectomy liver injury group (47% vs 3%; P < .001). The proper hepatic artery resistive index was lower in the clinically relevant postpancreatectomy liver injury group (0.52 vs 0.65; P = .034), whereas the following 48-hour-peak blood tests were significantly higher in this group: Lac, bilirubin, aspartate aminotransferase, and alanine aminotransferase (all P < .01). Combined portal vein/superior mesenteric vein + celiac axis/hepatic arteries and elevated alanine aminotransferase 48-hour peak above 1680 U/L remained significantly associated with the occurrence of clinically relevant postpancreatectomy liver injury in multivariable analyses. Forty percent of clinically relevant postpancreatectomy liver injury occurred in the absence of vascular complications. CONCLUSION/CONCLUSIONS:Clinically relevant postpancreatectomy liver injury is associated with significant mortality. Low resistive index and markedly elevated biochemical markers within the first 48 hours correlate with clinically relevant postpancreatectomy liver injury and may be used to trigger earlier intervention. Given the associated morbidity and mortality, defining, preventing, and mitigating clinically significant postpancreatectomy liver injury is of the utmost importance.

OBJECTIVE:While bovine aortic arch (BAA) is the most common aortic arch variant and has been associated with an increased risk of stroke in the general population, limited data exist on the impact of BAA on outcomes following carotid artery stenting (CAS). This study evaluates the association between BAA and post-operative outcomes in patients undergoing CAS. METHODS:A retrospective analysis of the multi-institutional Vascular Quality Initiative database identified all patients undergoing CAS for atherosclerotic carotid stenosis from January 2017 to February 2024. Patients were stratified by the presence of BAA. Procedures included transcarotid artery revascularisation (TCAR) with flow reversal, transfemoral CAS (TF-CAS), and transbrachial/transradial CAS (TB/TR-CAS) using distal embolic protection. The primary outcome was in hospital stroke or death. Secondary outcomes included stroke, death, myocardial infarction (MI), access-related complications, and stroke/transient ischaemic attack (TIA). Baseline characteristics were compared, and multivariable logistic regression was performed to adjust for potential confounders. RESULTS:Among 18 254 patients undergoing CAS, 2 037 (11.1%) had BAA. Patients with BAA were more likely to present with symptomatic and left sided carotid stenosis. After adjustment, BAA was not associated with increased odds of post-operative stroke, death, MI, or composite adverse events. Within the BAA cohort, peri-operative outcomes were comparable across TCAR, TF-CAS, and TB/TR-CAS, regardless of symptomatic status. Independent predictors of in hospital stroke or death included history of congestive heart failure and advanced age. Outcomes did not differ by lesion laterality in patients with BAA. CONCLUSION/CONCLUSIONS:In this large, contemporary, multicentre study, BAA was not independently associated with increased peri-operative risk following CAS. In current practice, where access selection is guided by pre-operative imaging and clinical judgement, CAS can be performed with comparable post-operative outcomes in select patients with BAA.

BACKGROUND/UNASSIGNED:Dysregulated proteolysis is implicated in thoracic (thoracic aortic aneurysm [TAA]) and abdominal aortic aneurysm (AAA) pathogenesis, but proteolytic landscapes (degradomes) of aneurysmal and normal aorta and contributions of individual proteases remain undefined. Here, a proteome-wide approach was used to define and compare TAA and AAA degradomes and uncover the specific role in aortic remodeling of 2 proteases consistently identified in the aneurysms, CMA1 (mast cell chymase) and MMP9 (matrix metalloprotease 9). METHODS/UNASSIGNED:The mass spectrometry-based N-terminomics strategy, terminal amine isotopic labeling of substrates, was applied to Marfan syndrome TAAs (n=5), AAAs (n=16), and nondiseased thoracic aorta (n=4), and abdominal aorta (n=4) in a forward degradomics application, that is, to define substrate and protease degradomes. 8-plex iTRAQ terminal amine isotopic labeling of substrates was used for quantitative comparison of the tissue cohorts. Cleavage sites of CMA1 and MMP9 were sought by reverse degradomics, that is, digestion of aortic proteins with these proteases, followed by terminal amine isotopic labeling of substrates. CMA1 and MMP9 proteolysis of biglycan was further resolved using amino-terminal oriented mass spectrometry of substrates. RESULTS/UNASSIGNED:We experimentally annotated 20 885 proteolytically derived peptides and identified 129 proteases in the aortic tissues. Quantitative substrate degradome comparisons identified specific differentially modulated pathways and networks in TAAs and AAAs. Reverse degradomics elucidated >300 CMA1 and MMP9 substrate cleavage sites, of which many, including orthogonally validated biglycan cleavages, occurred in the disease degradomes. CONCLUSIONS/UNASSIGNED:Unbiased forward degradomics of the aortic wall from TAA, AAA, and nondiseased tissue provides a systems biology view of aortic wall breakdown and a new resource for its hitherto occult proteolytic landscape, demonstrating widespread extracellular matrix remodeling with disproportionate impact on proteoglycans. The findings provided insights into aortic aneurysm pathways and disease biomarkers and suggest involvement of numerous proteases. Mapping of specific proteolytic contributions of CMA1 and MMP9 illustrates a strategy for defining the activities of all proteases involved in aortic disease.

OBJECTIVE:Ascending and descending aortic dissection (AD) carry significant morbidity and mortality and require regular follow up in surgery. The aim of this retrospective analysis is to compare the demographics and comorbidities of patients with aortic dissection who followed up in clinic to those who did not. The goal of this study is to identify barriers to follow up in AD to better mitigate complications in vulnerable populations. METHODS:The electronic medical record was queried for all acute presentations of aortic dissection in patients 18 or older during the period of January 2015 through May 2023. Records were reviewed for demographic descriptors, comorbidities, hospital courses, and follow up with vascular or cardiothoracic surgery. Univariate and multivariate regression analyses were conducted to compare follow up and non-follow up cohorts across the entire sample and in ascending and descending groups separately. RESULTS:122 patients with aortic dissection were identified and included. Patients who followed up were younger (p < 0.001) and had higher BMI (p < 0.05). A significantly higher number of patients on public insurance followed up compared to patients with private or union-based insurance (p < 0.05). Patients who underwent surgery on index admission also skewed more heavily into the follow up cohort (p < 0.05). In the ascending group (n = 68) analysis, patients who followed up in clinic were younger (p < 0.001) and had longer hospital and ICU LOS (p < 0.01). In the descending group (n = 54), patients with a history of substance abuse skewed significantly into the non-follow up cohort (p < 0.05). CONCLUSIONS:Age strongly determined follow up in the overall and type A group analyses. Insurance status was a significant factor in the whole sample analysis, while hospital and ICU LOS significantly impacted the type A subgroup. In the descending group, patients with a history of substance abuse showed reduced follow up. Further studies are required to evaluate these findings at other centers.

OBJECTIVE:Non-pneumatic compression devices (NPCDs) have demonstrated their clinical efficacy and safety in treating lymphedema (LED) in multiple studies, including two recent multi-centered, randomized head-to-head comparative studies with advanced pneumatic compression devices (APCD). In the most recent study, TEAYS (ClinicalTrials.gov Identifier: NCT05507346), NPCDs demonstrated better clinical utility as well as greater efficacy and adherence than APCDs in the treatment of lower extremity swelling. This current sub analysis of TEAYS focuses on the outcomes for patients whose secondary lymphedema is associated with underlying venous etiology or phlebolymphedema (PLED). METHODS:This trial was a randomized, crossover head-to-head study was performed across nine sites in the US in 2023. Patients were subjected to an initial 4-week washout period and then randomized to either the NPCD or a commercially available APCD. Patients used the randomly assigned initial device for 90 days followed by a second 4-week washout period before a 90-day use of the second device. The current study focuses specifically on the sub-analysis of the cohort of PLED patients. Primary efficacy outcomes assessed in this study included change in affected limb volume between baseline (day 0) and end of treatment (day 90), change in Lymphedema Quality of Life Questionnaire (LYMQOL), and treatment adherence. RESULTS:Analysis included a total of 71 patients with lower extremity lymphedema; 35 of whom were diagnosed with PLED and this subset comprises the study cohort for the current study. In the PLED cohort 13 (37%) were male, Average BMI was 36.2 +/- 1.68, and 19 had bilateral limbs affected (54%). Most patients had clinical stage II lymphedema: I (n=6), II (n=20) and III (n=9). These PLED patients achieved statistically greater mean limb volume reduction (424.49±100.9mL) while on NPCD vs (50.8± 112.1mL) for APCD (p=.0085). NPCD also showed significantly better improvement in overall Quality of Life (1.39±0.39) vs. APCD (0.18±0.29); (p=0.01). Statistically significant improvement in adherence was also observed while on NPCD 81% vs APCD 49% (p ≤ .001). No device-related adverse events were reported. CONCLUSION/CONCLUSIONS:The NPCD is a clinically effective treatment for decreasing limb volume in patients with lower extremity LED. The NPCD was more effective than an APCD and resulted in superior limb volume decrease, greater improved quality of life, adherence, mobility, and patient satisfaction. The outcomes for the subset of patients diagnosed with PLED corroborates the improvements seen in the overall LED study patient population previously reported. Additionally, results suggest that PLED patients may potentially benefit even more from NPCD than non-PLED patients.

The American Venous Forum has formulated evidence-based clinical practice guidelines to provide recommendations on the care of patients with upper extremity deep vein thrombosis. All recommendations follow a systematic review of workup and therapy options for patients with upper extremity deep vein thrombosis. Potential limitations of these guidelines are due to the lack of evidence on some specific sub-areas such as risk stratification and long-term outcomes.

IntroductionThis study assessed the relationship between venous leg ulcers (VLUs) and overall survival among patients treated for chronic venous insufficiency.MethodsPatients with CEAP C2-C6 disease who underwent superficial venous interventions at a single center from May 2016-April 2024 were identified from the Vascular Quality Initiative Varicose Vein Registry. Demographics, comorbidities, and venous disease severity were recorded at the index database procedure. Mortality was recorded from the electronic health record and Social Security Death Index. Patient characteristics and all-cause mortality were compared between VLU (C5-C6) and non-VLU (C2-C4) cohorts.ResultsAmong 7084 patients, 8.9% (n = 632) had a VLU history. Compared with non-VLU patients, those with a VLU history were older (p < .001) and disproportionately male (p < .001), Black/African American (p < .001), and Medicaid-insured (p = .009). They had greater body mass indices (p < .001), revised venous clinical severity scores (rVCSS) (p < .001), HASTI scores (p = .015), and work/activity limitations (p < .001). Prior venous thromboembolism (p < .001), anticoagulation use (p < .001), previous varicose vein (VV) treatment (p = .042), and deep venous reflux (DVR) (p < .001) were also more common. Mortality was higher among VLU patients than non-VLU patients (3.6% vs 0.7%, p < .001) over a similar mean follow-up (2.8 vs 3.0 years, p = .070). VLU history was associated with worse survival (HR 5.03, 95% CI [2.96-8.53], p < .001), in addition to older age (p < .001), male sex (p = .003), White race (p = .003), no prior VV treatment (p = .026), anticoagulation use (p < .001), higher rVCSS (p < .001), and DVR (p = .016). After adjusting for these latter variables, VLU history remained independently associated with mortality (adjusted HR 2.01, 95% CI [1.00-4.01], p = .049). Compared with C2, only C6 -not C3-C5 -was associated with increased mortality after multivariable adjustment (adjusted HR 3.40, 95% CI [1.08, 10.69], p = .036).ConclusionAmong patients undergoing superficial venous interventions, VLUs were associated with a two-fold hazard of all-cause death. The mechanism driving their increased mortality warrants further study.

OBJECTIVE:Fragmentation of care (FOC) is referred to as receipt of care across multiple unaffiliated health systems (HS). We evaluated whether FOC was associated with outcomes in patients with uncomplicated type B aortic dissection (uTBAD). METHODS:The Healthcare Cost and Utilization Project State Inpatient Databases, for California (2018-2021), New York/Maryland/Florida (2016-2020) were queried using International Classification of Disease-10th (ICD-10) edition to identify patients who underwent medical management for uTBAD. Patient's hospital affiliation and its linkage to a HS during follow up were verified using the American Hospital Association data (AHA). FOC was defined as receipt of care across multiple unaffiliated, AHA defined HS, care delivered among transitions within the same HS was not classified as FOC. Univariate analyses were conducted to compare outcomes between patients with and without FOC, employing Chi-square or Fisher's exact tests as appropriate. Multivariable logistic regression models were constructed to investigate associations between FOC and outcomes. Model validation was performed using Hosmer-Lemeshow test, and receiver operating characteristic curve analysis. RESULTS:Among 5,476 patients included in the analysis, FOC was observed in 3,046 (55.6%). Baseline characteristics between those with and without FOC differed significantly. During follow-up, while mortality rates were similar between groups, FOC group had significantly more computed tomography scans, higher rates of aortic interventions, and elevated complication rates. Furthermore, total costs were markedly higher with FOC. Multivariable analysis also showed that FOC was associated with increased aortic interventions [TEVAR: OR 1.47, 95%CI 1.26-1.74] and complication rates (renal failure [OR 1.3, 95% CI 1.17-1.50], paraplegia [OR 1.60, 95% CI 1.07-2.42], and stroke [OR 1.31, 95%CI 1.09-1.58]) during follow-up. Total costs were 31% higher in the FOC group (p<0.001). CONCLUSIONS:FOC in uTBAD patients is associated with increased likelihood of intervention with higher post-procedural complications and elevated healthcare costs. Coordinated care within a single HS should be prioritized to improve outcomes and reduce healthcare cost.

Pancreatic ductal adenocarcinoma (PDAC) with extensive peripancreatic vessel involvement is classified as locally advanced pancreatic cancer (LAPC). For this group of patients, the current standard of care does not include considering a potentially curative oncologic resection. However, recent advances in multiagent chemotherapy and surgical techniques are challenging this paradigm. Moreover, the current determination of anatomic resectability is vague and unreliable. Here we propose a definition of local resectability, based on pre- and intra-operative assessment. This anatomic definition of resectability assumes careful patient selection based on tumor biology and patient condition. The pre-operative evaluation of vascular anatomy and tumor involvement is conducted using 3D-rendering of pancreas-protocol computed tomography. Identifying a disease-free arterial or venous segment above and below the tumor involvement ("suitable target") is the single critical factor that determines anatomic resectability. Intraoperative isolation of these target vessels confirms the feasibility of vascular reconstruction before resection. This approach, which focuses on identifying target vessels rather than circumferential involvement, offers a more straightforward and clinically relevant method for assessing surgical eligibility in LAPC patients at centers of excellence. In summary, reconstructability-based on surgical expertise and guided by tumor biology-now defines the modern paradigm of resectability in LAPC.