Citations

Key Points The rat arteriovenous fistula (AVF) model exhibits marked upregulation of p16 Ink4a and p21 Cip1 and multiple markers of senescence. Fisetin, an established vasoprotective senolytic agent, when administered for 3 weeks, increases AVF blood flow and AVF outward remodeling. Heme is shown to be a novel prosenescence metabolite, and when chronically administered, it decreases AVF blood flow. Background Maturational failure of dialysis arteriovenous fistulas (AVFs) not uncommonly occurs and is of considerable and timely importance. Our prior studies demonstrate that senescence, a phenotypic process that promotes vascular and other diseases, occurs in the murine AVF. In this study, we examined whether senescence also occurs in the rat AVF model and the effect of compounds that inhibit or accelerate senescence. Methods The rat AVF was created in the femoral vessels by an end vein-side artery anastomosis. In the AVF, we assessed the expression of critical drivers of senescence, specifically, the cell cycle inhibitors p16 Ink4a and p21 Cip1 , and such indices of a senescence phenotype as senescence-associated β -galactosidase (SA- β -gal) activity, SA- β -gal staining, and a senescence-associated secretory phenotype. We examined the effects of compounds that retard or accelerate senescence on AVF blood flow. Results The AVF evinced upregulation of p16 Ink4a and p21 Cip1 when assessed 3 days after AVF creation. The AVF also demonstrated increased SA- β -gal activity in the artery and vein; staining for SA- β -gal in the AVF artery, anastomosis, and vein; and a prominent senescence-associated secretory phenotype. Fisetin, an established senolytic that is protective in other models of vascular injury, when administered for 3 weeks, increased AVF blood flow and outward remodeling. Hemin, when administered for 3 weeks, decreased AVF blood flow. We demonstrate that hemin is a novel inducer of a senescence phenotype in endothelial cells, as reflected by several senescence indices. However, when administered relatively acutely (for 5 days), hemin increased AVF blood flow by heme oxygenase–dependent mechanisms because the latter was entirely prevented by a competitive inhibitor of heme oxygenase activity. Conclusions The rat AVF exhibits senescence within 3 days of its creation. Chronic administration of a senolytic compound (fisetin) increases AVF blood flow, whereas chronic administration of a prosenescence compound (hemin) decreases AVF blood flow.

Historically, the management of carotid artery disease has primarily focused on the degree of stenosis as the main indicator for assessing stroke etiology, risk, and need for intervention. However, accumulating evidence suggests that structural and biological features within the arterial wall, such as intraplaque hemorrhage, may have superior diagnostic, prognostic, and therapeutic values. Under current guidelines, unless an atheroma results in ≥50% stenosis, it is not considered the cause of a cerebrovascular event. This results in extensive and often unproductive diagnostic workup, prescription of ineffective medical therapy, and preclusion of patients from receiving revascularization procedures that have been shown to prevent recurrent cerebrovascular events in cases of ≥50% stenosis. A subset of embolic strokes of undetermined source, which account for up to 25% of all ischemic cerebrovascular events, are thought to be due to thromboembolic phenomena from undiagnosed plaque disruptions in nonstenotic arteries (<50% stenosis). Recently, it has been proposed to reclassify this subgroup of patients as symptomatic nonstenotic carotid if the carotid plaque ipsilateral to the cerebrovascular event presents with high-risk features including intraplaque hemorrhage, lipid-rich necrotic core, thinning/rupture of the fibrous cap, and ulceration. In this review, we first provide a historical overview of the chain of events and circumstances that resulted in the present management of carotid artery disease. Second, we embed the contemporary biomarkers of plaque vulnerability in a modern mechanistic paradigm of carotid plaque disruption and thromboembolization. Third, we review the clinically available imaging tools to detect these biomarkers, and how their use has started to shed light on the prevalence and natural history of this underdiagnosed condition. Fourth, we review recent clinical studies employing a contemporary definition of symptomatic nonstenotic carotid and discuss targeted treatments for this condition. Finally, we make a case to generate the much-needed high-level evidence to align the clinical management of patients with symptomatic nonstenotic carotid with a contemporary understanding of plaque disruption and thromboembolization.

Abstract Disclosure: K. Leopold: None. S. Polites: None. L. Binkovitz: None. L. Casas: None. A.N. Lteif: None. Title: An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation. Introduction: Individuals with Succinate Dehydrogenase (SDHx) gene mutations have an increased risk of paragangliomas and pheochromocytomas beginning in childhood.Clinical Case: A 9 year old male with Cornelia de Lange syndrome and a paternally inherited SDHA pathogenic gene variant (c1534C&gt;T) presented with worsening migraine headaches and skin pallor with activity. 24 hour urine fractionated metanephrines were mildly elevated, with metanephrine 122 mcg/24h (29-92 mcg/24 h), normetanephrine 187 mcg/24 h (34-169 mcg/24 h), and total metanephrine 309 mcg/24 h (47-223 mcg/24 h). Ga-68 DOTATATE PET/CT showed a focus of moderately increased radiotracer activity in the anterior aspect of the distal gastric antrum with a max SUV 8.2 corresponding to a 9x7 mm nodule on CT in the same area, suggestive of underlying somatostatin receptor positive lesion such as a paraganglioma. MRI with contrast completed to further characterize the lesion showed no visible mass corresponding to the focal area of radiotracer uptake on DOTATATE PET/CT. Repeat 24 h urine metanephrines continued to show mild elevation of metanephrine (138 mcg/24h), normetanephrine (200 mcg/24h), and total metanephrines (338 mcg/24h). 24 hour urine catecholamines, 5-Hydroxyindoleacetic acid, and homovanillic acid were normal. An upper endoscopic ultrasound was completed which confirmed the presence of a lesion near the stomach but not arising from the stomach wall and not consistent with a gastrointestinal stromal tumor. CT enterography with IV contrast showed a 6x6 mm enhancing mass within the distal right lateral gastric wall. Due to ongoing symptoms, mild elevations in urine fractionated metanephrines, and a clear mass on US and CT, the patient underwent laparoscopic abdominal exploration where a 14x14x13 mm mass with surrounding gastric and duodenal serosa was excised with primary closure of the bowel. Pathology showed ectopic pancreatic tissue in the wall of the small bowel and stomach. Repeat Ga-68 DOTATATE PET/CT 5 months following surgery showed resolution of the distal gastric somatostatin receptor avidity. Clinical Lesson: This is the first case of ectopic pancreatic tissue mimicking a paraganglioma in a pediatric patient with hereditary paraganglioma-pheochromocytoma syndrome. False positive imaging should be considered in patients with SDHx mutations when the uptake is atypical in location and when the elevation in urine metanephrines is mild. Presentation: 6/3/2024

Abstract Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.

Abstract One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

ImportancePatients with atrial fibrillation (AF) who have ischemic stroke despite taking oral anticoagulation therapy (OAT) have a very high risk of recurrence. Left atrial appendage occlusion (LAAO) is a mechanical stroke prevention strategy that may provide additional protection in patients with thromboembolic events under OAT.ObjectiveTo compare percutaneous LAAO with continuing OAT alone regarding stroke prevention in patients with AF who had a thromboembolic event despite taking OAT.Design, Setting, and ParticipantsThis cohort study was a propensity score–matched comparison of the STR-OAC LAAO cohort, an international collaboration of 21 sites combining patients from multiple prospective registries of patients who underwent LAAO between 2010 and 2022. STR-OAC LAAO cohort patients who had follow-up longer than 3 months were propensity score–matched to a previously published control cohort comprising patients from an established international collaboration of investigator-initiated prospective studies. This control cohort included patients with nonvalvular AF, recent ischemic stroke or transient ischemic attack, and follow-up longer than 3 months who were taking OAT before the index event. Analyses were adjusted for imbalances in gender, age, hypertension, diabetes, and CHA2 DS2-VASc score.ExposureLeft atrial appendage occlusion vs continuation of oral anticoagulation therapy alone (control group).Main Outcomes and MeasuresThe primary outcome was time to first ischemic stroke.ResultsFour hundred thirty-three patients from the STR-OAC LAAO cohort (mean [SD] age, 72 [9] years; 171 [39%] females and 262 [61%] males; mean [SD] CHA2 DS2-VASc score, 5.0 [1.6]) were matched to 433 of 1140 patients (38%) from the control group. During 2-year follow-up, 50 patients experienced ischemic stroke: an annualized event rate of 2.8% per patient-year in the STR-OAC LAAO group vs 8.9% per patient-year in the control group. Left atrial appendage occlusion was associated with a lower risk of ischemic stroke (hazard ratio, 0.33; 95% CI, 0.19-0.58; P &amp;lt; .001) compared with the control group. After LAAO, OAT was discontinued in 290 patients (67%), and the remaining 143 patients (33%) continued OAT after LAAO as an adjunctive therapy.Conclusions and RelevanceIn patients with nonvalvular AF and a prior thromboembolic event despite taking OAT, LAAO was associated with a lower risk of ischemic stroke compared with continued OAT alone. Randomized clinical trial data are needed to confirm that LAAO may be a promising treatment option for this population with a very high risk of stroke.

Background: Residency programs have developed monetary initiatives for students underrepresented in medicine (URiM). Our team sought to provide a centralized resource for URiM students seeking plastic surgery subinternships with funded opportunities. Methods: A cross sectional analysis of URiM scholarships offered by US integrated plastic surgery programs (n = 91) between July and September 2023. The study used residency program web domains. Investigators collected information on the monetary value of scholarship, eligibility criteria, and required application documents. Inferential analyses were conducted to investigate whether programs’ geographic region or Doximity ranking played a role in likelihood of scholarship existence. Results: The study found that approximately 52.7% (n = 48) of programs have in place monetary support for underrepresented visiting medical students (eg, stipend or reimbursement). The average monetary support was $1670. A univariate test demonstrated that programs with lower rankings in both reputation and research were less likely to have a scholarship available than higher ranking programs (P = 0.002; P = 0.02, respectively). Programs located in the Midwest regions were 3.5 times more likely to have a diversity scholarship available (P = 0.034). In our multivariate analysis, reputation ranking and geographic region remained significant. A Pearson chi square test showed the greatest proportions of scholarships among geographically similar programs to be in the Midwest (70%), however, not statistically significant. Conclusions: This study provides a centralized resource for URiM students interested in completing away rotations. Further investigation into development of these scholarship opportunities would be of much benefit and could guide other programs in the funding their own diversity scholarships.

AbstractApixaban is a widely used direct oral anticoagulant that is recommended over warfarin therapy for many clinical indications. In patients with atrial fibrillation, dose reductions are recommended for patients with advanced age (≥80 years), low weight (≤60 kg) or elevated serum creatinine (≥1.5 mg/dL), but there is no routine laboratory monitoring necessary for long term‐use. Furthermore, apixaban dose reductions due to renal dysfunction are not recommended when treating acute venous thromboembolism. Apixaban‐calibrated anti‐Xa assays are readily available at some medical centres, and they may be of clinical utility in certain circumstances such as in patients with renal insufficiency, medication adherence assessment, periprocedural planning, extremes in body weight and advanced age. Here, we describe the case of an elderly patient with chronic kidney disease taking apixaban for acute pulmonary embolism. The patient had an unanticipated prolonged apixaban half‐life, with detectable apixaban‐calibrated anti‐Xa levels for >10 days after the last administered dose, which delayed a necessary surgical intervention by >1 week. This case is an example of appropriately using apixaban‐calibrated anti‐Xa levels to guide therapeutic decision making in perioperative planning.

OBJECTIVE The aim of this study was to compare the rate of achievement of the minimal clinically important difference (MCID) in patient-reported outcomes (PROs) and satisfaction between cervical spondylotic myelopathy (CSM) patients with and without class III obesity who underwent surgery. METHODS The authors analyzed patients from the 14 highest-enrolling sites in the prospective Quality Outcomes Database CSM cohort. Patients were dichotomized based on whether or not they were obese (class III, BMI ≥ 35 kg/m 2 ). PROs including visual analog scale (VAS) neck and arm pain, Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA), EQ-5D, and North American Spine Society patient satisfaction scores were collected at baseline and 24 months after cervical spine surgery. RESULTS Of the 1141 patients with CSM who underwent surgery, 230 (20.2%) were obese and 911 (79.8%) were not. The 24-month follow-up rate was 87.4% for PROs. Patients who were obese were younger (58.1 ± 12.1 years vs 61.2 ± 11.6 years, p = 0.001), more frequently female (57.4% vs 44.9%, p = 0.001), and African American (22.6% vs 13.4%, p = 0.002) and had a lower education level (high school or less: 49.1% vs 40.8%, p = 0.002) and a higher American Society of Anesthesiologists grade (2.7 ± 0.5 vs 2.5 ± 0.6, p < 0.001). Clinically at baseline, the obese group had worse neck pain (VAS score: 5.7 ± 3.2 vs 5.1 ± 3.3), arm pain (VAS score: 5.4 ± 3.5 vs 4.8 ± 3.5), disability (NDI score: 42.7 ± 20.4 vs 37.4 ± 20.7), quality of life (EQ-5D score: 0.54 ± 0.22 vs 0.56 ± 0.22), and function (mJOA score: 11.6 ± 2.8 vs 12.2 ± 2.8) (all p < 0.05). At the 24-month follow-up, however, there was no difference in the change in PROs between the two groups. Even after accounting for relevant covariates, no significant difference in achievement of MCID and satisfaction was observed between the two groups at 24 months. CONCLUSIONS Despite the class III obese group having worse baseline clinical presentations, the two cohorts achieved similar rates of satisfaction and MCID in PROs. Class III obesity should not preclude and/or delay surgical management for patients who would otherwise benefit from surgery for CSM.