Characteristics and Treatment of Exercise Intolerance in Patients With Long COVID.

The post-acute sequalae of SARS-CoV-2, also known as "Long COVID," is characterized by profound fatigue, impaired functional capacity with post-exertional malaise, orthostatic intolerance, and tachycardia. At least 25-30% of individuals impacted by SARS-CoV-2 will go on to experience the Long COVID syndrome, underscoring the detrimental impact this condition has on society. Although efforts are underway to further understand risk factors for Long COVID and identify strategies to prevent disease development entirely, implementation of treatment strategies is warranted to alleviate symptom burden among those affected. This review provides a rationale for exercise prescriptions tailored to the Long COVID patient based on the pathophysiology underlying this syndrome, as well as the previously demonstrated benefits of exercise training in other similar populations whose clinical manifestations result from cardiac deconditioning. Herein, we discuss methods to tailor exercise protocols, accommodating exercise intolerance and post-exertional malaise that may otherwise limit the ability to participate in a training protocol, as well as data demonstrating that a focused exercise prescription may effectively alleviate symptom burden in these patients. Long COVID results, in large part, from deconditioning, which may result from as little as 20 hr of inactivity. Exercise prescriptions tailored to patients with Long COVID may effectively alleviate symptom burden associated with this condition and in the absence of overt contraindications should be considered in management.

The FusX TALE Base Editor (FusXTBE) for Rapid Mitochondrial DNA Programming of Human Cells In Vitro and Zebrafish Disease Models In Vivo.

Functional analyses of mitochondria have been hampered by few effective approaches to manipulate mitochondrial DNA (mtDNA) and a lack of existing animal models. Recently a TALE-derived base editor was shown to induce C-to-T (or G-to-A) sequence changes in mtDNA. We report here the FusX TALE Base Editor (FusXTBE) to facilitate broad-based access to TALE mitochondrial base editing technology. TALE Writer is a de novo in silico design tool to map potential mtDNA base editing sites. FusXTBE was demonstrated to function with comparable activity to the initial base editor in human cells in vitro. Zebrafish embryos were used as a pioneering in vivo test system, with FusXTBE inducing 90+% editing efficiency in mtDNA loci as an example of near-complete induction of mtDNA heteroplasmy in vivo. Gene editing specificity as precise as a single nucleotide was observed for a protein-coding gene. Nondestructive genotyping enables single-animal mtDNA analyses for downstream biological functional genomic applications. FusXTBE is a new gene editing toolkit for exploring important questions in mitochondrial biology and genetics.

Acute and Midterm Outcomes of Antegrade vs Retrograde Crossing Strategies for Endovascular Treatment of Iliac Artery Chronic Total Occlusions.

PURPOSE: To examine whether an antegrade or retrograde crossing strategy for treatment of iliac artery chronic total occlusions (CTOs) is associated with differences in procedural or midterm outcomes. MATERIALS AND METHODS: A dual-center retrospective cohort study was conducted in 168 patients (mean age 66.4±10.6 years; 116 men) treated for CTOs in 110 common iliac arteries (CIA), 52 external iliac arteries (EIA), and 26 combined CIA/EIAs. Logistic regression models were developed to determine the association between crossing strategy and procedural complications, 1- and 3-year target lesion revascularization (TLR), and major adverse limb events (MALE). Results are presented as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: An initial antegrade strategy was more common for EIA CTOs (p<0.005), and an initial retrograde strategy was more often used in CIA (p<0.005) and combined CIA/EIA (p<0.005) CTOs. Crossover to an alternate approach was required in 27.6% of initial antegrade attempts and 9.6% of initial retrograde attempts. EIA CTOs were the most likely lesions to be treated successfully with the initial attempt (either strategy). In all, 123 (65.4%) lesions were successfully crossed with a final retrograde approach and 65 with a final antegrade approach. Overall target lesion success was high for both groups (95.1% vs 93.2%, p=0.456). Lesions treated with a final retrograde approach were shorter (75.3±34.9 vs 87.6±31.3 mm, p=0.005) and were more likely to be treated with a reentry device (34.2% vs 9.2%, p<0.001) and with balloon-expandable stents (39.2% vs 17.7%, p=0.005). The final antegrade approach was associated with a lower risk of target lesion complications (OR 0.07, 95% CI 0.01 to 0.81, p=0.034). The two crossing approaches were associated with similar estimates of 1- and 3-year TLR and MALE. CONCLUSION: A final antegrade approach was associated with lower rates for complications but the 2 approaches were similar in terms of lesion success, TLR, and MALE. The EIA CTOs were more likely to be treated with an antegrade approach and more likely to be crossed successfully with the initial approach irrespective of the crossing direction.

Exclusion of a Giant Coronary Artery Aneurysm With Covered Stents Using a Long Drug-Eluting Stent Scaffold.

Coronary artery aneurysms (CAA) are a rare cause of acute coronary syndrome and there is little consensus as to the optimal treatment. Based on case series as well as expert opinion, surgery has been suggested as the optimal treatment for a giant CAA. Here, we present the case of a patient with recurrent myocardial infarction and severe angina due to a giant CAA, who was deemed a poor surgical candidate due to his multiple medical comorbidities. Given his intractable anginal symptoms despite medical therapy, he chose to pursue percutaneous intervention. However, the aneurysm was larger than available covered coronary stents and the patient had significant atherosclerotic disease proximal and distal to the aneurysm itself. Our approach used a long drug-eluting stent as a scaffold to overlap covered coronary stents to successfully exclude the aneurysm. The patient's angina resolved and had no complications or readmissions after nearly 1 year of follow-up.

Long-term outcomes of carotid artery stenting in patients with a contralateral carotid artery occlusion.

OBJECTIVES: To examine the association between a contralateral carotid artery occlusion (CCO) and the rates of subsequent target-lesion restenosis and revascularization after carotid artery stenting (CAS). BACKGROUND: Patients with carotid artery disease undergoing revascularization often have a CCO. The association of a CCO with long-term outcomes after CAS is uncertain. METHODS: At two institutions, 267 CAS procedures were performed from 2006 to 2016 including 47 (18%) with a CCO. Regular follow-up with duplex carotid ultrasound was performed to assess for restenosis. Univariate Cox regression analysis was performed to evaluate the association between the presence of a CCO and repeat revascularization. RESULTS: The mean patient age was 70 years. There was no significant difference (P > 0.05) in procedural indication (asymptomatic vs ischemic symptoms) or medical comorbidities between groups. During 5-year follow up, the rate of duplex-derived >80% stenosis was 6% in the non-CCO group and 9% in the CCO group (P = 0.45). Despite similar rates of >80% restenosis, there was a significant association between CCO and subsequent target-lesion revascularization (TLR), with rates of 6.4% vs 0.9% at 5 years (HR 7.2, confidence interval (CI) 1.2-43, P = 0.04). There were no significant differences between groups in the 5-year rates of stroke (4.3% in CCO group vs 4.5% in non-CCO group, HR 0.53, CI 0.07-4.22, P = 1.0) or MACCE (15% vs 18%, HR 0.55, CI 0.2-1.55, P = 0.68). CONCLUSIONS: Patients undergoing CAS with a CCO were more likely to undergo TLR during long-term follow up, but they did not have any differences in procedural success or short- and long-term outcomes.

Novel zebrafish behavioral assay to identify modifiers of the rapid, nongenomic stress response.

When vertebrates face acute stressors, their bodies rapidly undergo a repertoire of physiological and behavioral adaptations, which is termed the stress response. Rapid changes in heart rate and blood glucose levels occur via the interaction of glucocorticoids and their cognate receptors following hypothalamic-pituitary-adrenal axis activation. These physiological changes are observed within minutes of encountering a stressor and the rapid time domain rules out genomic responses that require gene expression changes. Although behavioral changes corresponding to physiological changes are commonly observed, it is not clearly understood to what extent hypothalamic-pituitary-adrenal axis activation dictates adaptive behavior. We hypothesized that rapid locomotor response to acute stressors in zebrafish requires hypothalamic-pituitary-interrenal (HPI) axis activation. In teleost fish, interrenal cells are functionally homologous to the adrenocortical layer. We derived eight frameshift mutants in genes involved in HPI axis function: two mutants in exon 2 of mc2r (adrenocorticotropic hormone receptor), five in exon 2 or 5 of nr3c1 (glucocorticoid receptor [GR]) and two in exon 2 of nr3c2 (mineralocorticoid receptor [MR]). Exposing larval zebrafish to mild environmental stressors, acute changes in salinity or light illumination, results in a rapid locomotor response. We show that this locomotor response requires a functioning HPI axis via the action of mc2r and the canonical GR encoded by nr3c1 gene, but not MR (nr3c2). Our rapid behavioral assay paradigm based on HPI axis biology can be used to screen for genetic and environmental modifiers of the hypothalamic-pituitary-adrenal axis and to investigate the effects of corticosteroids and their cognate receptor interactions on behavior.

Long-term outcomes after re-entry device use for recanalization of common iliac artery chronic total occlusions.

OBJECTIVE: To examine the impact of re-entry device (RED) use on 1- and 5-year outcomes after endovascular treatment of common iliac artery (CIA) chronic total Occlusions (CTOs). BACKGROUND: There are not enough data regarding the long-term safety and efficacy of RED. METHODS: We performed a two-center retrospective study of 115 patients (140 lesions) undergoing CIA CTO endovascular intervention between 2006 and 2016. Baseline characteristics and long-term outcomes were described. A Cox proportional hazard model was developed to determine if REDs were associated with target lesion revascularization (TLR) or major adverse limb events (MALE) after 1 and 5 years. RESULTS: Among 140 lesions, 43 (31%) required use of a RED. The mean age was 63.9 years and the majority (n = 80) of patients were male. An antegrade crossing approach and treatment of restenotic lesions were less common in the RED group (10% vs. 29%, P < .05 and 0% vs. 21%, P < .05, respectively). There were no significant differences in Rutherford class, pre-procedure ABI, or patient presentation. The procedural complication rates were similar between the two groups. The 1- and 5-year TLR rates for lesions treated with re-entry device vs. standard approaches were 11% vs. 9%; P = 0.8 and 29% vs. 29%; P = 0.9 respectively. The 1 and 5-year MALE rates for lesions treated with re-entry device were 5% vs. 6%; P = 0.8 and 11% vs. 11%; P = 0.9 respectively. CONCLUSIONS: This retrospective analysis found that recanalization of CIA occlusions using a RED is safe and is associated with long-term clinical outcomes similar to that of standard crossing techniques.

Long-term outcomes after carotid artery stenting of patients with prior neck irradiation or surgery.

BACKGROUND: Carotid artery stenting (CAS) is often performed in patients with carotid artery stenosis who have relative contraindications to carotid endarterectomy (CEA), including hostile neck anatomy (e.g., history of neck irradiation or prior surgery). We examined the impact of hostile neck anatomy on long-term outcomes after CAS. METHODS: All carotid artery stent procedures performed at two institutions from 2006 to 2016 were reviewed. Routine duplex carotid ultrasound was used to assess target lesion restenosis at regular intervals. The primary endpoint was rates of target lesion revascularization (TLR). Secondary endpoints included peri-procedural outcomes, restenosis, stroke, major adverse cardiovascular and cerebrovascular events (MACCE), and mortality during long-term follow up. A Cox proportional hazard model was developed to determine the association between hostile neck anatomy and outcome after CAS. RESULTS: 304 CAS procedures were performed in 268 patients (hostile neck=53, non-hostile neck=215). Patients with hostile neck anatomy were more likely to have a history of smoking and history of prior carotid artery revascularization. There were no differences in peri-procedural outcomes including stroke. During follow-up to five years there were no significant differences in rates of TLR (1.4% vs. 3.8%, P=0.25), restenosis (1.9% vs. 5.1%, P=0.31), MACCE (26% vs. 18%, P=0.15), ipsilateral stroke (7.5% vs. 2.8%, P=0.101), or mortality (13% vs. 14%, P=0.89). Hostile neck anatomy was not associated with significantly increased 5-year TLR rates in the Cox regression analysis (HR=2.64; 95% CI: 0.44-15.83; P=0.289). CONCLUSIONS: Despite greater comorbidities, patients with hostile neck anatomy and carotid artery stenosis have favorable outcomes after carotid artery stenting.

Mid-term outcomes of orbital atherectomy combined with drug-coated balloon angioplasty for treatment of femoropopliteal disease.

PURPOSE: To assess the intraprocedural and mid-term outcomes of orbital atherectomy (OA) combined with drug-coated balloon (DCB) angioplasty for the treatment of calcified femoropopliteal disease. METHODS: In this single-center cohort, 89 patients (139 lesions) were treated with DCB angioplasty for claudication or critical limb ischemia (CLI). Angiographic characteristics and procedural outcomes were reviewed for patients treated with or without adjunctive OA. Lesion calcification was graded using two previously published scoring systems, the angiographic calcium score (ACS) and the peripheral artery calcification scoring system (PACSS). RESULTS: Among 139 lesions, 40 (29%) were treated with OA + DCB. Mean lesion length was 135 ± 100 mm for lesions treated with OA + DCB and 139 ± 100 mm for DCB alone (P = 0.9). Moderate to severe calcification was present in 83% of patients treated with OA, compared to 42% of patients treated with DCB alone (P < 0.001). Lesions treated with OA + DCB were less likely to require bailout stenting (18% vs. 39%, P =0.01). Rates of embolization (0% in OA + DCB vs. 2% in DCB only, P = 0.4), dissection (13% vs. 14%, P = 0.8), and perforation (0%) did not differ significantly between groups. The freedom from TLR at 1 year was 82% in both groups (P = 0.6) while primary patency was 81% in-patients treated with DCB alone and 77% in-patients treated with DCB with concomitant OA (P = 0.8). CONCLUSION: In this single-center analysis of patients undergoing DCB angioplasty for claudication or CLI, OA was most often used for the treatment of severely calcified lesions. These lesions were more likely to be treated with scoring balloons and less likely to require bailout stenting. At 1 year, target lesion revascularization and primary patency was similar in patients treated with and without adjunctive OA, despite the higher lesion complexity among those receiving the combination procedure. © 2017 Wiley Periodicals, Inc.

An unusual case of donor-derived myelodysplastic syndrome following double-unit umbilical cord blood transplantation in acute lymphoblastic leukemia.

Umbilical cord-blood transplantation is considered an effective treatment strategy for acute lymphoblastic leukemia (ALL) when a human leukocyte antigen (HLA)-matched donor is unavailable. The use of a second unit helps ensure engraftment in larger adults and those with comorbidities, even though only one unit engrafts in most patients. Herein, we present the clinical and laboratory characteristics of a patient who developed donor-derived myelodysplastic syndrome (ddMDS) after double umbilical cord-blood transplantation (dUCB HSCT). To our knowledge, no cases of ddMDS have been described in a patient with a history of ALL in molecular remission after receiving a dUCB HSCT. Current molecular techniques, including analysis of short tandem repeats (STR) and fluorescence in situ hybridization (FISH) allowed us to firmly establish donor origin.