Intrathecal Gene Therapy for Giant Axonal Neuropathy.

BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).

Long-term outcomes of autologous vein bypass for repair of upper and lower extremity major arterial trauma.

OBJECTIVE: Autologous vein is the preferred bypass conduit for extremity arterial injuries owing to superior patency and low infection risk; however, long-term data on outcomes in civilians are limited. Our goal was to assess short- and long-term outcomes of autologous vein bypass for upper and lower extremity arterial trauma. METHODS: A retrospective review was performed of patients with major extremity arterial injuries (2001-2019) at a level I trauma center. Demographics, injury and intervention details, and outcomes were recorded. Primary outcomes were primary patency at 1 year and 3 years. Secondary outcomes were limb function at 6 months, major amputation, and mortality. Multivariable analysis determined risk factors for functional impairment. RESULTS: There were 107 extremity arterial injuries (31.8% upper and 68.2% lower) treated with autologous vein bypass. Mechanism was penetrating in 77% of cases, of which 79.3% were due to firearms. The most frequently injured vessels were the common and superficial femoral (38%), popliteal (30%), and brachial arteries (29%). For upper extremity trauma, concomitant nerve and orthopedic injuries were found in 15 (44.1%) and 11 (32.4%) cases, respectively. For lower extremities, concomitant nerve injuries were found in 10 (13.7%) cases, and orthopedic injuries in 31 (42.5%). Great saphenous vein was the conduit in 96% of cases. Immediate intraoperative bypass revision occurred in 9.3% of patients, most commonly for graft thrombosis. The in-hospital return to operating room rate was 15.9%, with graft thrombosis (47.1%) and wound infections (23.5%) being the most common reasons. The median follow-up was 3.6 years. Kaplan-Meier analysis showed 92% primary patency at 1 year and 90% at 3 years. At 6 months, 36.1% of patients had functional impairment. Of patients with functional impairment at 6 months, 62.9% had concomitant nerve and 60% concomitant orthopedic injuries. Of those with nerve injury, 91.7% had functional impairment, compared with 17.8% without nerve injury (P < .001). Of patients with orthopedic injuries, 51.2% had functional impairment, vs 25% of those without orthopedic injuries (P = .01). On multivariable analysis, concomitant nerve injury (odds ratio, 127.4; 95% confidence interval, 17-957; P <. 001) and immediate intraoperative revision (odds ratio, 11.03; 95% confidence interval, 1.27-95.55; P = .029) were associated with functional impairment. CONCLUSIONS: Autologous vein bypass for major extremity arterial trauma is durable; however, many patients have long-term limb dysfunction associated with concomitant nerve injury and immediate intraoperative bypass revision. These factors may allow clinicians to identify patients at higher risk for functional impairment, to outline patient expectations and direct rehabilitation efforts toward improving functional outcomes.

Outcomes of lower extremity revascularization in octogenarians and nonagenarians for intermittent claudication.

OBJECTIVE: Revascularization for intermittent claudication (IC) due to infrainguinal peripheral arterial disease (PAD) is dependent on durability and expected benefit. We aimed to assess outcomes for IC interventions in octogenarians and nonagenarians (age ≥80 years) and those younger than 80 years (age <80 years). METHODS: The Vascular Quality Initiative was queried (2010-2020) for peripheral vascular interventions (PVIs) and infrainguinal bypasses (IIBs) performed to treat IC. Baseline characteristics, procedural details, and outcomes were analyzed (comparing age ≥80 years and age <80 years). RESULTS: There were 84,210 PVIs (12.1% age ≥80 years and 87.9% age <80 years) and 10,980 IIBs (7.4% age ≥80 years and 92.6% age <80 years) for IC. For PVI, patients aged ≥80 years more often underwent femoropopliteal (70.7% vs 58.1%) and infrapopliteal (19% vs 9.3%) interventions, and less often iliac interventions (32.1% vs 48%) (P < .001 for all). Patients aged ≥80 years had more perioperative hematomas (3.5% vs 2.4%) and 30-day mortality (0.9% vs 0.4%) (P < .001). At 1-year post-intervention, the age ≥80 years cohort had fewer independently ambulatory patients (80% vs 91.5%; P < .001). Kaplan-Meier analysis showed patients aged ≥80 years had lower reintervention/amputation-free survival (81.4% vs 86.8%), amputation-free survival (87.1% vs 94.1%), and survival (92.3% vs 96.8%) (P < .001) at 1-year after PVI. Risk adjusted analysis showed that age ≥80 years was associated with higher reintervention/amputation/death (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.1-1.35), amputation/death (HR, 1.85; 95% CI, 1.61-2.13), and mortality (HR, 1.92; 95% CI, 1.66-2.23) (P < .001 for all) for PVI. For IIB, patients aged ≥80 years more often had an infrapopliteal target (28.4% vs 19.4%) and had higher 30-day mortality (1.3% vs 0.5%), renal failure (4.1% vs 2.2%), and cardiac complications (5.4% vs 3.1%) (P < .001). At 1 year, the age ≥80 years group had fewer independently ambulatory patients (81.7% vs 88.8%; P = .02). Kaplan-Meier analysis showed that the age ≥80 years cohort had lower reintervention/amputation-free survival (75.7% vs 81.5%), amputation-free survival (86.9% vs 93.9%), and survival (90.4% vs 96.5%) (P < .001 for all). Risk-adjusted analysis showed age ≥80 years was associated with higher amputation/death (HR, 1.68; 95% CI, 1.1-2.54; P = .015) and mortality (HR, 1.85; 95% CI, 1.16-2.93; P = .009), but not reintervention/amputation/death (HR, 1.1; 95% CI, 0.85-1.44; P = .47) after IIB. CONCLUSIONS: Octogenarians and nonagenarians have greater perioperative morbidity and long-term ambulatory impairment, limb loss, and mortality after PVI and IIB for claudication. Risks of intervention on elderly patients with claudication should be carefully weighed against the perceived benefits of revascularization. Medical and exercise therapy efforts should be maximized in this population.

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

The Effect of Chronic and End-Stage Renal Disease on Long-Term Outcomes after Infrainguinal Bypass.

BACKGROUND: Patients undergoing infrainguinal bypass for chronic limb threatening ischemia (CLTI) with renal dysfunction are at an increased risk for perioperative and long-term morbidity and mortality. Our goal was to examine perioperative and 3-year outcomes after lower extremity bypass for CLTI stratified by kidney function. METHODS: A retrospective, single-center analysis of lower extremity bypass for CLTI was performed between 2008 and 2019. Kidney function was categorized as normal (estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2), chronic kidney disease (CKD) (eGFR 15-59 mL/min/1.73 m2), and end-stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m2). Kaplan-Meier and multivariable analysis were performed. RESULTS: There were 221 infrainguinal bypasses performed for CLTI. Patients were classified by renal function as normal (59.7%), CKD (24.4%), and ESRD (15.8%). Average age was 66 years and 65% were male. Overall, 77% had tissue loss with 9%, 45%, 24%, and 22% being Wound, Ischemia, and foot Infection stages 1-4, respectively. The majority (58%) of bypass targets was infrapopliteal and 58% used ipsilateral greater saphenous vein. The 90-day mortality and readmission rates were 2.7% and 49.8%, respectively. ESRD, compared to CKD and normal renal function, respectively, had the highest 90-day mortality (11.4% vs. 1.9% vs. 0.8%, P = 0.002) and 90-day readmission (69% vs. 55% vs. 43%, P = 0.017). On multivariable analysis, ESRD, but not CKD, was associated with higher 90-day mortality (odds ratio (OR) 16.9, 95% confidence interval (CI) 1.83-156.6, P = 0.013) and 90-day readmission (OR 3.02, 95% CI 1.2-7.58, P = 0.019). Kaplan-Meier 3-year analysis showed no difference between groups for primary patency or major amputation; however, ESRD, compared to CKD and normal renal function, respectively, had worse primary-assisted patency (60% vs. 76% vs. 84%, P = 0.03) and survival (72% vs. 96% vs. 94%, P = 0.001). On multivariable analysis, ESRD and CKD were not associated with 3-year primary patency loss/death, but ESRD was associated with higher primary-assisted patency loss (hazard ratio (HR) 2.61, 95% CI 1.23-5.53, P = 0.012). ESRD and CKD were not associated with 3-year major amputation/death. ESRD was associated with higher 3-year mortality (HR 4.95, 95% CI 1.52-16.2, P = 0.008) while CKD was not. CONCLUSIONS: ESRD, but not CKD, was associated with higher perioperative and long-term mortality after lower extremity bypass for CLTI. Although ESRD was associated with lower long-term primary-assisted patency, there were no differences in loss of primary patency or major amputation.

Analysis of Early Death after Elective Open Abdominal Aortic Aneurysm Repair.

BACKGROUND: Mortality after open abdominal aortic aneurysm repair is a quality measure and early death may represent a technical complication or poor patient selection. Our objective was to analyze patients who died in the hospital within postoperative day (POD) 0-2 after elective abdominal aortic aneurysm repair. METHODS: The Vascular Quality Initiative was queried from 2003-2019 for elective open abdominal aortic aneurysm repairs. Operations were categorized as in-hospital death on POD 0-2 (POD 0-2 Death), in-hospital death beyond POD 2 (POD ≥3 Death), and those alive at discharge. Univariable and multivariable analyses were performed. RESULTS: There were 7,592 elective open abdominal aortic aneurysm repairs with 61 (0.8%) POD 0-2 Death, 156 (2.1%) POD ≥3 Death, and 7,375 (97.1%) alive at discharge. Overall, median age was 70 years and 73.6% were male. Iliac aneurysm repair and surgical approach (anterior/retroperitoneal) were similar among groups. POD 0-2 Death, compared to POD ≥3 Death and those alive at discharge, had the longest renal/visceral ischemia time, more commonly had proximal clamp placement above both renal arteries, an aortic distal anastomosis, longest operative time, and largest estimated blood loss (all P < 0.05). Postoperative vasopressor usage, myocardial infarction, stroke, and return to the operating room were most frequent in POD 0-2 Death and extubation in the operating room was least frequent (all P < 0.001). Postoperative bowel ischemia and renal failure occurred most commonly among POD ≥3 Death (all P < 0.001).On multivariable analysis, POD 0-2 Death was associated with congestive heart failure, prior peripheral vascular intervention, female sex, preoperative aspirin use, lower center volume quartile, renal/visceral ischemia time, estimated blood loss, and older age (all P < 0.05). CONCLUSIONS: POD 0-2 Death was associated with comorbidities, center volume, renal/visceral ischemia time, and estimated blood loss. Referral to high-volume aortic centers could improve outcomes.

Brachiocephalic and Radiocephalic Arteriovenous Fistulas in Patients with Tunneled Dialysis Catheters Have Similar Outcomes.

BACKGROUND: Patients with tunneled dialysis catheters (TDCs) have a time-sensitive need for a functional permanent access due to high risk of catheter-associated morbidity. Brachiocephalic arteriovenous fistulas (BCF) have been reported to have higher maturation and patency compared to radiocephalic arteriovenous fistulas (RCF), although more distal creation is encouraged when possible. However, this may lead to a delay in establishing permanent vascular access and, ultimately, TDC removal. Our goal was to assess short-term outcomes after BCF and RCF creation for patients with concurrent TDCs to see if these patients would potentially benefit more from an initial brachiocephalic access to minimize TDC dependence. METHODS: The Vascular Quality Initiative hemodialysis registry was analyzed from 2011 to 2018. Patient demographics, comorbidities, access type, and short-term outcomes including occlusion, reinterventions, and access being used for dialysis, were assessed. RESULTS: There were 2,359 patients with TDC, of whom 1,389 (58.9%) underwent BCF creation and 970 (41.1%) underwent RCF creation. Average patient age was 59 years, and 62.8% were male. Compared with RCF, those with BCF were more often older, of female sex, obese, nonindependently ambulatory, have commercial insurance, diabetes, coronary artery disease, chronic obstructive pulmonary disease, be on anticoagulation, and have a cephalic vein diameter of ≥3 mm (all P < 0.05). Kaplan-Meier analysis for 1-year outcomes for BCF and RCF, respectively, showed that primary patency was 45% vs. 41.3% (P = 0.88), primary assisted patency was 86.7% vs. 86.9% (P = 0.64), freedom from reintervention was 51.1% vs. 46.3% (P = 0.44), and survival was 81.3% vs. 84.9% (P = 0.02). Multivariable analysis showed that BCF was comparable to RCF with respect to primary patency loss (hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.91-1.36, P = 0.316), primary assisted patency loss (HR 1.11, 95% CI 0.72-1.29, P = 0.66), and reintervention (HR 1.01, 95% CI 0.81-1.27, P = 0.92). Access being used at 3 months was similar but trending towards RCF being used more often (odds ratio 0.7, 95% CI 0.49-1, P = 0.05). CONCLUSIONS: BCFs do not have superior fistula maturation and patency compared to RCFs in patients with concurrent TDCs. Creation of radial access, when possible, does not prolong TDC dependence.

Postoperative disability and one-year outcomes for patients suffering a stroke after carotid endarterectomy.

OBJECTIVE: Although post-carotid endarterectomy (CEA) strokes are rare, they can be devastating. The degree of disability that patients develop after such events and its effects on long-term outcomes are unclear. Our goal was to assess the extent of postoperative disability in patients suffering strokes after CEA and evaluate its association with long-term outcomes. METHODS: The Vascular Quality Initiative CEA registry (2016-2020) was queried for CEAs performed for asymptomatic or symptomatic indications in patients with preoperative modified Rankin Scale (mRS) scores of 0 to 1. The mRS grades stroke-related disability as 0 (none), 1 (not significant), 2 to 3 (moderate), 4 to 5 (severe), and 6 (dead). Patients suffering postoperative strokes with recorded mRS scores were included. Postoperative stroke-related disability based on mRS and its association with long-term outcomes were analyzed. RESULTS: Among 149,285 patients undergoing CEA, there were 1178 patients without preoperative disability who had postoperative strokes and reported mRS scores. Mean age was 71 ± 9.2 years, and 59.6% of patients were male. Regarding ipsilateral cortical symptoms within 6 months preoperatively, 83.5% of patients were asymptomatic, 7.3% had transient ischemic attacks, and 9.2% had strokes. Postoperative stroke-related disability was classified as mRS 0 (11.6%), 1 (19.5%), 2 to 3 (29.4%), 4 to 5 (31.5%), and 6 (8%). One-year survival stratified by postoperative stroke-related disability was 91.4% for mRS 0, 95.6% for mRS 1, 92.1% for mRS 2 to 3, and 81.5% for mRS 4 to 5 (P < .001). Multivariable analysis demonstrated that while severe postoperative disability was associated with increased death at 1 year (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.5-5.89; P = .002), moderate postoperative disability had no such association (HR, 0.95; 95% CI, 0.45-2; P = .88). One-year freedom from subsequent ipsilateral neurological events or death stratified by postoperative stroke-related disability was 87.8% for mRS 0, 93.3% for mRS 1, 88.5% for mRS 2 to 3, and 77.9% for mRS 4 to 5 (P < .001). Severe postoperative disability was independently associated with increased ipsilateral neurological events or death at 1 year (HR, 2.34; 95% CI, 1.25-4.38; P = .01). However, moderate postoperative disability exhibited no such association (HR, 0.92; 95% CI, 0.46-1.82; P = .8). CONCLUSIONS: The majority of patients without preoperative disability who suffered strokes after CEA developed significant disability. Severe stroke-related disability was associated with higher 1-year mortality and subsequent neurological events. These data can improve informed consent for CEA and guide prognostication after postoperative strokes.

Outcomes following ipsilateral great saphenous vein bypass for lower extremity arterial injuries.

OBJECTIVE: Use of autologous great saphenous vein (GSV) grafts for repair of extremity arterial injuries is well established. Contralateral great saphenous vein (cGSV) is traditionally used in the setting of lower extremity vascular injury given the risk of occult ipsilateral superficial and deep venous injury. We evaluated outcomes of ipsilateral GSV (iGSV) bypass in patients with lower extremity vascular trauma. METHODS: Patient records at an ACS verified Level I urban trauma center between 2001 and 2019 were retrospectively reviewed. Patients who sustained lower extremity arterial injuries managed with autologous GSV bypass were included. Propensity-matched analysis compared the iGSV and cGSV groups. Primary graft patency was assessed via Kaplan-Meier analysis at 1-year and 3-years following the index operation. RESULTS: A total of 76 patients underwent autologous GSV bypass for lower extremity vascular injuries. 61 cases (80%) were secondary to penetrating trauma, and 15 patients (20%) underwent repair with iGSV bypass. Arteries injured in the iGSV group included popliteal (33.3%), common femoral (6.7%), superficial femoral (33.3%), and tibial (26.7%), while those in the cGSV group included common femoral (3.3%), superficial femoral (54.1%), and popliteal (42.6%). Reasons for using iGSV included trauma to the contralateral leg (26.7%), relative accessibility (33.3%), and other/unknown (40%). On unadjusted analysis, iGSV patients had a higher rate of 1-year amputation than cGSV patients (20% vs. 4.9%), but this was not statistically significant (P = 0.09). Propensity matched analysis also found no significant difference in 1-year major amputation (8.3% vs. 4.8%, P = 0.99). Regarding ambulatory status, iGSV patients had similar rates of independent ambulation (33.3% vs. 38.1%), need for assistive devices (58.3% vs. 57.1%), and use of a wheelchair (8.3% vs. 4.8%) compared cGSV patients at subsequent follow-up (P = 0.90). Kaplan-Meier analysis of bypass grafts revealed comparable primary patency rates for iGSV versus cGSV bypasses at 1-year (84% vs. 91%) and 3-years post-intervention (83% vs. 90%, P = 0.364). CONCLUSION: Ipsilateral GSV may be used as a durable conduit for bypass in cases of lower extremity arterial trauma where use of contralateral GSV is not feasible, with comparable long-term primary graft patency rates and ambulatory status.

Variations in Practice Patterns for Peripheral Vascular Interventions Across Clinical Settings.

BACKGROUND: Peripheral vascular interventions (PVIs) for lower extremity peripheral artery disease have been increasing, particularly in the office-based setting. Our goal was to evaluate practice patterns for PVI by site of service using a contemporary real-world dataset. METHODS: The Vascular Quality Initiative PVI registry was queried from 2010-2021. Site of service was classified as hospital/inpatient, hospital/outpatient, and ambulatory/office-based center. Patient demographics, comorbidities, procedural details, and periprocedural outcomes were analyzed. RESULTS: There were 54,897 hospital/inpatient (43.2%), 64,105 hospital/outpatient (50.4%), and 8,179 ambulatory/office-based center (6.4%) PVI. When comparing the 2 outpatient settings, ambulatory/office-based center patients were older than hospital/outpatient (mean age 70.7 vs. 68.7 years), more often female sex (41.4% vs. 39.1%), never smokers (27.5% vs. 18.5%), primary Medicare (61.6% vs. 55.9%), nonambulatory (6.5% vs. 4.7%), less often with coronary artery disease (30.2% vs. 34.1%), chronic obstructive pulmonary disease (18.1% vs. 26.9%), congestive heart failure (13% vs. 17.2%), obesity (30.9% vs. 33.6%), and less often on a statin (71.4% vs. 76.1%) (P < 0.001). Ambulatory/office-based center procedures were more likely for claudication (60.1% vs. 55.8%), more often involved femoro-popliteal (73.1% vs. 64.6%) and infrapopliteal (36.7% vs. 24.3%), and less often iliac interventions (24.1% vs. 33.6%) (P < 0.001).Overall, atherectomy was used in 14.2% of hospital/inpatient, 19.4% of hospital/outpatient, and 63.4% of ambulatory/office-based center procedures. Stents were used in 41.8% of hospital/inpatient, 45.1% of hospital/outpatient, and 48.8% of ambulatory/office-based center procedures. However, stent grafts were used in 12.5% of hospital/inpatient, 8.8% of hospital/outpatient, and only 1.3% of ambulatory/office-based center procedures. On multivariable analysis, compared with hospital/inpatient, atherectomy use was associated with ambulatory/office-based center setting (Odds ratio 10.9, 95% confidence interval 10.3-11.5, P < 0.001) and hospital/outpatient setting (Odds ratio 1.57, 95% confidence interval 1.51-1.62, P < 0.001). Periprocedure complications including hematoma requiring intervention (0.3%), any stenosis/occlusion (0.2%), and distal embolization (0.6%) were quite low across all settings. CONCLUSIONS: There are substantial variations in patient populations, procedural indications, and types of interventions undertaken during PVI across different locations. Ambulatory/office-based procedures more commonly treat claudicants, use atherectomy, and less often use stent grafts. Further research is warranted to investigate long-term trends in practice patterns and long-term outcomes, for PVI in the ever-expanding ambulatory/office-based setting.

Outcomes of upper arm axillary artery and brachial artery arteriovenous grafts.

BACKGROUND: We compared the outcomes of upper arm arteriovenous grafts (AVGs) in a large, prospectively collected data set to determine if there are clinically significant differences in axillary artery-based and brachial artery-based AVGs. METHODS: Patients who received upper arm AVGs within the Society of Vascular Surgery Vascular Quality Initiative (VQI) dataset were identified. The primary outcome measures were primary and secondary patency loss at 12-month follow-up. Other outcomes included were wound infection, steal syndrome, and arm swelling at 6-month follow-up. The log-rank test was used to evaluate patency loss using Kaplan-Meier analysis, and Cox proportional hazards models were used to examine adjusted association between inflow artery (brachial artery vs axillary artery) and outcomes, adjusting for configuration (straight vs looped). RESULTS: Among 3637 upper extremity AVGs in the VQI (2010-2017), there were 510 upper arm brachial artery AVGs and 394 upper arm axillary artery AVGs. Patients with axillary artery AVGs were more likely to be female (72% vs 56%, p < 0.001) and underwent general anesthesia (61% vs 57%, p < 0.05). In univariable analysis, the 12-month primary patency (54% vs 63%, p = 0.03) and secondary patency (81% vs 89%, p = 0.007) were lower for axillary artery AVGs than upper arm brachial artery AVGs. In multivariable analysis, although wound infection and arm swelling were similar at 6-month follow up, axillary artery AVGs were more likely to have steal syndrome (adjusted Hazard Ratio (aHR) = 2.6, 95% Confidence Interval (CI) 1.2,5.6, p = 0.017). In addition, axillary artery AVGs were associated with higher rates of 12-month primary patency loss (aHR = 1.6, 95% CI 1.2-2.2, p = 0.002) and 12-month secondary patency loss (aHR = 2.0, 95% CI 1.3-3.3, p = 0.005). CONCLUSIONS: From this observational study analyzing the outcomes of upper extremity hemodialysis access, axillary artery AVGs were associated with significantly lower patency rates and higher risk of steal syndrome than brachial artery AVGs.

CRISPR-mediated correction of skeletal muscle Ca2+ handling in a novel DMD patient-derived pluripotent stem cell model.

Mutations in the dystrophin gene cause the most common and currently incurable Duchenne muscular dystrophy (DMD) characterized by progressive muscle wasting. Although abnormal Ca2+ handling is a pathological feature of DMD, mechanisms underlying defective Ca2+ homeostasis remain unclear. Here we generate a novel DMD patient-derived pluripotent stem cell (PSC) model of skeletal muscle with an isogenic control using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated precise gene correction. Transcriptome analysis identifies dysregulated gene sets in the absence of dystrophin, including genes involved in Ca2+ handling, excitation-contraction coupling and muscle contraction. Specifically, analysis of intracellular Ca2+ transients and mathematical modeling of Ca2+ dynamics reveal significantly reduced cytosolic Ca2+ clearance rates in DMD-PSC derived myotubes. Pharmacological assays demonstrate Ca2+ flux in myotubes is determined by both intracellular and extracellular sources. DMD-PSC derived myotubes display significantly reduced velocity of contractility. Compared with a non-isogenic wildtype PSC line, these pathophysiological defects could be rescued by CRISPR-mediated precise gene correction. Our study provides new insights into abnormal Ca2+ homeostasis in DMD and suggests that Ca2+ signaling pathways amenable to pharmacological modulation are potential therapeutic targets. Importantly, we have established a human physiology-relevant in vitro model enabling rapid pre-clinical testing of potential therapies for DMD.

Nanoscale Detonation Carbon Demonstrates Biosafety in Human Cell Culture.

The production method of nanoscale detonation carbon (NDC) has recently been developed at Lavrentyev Institute of Hydrodynamics SB RAS. This method uses the reaction of acetylene with oxygen conducted in the detonation mode in fuel-rich acetylene-oxygen mixtures. The morphology and structural features of the NDC particles can be varied by changing the concentration of oxygen in the gaseous mixtures. The particles of NDC can serve as reinforcements in metal matrix composites and additives imparting electrical conductivity to polymer matrix composites. Before NDC can be considered for industrial applications, it is necessary to address the related biological safety concerns. The present work was aimed at determining the cytotoxicity of NDC. The NDC powders with two morphologies (obtained using different acetylene/oxygen ratios) were tested on HEK293A human cells. The NDC powder was added to the culture medium in concentrations ranging from 10 ng/mL to 400 µg/mL. The cell viability was determined by a colorimetric EZ4U test and a real-time cell analyzer xCELLigence. None of the NDC samples showed a cytotoxic effect. The results of this study allow us to recommend NDC as a safe and useful product for the development of advanced carbon-based and composite materials.

Unplanned Shunting Is Associated with Higher Stroke Risk after Eversion Carotid Endarterectomy.

BACKGROUND: Shunting during eversion carotid endarterectomy (eCEA) may be technically challenging. Whether shunting practice patterns modify perioperative stroke risk after eCEA is unclear. We aimed to compare eCEA outcomes based on shunting practice. METHODS: The Vascular Quality Initiative (2011-2019) was queried for eCEAs performed for symptomatic and asymptomatic carotid stenosis. Univariable and multivariable analyses compared outcomes based on whether shunting was routine practice, preoperatively-indicated, intraoperatively-indicated, or not performed. RESULTS: There were 13,207 eCEAs identified. Average age was 71.4 years and 59.4% of patients were male sex. Ipsilateral carotid stenosis was >80% in 45.6% and there was severe contralateral carotid stenosis in 8.6%. Early ipsilateral symptoms within 14 days of eCEA were transient ischemic attack in 5.6% and stroke in 7%. The majority of cases were performed under general anesthesia (82.7%). Electroencephalogram monitoring and stump pressures were utilized in 30.9% and 14.7%, respectively. Shunting was routine (25.4%), preoperatively-indicated (1.9%), intraoperatively-indicated (4.7%), or not implemented (68%). Preoperatively-indicated shunting was more often performed in patients with early symptomatic carotid stenosis or severe contralateral carotid stenosis. After routine shunting, preoperatively-indicated shunting, intraoperatively-indicated shunting, and no shunting, median operative duration was 110, 101, 112, and 97 min, respectively (P < 0.001), and ipsilateral perioperative stroke prevalence was 0.6%, 1.2%, 1.9%, and 0.7%, respectively (P = 0.004). On multivariable analysis, longer operative time was associated with routine shunting (MR 1.17, 95% CI 1.15-1.19, P < 0.001), preoperatively-indicated shunting (MR 1.09, 95% CI 1.04-1.15, P < 0.001), and intraoperatively-indicated shunting (MR 1.12, 95% CI 1.09-1.16, P < 0.001) compared with no shunting. Compared with no shunting, routine shunting (OR 0.91, 95% CI 0.54-1.54, P = 0.74) and preoperatively-indicated shunting (OR 1.53, 95% CI 0.47-4.99, P = 0.48) were not associated with stroke; however, intraoperatively-indicated shunting was associated with increased stroke (OR 2.74, 95% CI 1.41-5.3, P = 0.003). Shunting type was not associated with perioperative mortality. CONCLUSIONS: Intraoperatively-indicated shunting during eCEA was associated with longest operative duration and increased perioperative stroke risk. Surgeon familiarity with shunting and planning to shunt in advance may permit more expeditious shunting and prevent stroke.

Female Sex is Associated with More Reinterventions after Endovascular and Open Interventions for Intermittent Claudication.

BACKGROUND: Intermittent claudication (IC) is a commonly treated vascular condition. Patient sex has been shown to influence outcomes of interventions for other vascular disorders; however, whether outcomes of interventions for IC vary by sex is unclear. We sought to assess the association of patient sex with outcomes after IC interventions. METHODS: The Vascular Quality Initiative was queried from 2010-2020 for all peripheral endovascular interventions (PVI), infra-inguinal bypasses (IIB), and supra-inguinal bypasses (SIB) for any degree IC. Univariable and multivariable analyses compared peri-operative and long-term outcomes by patient sex. RESULTS: There were 24,701 female and 40,051 male patients undergoing PVI, 2,789 female and 6,525 male patients undergoing IIB, and 1,695 female and 2,370 male patients undergoing SIB for IC. Guideline-recommended pre-operative medical therapy differed with female patients less often prescribed aspirin for PVI (73.4% vs. 77.3%), IIB (71.5% vs. 74.8%), and SIB (70.9% vs. 74.3%) or statins for PVI (71.8% vs. 76.7%) and IIB (73.1% vs. 76.0%) (all P < 0.05). Female compared with male patients had lower 1-year reintervention-free survival after PVI (84.4% ± 0.3% vs. 86.3% ± 0.2%, P < 0.001), IIB (79.0% ± 0.9% vs. 81.2% ± 0.6%, P = 0.04), and SIB (89.4% ± 0.9% vs. 92.6% ± 0.7%, P = 0.005), but similar amputation-free survival and survival across all procedures. Multivariable analysis confirmed that female sex was associated with increased 1-year reintervention for PVI (HR 1.16, 95% CI 1.09-1.24, P < 0.001), IIB, (HR 1.16, 95% CI 1.03-1.31, P = 0.02), and SIB (HR 1.60, 95% CI 1.20-2.13, P = 0.001). CONCLUSIONS: Female patients undergoing interventions for IC were less often pre-operatively medically optimized than male patients, though the difference was small. Furthermore, female sex was associated with more reinterventions after interventions. Interventionists treating female patients should increase their efforts to maximize medical therapy. Future research should clarify reasons for poorer intervention durability in female patients.

Access site complications are uncommon with vascular closure devices or manual compression after lower extremity revascularization.

OBJECTIVE: Vascular closure devices (VCDs) and manual compression (MC) are used to achieve hemostasis after peripheral vascular interventions (PVIs). We sought to compare perioperative outcomes between MC and four VCDs after PVI in a multicenter setting. METHODS: The Vascular Quality Initiative was queried for all lower extremity PVIs with common femoral artery access performed from 2010 to 2020. The VCDs included were MynxGrip (Cordis, Santa Clara, CA), StarClose SE (Abbott Vascular, Redwood City, CA), Angio-Seal (Terumo, Somerset, NJ), and Perclose ProGlide (Abbott Vascular). In a blinded fashion, these four VCDs (labeled A, B, C, and D) were compared to MC for baseline characteristics, procedural details, and outcomes (access site hematoma and stenosis/occlusion). Those with a sheath size >8F were excluded. Propensity score matching (1:1) was performed. Univariable and multivariable analyses were completed for unmatched and matched data. RESULTS: A total of 84,172 lower extremity PVIs were identified. Of these, 32,013 (38%) had used MC and 52,159 (62%) had used VCDs (A, 12,675; B, 6224; C, 19,872; D, 13,388). The average age was 68.7 years, and 60.4% of the patients were men. The most common indications for intervention were claudication (43.8%) and tissue loss (40.1%). Compared with MC, VCDs were used more often for patients with obesity, diabetes, and end-stage renal disease (P < .001 for all). VCDs were used less often for patients with hypertension, chronic obstructive pulmonary disease, coronary artery disease, prior percutaneous coronary and extremity interventions, and major amputation (P < .001 for all). VCD use was more common than MC during femoropopliteal (73% vs 63.8%) and tibial (33.8% vs 22.3%) interventions but less common with iliac interventions (20.6% vs 34.7%; P < .001 for all). Protamine was used less often with VCDs (19.1% vs 25.6%; P < .001). Overall, 2003 hematomas had developed (2.4%), of which 278 (13.9%) had required thrombin or surgical intervention. Compared with MC, the use of any VCD had resulted in fewer hematomas (1.7% vs 3.6%; P < .001) and fewer hematomas requiring intervention (0.2% vs 0.5%; P < .001). When divided by hemostatic technique, the rate of the development of any hematoma was as follows: MC, 3.6%; VCD A, 1.4%; VCD B, 1.2%; VCD C, 2.3%; and VCD D, 1.1% (P < .001). The rate of hematomas requiring intervention was as follows: MC, 0.5%; VCD A, 0.2%; VCD B, 0.2%; VCD C, 0.3%; and VCD D, 0.1% (P < .001). Access site stenosis/occlusion was similar between the MC and any VCD groups (0.2% vs 0.2%; P = .12). Multivariable analysis demonstrated that any VCD use and the use of the individual VCDs compared with MC were independently associated with the development of fewer hematomas. The incidence of access site stenosis/occlusion was similar between the use of any VCD and MC. The matched analysis revealed similar findings. CONCLUSIONS: Although the overall rates of hematomas requiring intervention were low regardless of hemostatic technique, VCD use, irrespective of type, compared favorably with MC, with significantly fewer access site complications after PVI.

Outcomes of axillofemoral bypass for intermittent claudication.

OBJECTIVE: Although endovascular therapy is often the first-line option for medically refractory intermittent claudication (IC) caused by aortofemoral disease, suprainguinal bypass is often performed. Although this will often be aortofemoral bypass (AoFB), axillofemoral bypass (AxFB) is still sometimes performed despite limited data evaluating its utility in the management of IC. Our goal was to assess the safety and durability of AxFB performed for IC. METHODS: The Vascular Quality Initiative (2009-2019) was queried for suprainguinal bypass performed for IC. Univariable and multivariable analyses were used to compare the perioperative and 1-year outcomes between AxFB and a comparison cohort of AoFB. RESULTS: We identified 3261 suprainguinal bypasses performed for IC: 436 AxFBs and 2825 AoFBs. The mean age was 61.4 ± 9.1 years, 58.8% of the patients were men, and 59.7% currently smoked. Patients undergoing AxFB, compared with AoFB, were more often older, male, never smokers and ambulated with assistance (P < .001 for all). They had more often had hypertension, diabetes, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, and end-stage renal disease and had more often undergone previous outflow peripheral endovascular interventions and previous inflow or outflow bypass. The AxFBs, compared with the AoFBs, were more often unifemoral (P < .05). Patients who had undergone AxFB, compared with AoFB, had had a shorter postoperative length of stay (median, 4 vs 6 days) and fewer perioperative pulmonary (3% vs 7.9%) and renal (5.5% vs 9.9%) complications but had required more perioperative ipsilateral major amputations (0.9% vs 0.04%; P < .05 for all). No significant differences were found in the incidence of perioperative myocardial infarction (2.8% vs 2.7%), stroke (0.7% vs 1.1%), or death (1.8% vs 1.7%). At 1 year, the Kaplan-Meier analysis demonstrated that the AxFB cohort, compared with the AoFB cohort, had had higher rates of death (7.3% vs 3.6%; P = .002), graft occlusion or death (14.3% vs 7.2%; P = .001), ipsilateral major amputation or death (12.5% vs 5.6%; P < .001), and reintervention, amputation, or death (19% vs 8.6%; P < .001). On multivariable analysis, AxFB was independently associated with an increased risk of 1-year reintervention, amputation, or death (hazard ratio, 1.6; 95% confidence interval, 1.03-2.4; P = .04). CONCLUSIONS: The results from the present retrospective analysis suggest that long-term complications were more frequent in patients who had undergone AxFB compared with AoFB, although patients treated with AxFB had had a greater risk with more comorbidities. Because AxFB was associated with significant perioperative morbidity, mortality, and long-term complications, serious consideration should be given before its use to treat IC.

Percutaneous radial artery access for peripheral vascular interventions is a safe alternative for upper extremity access.

OBJECTIVE: Percutaneous radial artery access has been increasingly used for peripheral vascular interventions (PVIs). Our goal was to characterize the practice patterns and perioperative outcomes among patients treated using PVI performed via radial artery access. METHODS: The Vascular Quality Initiative was queried from 2016 to 2020 for PVI performed via upper extremity access. Univariable and multivariable analyses were used to evaluate the periprocedure outcomes of radial artery access cases. A separate sample of brachial artery access cases was used as a comparator. RESULTS: A total of 520 radial artery access cases were identified. The mean age was 69 ± 10 years, and 41.3% were women. Most procedures were performed in the hospital outpatient setting (71.7%). The sheath size was ≤5F for 10%, 6F for 78%, and 7F for 12%. Ultrasound-guided access and protamine were used in 68.3% and 17.3% of cases, respectively. The interventions were aortoiliac (55%), femoropopliteal (55%), and infrapopliteal (9%). Stenting and atherectomy were performed in 55% and 19% of cases, respectively, and more often with 7F sheaths. Access site complications were any hematoma (4.8%), including hematomas resulting in intervention (0.8%), pseudoaneurysms (1%), and access stenosis or occlusion (0.8%). On multivariable analysis, sheath size was not associated with access site complications. Percutaneous brachial artery access (n = 1135) compared with radial access was independently associated with more overall hematomas (odds ratio, 1.73; 95% confidence interval, 1.06-2.81; P = .03). However, access type was not associated with hematomas resulting in intervention (odds ratio, 2.15; 95% confidence interval, 0.69-6.72; P = .19). CONCLUSIONS: PVIs via radial artery access exhibited a low prevalence of postprocedural access site complications and were associated with fewer minor hematoma complications compared with interventions performed using brachial artery access. Radial artery access compared with brachial artery access should be the preferred technique for PVIs.

Detonation Spraying of Hydroxyapatite on a Titanium Alloy Implant.

Hydroxyapatite (HA), the major mineral component of tooth enamel and natural bones, is a good candidate for bone tissue engineering. Synthetic HA is used for making coatings on metallic implants intended for medical applications. A HA coating renders the implant biocompatible and osteoinductive. In addition, it improves fixation and the overall performance of the implanted object. In the present work, HA coatings were deposited on a medical titanium alloy implant with mesh geometry and a developed surface by detonation spraying. The feedstock powder was HA obtained by the dry mechanochemical method. Single-phase HA coatings were obtained. The coatings were formed not only on the surfaces normal to the particle flow direction, but also on the sides of the mesh elements. Despite partial melting of the powder, no decomposition of HA occurred. This work demonstrates the prospects of detonation spraying for the production of HA coatings on metallic implants with complex geometries.

The Association of Body Mass Index with Outcomes after Carotid Endarterectomy.

BACKGROUND: Patients who are obese or underweight are traditionally at higher risk for perioperative morbidity and mortality. The effect of body mass index (BMI) on outcomes after carotid endarterectomy (CEA) is unclear. Our goal was to analyze the association of BMI with perioperative and long-term outcomes after elective CEA. METHODS: The Vascular Quality Initiative (VQI) database was queried from 2003-2018 for patients undergoing elective CEAs. Patients were categorized into 5 BMI cohorts - underweight (UW, BMI < 18.5 kg/m2), normal weight (NW, BMI 18.5-24.9 kg/m2), overweight (OW, BMI 25-29.9 kg/m2), obese (OB, BMI 30-39.9 kg/m2), and morbidly obese (MO, BMI ≥ 40 kg/m2). Perioperative and long-term outcomes were assessed with univariable and multivariable analyses. RESULTS: There were 89,079 patients included: 2% UW, 26% NW, 38.4% OW, 29.9% OB, and 3.6% MO. Overall, the mean age was 70.6 years, 60% were male, and 91.8% were of white race. There were significant differences among the BMI cohorts in regards to age, sex, smoking status, and comorbidities (all P < 0.05). For perioperative outcomes, the BMI cohorts differed significantly in reoperation for bleeding and 30-day mortality. On multivariable analysis, BMI was not associated with stroke or perioperative mortality. MO was associated with perioperative cardiac complications (Odds Ratios [OR] 1.26, 95% CI 1-1.57, P = 0.05). UW status was associated with increased return to the operating room (OR 1.89, 95% confidence interval [95% CI] 1.28-2.78, P = 0.001), 30-day mortality (OR 1.68, 95% CI 1-2.86, P =0.05), 1-year mortality (Hazard ratio [HR] 1.37, 95% CI 1.08-1.74, P = 0.01), and 5-year mortality (HR 1.22, 95% CI 1.06-1.41, P =0.005). CONCLUSIONS: BMI status was not associated with perioperative stroke, cranial nerve injury, or surgical site infections. Patients with MO had higher perioperative cardiac complications. UW patients have lower short and long-term survival and should be a focus for long-term targeted risk factor stratification and modification.