Implementation of a Vascular Acute Care Surgery Service Model is Associated with Decreased Surgeon Burnout.

Vascular surgeons have one of the highest rates of burnout among surgical specialties, often attributed to high patient acuity and clinical workload. Acute Care Surgery (ACS) models are a potential solution used among general and trauma surgeons. This is a retrospective analysis of prospectively collected Accreditation Council for Graduate Medical Education (ACGME) survey results from faculty and residents before and after implementation of a vascular ACS (VACS) model. The VACS model assigns a weekly rotation of an attending surgeon with no elective cases or clinic responsibilities and a monthly rotating resident team. Residents and attendings are in-house to cover all urgent and emergent vascular daytime consultations and procedures, while nights and weekend coverage remain a typical rotating schedule. Survey question results were binned into domains consistent with the Maslach Burnout Inventory (MBI). Both residents and faculty reported an increase in median scores in MBI domains of Emotional Exhaustion (Faculty:2.9 vs. 3.4, p<0.001; Residents:3.1 vs. 3.6, p<0.001) and faculty reported higher Personal Accomplishment scores (Faculty:3.3 vs. 3.8, p=0.005) after the VACS model implementation. A VACS model is a tangible practice change that can address a major problem for current vascular surgeons as it is associated with decreased burnout for faculty and residents through improvement in both emotional exhaustion and personal accomplishment. Improved longitudinal assessment of resident and faculty burnout is needed and future work should identify specific practice patterns related to decreased burnout.

Stenting of a hepatic artery pseudoaneurysm rupture secondary to a celiac artery dissection.

Hepatic artery (HA) pseudoaneurysm rupture is a rare and potentially lethal pathology. We present the case of a celiac artery dissection complicated by an HA pseudoaneurysm rupture that was treated successfully with endovascular stenting. The patient's postoperative course was uncomplicated, and he was further evaluated for an underlying connective tissue disorder. There is no standard treatment for a ruptured HA pseudoaneurysm, although transarterial embolization is most frequently reported. This report demonstrates that self-expanding stent grafts are effective in the emergent repair of HA pseudoaneurysm rupture.

Early Financial Outcomes of Physician Modified Endograft Programs are Dictated by Device Cost.

INTRODUCTION: Physician-modified endografts (PMEGs) have been used for repair of thoracoabdominal aortic aneurysms (TAAAs) for 2 decades with good outcomes but limited financial data. This study compared the financial and clinical outcomes of PMEGs to the Cook Zenith-Fenestrated (ZFEN) graft and open surgical repair (OSR). METHODS: A retrospective review of financial and clinical data was performed for all patients who underwent endovascular or OSR of juxtarenal aortic aneurysms and TAAAs from January 2018 to December 2022 at an academic medical center. Clinical presentation, demographics, operative details, and outcomes were reviewed. Financial data was obtained through the institution's finance department. The primary end point was contribution margin (CM). RESULTS: Thirty patients met inclusion criteria, consisting of twelve PMEG, seven ZFEN, and eleven open repairs. PMEG repairs had a total CM of -$110,000 compared to $18,000 for ZFEN and $290,000 for OSR. Aortic and branch artery implants were major cost-drivers for endovascular procedures. Extent II TAAA repairs were the costliest PMEG procedure, with a total device cost of $59,000 per case. PMEG repairs had 30-d and 1-y mortality rates of 8.3% which was not significantly different from ZFEN (0.0%, P = 0.46; 0.0%, P = 0.46) or OSR (9.1%, P = 0.95; 18%, P = 0.51). Average intensive care unit and hospital stay after PMEG repairs were comparable to ZFEN and shorter than OSR. CONCLUSIONS: Our study suggests that PMEG repairs yield a negative CM. To make these cases financially viable for hospital systems, device costs will need to be reduced or reimbursement rates increased by approximately $8800.

Obese patients with CEAP (clinical, etiology, anatomy, pathophysiology) C2 and C3 disease show enhanced symptom improvement after endovenous thermal ablation.

OBJECTIVE: Endovenous thermal ablation (EVTA) is a prevalent treatment option for patients with severe venous disease. However, the decision to intervene for patients with less severe disease (CEAP [clinical, etiology, anatomy, pathophysiology] C2 and C3) is less clear and becomes further complicated for patients with obesity, a pathology known to increase venous disease symptom severity. Therefore, the objective of this study was to use the Society for Vascular Surgery Vascular Quality Initiative database to evaluate outcomes after EVTA in obese patients with CEAP C2 and C3 venous insufficiency. METHODS: Using the Society for Vascular Surgery Vascular Quality Initiative database, we retrospectively analyzed the initial procedure of all patients with a CEAP clinical class of C2 or C3 who underwent EVTA from January 2015 to December 2021. Patients were grouped by obesity, defined as a body mass index of ≥30 kg/m2. The primary outcome was the change in venous clinical severity score (VCSS) from the procedure to the patient's initial follow-up. The secondary outcomes included the change in patient-reported outcomes at follow-up via the HASTI (heaviness, achiness, swelling, throbbing, itching) score, incidence of follow-up complications, and recanalization of treated veins. The change in the VCSS and HASTI score were analyzed using Student t tests, and complications and recanalization were assessed using the Fisher exact test. Significant outcomes were confirmed by multiple variable logistic regression. The remaining significant variables were then analyzed, with obesity categorized using the World Health Organization classification system to analyze how increasing obesity levels affect outcomes. RESULTS: There were 8146 limbs that met the inclusion criteria, of which 5183 (63.6%) were classified as nonobese and 2963 (36.4%) as obese. Obesity showed no impact on improvement in the VCSS (-3.29 vs -3.35; P = .408). Obesity was found to be associated with a larger improvement in overall symptoms, as evidence by a greater improvement in the HASTI score (-7.24 vs -6.62; P < .001). Obese limbs showed a higher incidence of superficial phlebitis (1.5% vs 0.7%; P = .001), but no difference was found in recanalization or any other complication. CONCLUSIONS: These data suggest that obese patients with CEAP clinical class C2 or C3 experience greater improvement in their perceived symptoms after EVTA with little difference in clinical improvement and complications compared with nonobese patients. Although obesity has been associated with increased severity of venous disease symptoms, obese patients are able to derive significant relief after treatment during the short term and may experience greater relief of symptoms than nonobese patients when treated at more mild disease presentations.

Strategies to reduce rates of severe endothermal heat-induced thrombosis following radiofrequency ablation.

OBJECTIVE: Endothermal heat-induced thrombosis (EHIT) is a potential complication of radiofrequency ablation (RFA). Data on effective prophylaxis of EHIT are limited. In 2018, a high-volume, single institution implemented strategies to decrease the incidence of EHIT, including a single periprocedural prophylactic dose of low-molecular-weight heparin to patients with a great saphenous vein (GSV) diameter of ≥8 mm or saphenofemoral junction (SFJ) diameter of ≥10 mm and limiting treatment to one vein per procedure. The size threshold was derived from existing literature. The study objective was to evaluate the effects of these institutional changes on thrombotic complication rates after RFA. METHODS: A retrospective cohort control study was conducted using the Vascular Quality Initiative database. Data were collected for patients who underwent RFA with a GSV diameter of ≥8 mm or SFJ diameter of ≥10 mm from January 2015 to July 2022. The clinical end points were thrombotic complications (ie, thrombophlebitis, EHIT, deep vein thrombosis) and bleeding complications. Patient demographic and procedural variables were included in the analysis, and significant variables after univariable logistic regression were included in a multivariable logistic regression. RESULTS: After the policy change, the overall vein center EHIT rate decreased from 2.6% to 1.5%, with a trend toward significance (P = .096). The inclusion criterion of a GSV diameter of ≥8 mm or an SFJ diameter of ≥10 mm yielded 845 patients, of whom 298 were treated before the policy change and 547 after. There was a significant reduction in the rate of EHIT classified as class ≥III (2.34 vs 0.366; P = .020) after the institutional changes. Treatment of two or more veins and an increased vein diameter were associated with an increased risk of EHIT (P = .049 and P < .001, respectively). No significant association was found between periprocedural anticoagulation and all-cause thrombotic complications or EHIT (P = .563 and P = .885, respectively). CONCLUSIONS: The institutional policy changes have led to lower rates of EHIT, with a reduction in severe EHIT rates in patients with an ≥8-mm diameter GSV or a ≥10-mm diameter SFJ treated with RFA. Of the changes implemented, restricting treatment to one vein was associated with a reduction in severe EHIT. No association was found with periprocedural low-molecular-weight heparin, although a type 2 error might have occurred. Alternative strategies to prevent thrombotic complications should be explored, such as increasing the dosage and duration of periprocedural anticoagulation, antiplatelet use, and nonpharmacologic strategies.

Survival, Reintervention, and Value of Open and Endovascular Repair for Chronic Mesenteric Ischemia.

BACKGROUND: There are limited analyses of survival and postoperative outcomes in chronic mesenteric ischemia (CMI) using data from large cohorts. Current guidelines recommend open repair (OR) for younger, healthier patients when long-term benefits outweigh increased perioperative risks or for poor endovascular repair (ER) candidates. This study investigates whether long-term survival, reintervention, and value differ between these treatment modalities. METHODS: A retrospective cohort analysis was performed on data extracted from the Statewide Planning and Research Cooperative System, the New York statewide all-payer database containing demographics, diagnoses, treatments, and charges. Patients were selected for CMI and subsequent ER or OR using International Classification of Diseases, Ninth Revision codes. Patients with peripheral arterial disease were excluded to account for ambiguity in the International Classification of Diseases, Ninth Revision procedure code for angioplasty of noncoronary vessels, which includes angioplasty of upper and lower extremity vessels. Kaplan-Meier analysis was used to compare 1-year and 5-year survival and reintervention between treatment modalities using a propensity-matched cohort. Cox proportional hazards testing was performed to find factors associated with 1-year and 5-year survival and reintervention. Analysis of procedural value was performed using linear regression. RESULTS: From 2000 to 2014, 744 patients met inclusion criteria. Of these, 209 (28.1%) underwent OR and 535 (71.9%) ER. No difference between propensity-matched groups was found in 1-year (P = 0.46) or 5-year (P = 0.91) survival. Congestive heart failure (hazard ratio [HR]: 2.8, 95% confidence interval [CI]: 1.7-4.4; P < 0.01), cancer (HR: 2.8, 95% CI: 1.3-5.8; P < 0.01), and dysrhythmia (HR: 1.8, 95% CI: 1.1-2.8; P = 0.02) correlated with 1-year mortality. Cancer (HR: 2.9, 95% CI: 1.6-5.5; P < 0.01), congestive heart failure (HR: 2.2, 95% CI: 1.5-3.2; P < 0.01), chronic pulmonary disease (HR: 1.4, 95% CI: 1.0-2.0; P = 0.04), and age (HR: 1.03, 95% CI: 1.01-1.05; P < 0.01) correlated with 5-year mortality. Treatment modality was not associated with reintervention at 1 year on Kaplan-Meier analysis (P = 0.29). However, ER showed increased instances of reintervention at 5 years (P < 0.01). Additionally, ER was associated with an increased 5-year value (0.7 ± 0.9 vs. 0.5 ± 0.5 life years/charges at index admission [$10k], P < 0.01; b coefficient: 0.2, 95% CI: 0.1-0.4, P < 0.01). CONCLUSIONS: This is the largest retrospective propensity-matched single-study cohort to analyze long-term survival outcomes after intervention for CMI. Long-term mortality was independent of treatment modality and rather was associated with patient comorbidities. Therefore, treatment selection should depend on anatomic considerations and long-term value. ER should be considered over OR in patients with amenable anatomy based on the superior procedural value.

Guideline Compliant Minimum Asymptomatic Carotid Endarterectomy Surgeon and Hospital Volume Cutoffs.

BACKGROUND: There is a known association between volume and outcomes after carotid endarterectomy (CEA). A recent analysis suggested rates of stroke and death do not significantly reduce after a surgeon volume cutoff of 20 CEAs per year. However, these results would severely limit access. The objective here is to identify a lower optimal cutpoint for surgeon and hospital volume for asymptomatic CEA. METHODS: We evaluated asymptomatic CEA patients using The New York Statewide Planning and Research Cooperative System database from 2000-2014. The relationship of 3-year averaged volumes for surgeons and hospitals to 30-day stroke was assessed using multiple logistic regression and included both hospital and surgeon volume in all analyses. Optimized cut points were the lowest significant volume cutoff that minimized the adjusted odds ratio of stroke. RESULTS: We studied 32,549 CEAs performed by 271 surgeons in 136 centers by vascular surgeons. The median surgeon volume was 26.3 (interquartile range: 12.3-51.7) and the median hospital volume was 67 (interquartile range: 36.3-119.3). The surgeon volume cut point was 3 and the hospital volume cut point was 6 cases per year. There were 756 (2.3%) procedures performed by surgeons with a volume < 3 and 560 (1.7%) procedures performed by hospitals with a volume < 6. Perioperative stroke and death rates were 2.0% (95% confidence interval [CI]: 1.8-2.1) and 3.8% (95% CI: 2.6-5.5) for an average yearly surgeon volume ≥ 3 and < 3 (P = 0.070), respectively. The combined stroke and death rate was 2.0% (95% CI: 1.8-2.1) and 4.8% (95% CI: 3.2-7.0) for an average yearly center volume ≥ 6 and < 6 (P = 0.007), respectively. A combined surgeon and hospital volume variable also predicted outcomes and low-volume procedures did not meet previously proposed American Heart Association and Society for Vascular Surgery quality measures. CONCLUSIONS: These data demonstrate an improvement in outcomes at a lower volume threshold than previously reported. These modest cutoff values should be used for asymptomatic CEA volume guideline formation and for future studies, after accounting for the impact of other important factors that may be driving volume-outcome relationships in asymptomatic CEA.

Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart.

The developing mammalian heart undergoes an important metabolic shift from glycolysis toward mitochondrial oxidation, such that oxidative phosphorylation defects may present with cardiac abnormalities. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mice with systemic loss of the mitochondrial citrate carrier SLC25A1. Slc25a1 null embryos displayed impaired growth, cardiac malformations, and aberrant mitochondrial function. Importantly, Slc25a1 haploinsufficient embryos, which are overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 dose-dependent effects. Supporting clinical relevance, we found a near-significant association between ultrarare human pathogenic SLC25A1 variants and pediatric congenital heart disease. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of PPARγ to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of ventricular morphogenesis and cardiac metabolic maturation and suggests a role in congenital heart disease.

Neither cardiac mitochondrial DNA variation nor copy number contribute to congenital heart disease risk.

The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtDNA mutations were identified in 1,837 CHD-affected proband-parent trios, 116 CHD-affected singletons, and 114 paired cardiovascular tissue/blood samples. The variant allele fraction (VAF) of heteroplasmic variants in mitochondrial RNA from 257 CHD cardiovascular tissue samples was also calculated. On average, mtDNA from blood had 0.14 rare variants and 52.9 mtDNA copies per nuclear genome per proband. No variation with parental age at proband birth or CHD-affected proband age was seen. mtDNAcns in valve/vessel tissue (320 ± 70) were lower than in atrial tissue (1,080 ± 320, p = 6.8E-21), which were lower than in ventricle tissue (1,340 ± 280, p = 1.4E-4). The frequency of rare variants in CHD-affected individual DNA was indistinguishable from the frequency in an unaffected cohort, and proband mtDNAcns did not vary from those of CHD cohort parents. In both the CHD and the comparison cohorts, mtDNAcns were significantly correlated between mother-child, father-child, and mother-father. mtDNAcns among people with European (mean = 52.0), African (53.0), and Asian haplogroups (53.5) were calculated and were significantly different for European and Asian haplogroups (p = 2.6E-3). Variant heteroplasmic fraction (HF) in blood correlated well with paired cardiovascular tissue HF (r = 0.975) and RNA VAF (r = 0.953), which suggests blood HF is a reasonable proxy for HF in heart tissue. We conclude that mtDNA mutations and mtDNAcns are unlikely to contribute significantly to CHD risk.

Surgeon volume and established hospital perioperative mortality rate together predict for superior outcomes after open abdominal aortic aneurysm repair.

BACKGROUND: In 2018, the Society for Vascular Surgery (SVS) published hospital volume guidelines for elective open abdominal aortic aneurysm (AAA) repair, recommending that elective open surgical repair of AAAs should be performed at centers with an annual volume of ≥10 open aortic operations of any type and a documented perioperative mortality of ≤5%. Recent work has suggested a yearly surgeon volume of at least seven open aortic cases for improved outcomes. The objective of the present study was to assess the importance of hospital volume and surgeon volume at these cut points for predicting 1-year mortality after open surgical repair of AAAs. METHODS: We evaluated patients who had undergone elective open AAA repair using the New York Statewide Planning and Research Cooperative System database from 2003 to 2014. The effect of the SVS guidelines on postoperative mortality and complications was evaluated. Confounding between the hospital and surgeon volumes was identified using mixed effects multivariate Cox proportional hazards analysis. The effect of the interactions between hospital volume, established hospital perioperative survival, and surgeon volume on postoperative outcomes was also investigated. RESULTS: The cohort consisted of 7594 elective open AAA repairs performed by 542 surgeons in 137 hospitals during the 12-year study period. Analysis of the 2018 guidelines using the Statewide Planning and Research Cooperative System database revealed 1-year and 30-day mortality rates of 9.2% (range, 8.3%-10.1%) and 3.5% (range, 2.9%-4.1%) for centers that were within the SVS guidelines and 13.6% (range, 12.5%-14.7%) and 6.9% (range, 6.1%-7.8%) for those that were outside the guidelines, respectively (P < .001 for both). Multivariate survival analysis revealed a hazard ratio for a surgeon volume of ≥7, hospital volume of ≥10, and hospital 3-year perioperative mortality of ≤5% of 0.80 (95% confidence interval [CI], 0.70-0.93; P = .003), 0.91 (95% CI, 0.77-1.08; P = .298), and 0.72 (95% CI, 0.62-0.82; P < .001), respectively. Additionally, procedures performed by surgeons with a yearly average volume of open aortic operations of at least seven and at hospitals with an established elective open AAA repair perioperative mortality rate of ≤5% showed improved 1-year (33.2% relative risk reduction; P < .001) and 30-day (P = .001) all-cause survival and improved postoperative complication rates. CONCLUSIONS: These data have demonstrated that centers that meet the SVS AAA volume guidelines are associated with improved 1-year and 30-day all-cause survival. However, the results were confounded by surgeon volume. A surgeon open aortic volume of at least seven procedures and an established hospital perioperative mortality of ≤5% each independently predicted for 1-year survival after open AAA repair, with the hospital volume less important. These results indicate that surgeons with an annual volume of at least seven open aortic operations of any type should perform elective open AAA repair at centers with a documented perioperative mortality of ≤5%.

A Reappraisal of CT Angiography Derived Duplex Ultrasound Velocity Criteria With a Comparison to Digital Subtraction Angiography in Patients With Carotid Artery Stenosis.

BACKGROUND: Traditionally, carotid duplex ultrasound (CDUS) velocity criteria have been derived from angiography. Recent studies support a shift toward computed tomography angiography (CTA) derived velocity criteria; however, they lack a comparison to angiography. The purposes of this study are to validate CTA derived measurements with digital subtraction angiography (DSA) and to update our previous CTA-derived velocity criteria for 50% and 80% stenosis. METHODS: All patients between 2010 and 2019 who underwent CDUS and a neck CTA within 6 months were identified for a retrospective review. Vessel diameter and corresponding CDUS data were recorded. Additional DSA measurements were recorded for a subset of patients. Data from this cohort were added to a previously reported deidentified data set from patients between 2000 and 2009. Receiver operating characteristic (ROC) curves were generated to determine optimal velocity thresholds. Spearman rank correlation was used to correlate measurements obtained by CTA to those obtained by DSA. RESULTS: A total of 1139 vessels from 636 patients were analyzed. ROC analysis to identify ≥ 50% stenosis resulted in optimized thresholds of 143 cm/sec, 46.2 cm/sec, and 2.15 for peak systolic velocity (PSV), end-diastolic velocity (EDV), and PSV to common carotid artery PSV ratio (PSVR), respectively. ROC analysis to identify ≥ 80% stenosis resulted in optimized thresholds of 319 cm/sec, 87.2 cm/sec, and 3.49 for PSV, EDV, and PSVR, respectively. The degree of carotid artery stenosis for a subset of 124 vessels on CTA correlated well with that of DSA (ρ = 0.89, P< 0.0001). CONCLUSIONS: These data demonstrate a high correlation between measurements obtained on CTA and DSA while forming reliable CTA-derived CDUS velocity criteria.

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

One-year patient survival correlates with surgeon volume after elective open abdominal aortic surgery.

OBJECTIVE: Volume-outcome relationships in surgery have been well established. Studies have shown that high-volume surgeons provide improved outcomes in performing open abdominal aneurysm repairs. The hypothesis of this study was that high-volume surgeons provide superior short-term and midterm outcomes of elective open aortic operations compared with low-volume surgeons. METHODS: We evaluated patients undergoing elective open abdominal aortic aneurysm repair, aortofemoral bypass, and aortomesenteric bypass by board-certified vascular surgeons using the New York Statewide Planning and Research Cooperative System database from 2002 to 2014. The Contal and O'Quigley technique was used to estimate a cut point objectively and provided an estimate of significance. A division using average yearly volumes (averaged during 3 years) of seven or more cases and fewer than seven cases per year returned the highest Q statistic, and this grouping was used to classify high-volume and low-volume provider groups. Rates of complications during index hospitalization, length of stay, 30-day survival, 90-day survival, 1-year survival, and cause of death were analyzed using mixed effect models. RESULTS: In 118 hospitals during the 13-year period, 266 board-certified vascular surgeons performed 244 aortomesenteric bypasses, 4202 aortofemoral bypasses, and 6126 abdominal aortic aneurysm repairs. High-volume surgeons' rates of complications during index hospitalization, 30-day survival, 90-day survival, and 1-year survival were superior to those of low-volume surgeons. The Contal and O'Quigley technique returned an estimate of seven operations per year for optimal survival during 1 year. This cutoff is associated with an adjusted 1-year hazard ratio of 0.687 (P = .003), a 2.69% difference in 1-year all-cause survival (P = .003), and a 1.76-day reduction in the mean length of stay at index hospitalization (P < .001). Higher volume surgeons showed a 25.0%, 43.4%, 42.4%, 40.6%, and 45.0% reduction in postoperative rates of acute renal failure (P < .001), hemorrhage (P < .001), pulmonary failure (P < .001), sepsis (P < .001), and venous thromboembolism (P < .001), respectively. Abdominal abscess, acute renal failure, hemorrhage, myocardial infarction, and sepsis were associated with increased cardiovascular cause-specific mortality after open aortic operations (P < .001). CONCLUSIONS: These data demonstrate that high-volume surgeons performing elective open aortic operations provide reduced complications and improved short-term and midterm survival compared with low-volume surgeons. Clinical and postoperative variables that are associated with increased cardiovascular cause-specific mortality are also identified. These data provide further evidence that elective open abdominal vascular surgery should be centralized to high-volume surgeons.

Association Between the Atherosclerotic Disease Risk Score and Carotid Artery Stenosis.

BACKGROUND: Carotid artery stenosis (CAS) is the most frequently detected treatable cause of ischemic stroke. However, there are no recommendations to screen asymptomatic patients. The atherosclerotic cardiovascular disease (ASCVD) risk score estimates individuals' 10-year risk for developing cardiovascular disease. The objective of this study is to identify a relationship between the ASCVD risk score and moderate/severe CAS based on ultrasound findings. MATERIALS AND METHODS: We performed a single-institution retrospective review of patients who underwent a surveillance ultrasound for CAS between 2015 and 2018. We used Strandness velocity criteria to separate patients into two cohorts: none to mild CAS (<50%) and moderate/severe CAS (≥50%). We performed Student's t-test, multivariate analysis, and receiver operator characteristic (ROC) curve analysis to determine a relationship between the ASCVD risk score and degree of CAS. We evaluated a new risk score model based on stepwise logistic regression of significant variables on univariate analysis. RESULTS: Two thousand eight hundred and fifty-six patients with carotid ultrasounds (1623 with none to mild, 1161 with moderate, and 72 with severe disease) were included in the study. The ASCVD risk score significantly predicted moderate/severe CAS in an adjusted multivariate analysis. Each 10% increase in the ASCVD risk score corresponded to an additional 11% likelihood of moderate/severe stenosis (OR: 1.11 [1.04-1.20], P = 0.004). The ROC area under the curve for predicting moderate/severe CAS based on the ASCVD risk score was 0.59 (Youden index (J) = 0.14); the optimized ASCVD cutoff point was 28.4%. Our new atherosclerotic disease model demonstrated increased odds of moderate/severe CAS with scores greater than zero (ROC area under the curve = 0.57). CONCLUSIONS: This is the first study to demonstrate an association between atherosclerotic disease risk factors as measured by the ASCVD risk score and moderate/severe CAS. However, this tool is not sensitive or specific for using the ASCVD risk score as a screening mechanism for moderate/severe CAS.

Genetic analysis of neurodegenerative diseases in a pathology cohort.

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

TUBB2B Mutation in an Adult Patient with Myoclonus-Dystonia.

BACKGROUND: Tubulin mutations are a cause of neuronal migrational disorders referred to as tubulinopathies. Mutations in tubulin genes can have a severe impact on microtubule function and result in heterogeneous clinical presentations. Current understanding of the clinical spectrum of tubulinopathies is predominantly based on research in fetal tissue and early-childhood cases. METHODS: Testing of candidate genes followed by whole-exome sequencing was performed in an adult woman with a neurodevelopmental, hyperkinetic movement disorder, to identify the underlying genetic cause. Bioinformatic modeling and a systematic review of literature was conducted to investigate genotype-phenotype correlations. RESULTS: The patient was found to carry a heterozygous, de novo c.722G>A, p.R241H mutation in a conserved domain of TUBB2B, encoding the ß-isoform of tubulin. In silico analysis indicated that this mutation was pathogenic. On neuroimaging, the patient had asymmetric pachygyria and dysmorphic basal ganglia. Her neurological examination demonstrated mild cognitive impairment, myoclonus-dystonia, and skeletal anomalies. CONCLUSIONS: Here, we report the unique phenotype of an adult TUBB2B mutation carrier. This case illustrates a relatively mild phenotype compared to previously described fetal and early childhood cases. This highlights the importance of obtaining molecular genetic testing in individuals with a high probability of a genetic disease, including undiagnosed adult patients.

NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases.

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.

Projected increase in amyotrophic lateral sclerosis from 2015 to 2040.

Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources.