Crosstalk between NLRP3 inflammasome and calpain in Alzheimer's disease.

Amyloid plaques are considered to be the pathological hallmark of Alzheimer's disease (AD). Neuroinflammation further aggravates the pathogenesis of Alzheimer's disease. Calpains and NOD-like receptor protein-3 (NLRP3) inflammasomes are involved in the neuroinflammatory pathway and affect the progression of Alzheimer's disease. Hyperactivation of calpains is responsible for the activation of NLRP3 inflammasome, thereby affecting each other's molecular mechanism and causing astrogliosis, microgliosis, and neuronal dysfunction. Further, calpain hyperactivation is also associated with calcium homeostasis that acts as one of the triggers in the activation of NLRP3 inflammasome. Calpain activity is required for the maturation of interleukin-1ß, a key mediator of neuroinflammatory responses. The membrane potential/calcium/calpain/caspase-1 axis acts as an unconventional regulator of inflammasomes. The complex crosstalk between NLRP3 inflammasome and calpain leads to a series of events. Targeting the molecular mechanism associated with calpain-NLRP3 inflammasome activation and regulation can be a therapeutic and prophylactic perspective towards Alzheimer's disease. This review discusses calpains and NLRP3 inflammasome crosstalk in the pathogenesis of AD.

Carrollian Origins of Bjorken Flow.

Bjorken flow is among the simplest models of fluids moving near the speed of light (c), while Carroll symmetry arises as a contraction of Poincaré group when c→0. We show that Bjorken flow and its phenomenological approximations are completely captured by Carrollian fluids. Carrollian symmetries arise on generic null surfaces, and a fluid moving at c is restricted to such a surface, thereby naturally inheriting the symmetries. Carrollian hydrodynamics is, thus, not exotic, but rather ubiquitous, and provides a concrete framework for fluids moving at or near the speed of light.

Safety outcomes of pembrolizumab with platinum agent chemotherapy combined with 5-fluorouracil or taxane derivative in head and neck cancer.

INTRODUCTION: For patients with metastatic head and neck squamous cell cancer (HNSCC), the outcomes of pembrolizumab in combination with a platinum agent and taxane as first-line therapy remain unknown. The purpose of this study is to characterize the impact of substituting the 5-fluorouracil (5-FU) backbone for a taxane in this chemoimmunotherapy regimen on safety/tolerability and survival outcomes. METHODS: This was an IRB-approved, single-center, retrospective, active comparator, new-user design study in adult patients with HNSCC treated between January 2018 and September 2021. The primary objective was to assess safety and tolerability of pembrolizumab in combination with a platinum agent and taxane against an active comparator arm of pembrolizumab in combination with a platinum agent and 5-FU. Safety and tolerability were evaluated by assessing differences in overall toxicities, with further secondary analysis evaluating differences in hematologic toxicities and pre-defined non-hematologic toxicities. RESULTS: There was no statistical difference demonstrated with the primary endpoint between the cohorts. Reduced toxicity rates were found in the taxane arm for mucositis and creatinine levels. No grade 4 non-hematologic toxicities were reported. Patients receiving 5-FU were more likely to have dose reductions upfront, discontinue treatment due to intolerances and had significantly higher mucositis. CONCLUSIONS: This study helps to characterize the safety profile and activity of pembrolizumab in combination with a platinum agent and taxane derivative in HNSCC patients. Within our study, substitution of 5-FU with a taxane did not show an increased risk of toxicities, worsened survival, or decreased odds of achieving a response. Mucositis and elevated creatinine rates were significantly reduced within the taxane arm.

Carotid artery dissections from transcarotid artery revascularization as reported by the Food and Drug Administration.

OBJECTIVES: Transcarotid artery revascularization (TCAR) is a hybrid procedure that allows reversal of blood flow away from the brain while placing a stent through direct surgical access of the common carotid artery. It has been shown to have a lower risk of perioperative stroke compared with any prospective trial of transfemoral carotid artery stenting. However, intraoperative injuries related to the procedure and its management are not well characterized. One of the intraoperative complications seen in TCAR is iatrogenic carotid artery dissection (CD). We aim to add qualitative insight in further characterizing CDs and its management in this emerging technology. METHODS: The Food and Drug Administration (FDA) maintains the Manufacturer and User Facility Device Experience (MAUDE) database for surveillance of all medical devices approved for use. This database was queried for all cases associated with Silk Road Medical's ENROUTE Transcarotid Neuroprotection System from September 2016 to October 2020. Case narratives related to CD were individually analyzed to determine time of injury (intraoperative, recovery, and post-discharge follow-up). CD reporting was further analyzed for the associated procedural event at the time of injury, number of access attempts to CD repair, and type of CD repair. Reports associated with CD repair were further categorized into endovascular repair and open surgical repair. RESULTS: Of the 115 unique adverse events in the database, there were 58 CDs. Most were identified intraoperatively (n = 55), while three were incidentally found postoperatively. Overall, sheath placement was the most common procedural event attributed to CD (N = 34). There was adequate narrative information about CD repair in 54 patients. Intraoperative repair was performed in 52 cases and two were repaired after post-discharge follow-up imaging was performed.Among CDs that did not require additional access to engage the true lumen, the proportion of endovascular repair (62.5%) was significantly higher (p = .044) compared to the proportion of open surgical repair (37.5%). However, the proportion of open surgical repair (75%) was significantly higher than the proportion of endovascular repair (25%) in CDs with persistent failure to engage the true lumen despite ≥2 access attempts (p = .039). CONCLUSION: CD is the most common injury related to TCAR as reported on MAUDE. The most commonly reported procedural event associated with CD was sheath placement. The rate of intraoperative endovascular and open surgical CD repair was associated with whether the access to the true lumen of the carotid artery required additional access attempts or not. This should add qualitative insight among the vascular surgery community regarding intraoperative management of CDs from a TCAR procedure.

Gender trends of authors presenting at a regional vascular surgery meeting.

OBJECTIVE: We hypothesized a potential gender disparity within a regional society like the Southern Association of Vascular Surgery (SAVS) when compared with vascular surgery demographics in the region. To assess this, we analyzed meeting and membership participation at the SAVS compared with regional data from the Society of Vascular Surgery as well as board certification in vascular surgery published by the American Board of Surgery (ABS). METHODS: The published programs from the SAVS Annual Meeting from 2012 to 2019 were analyzed for membership, presenter gender, type, topic, discussant gender, moderator gender, postgraduate course presenter gender, and manuscript publication demographics. The ABS was petitioned and yearly Vascular Surgery diplomate (ABS-VS) gender from member states of the SAVS was examined for the same period. Fisher's exact Student's t-test and analysis of covariance were used. RESULTS: There were 257 total presentations (184 podium, 71.6%; 73 poster, 28.4%). A total of 61.4% (n = 43) of presentations by females were podium presentations, compared with 75.4% (n = 141) by males (P = .03). Females were less likely to be published when compared with their male counterparts (41.8% vs 58.7%, P = .02). The percentage of female gendered presenters statistically increased over the time period examined compared with a decrease in male presenters (R2 = 0.61, m = 1.27 vs R2 = 0.08, m = -0.35, P = .02). Female presenters had a female discussant 10.5% of the time compared with male presenters who had a male discussant 95.1% of the time (P < .0001). Females comprised 3.8% ± 1.1% of SAVS yearly membership compared with 12.0% ± 4.6% ABS-VS diplomates among SAVS member states (P < .0001). SAVS female membership significantly lagged behind the increase in ABS-VS female diplomate rate (P = .001). Only 39.1% of SAVS members were cross-listed in Society of Vascular Surgery membership rolls, with a total of 464 potential SAVS members, 11.2% or 52 of whom are female. CONCLUSIONS: We found that female presenters at the SAVS Annual Meeting were less likely to be podium presenters, interface with other female discussants, and publish manuscripts when compared with their male counterparts. Statistically, female members were underrepresented within the SAVS membership rolls when compared with known boarded female vascular surgeons among southern member states. This gender gap highlights a unique opportunity to enhance and potentially increase mentorship opportunities for female trainees who are presenting and/or attending this regional vascular surgery meeting.

Using the risk analysis index to assess frailty in a veteran cohort undergoing endovascular aortic aneurysm repair.

OBJECTIVE: Surgical frailty is strongly associated with increased perioperative morbidity and mortality. The risk analysis index (RAI) is a validated frailty score system, which has been shown to predict for short-term outcomes and long-term mortality in various surgical subspecialties. In the present study, we applied the frailty score to a veteran aneurysm population who had undergone nonemergent endovascular aortic aneurysm repair (EVAR). METHODS: After obtaining institutional review board approval, the Veteran Affairs Surgical Quality Improvement Program data were queried for endovascular repair of infrarenal abdominal aortic aneurysm or dissection using the Current Procedural Terminology codes 34,800, 34,803, and 34,805 from 2001 to 2018. The preoperative variables were used to calculate the RAI score. The patients were placed into six cohorts according to the RAI score (≤20, 21-25, 26-30, 31-35, 35-40, and ≥41). The χ2 test and analysis of variance test were used compare the cohorts. Forward logistic regression modeling was used to determine the risks of each cohort. RESULTS: From 2001 to 2018, 5568 patients had undergone EVAR. Of the 5568 patients, 99.6% were male, with a mean age of 71 ± 8 years. Of these patients, 4.5%, 43.8%, 33.9%, 11.7%, 4.2%, and 1.8% were included in the following RAI groups: ≤20, 21 to 25, 26 to 30, 31 to 35, 35 to 40, and ≥41, respectively. Frailty was associated with increased rates of overall complications, death, and an increased length of stay. When risk adjusted, frailty at the highest vs lowest level was associated with 2.7 times the odds of any complication developing and 4.4 times the odds of mortality ≤30 days. CONCLUSIONS: Frailty, as determined by the RAI, was associated with postoperative outcomes in a dose-dependent manner. Frailty was associated with higher rates of major cardiac (myocardial infarction, cardiac arrest), pulmonary (pneumonia, failure to wean from ventilation, reintubation), renal (renal failure), overall complications, length of stay, and death. We recommend the use of this frailty index as a screening tool to guide discussions with patients scheduled to undergo EVAR.

Assessing Resident Impact on Surgical Outcomes in Below-the-Knee Amputations Based on Operative Autonomy.

BACKGROUND: Gradual increases in resident autonomy with attending physician oversight is crucial to developing safe and competent surgeons1. The Veterans Affairs Surgical Quality Improvement Program (VASQIP) follows surgical outcomes within the VA. We set forth to examine the VASQIP database to compare outcomes between resident independent cases and nonindependent cases during below-the-knee amputations (BKA). METHODS: All VASQIP records for BKA from 2000 to 2020 were examined and categorized based on whether the attending was scrubbed during the case. Case matching was performed based on preoperative comorbidities; 30-day postoperative outcomes, including a return to the operating room, wound infection, and mortality, were assessed in addition to operative time, hospital length of stay, and transfusion requirements. Student's t-test and Fisher's Exact Test were utilized. RESULTS: A total of 13,208 BKA VASQIP records were obtained. After case control matching, 2,688 cases remained. Cases were identified with the attending surgeon noted as being scrubbed during the case (n = 1,344), or not scrubbed (n = 1,344). Patients were similar in comorbidities across both groups. No statistically significant difference in operative time (1.52 hr ± 0.78 vs. 1.47 hr ± 0.75, P = 0.08), 30-day mortality (3.3% vs. 4.8%, P = 0.05), or complication rate (19.5% vs. 21.3%, P = 0.25). Resident independent cases were noted to have slightly longer postop length of stay (12.47 days ± 12.69 vs. 15.33 days ± 20.56, P < 0.01) and operative bleeding requiring more than 4 units transfused (0.3% vs. 1.3%, P ≤ 0.01). CONCLUSIONS: Resident independent operating during below-the-knee amputation at VA hospitals is associated with an increased length of stay and blood transfusion. There was no statistically significant increase in operative time, 30-day mortality, or total complication rate. Further research is required to assess the risks associated with surgical training, resident supervision, and resident preparedness for independent practice.

Elevated Risk Analysis Index (RAI) Frailty Scores Are Independently Associated with Adverse Outcomes in Lower Extremity Surgical Revascularizations Similarly Across Genders.

BACKGROUND: The Risk Analysis Index (RAI) frailty scoring system has recently undergone revision and external validation using the National Surgical Quality Improvement Program (NSQIP) database. We set forth to evaluate the association of RAI-rev ranges with outcomes following lower extremity surgical revascularization and verify equivalent applicability across genders. METHODS: All elective NSQIP Targeted Lower Extremity Open cases from 2015-2019 were divided by EMR-recorded gender. Aggregate demographics, perioperative factors, and 30-day outcomes were compared using unpaired t-test and Fisher's exact test. Adjusted odds-ratios (aOR) for each outcome were generated by applying a multivariate binary logistic regression model (IBM SPSSTM) for five-point RAI-rev score increments from 25-45 and a most-frail group with scores >45 with a non-frail reference of <25. Covariates included surgical indication, prior ipsilateral revascularization, graft utilization, dirty/infected wound, smoking, hypertension, diabetes, and steroid use. RESULTS: 8,155 cases included 2,498 (31%) performed in women who demonstrated slightly lower RAI-rev scores than men (22.1 ± 5.8 vs. 24.2 ± 5.1; P = 0.0001). Univariate trends demonstrated dose-dependent increases in frequency of most outcomes with rising frailty score ranges, most substantially regarding mortality (0.4% non-frail to 14.7% most-frail), disposition to skilled nursing facility (8% non-frail to 27% most-frail), and extended length of stay (16% non-frail to 44% most-frail). After adjusting for co-variates, patients with RAI-rev scores of 26-30 had aOR of 1.4 (95% CI: 1.2-1.6; P < 0.001), 1.9 (95% CI: 1.6-2.2; P < 0.001), and 2.4 (95% CI:1.3-4.4; P < 0.001) for extended stay, disposition to skilled nursing, and mortality respectively. Trends were similar across genders in both univariate and multivariate analyses. CONCLUSIONS: Mortality, extended stay, and increased rehabilitation needs after surgical revascularization were associated with higher RAI-rev score ranges in a dose dependent manner similarly across genders.

Modern Lower Extremity Bypass Outcomes by Anesthesia Type in the Veteran Population.

BACKGROUND: Lower extremity bypass (LEB) revascularization can be performed under general (GA) or neuraxial anesthesia (NA). Studies show that the use of NA may decrease morbidity, 30-day mortality, and hospital length-of-stay (LOS). The goal of our analysis is to examine the differences in postsurgical outcomes following LEB between patients who undergo GA compared to NA in the Veteran Affairs Surgical Quality Improvement Program (VASQIP) database. METHODS: After IRB approval, the VASQIP database was assessed for patients who underwent LEB between 1998-2018. Only infrainguinal bypass procedures and anesthesia type classified as "general," "epidural," or "spinal" were included. The neuraxial cohort includes both spinal and epidural anesthesia patients. The Risk Analysis Index (RAI), a validated measure of frailty, was additionally calculated for each patient. Chi squared, paired t-test, and binary logistic regression were used to compare the cohorts. RESULTS: During this period, 22,960 veterans underwent LEB recorded in VASQIP. Compared to those who underwent surgery under GA, patients with procedures performed using NA were older (66.4 ± 9.6 years vs. 65.3 ± 9 years respectively; P <0.001) and more frail (average RAI score 25.7 ± 7.0 vs. 24.9 ± 6.7; P < 0.001). Operative time was shorter in the NA group (4.1 ± 1.7 hrs vs. 4.7 ± 3.0 hrs; P < 0.001) and fewer cases were emergent (1.55% vs. 4.13%; P <0.001). Patients in the GA group had higher rates of postoperative prolonged ileus (0.31% vs. 0.00%; P = 0.03), pneumonia (1.60% vs. 1.06%; P = 0.025), deep wound infection (2.67% vs. 2.61%; P = 0.01), sepsis (1.68% vs. 0.79%; P < 0.001), reintubation (1.80% vs. 1.30%) (P = 0.04),and number of packed red blood cell (pRBC) transfused intraoperatively (0.39 ± 1.21 units vs. 0.22 ± 0.79 units; P <0.001). There was no significant difference in rate of graft failure, return to the OR, myocardial infarction, death, or LOS. In regression analysis, those undergoing NA were less likely to require pRBC transfusion intraoperatively (OR: 0.43; 95% CI: 0.31-0.61; P < 0.001), however no other outcomes reached statistical significance. CONCLUSION: Although younger and less frail, veteran patients undergoing GA for lower extremity revascularization had higher rates of postoperative ileus, pneumonia, deep wound infection, sepsis, and need for transfusion as compared to those undergoing NA. There was no significant difference in the rate of other major complications, myocardial infarction, death or LOS. After adjustment, only intraoperative transfusion remained statistically significant, likely reflecting longer and more complex cases for those that undergo general anesthesia rather than the effect of anesthetic choice itself.

A Comparison of Patient and Device Issues Reported for Recalled Venous Stent Systems.

BACKGROUND: The first two Food and Drug Administration (FDA)-approved stents for treatment of iliofemoral vein obstruction, Boston Scientific's Vici and BD's Venovo venous stent systems, were both recalled in early 2021 within years of entering the market. Given the recent addition of patient issues as a publicly reported variable by the FDA Manufacturer and User Facility Device Experience (MAUDE) database, we set forth to analyze adverse event reports in MAUDE to better characterize issues reported for each system. METHODS: MAUDE was queried for all adverse event reports for brands "Vici" and "Venovo" from their respective US FDA market approval dates to August 19, 2021. Reported device issues, patient issues, and interventions performed for each adverse event were compiled and compared using Fisher's exact test. RESULTS: A total of 50 unique adverse event reports were compiled for the Vici system and 341 for the Venovo system. The most common device issue reported for the Vici system was migration (48% vs. 0%; P = 0.0001) versus activation failure in Venovo (85% vs. 4%; P = 0.0001). A significantly higher proportion of Venovo reports specified no patient complications or symptoms (90% vs. 26%; P = 0.0001), with no intervention performed (89% vs. 32%; P = 0.001). A significantly higher proportion of Vici devices were extracted (8% vs. 2%; P = 0.01), required use of a new device (26% vs. 5%; P = 0.0001), and required application of a second stent within the venous stent initially placed (28% vs. 2%; P = 0.0001). The rate of intervention with balloon expansion was not significantly different between the Vici and Venovo systems (6% vs. 2%; P = 0.08). CONCLUSIONS: While 2 venous stent systems were recalled simultaneously, significant differences exist between reported device issues in MAUDE and whether patient injury was involved and well described. Our data suggest that despite recent improvements to MAUDE reporting, additional standardization with specificity regarding patient issues and interventions is needed to assist vascular surgeons monitoring real-time adverse event trends for vascular devices.

Emerging targets signaling for inflammation in Parkinson's disease drug discovery.

Parkinson's disease (PD) patients not only show motor features such as bradykinesia, tremor, and rigidity but also non-motor features such as anxiety, depression, psychosis, memory loss, attention deficits, fatigue, sexual dysfunction, gastrointestinal issues, and pain. Many pharmacological treatments are available for PD patients; however, these treatments are partially or transiently effective since they only decrease the symptoms. As these therapies are unable to restore dopaminergic neurons and stop the development of Parkinson's disease, therefore, the need for an effective therapeutic approach is required. The current review summarizes novel targets for PD, that can be utilized to identify disease-modifying treatments.

Synergistic therapeutic benefit by combining the antibody drug conjugate, depatux-m with temozolomide in pre-clinical models of glioblastoma with overexpression of EGFR.

PURPOSE: Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2-7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic. METHODS: The efficacy of ADCs, antibodies, TMZ and radiation was tested in xenograft models of GBM, U-87MG and U-87MG EGFRvIII. Both models express EGFR. U-87MG EGFRvIII was transduced to express EGFRvIII. Changes in tumor volume, biomarkers of cell death and apoptosis after treatment were used to measure efficacy of the various treatments. Synergism of depatux-m and TMZ was verified in three-dimensional cultures of U-87MG and U-87MG EGFRvIII by the method of Chou and Talalay. RESULTS: Combined with TMZ and radiotherapy (RT), depatux-m inhibited xenograft growth of U-87MG and U-87MG EGFRvIII more than either treatment with depatux-m or TMZ + RT. Durability of the response to depatux-m + TMZ + RT or depatux-m + TMZ was more pronounced in U-87MG EGFRvIII than in U-87MG. Efficacy of depatux-m + TMZ was synergistic in U-87MG EGFRvIII and additive in U-87MG. CONCLUSION: Adding depatux-m enhances the efficacy of standard of care therapy in preclinical models of GBM. Durability of response to depatux-m + TMZ in vivo and synergy of the drug-drug interaction correlates with the amount of antigen expressed by the tumor cells.

Analysis of Twitter Activity and Engagement From Annual Meetings of the Society for Vascular Surgery and the Society of Interventional Radiology.

BACKGROUND: Medical societies such as the Society for Vascular Surgery (SVS) and the Society of Interventional Radiology (SIR) have been encouraging the use of social media at annual meetings by establishing unique meeting hashtags (eg. #VAM19, #SIR19ATX). These two specialties have similar number of active physicians and share procedural interests. We set forth to understand differences in Twitter activity and engagement by analyzing Twitter outputs from the vascular annual meeting (VAM) and the interventional radiology annual meeting (IRAM) in 2019. METHODS: Tweets with "#VAM19" and "#SIR19ATX" from 30 days before and 30 days after respective meetings were collected. Proportion of distinct Twitter users relative to total number of meeting attendees, number of posts per user, number of hashtags per post, and number of engagement metrics (likes, replies, and retweets) were collected for comparison. As for the top 100 most liked tweets, specialty-related hashtags were categorized into identity, diversity, education, procedure, and medical care, and the authors of these tweets were also identified for comparison. Student's t-test* and Fisher's Exact⁎⁎ were utilized for analysis. RESULTS: A total of 362 and 1944 tweets were collected from the VAM and IRAM in 2019. There was no difference in proportion of active Twitter users relative to total number of meeting attendees between the VAM (7.5%) and IRAM (7.7%). Average number of posts per user from the VAM and IRAM showed no significant difference. However, tweets related to IRAM had significantly higher number of hashtags per post (2.67±1.96) than ones related to VAM (1.78±1.26) (P < 0.0001*). Additionally, these tweets on average received significantly higher number of likes (P < 0.0001*), retweets (P < 0.0001*), and replies (P < 0.0001*) than ones related to the VAM. Specialty-related hashtags from the 100 most liked tweets showed significantly greater proportion of hashtags associated with specialty identity (4% vs 28.6%, P < 0.0001**), diversity (2.9% vs 8.0%, p=0.0268**), and education (1.1% vs 9.1%, p=0.0004**) in tweets related to the IRAM whereas the proportion of hashtags associated with procedure and medical care was similar between the two meetings. Lastly, the 100 most liked tweets were authored by trainees (p=0.005*) and official societies (p=0.003*) in significantly greater proportion in IRAM whereas academic institutions/training hospitals authored in significantly greater proportion (p=0.004*) from the VAM. Contributions from attending physician users to the 100 most liked tweets were similar between the two meetings. CONCLUSION: Analysis of Twitter activity centered around #VAM19 and #SIR19ATX indicates that there was no significant difference in proportion of Twitter users relative to meeting attendees and average number of posts per user. However, tweets with #SIR19ATX had significantly higher number of hashtags per post and had greater level of engagement than ones with #VAM19. The top 100 most liked tweets from the two meetings differed in proportion of hashtags related to specialty identity, diversity, and education, as well as proportion of contributing authors identified as trainees, official societies, and academic institutions/training hospitals. These data should help the SVS and its members to establish a more directed social media effort to facilitate its use during national gatherings.

Multivessel tibial revascularization does not improve outcomes in patients with critical limb ischemia.

OBJECTIVE: Multivessel tibial revascularization for critical limb ischemia (CLI) remains controversial. The purpose of this study was to evaluate single vs multiple tibial vessel interventions in patients with multivessel tibial disease. We hypothesized that there would be no difference in amputation-free survival between the groups. METHODS: Using the Vascular Quality Initiative registry, we reviewed patients undergoing lower extremity endovascular interventions involving the tibial arteries. Patients with CLI were included only if at least two tibial vessels were diseased and adequate perioperative data and clinical follow-up were available for review. The primary outcome was amputation-free survival. RESULTS: There were 10,849 CLI patients with multivessel tibial disease evaluated from 2002 to 2017; 761 limbs had adequate data and follow-up available for review. Mean follow-up was 337 ± 62 days. Of these, 473 (62.1%) underwent successful single-vessel tibial intervention (group SV), whereas 288 (37.9%) underwent successful multivessel (two or more) intervention (group MV). Patients in group MV were younger (69.1 vs 73.2 years; P < .001), with higher tobacco use (29.5% vs 18.2%; P < .001). Group SV more commonly had concurrent femoral or popliteal inflow interventions (83.7% vs 78.1%; P = .05). Multivessel runoff on completion was significantly greater for group MV (99.9% vs 39.9%; P < .001). No differences were observed between group SV and group MV for major amputation (9.0% and 7.6%; P = .6), with similar amputation-free survival at 1 year (90.6% vs 92.9%; P = .372). In a multivariate Cox model, loss of patency was the only significant predictor of major amputation (hazard ratio, 5.36 [2.7-10.6]; P = .01). A subgroup analysis of 355 (46.6%) patients with tissue loss data showed that tissue loss before intervention was not predictive of future major amputation. CONCLUSIONS: In the Vascular Quality Initiative registry, patients with CLI and occlusive disease involving multiple tibial vessels did not appear to have a limb salvage benefit from multiple tibial revascularization compared with single tibial revascularization.

Early Real-World Experience with EndoAnchors by Indication.

BACKGROUND: The Heli-FX EndoAnchor (EA) system is a transmural aortic fixation device with Federal Drug Administration (FDA) approval for treatment of endoleaks, endograft migration, or high-risk seal zones. Published data are primarily from industry-sponsored registries highlighting safety and efficacy. Our objective is to evaluate real-world outcomes of EA usage after FDA approval across a variety of stent grafts and indications at a single institution. METHODS: We retrospectively reviewed our prospectively maintained aneurysm database for patients undergoing endovascular aortic repair (EVAR) with Heli-FX EAs. Technical success was defined as successful EA deployment, while procedural success was defined as absence of endoleak on completion aortogram. Cohorts were divided by indication and outcomes assessed via review of clinical and radiographic data. RESULTS: From 2016 to 2018, 37 patients underwent EA fixation. We divided the cohort by indication: Group A (prior EVAR with endoleak), B (intraoperative type 1A endoleak), C (high-risk seal zone), and D (thoracic EVAR). In Group A (n = 11), all endoleaks were type 1A and a mean of 10 EAs were deployed with 100% technical and 45.4% procedural success. Two perioperative reinterventions were performed (translumbar coil embolization and proximal graft extension with bilateral renal artery stents). At a mean 10.6 months of follow-up, 45.4% of patients had persistent endoleaks, with 100% aortic-related survival. In Group B (n = 10), a mean of 8.7 EAs were used with 100% technical and procedural success. One immediate adverse event occurred (right iliac dissection from wire manipulation, treated with a covered stent). At 13.6-month mean follow-up, there was significant sac regression (mean 9.75 mm) with no type 1A endoleaks. In Group C (n = 10), a mean of 9.5 EAs were deployed with 100% technical and procedural success. At 11.2-month mean follow-up, there were no residual endoleaks and significant sac regression (mean 3.4 mm). Overall survival was 100%. In Group D (n = 6), a mean of 8.3 EAs were used with 83.3% technical and 66.6% procedural success. One immediate adverse event occurred, in which an EA embolized to the left renal artery. At 9.4-month mean follow-up, overall survival was 83.3% with a mean 2.2-mm increase in sac diameter. CONCLUSIONS: Early experience suggests that EAs effectively treat intraoperative type 1A endoleaks and high-risk seal zones, with significant sac regression and no proximal endoleaks on follow-up. In patients treated for prior EVAR with postoperative type 1A endoleaks, fewer than half resolved after EA attempted repair. Further experience and longer term follow-up will be necessary to determine which patients most benefit from postoperative EA fixation.

Transplant-Associated Thrombotic Microangiopathy Is a Multifactorial Disease Unresponsive to Immunosuppressant Withdrawal.

Transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic cell transplantation (HCT) has not been well characterized in large population studies with clinically adjudicated cases. We performed a retrospective cohort study of adults who underwent allogeneic HCT between 2006 and 2015 to determine the incidence of and risk factors for TA-TMA and to describe its natural history and response to immunosuppressant withdrawal management. Among 2145 patients in this study, 192 developed TA-TMA with a cumulative incidence of 7.6% by 100days post-transplant. Independent pretransplant risk factors included the receipt of a second (or third) allogeneic HCT, HLA-mismatched donor, and myeloablative conditioning with or without total body irradiation; post-transplant risk factors included the antecedent development of acute graft-versus-host disease, diffuse alveolar hemorrhage, bacteremia, invasive aspergillosis, BK viremia, and higher sirolimus trough level. Among TA-TMA patients 27% achieved hematologic resolution and 57% remained alive as of 90days after diagnosis. Antecedent risk factors stratified patients into different survival groups, and immunosuppressant withdrawal alone did not improve patient outcomes. In conclusion, TA-TMA is a heterogenous disease that occurs after allogeneic transplantation. Management with immunosuppressant withdrawal does not impact patient outcomes. Until further evidence becomes available, the management of TA-TMA should focus on the treatment of underlying diseases.

Surgical management of functional popliteal entrapment syndrome in athletes.

BACKGROUND: Functional popliteal artery entrapment syndrome (FPAES) is a rare disorder described in young, physically active adults that can be limb or performance threatening if untreated. We used provocative computed tomography angiography (CTA) in these patients to guide partial debulking of the anterolateral quadrant of the medial head of the gastrocnemius muscle for FPAES and reviewed the outcomes of this technique in this highly specialized cohort. METHODS: Athletes referred with symptoms of FPAES underwent a CTA protocol with provocative plantarflexion and dorsiflexion to confirm compression and were offered surgery. All patients underwent posterior approach operative exposure of the popliteal artery, adhesiolysis, side branch ligation, and partial excision of the gastrocnemius muscle with or without fasciotomies. Preoperative imaging, operative findings, and midterm follow-up, including return to baseline function and return to competitive function, as well as symptom recurrence, were retrospectively reviewed. RESULTS: Thirty-six athletes had a total of 56 limbs treated. The average patient age was 26.9 years and the majority were female (56%). Thirty-one percent of patients were referred after already having undergone prior fasciotomies. Sports involved included track and field or running (47%), soccer (25%), water sports (8%), basketball (6%), lacrosse (6%), climbing (3%), skiing (3%), and gymnastics (3%). Of the patients, 27 (75%) had bilateral symptoms and evidence of entrapment; however, only 20 of the 36 (56%) underwent bilateral surgical treatment for symptom resolution. The mean amount of gastrocnemius muscle removed was 7.6 cm3. Nine percent of limbs underwent a bypass along with debulking owing to arterial occlusion at presentation. Postoperatively, there were no nerve or vascular complications noted, although two patients had wound/seroma complications (6%). At the first follow-up, all patients reported mild symptom improvement, but at the midterm follow-up (mean follow-up time, 16 months), six (17%) reported mild to moderate recurrence of symptoms. Of the patients, 78% were able to fully return to their previous competitive levels of sports. All patients were able to resume their athletic endeavor at a recreational level. CONCLUSIONS: More than three-fourths of athletes limited by FPAES demonstrate full return to prior competitive levels with fasciotomy and surgical debulking of the anterolateral quadrant of the medial gastrocnemius muscle. Provocative CTA protocols can help to guide the location of muscle debulking to alleviate the functional entrapment that occurs in these athletes with exercise. This technique is a viable option in athletes with FPAES looking to return to competitive athletics.

Early Experience with the Octopus Endovascular Strategy in the Management of Thoracoabdominal Aneurysms.

BACKGROUND: The Octopus endovascular strategy involves placement of multiple, stacked bifurcated grafts in the thoracic segment of a thoracoabdominal aneurysm (TAAA) to facilitate deployment of multiple parallel covered stents for visceral perfusion. This study aimed to review early outcomes of the Octopus TAAA repair strategy at a tertiary, high-volume referral center. METHODS: All patients who underwent this Octopus procedure from 2015 to 2018 were reviewed from a prospectively collected single-institution registry. Demographics, comorbidities, and aneurysm anatomy including side and extent, perioperative data including blood loss, length of procedure length of stay, morbidity, and mortality up to 3 years after the procedure were elevated. RESULTS: A total of 21 patients (48% female, age 72.9 years) underwent the Octopus procedure over the study period. Mean TAAA diameter was 6.7 cm, with 14% dissection related and 86% degenerative TAAA. All patients had been turned down for open repair and 3 (14%) were performed urgently of which 2 were ruptures. TAAA extent was 9% type 2, 62% type 3, and 29% type 4. A mean of 3.04 branches were revascularized per patient, with the superior mesenteric artery (SMA) (90%) perfused through its own limb, and both renals usually reconstructed in parallel graft fashion (left 90%, right 85.7%) with the distal abdominal extension through one of the limbs. Mean operative time was 8 hr, fluoroscopy time 164 min, contrast 182 mL, and blood loss 807 mL. We staged the thoracic and juxtavisceral portions of the cases in 24% of patients. 90% of cases were able to be completed with exclusion of the TAAA and all planned visceral branches cannulated. Perioperative complications included paraplegia (19%) (13.3% permanent, 26.6% temporary), acute kidney injury (24%), prolonged ventilation (19%), myocardial infarction (4.9%), and ischemic bowel (4.8%). Median follow-up was 13.5 months (range 1-26 months). At latest follow-up, type I endoleak rate was 9.5%, with all being treated with proximal cuffs. Other second interventions included restenting of a right renal, angioplasty of an iliac limb kink, and type 2 endoleak coiling. Primary patency of visceral branches was 93.8% at latest follow-up (celiac 100%, SMA 94.7%, right renal 88.9%, left renal 94.8%). In-hospital all-cause mortality rate was 14.2%, with 30-day survival being 90.5%, 6-month survival was 88.3%, one-year survival 71.4%, and 3-year survival was 52.1%. CONCLUSIONS: The Octopus procedure is a high-risk option for urgent or emergent endovascular TAAA repair with off-the-shelf devices in patients who are not candidates for open repair.

Experimental animal models for rheumatoid arthritis.

Rheumatoid Arthritis (RA) is an autoimmune systemic disorder of unknown etiology and is characterized by chronic inflammation and synovial infiltration of immune cells. RA is associated with decreased life expectancy and quality of life. The research on RA is greatly simplified by animal models that help us to investigate the complex system involving inflammation, immunological tolerance and autoimmunity. The animal models of RA with a proven track record of predictability for efficacy in humans include: collagen type II induced arthritis in rats as well as mice, adjuvant induced arthritis in rats and antigen induced arthritis in several species. The development of novel treatments for RA requires the interplay between clinical observations and studies in animal models. However, each model features a different mechanism driving the disease expression; the benefits of each should be evaluated carefully in making the appropriate choice for the scientific problem to be investigated. In this review article, we focus on animal models of arthritis induced in various species along with the genetic models. The review also discussed the similarity and dissimilarities with respect to human RA.