SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action.

For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors. Drug development of non-D2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D2 signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.

Clinical Outcome of Carotid Artery Stenting According to Provider Specialty and Volume.

BACKGROUND: Several studies have demonstrated better outcomes for carotid endarterectomy with high-volume hospitals and providers. However, only a few studies have reported on the impact of operator specialty/volume on the perioperative outcome of carotid artery stenting (CAS). This study will analyze the correlation of CAS outcomes and provider specialty and volume. METHODS: Prospectively collected data of CAS procedures done at our institution during a 10-year period were analyzed. Major adverse events (MAEs; 30-day stroke, myocardial infarction, and death) were compared according to provider specialty (vascular surgeons [VSs], interventional cardiologists [ICs], interventional radiologists [IRs], interventional vascular medicine [IVM]), and volume (≥5 CAS/year vs. <5 CAS/year). RESULTS: Four hundred fourteen CAS procedures (44% for symptomatic indications) were analyzed. Demographics/clinical characteristics were somewhat similar between specialties. MAE rates were not significantly different between various specialties: 3.1% for IC, 6.3% for VS, 7.1% for IR, 6.7% for IVM (P = 0.3121; 6.3% for VS and 3.8% for others combined, P = 0.2469). When physicians with <5 CAS/year were excluded: the MAE rates were 3.1% for IC, 4.7% for VS, and 6.7% for IVM (P = 0.5633). When VS alone were compared with others, and physicians with <5 CAS/year were excluded, the MAE rates were 4.7% for VS vs. 3.6% for non-VS (P = 0.5958). The MAE rates for low-volume providers, regardless of their specialty, were 9.5% vs. 4% for high-volume providers (P = 0.1002). Logistic regression analysis showed that the odds ratio of MAE was 0.4 (0.15-1.1, P = 0.0674) for high-volume providers, while the odds ratio for VS was 1.3 (0.45-3.954, P = 0.5969). CONCLUSIONS: Perioperative MAE rates for CAS were similar between various providers, regardless of specialties, particularly for vascular surgeons with similar volume to nonvascular surgeons. Low-volume providers had higher MAE rates.

Ten-Year Experience of Vascular Surgeon Management of Iatrogenic Pseudoaneurysms: Do Anticoagulant and/or Antiplatelet Medications Matter?

BACKGROUND: Previous studies examining the natural history of femoral pseudoaneurysms (PSAs) were performed before the current era of anticoagulant and/or antiplatelet therapy. The purpose of our study was to elucidate in a vascular surgeon directed approach to PSAs, the association between medication use and the failure of conservative, observation-only management. METHODS: We retrospectively examined 308 femoral iatrogenic PSAs diagnosed via duplex imaging at our institution during a 10-year time period (2004-2013). Information on PSA characteristics, treatment, and antiplatelet and/or anticoagulant medication usage was obtained. We identified patients who failed observation-only conservation management, with failure defined as the need for delayed treatment because of PSAs triggered by either expansion (≥ 1 cm increase or size enlarging to ≥ 3 cm) and/or persistence (≥ 15 days). RESULTS: Immediate and/or acute treatments of PSAs included 1 ultrasound-guided compression, 14 surgical repairs, and 126 thrombin injections. Of the 167 PSAs initially managed by observation only, 70 (42%) were found by ultrasound imaging to thrombosis spontaneously. An additional 70 (42%) patients had the diagnosis of PSA <3 cm and were managed conservatively with only clinical follow-up. Twenty-seven PSAs (16%) originally managed conservatively required additional treatment because of expansion and/or persistence. Patients receiving dual-antiplatelet therapy had higher rates of failed conservative management (44%) than patients not on dual therapy (9%, P < 0.01). The number of antiplatelet and/or anticoagulant medications used during observation was larger in patients failing conservative management (2.0 ± 0.7) versus patients not requiring additional intervention (1.5 ± 0.7, P < 0.01). CONCLUSIONS: Most of the PSAs initially managed with observation-only did not require additional intervention. However, anticoagulant and/or antiplatelet agents use associated with PSAs required further intervention after failing observation-only management. When observation is the chosen strategy for PSA management, especially in the setting of aggressive antithrombotic and dual-antiplatelet therapy, surveillance is required to ensure proper resolution.

Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

Early results with LifeStent implantation in RESILIENT and non-RESILIENT inclusion criteria patients.

The purpose of our study was to determine outcomes of patients receiving the LifeStent (Bard Peripheral Vascular, Tempe, AZ) for femoropopliteal peripheral arterial disease in real-world academic practice outside the limitations of an industry supported trial. All patients from 2009 to 2012 at our institution who received a LifeStent during endovascular interventions and had follow-up were included. Outcomes evaluated included patency and freedom from limb loss. A total of 166 limbs in 151 patients had the LifeStent implanted in de novo vessels (54% male; 68 ± 12 years). Eighty-percent of limbs did not meet RESILIENT criteria due to Rutherford category >3 (51%), TransAtlantic Inter-Society Consensus II classifications C/ D (51%), zero runoff vessels (6%), or stent location (17%). Primary patency rates were 81% at 6 months and 58% at 12 months with predictors for primary patency loss at 1 year including Rutherford category >3 (HR: 1.8 (95% CI: 1.0-3.1), p = 0.04), tobacco use (HR: 1.8 (95% CI: 1.0-3.3), p = 0.04), and no clopidogrel at discharge (HR: 3.2 (95% CI: 1.6-6.7), p < 0.01). A preintervention Rutherford category >3 predicted 24-month limb loss (HR, 16.0 (95% CI: 2.0-122.0), p < 0.01). The LifeStent is a viable option regardless of the TransAtlantic Inter-Society Consensus II classification; however, critical limb ischemia, current tobacco use, and absence of clopidogrel on discharge predict decreased patency on follow-up.

Femoral pseudoaneurysms after percutaneous access.

The femoral artery has been the primary percutaneous-based arterial access site for coronary artery catheterizations for more than three decades. Noncardiac percutaneous-based procedures have also been performed primarily with femoral access and have increased in number exponentially by vascular specialists in past decades. Groin complications are infrequent in incidence after femoral arterial access for cardiac and peripheral diagnostic and interventional cases, with groin hematomas and pseudoaneurysms being the most common. Until ultrasound-based treatment modalities became the mainstay of treatment, vascular surgeons were the primary specialty managing pseudoaneurysms, but now other specialties also manage these cases. This review outlines the clinical implications and current issues relevant to understanding the ideal treatment strategy for this common complication.

C-reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization.

BACKGROUND: High-sensitivity C-reactive protein (hsCRP) and brain natriuretic peptide (BNP) have been shown to be independent predictors of adverse cardiovascular outcomes and increased risk of secondary interventions or limb loss in patients with peripheral arterial disease (PAD). To assist clinicians in decision-making about treatment approaches and predicting postprocedure mortality and morbidity, we retrospectively examined patients with preprocedure hsCRP and BNP levels who underwent elective angioplasty or stent placement for lower extremity PAD. METHODS: The study period was from January 1, 2007, to December 31, 2012, and patients were included who had angioplasty or stenting for PAD. Minimal required follow-up for study inclusion was at least one postoperative ankle-brachial index, contrast angiography, or duplex imaging of the treated limb. Events of interest included major adverse limb events (MALE), defined as target vessel revascularization, amputation, or disease progression by 1 year, and major adverse cardiovascular events (MACE; stroke, myocardial infarction, or death) by 2 years. Elevated/abnormal values for our biomarkers of interest were established by the upper limits of our institution's clinical laboratory reference range (hsCRP, >0.80 mg/dL; BNP, >100 pg/mL). RESULTS: A total of 159 limbs in 118 patients were included in analysis (42% men; median age [range], 64 [42-87] years). All limbs were symptomatic (Rutherford classification: 1-6). Iliac artery revascularization without other adjunct lower extremity intervention was performed in 60% of the limbs. High hsCRP levels (>0.80 mg/dL) were present in 32 patients (27%) and high BNP values (>100 pg/mL) in 24 patients (20%). Kaplan-Meier analysis with log-rank comparison demonstrated that elevated hsCRP levels were associated with MALE but only in limbs receiving interventions distal to the iliac arteries (P = .005). High BNP levels did not affect MALE rates (P = .821). Conversely, both elevated BNP levels (hazard ratio, 5.6; 95% confidence interval [CI], 2.0-5.8; P = .001) and hsCRP levels (hazard ratio, 2.9; 95% CI, 1.1-7.6; P = .034) predicted MACE at 2 years in the presence of confounders in Cox proportional hazards multivariate analysis. Patients with high preintervention values of hsCRP and BNP were 10.6 times (95% CI, 2.6-42.9; P = .001) more likely to experience MACE than were patients with normal hsCRP and BNP values. CONCLUSIONS: After lower extremity endovascular interventions, elevated preprocedural hsCRP levels are associated with MALE (femoral-popliteal interventions), and elevated levels of hsCRP and BNP are associated with late cardiovascular events.

Splenic artery embolization for the treatment of bleeding gastric varices secondary to splenic vein thrombosis.

Splenic vein thrombosis can lead to gastric varices. Subsequent upper gastrointestinal bleeding may ensue related to the change in venous outflow to the portal system. Vascular surgeons are infrequently asked to assist in the management of this entity. However, with many vascular surgeons providing diverse endovascular-based interventions, understanding catheter-based solutions is imperative. This report presents a case in which arterial embolization was used to treat gastric variceal bleeding.

The effect of surgeon's specialty and volume on the perioperative outcome of carotid endarterectomy.

BACKGROUND: Several studies have demonstrated better outcomes for carotid endarterectomy (CEA) at high-volume hospitals and providers. However, only a few studies have reported on the impact of surgeons' specialty and volume on the perioperative outcome of CEA. METHODS: This is a retrospective analysis of CEA during a recent 2-year period. Surgeons' specialties were classified according to their Board specialties into general surgeons (GS), cardiothoracic surgeons (CT), and vascular surgeons (VS). Surgeons' annual volume was categorized into low volume (<10 CEAs), medium volume (10 to <30 CEAs), and high volume (≥30 CEAs). The primary outcome was 30-day perioperative stroke and/or death; however, other perioperative complications were analyzed. Both univariate and multivariate analyses were done to predict the effect of specialty/volume and any other patient risk factors on stroke outcome. RESULTS: Nine hundred and fifty-three CEAs were performed by 24 surgeons: 122 by seven GS, 383 by 13 CT, and 448 by 4 VS. Patients' demographics/clinical characteristics were similar between specialties, except the incidence of coronary artery disease, which was higher for CT (P < .0001). The indications for CEA were symptomatic disease in 38% for VS, 31% for GS, and 23% for CT (P < .0001). The perioperative stroke and death rates were 4.1%, 2.9%, and 1.3% for GS, CT, and VS, respectively (P = .126). A subgroup analysis showed that the perioperative stroke rates for symptomatic patients were 5.3%, 2.3%, and 2.3% (P = .511) and for asymptomatic patients were 3.6%, 3%, and 0.72% (P = .099) for GS, CT, and VS, respectively. Perioperative stroke rates were significantly higher for nonvascular surgeons (GS and CT combined) vs VS in asymptomatic patients (3.2% vs 0.72%; P = .033). Perioperative stroke/death was also significantly lower for high-volume surgeons: 1.3% vs 4.1% and 4.3% for medium- and low-volume surgeons (P = .019) (1.3% vs 4.15% for high vs low/medium combined; P = .005). More CEAs were done for asymptomatic patients in the low/medium-volume surgeons (78%) vs high-volume surgeons (64%; P < .0001) with a stroke rate of 4.6% for low/medium-volume surgeons vs 0.51% for high-volume surgeons (P = .0005). A univariate logistic analysis showed that the odds ratio of having a perioperative stroke was 0.3 (95% confidence interval [CI], 0.13-0.73; P =.008) for high-volume surgeons vs low/medium-volume surgeons, 0.4 (95% CI, 0.16-1.07; P = .069) for VS vs CT/GS and 0.2 (95% CI, 0.06-0.45; P = .0004) when patching was used. A multivariate analysis showed that the odds ratio of having a perioperative stroke for CT VS was 2.1 (95% CI, 0.71-5.92; P = .183); for GS vs VS, 1.8 (95% CI, 0.49-6.90; P = .3709); for low-volume surgeons (vs high-volume) 3.4 (95% CI, 0.96-11.77; P = .0581); medium- vs high-volume surgeons 2.2 (95% CI, 0.75-6.42; P = .1509). CONCLUSIONS: High-volume surgeons had significantly better perioperative stroke/death rates for CEA than low/medium-volume surgeons. Perioperative stroke/death rates were also higher for nonvascular surgeons in asymptomatic patients.

Perioperative and late clinical outcomes of percutaneous transluminal stentings of the celiac and superior mesenteric arteries over the past decade.

BACKGROUND: Several authorities have proposed stenting of the superior mesenteric artery (SMA)/celiac artery (CA) as the primary treatment for patients with chronic mesenteric ischemia. However, most of these reports had small samples and short follow-up periods. METHODS: Eighty-three patients were treated over a 10-year period. Clinical follow-up and duplex ultrasound exams were done to evaluate long-term patency. We used our newly validated duplex criteria to detect ≥70% in-stent stenosis of the SMA and CA. A Kaplan-Meier life-table analysis was used to estimate freedom from in-stent stenosis and late symptom and survival rates. RESULTS: Fifty-four SMA and 51 CA stents were analyzed. The initial technical and clinical success rates were 97% and 96%, respectively, with 2% procedure morbidity and 2% mortality. The primary late clinical success rate was 59%, and the late ≥70% in-stent stenosis rate was 51% at a mean follow-up of 31 months (range, 1-124). Freedom from late recurrent symptoms at 1, 2, 3, 4, and 5 years was 83, 77, 70, 70, and 65%, respectively. Survival rates at the same intervals were 88%, 82%, 70%, 64%, and 51%. Primary patency rates for the whole series were 69%, 48%, 39%, 28%, and 19% at 1, 2, 3, 4, and 5 years, respectively. Assisted primary patency rates for the whole series were 80%, 61%, 54%, 43%, and 34% at 1, 2, 3, 4, and 5 years, respectively. Primary patency rates for the SMA at 1, 2, 3, 4, and 5 years were 71%, 47%, 37%, 28%, and 18%, respectively; and assisted primary rates were 82%, 64%, 57%, 45%, and 32%, respectively. Primary patency rates for the CA were 68%, 50%, 40%, 29%, and 21%; and assisted primary rates were 79%, 58%, 52%, 42%, and 36% for 1, 2, 3, 4, and 5 years, respectively. There were no significant differences in either primary or assisted primary patency between the SMA and CA (P = .7729 and .8169). A secondary intervention was carried out in 30% of the series. Freedom from ≥70% in-stent stenosis for the SMA was 82%, 65%, 56%, 42%, and 34%, and that for the CA was 73%, 59%, 48%, 34%, and 25%, at 1, 2, 3, 4, and 5 years, respectively. CONCLUSIONS: Stenting of SMA/CA stenosis has high technical/early clinical success rates with a satisfactory late clinical outcome; however, it is associated with high rates of late in-stent stenosis and intervention.

Evolving treatment of popliteal artery aneurysms.

BACKGROUND: Over the past decade, the treatment of popliteal aneurysms has evolved at our institution from sole operative intervention during the initial part of the study period, to combined surgical and endovascular treatment, and finally to endovascular-centered management in more recent years. METHODS: This is a retrospective review of all patients with popliteal aneurysms treated at our institution from 2001 to 2011. Data collection included the indication for intervention, treatment details, interventional patency, limb salvage, perioperative outcome, and midterm survival. RESULTS: Eighty-eight aneurysms (72 patients) were treated during this period. Indications for intervention included symptomatic presentations in 53% (n = 47) and asymptomatic in 47% (n = 41). Treatment included endovascular exclusion in 24, surgical repair in 63 (14 posterior approach and 49 medial approach with bypass and exclusion), and primary amputation in one patient. Nine aneurysms (10.2%) received catheter-directed thrombolysis. Demographics were similar between the two treatment cohorts, except for age with endovascular stenting patients being significantly older (76.0 vs 66.0 years; P = .002). The mean length of stay was 3.9 days vs 9.5 days (P < .001), favoring endovascular treatment. There were no perioperative (30-day) deaths in the endovascular group and one in the surgical cohort. The mean patency follow-up was 21.2 vs 28.3 months. Primary patency did not differ between endovascular and surgically treated patients at 1 year (92.9% vs 83.3%; P = .26) and 3 years (63.7% vs 77.8%; P = .93). No limbs were lost in the endovascular group during the follow-up period of 22.4 months, and one late limb loss occurred in the surgical cohort (mean follow-up, 29.2 months). Endovascular patients had a midterm survival rate of 65% (mean follow-up, 33.9 months), whereas surgical patients experienced a survival rate of 80.8% (mean follow-up, 42.9 months; P = .22). CONCLUSIONS: Endovascular treatment of popliteal aneurysms provides similar short-term patency to that of the traditional gold standard approach with surgical bypass, with shorter hospitalizations in both symptomatic and asymptomatic patients. Further long-term follow-up is required to compare these two treatment modalities for durability to determine the optimal popliteal aneurysm management.

Predictors of percutaneous access failure requiring open femoral surgical conversion during endovascular aortic aneurysm repair.

OBJECTIVE: To determine predictors of percutaneous (PEVAR) access failure requiring conversion to an open approach (OEVAR) during endovascular aortic aneurysm repair (EVAR). METHODS: A single-center retrospective review of all EVAR patients from January 2009 through June 2011 with multivariate analysis of clinical and anatomic variables that could impact access outcome was conducted. Target vessel calcification was categorized as mild, moderate, or severe based on circumferential calcium arc (<⅓, ⅓ to ½, and >½ respectively), dyslipidemia (defined as low-density lipoprotein >130 mg/dL or receiving lipid lowering medication), and obesity (defined as body mass index [BMI] >30). RESULTS: We investigated 400 access sites for 200 patients who underwent EVAR. The study cohort's characteristics included an average age of 72.8 ± 9.0 years, vessel size of 9.6 ± 1.8 mm, sheath size of 17.1 ± 3.0 Fr, BMI of 27.6 ± 5.3, and estimated glomular filtration rate of 68.5 ± 24.2 mL/min. Comorbidities included dyslipidemia in 129 patients (64.5%) and diabetes in 54 patients (27%). There were 132 OEVAR (66 patients), two mixed OEVAR with contralateral PEVAR (one patient), and 266 (133 patients) PEVAR approaches. Use of PEVAR increased over time (45.5% [2009], 77.8% [2010], and up to 88.5% [2011]; P = .001) while conversions decreased (24.3% [2009], 8.7% [2010], and 4.3% [2011]; P = .001]. More OEVAR patients (35.8%) stayed longer than 3 days compared with 21.1% for PEVAR (P = .028). For the 266 PEVAR approaches, 32 access sites (12.0%) had to be converted. Severely calcified arteries were most predictive of conversion (odds ratio [OR], 36.4; P < .001). Year of procedure (2010; OR, 0.17; P = .001; 2011, OR, 0.20; P = .049), female gender (OR, 3.1; P = .017), moderately calcified arteries (OR, 2.5; P = .085), and age (OR, 2.3 [per decade]; P = .002) were all also significant. Vessel size, sheath size, and BMI were found to be nonsignificant predictors of conversion. CONCLUSIONS: PEVAR was found to be safe, reliable, and feasible. Several factors, including learning curve, vessel calcification, age, and female gender predicted conversion of PEVAR to OEVAR.

Basic data underlying clinical decision making in vascular surgery: arterial access for percutaneous procedures.

Percutaneous arterial access has become a mainstay in the armamentarium of vascular specialists. Vascular surgeons for decades have managed iatrogenic complications sustained by other specialists and now are more frequently performing catheter-based procedures themselves. A thorough understanding of the basic data underlying complications related to these procedures is imperative and is thoroughly reviewed.

Current update of cerebral embolic protection devices.

Carotid artery stenting (CAS) has evolved into a viable alternative to carotid endarterectomy. Although CAS outcomes have improved during the last decade, the associated stroke rate remains higher when compared with carotid endarterectomy. Therefore, the pivotal role of embolic protection devices (EPDs) in minimizing stroke risk cannot be underestimated as a vital component of CAS. As technology advances, EPDs continue to be refined, and each device currently on the market has its own advantages and disadvantages. This review provides an overview of the current status of EPDs and highlights the unique features of each device, followed by suggestions for application in specific clinical scenarios.

Short- and long-term outcomes of percutaneous transluminal angioplasty/stenting of renal fibromuscular dysplasia over a ten-year period.

OBJECTIVES: The purpose of this study was to evaluate short and long-term outcomes of percutaneous transluminal intervention in patients with symptomatic renal artery stenosis due to fibromuscular dysplasia (RAFMD) and/or the combination of RAFMD with aorto-ostial atherosclerotic disease. METHODS: A retrospective analysis of all patients with renal artery RAFMD who underwent transcatheter therapy between January 1999 and December 2009 was performed. Blood pressure (BP) measurement, number of BP medications, and hypertension defined by a systolic BP >140 ± diastolic BP >90 were recorded. Renal function was defined by estimated glomerular filtration rate (eGFR). Restenosis was defined by stenosis >60% and was determined by renal artery duplex and/or angiography. Freedom from event (restenosis, renal failure, or recurrent hypertension) was performed using life table analysis. RESULTS: Forty-three procedures were performed on 35 patients with RAFMD. Thirty-two patients (91%) were women, with mean age of 61.9 years old. Technical success was 100% with adjunctive stent placement required in the FMD segment for dissection in 1 patient (2.3%) and in the non-FMD aorto-ostial atherosclerotic lesion in 4 patients (9.3%). Short-term outcomes: the majority (69%) had an immediate clinical benefit for hypertension, 6% were cured without BP medications, and 63% improved with less than or equal to preoperative BP medications. Postintervention, 17% remained at moderately reduced renal function (<60), whereas the percent above >60 mL/minute eGFR increased significantly (from 51% to 69%; P = .002). For the entire cohort, renal function (mean eGFR) significantly increased from 71.9 mL/minute + 5.8 to 80.8 mL/minute + 5.2 (P = .007). Long-term outcomes: freedom from recurrent or worsening hypertension (>140 systolic blood pressure [SBP] and >90 diastolic blood pressure [DBP]) was (93%, 75%, and 41%) and freedom from reduced renal function (eGFR <30 mL/minute) was (100%, 95%, and 64%) at 1, 5, and 8 years, respectively. Patients with reduced baseline renal function (<60 mL/minute) and combined atherosclerotic disease were more likely to experience long-term reduced renal function (eGFR <30 mL/minute; P = .003). Primary and assisted primary patency was (95%, 71%, and 50%) and (100%, 100%, and 100%) at 1, 5, and 9 years, respectively. CONCLUSION: Renal angioplasty is a safe and durable modality for treating RAFMD with favorable short and long-term clinical outcomes. Patients with combined atherosclerotic disease and FMD were older and were more likely to have declining renal function over time. Early intervention may be imperative to achieve possible cure of hypertension.

Dialysis access.

Although hemodialysis access procedures are considered the most common vascular procedures performed by either general or vascular surgeons, there is a paucity of level-one evidence in the literature. Randomized controlled trials are limited, and most of these studies have small sample sizes compared with other areas of vascular surgery, that is, carotid or aneurysm studies. We summarize the results of the world's literature for arteriovenous access in table format as a tool for those specialists managing patients with arteriovenous access procedures.

Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia.

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure-activity relationships.

Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.

While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.

Ten-year experience with renal artery in-stent stenosis.

BACKGROUND: Atherosclerotic renal artery stenosis (RAS) is the most common cause of secondary hypertension. Renal stenting has become the treatment of choice for RAS in most centers. Primary patency of RAS is well defined, but limited data are available on outcomes of secondary interventions for treatment of in-stent restenosis. METHODS: This was a retrospective analysis of a 10-year experience with renal artery stenting in patients presenting with recurrent symptomatic stenosis. End points included freedom from tertiary procedures, change in baseline renal function by ≥20% measured by estimated glomerular filtration rate (eGFR), patency confirmed by duplex imaging, long-term hypertension response, freedom from hemodialysis, and survival. RESULTS: We reviewed 948 patients with 1150 treated renal arteries. Of these, 107 patients (122 renal stents) returned with symptomatic in-stent restenosis and required reintervention (target vessel revascularization [TVR] rate, 10.6%): 97% had recurrent or worsening hypertension, and 67% had worsening renal function. There were 69 women (64%) and 38 men (35%) with an average age of 68.9 years. Mean follow-up was 35.5 months (range, 1.0-104.7 months) for patency and 37.7 months (range, 0.03-100.9 months) for renal function (creatinine). Secondary interventions included 27 percutaneous transluminal angioplasties (PTAs), 10 PTAs with cutting balloon, 77 repeat renal artery stenting, and 8 placements of drug-eluting stents (DES). Twenty-five of the 122 arteries (20%) required tertiary interventions in 23 patients, a significantly higher TVR rate vs de novo interventions (11%; P = .003). Freedom from tertiary interventions at 60 months was similar among treatment groups undergoing PTA (66%), cutting balloon (100%), stent (80%), and DES (75%; P = .348). Seventeen (16%) had an increase of >20%, 50 (47%) had a decrease of >20%, and 30 (28%) had no change in renal function. Ultimately 25 (23%) remained or progressed to renal failure (eGFR < 30%), and 8 required hemodialysis. The survival rate was 73% at 5 years. Mean follow-up for long-term hypertension response was 3.2 years, with 56% improved, 28% with no improvement or deterioration, 16% without long-term data available, and no patients cured. CONCLUSIONS: Secondary interventions for renal in-stent restenosis had higher TVR vs de novo renal stents in this large series (21% vs 11%; P = .003). Definitive recommendations on the best secondary treatment strategy cannot be made because a medical treatment control group was not available for comparison.