Pulsed Field vs Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation: Recurrent Atrial Arrhythmia Burden.

BACKGROUND: The ADVENT randomized trial revealed no significant difference in 1-year freedom from atrial arrhythmias (AA) between thermal (radiofrequency/cryoballoon) and pulsed field ablation (PFA). However, recent studies indicate that the postablation AA burden is a better predictor of clinical outcomes than the dichotomous endpoint of 30-second AA recurrence. OBJECTIVES: The goal of this study was to determine: 1) the impact of postablation AA burden on outcomes; and 2) the effect of ablation modality on AA burden. METHODS: In ADVENT, symptomatic drug-refractory patients with paroxysmal atrial fibrillation underwent PFA or thermal ablation. Postablation transtelephonic electrocardiogram monitor recordings were collected weekly or for symptoms, and 72-hour Holters were at 6 and 12 months. AA burden was calculated from percentage AA on Holters and transtelephonic electrocardiogram monitors. Quality-of-life assessments were at baseline and 12 months. RESULTS: From 593 randomized patients (299 PFA, 294 thermal), using aggregate PFA/thermal data, an AA burden exceeding 0.1% was associated with a significantly reduced quality of life and an increase in clinical interventions: redo ablation, cardioversion, and hospitalization. There were more patients with residual AA burden <0.1% with PFA than thermal ablation (OR: 1.5; 95% CI: 1.0-2.3; P = 0.04). Evaluation of outcomes by baseline demographics revealed that patients with prior failed class I/III antiarrhythmic drugs had less residual AA burden after PFA compared to thermal ablation (OR: 2.5; 95% CI: 1.4-4.3; P = 0.002); patients receiving only class II/IV antiarrhythmic drugs pre-ablation had no difference in AA burden between ablation groups. CONCLUSIONS: Compared with thermal ablation, PFA more often resulted in an AA burden less than the clinically significant threshold of 0.1% burden. (The FARAPULSE ADVENT PIVOTAL Trial PFA System vs SOC Ablation for Paroxysmal Atrial Fibrillation [ADVENT]; NCT04612244).

Preliminary Investigation Into the Effectiveness of Group webSTAIR for Trauma-exposed Veterans in Primary Care.

INTRODUCTION: A substantial number of trauma-exposed veterans seen in primary care report significant symptoms of PTSD and depression. While primary care mental health integration (PCMHI) providers have been successful in delivering brief mental health treatments in primary care, few studies have evaluated interventions that combine mobile health resources with PCMHI groups. This pilot study assessed the potential benefits of webSTAIR, a 10-module transdiagnostic treatment for trauma-exposed individuals, supported by 5 biweekly group sessions delivered via telehealth. The transdiagnostic and mobile health nature of the treatment, as well as the therapist and peer support provided through group sessions, may offer an innovative approach to increasing access to patient-centered and trauma-informed treatment in primary care settings. MATERIALS AND METHODS: Thirty-nine male and female veterans with trauma-related symptoms (i.e., PTSD and/or depression) participated in group webSTAIR. Mixed effects analyses were conducted to assess changes in PTSD and depression at pre-, mid-, and post-treatment. Baseline symptom severity was assessed as a predictor of module completion and group attendance. The project was part of a VHA quality improvement project, and IRB approval was waived by the affiliated university. RESULTS: Analyses revealed significant pre-to-post improvement in both PTSD and depression outcomes with a large effect size for PTSD (Hedges' gav = 0.88) and medium to large for depression (Hedges' gav = 0.73). Of participants who completed the baseline assessment, 90% began webSTAIR; of those, 71% completed the program. Baseline symptoms of PTSD and depression did not predict group attendance or module completion. CONCLUSIONS: Good outcomes and a satisfactory retention rate suggest that group webSTAIR may provide easily accessible, high-quality, and effective treatment for patients presenting with trauma-related problems without increasing therapist or system burdens. The results suggest the value of conducting a randomized controlled trial to test the effectiveness of group webSTAIR relative to PCMHI usual care or other evidence-based, disorder-specific (e.g., PTSD) treatments for trauma-exposed individuals in PCMHI.

Supporting equitable engagement and retention of women patients in a trauma-informed virtual mental health intervention: Acceptability and needed adaptations.

OBJECTIVE: This study examines barriers and facilitators to participation in webSTAIR, a telemental health program providing virtual coaching sessions for veterans with posttraumatic stress disorder (PTSD) and depression symptoms, among women veterans from racial and ethnic minority groups. METHOD: Using qualitative interviews (n = 26), we compared women veterans from racial and ethnic minority groups who completed (completers; n = 16) and did not complete (noncompleters; n = 11) webSTAIR at rural-serving facilities in the Veterans Health Administration (VA). Interview data were analyzed using rapid qualitative analysis. Chi-square and t tests assessed differences between completers and noncompleters by sociodemographic characteristics and baseline PTSD and depression symptomatology. RESULTS: There were no statistically significant sociodemographic differences at baseline between completers and noncompleters; completers reported significantly higher baseline PTSD and depression symptomatology. Noncompleters were more likely to describe feeling angry, depressed, and unable to control their environments during participation in the program as barriers to webSTAIR completion. Completers, despite higher symptomatology, cited internal motivation and support from concurrent mental health services as facilitators. Both groups made recommendations for how VA can better support women veterans from racial and ethnic minority groups, including providing space for peer support and community building, addressing stigma associated with seeking mental health services and fostering mental health provider diversity and retention. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Although previous research has identified racial and ethnic disparities in PTSD treatment retention, mechanisms to improve retention have been unclear. Women veterans from racial and ethnic minority groups should be collaboratively engaged in the design and implementation of telemental health programs for PTSD to improve equitable retention. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Two-Year Outcomes With a Next-Generation Left Atrial Appendage Device: Final Results of the PINNACLE FLX Trial.

Background The PINNACLE FLX (Protection Against Embolism for Non-valvular AF [Atrial Fibrillation] Patients: Investigational Device Evaluation of the Watchman FLX LAA [Left Atrial Appendage] Closure Technology) trial evaluated the safety and efficacy of a next-generation left atrial appendage closure device (WATCHMAN FLX; Boston Scientific, Marlborough, MA). At 1 year, the study met the primary end points of safety and anatomical efficacy/appendage closure. This final report of the PINNACLE FLX trial includes the prespecified secondary end point of ischemic stroke or systemic embolism at 2 years, also making it the first report of 2-year outcomes with this next-generation left atrial appendage closure device. Methods and Results Patients with nonvalvular atrial fibrillation with CHA2DS2-VASc score ≥2 (men) or ≥3 (women), with an appropriate rationale for left atrial appendage closure, were enrolled to receive the left atrial appendage closure device at 29 US centers. Adverse events were assessed by an independent clinical events committee, and imaging was assessed by independent core laboratories. Among 395 implanted patients (36% women; mean age, 74 years; CHA2DS2-VASc, 4.2±1.5), the secondary efficacy end point of 2-year ischemic stroke or systemic embolism was met, with an absolute rate of 3.4% (annualized rate, 1.7%) and an upper 1-sided 95% confidence bound of 5.3%, which was superior to the 8.7% performance goal. Two-year rates of adverse events were as follows: 9.3% all-cause mortality, 5.5% cardiovascular death, 3.4% all stroke, and 10.1% major bleeding (Bleeding Academic Research Consortium 3 or 5). There were no additional systemic embolisms, device embolizations, pericardial effusions, or symptomatic device-related thrombi after 1 year. Conclusions The secondary end point of 2-year stroke or systemic embolism was met at 3.4%. In these final results of the PINNACLE FLX trial, the next-generation WATCHMAN FLX device demonstrated favorable safety and efficacy outcomes.

Final analysis of the phase 3 randomized clinical trial comparing HD201 vs. referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting.

BACKGROUND: The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. METHODS: In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan-Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. RESULTS: The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3-38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28-89.52) and 84.9% (95% CI: 79.54-88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63-1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90-97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45-97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. CONCLUSIONS: This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03013504.

Management of Intracranial Sinusitis Complications in Children and Adolescents: Similarities and Differences Among Otolaryngology Subspecialists.

The purpose of this study was to compare the management of intracranial sinusitis complications in pediatric patients between members of the American Rhinologic Society (ARS) and the American Society of Pediatric Otolaryngology (ASPO). A cross-sectional web-based survey was distributed twice to the ASPO and ARS membership over an 8-month period. The overall survey response rate was 12.1% (7.5% of ARS members and 17.3% of ASPO members). Recommended management was similar with respect to the use of intravenous antibiotics, nasal saline irrigations, topical decongestants, and nasal steroid sprays. Recommendations diverged with regards to systemic steroid use and urgent/emergent endoscopic sinus surgery (ESS). ARS members were more likely to recommend systemic corticosteroids. ASPO members were more likely to recommend immediate ESS. Based on survey responses, we found differences in practice patterns among subspecialists, which indicates additional collaborative research between societies is necessary to develop and disseminate evidence-based guidelines for these patients. Level of Evidence: 4.

Efficacy of HD201 vs Referent Trastuzumab in Patients With ERBB2-Positive Breast Cancer Treated in the Neoadjuvant Setting: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: The drug HD201 is a biosimilar candidate for breast cancer treatment as the reference trastuzumab. Objective: To compare the efficacy of HD201 with referent trastuzumab. Design, Setting, and Participants: This randomized clinical trial (TROIKA) included 502 women with ERBB2-positive early breast cancer treated with either HD201 or referent trastuzumab. It was conducted across 70 centers in 12 countries, including Western and Eastern Europe and Asian countries. Randomization was stratified by tumor hormone receptor status, clinical stage, and geographic region of recruitment. This analysis was conducted on February 12, 2021, after the completion of the adjuvant phase at a median of 31 months (IQR, 28-33 months) of follow-up. Interventions: Patients with ERBB2-positive early breast cancer were randomly assigned to receive HD201 or referent trastuzumab in the neoadjuvant setting for 8 cycles, concurrently with 4 cycles of docetaxel, which was followed by 4 cycles of epirubicin and cyclophosphamide. Patients then underwent surgery, which was followed by treatment with 10 cycles of adjuvant HD201 or referent trastuzumab. Main Outcome and Measures: The primary end point was the total pathological complete response (tpCR) assessed after neoadjuvant treatment. Equivalence was concluded if the 95% CI of the absolute difference in tpCR between arms in the per-protocol set was within the margin of more or less than 15%. Other objectives included the breast pathological complete response, overall response, event-free and overall survival, safety, pharmacokinetics, and immunogenicity. Results: A total of 502 female patients (mean [range] age, 53 [26-82] years) were randomized to receive either HD201 or referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. The baseline characteristics were well balanced between the 2 arms; 195 tumors (38.8%) were hormone receptor-negative , and 213 patients (42.4%) had clinical stage III disease. The tpCR rates were 45% and 48.7% for HD201 and referent trastuzumab, respectively. The difference between the 2 groups was not significant at -3.8% (95% CI, -12.8% to 5.4%) and fell within the predefined equivalence margins. The ratio of the tpCR rates between the 2 arms was 0.92 (95% CI, 0.76 to 1.12). A total of 433 patients (86.1%) presented with 2232 treatment-emergent adverse events of special interest for trastuzumab during the entire treatment period, with 220 (88.0%) and 213 (84.5%) patients in the HD201 and referent trastuzumab groups, respectively. Conclusions and Relevance: The results of this randomized clinical trial found that HD201 demonstrated equivalence to referent trastuzumab in terms of efficacy for the end point of tpCR, with a similar safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03013504.

Conformal Left Atrial Appendage Seal Device for Left Atrial Appendage Closure: First Clinical Use.

OBJECTIVES: The authors report the first clinical experience with the Conformal Left Atrial Appendage Seal (CLAAS) device. BACKGROUND: The CLAAS device was designed to address the limitations of first-generation left atrial appendage closure (LAAC) devices by providing an implant that is minimally traumatic, can be deployed in a noncoaxial fashion, and does not require postprocedural oral anticoagulation. METHODS: Patients with atrial fibrillation at high stroke risk (CHA2DS2-VASc score ≥2) were recruited using standard selection criteria. The LAAC procedure was guided by transesophageal echocardiography with patients under general anesthesia. The CLAAS device is composed of a foam cup, with a Nitinol endoskeleton with an expanded polytetrafluoroethylene cover, delivered with a standard delivery system using a tether for full recapture. All patients received dual-antiplatelet therapy for 6 months, followed by aspirin alone. Transesophageal echocardiographic follow-up was scheduled for 45 days and 1 year. RESULTS: Twenty-two patients (63.7% with CHA2DS2-VASc scores ≥3, 76.2% with HAS-BLED scores ≥3) were enrolled. The device was successfully implanted in 18 patients and unsuccessfully in 4 patients. There were no serious procedural complications. On transesophageal echocardiography performed at 45 days, 1 significant leak (≥5 mm) was seen, which was due to a large posterior lobe not appreciated at the time of implantation, and 1 device-related thrombus was noted, which resolved on oral anticoagulation. There were no periprocedural strokes, major pericardial effusions, or systemic or device embolization. CONCLUSIONS: This first-in-human study demonstrates the clinical feasibility of the CLAAS device for LAAC.

Primary Outcome Evaluation of a Next-Generation Left Atrial Appendage Closure Device: Results From the PINNACLE FLX Trial.

BACKGROUND: Left atrial appendage (LAA) occlusion provides an alternative to oral anticoagulation for thromboembolic risk reduction in patients with nonvalvular atrial fibrillation. Since regulatory approval in 2015, the WATCHMAN device has been the only LAA closure device available for clinical use in the United States. The PINNACLE FLX study (Protection Against Embolism for Nonvalvular AF Patients: Investigational Device Evaluation of the Watchman FLX LAA Closure Technology) evaluated the safety and effectiveness of the next-generation WATCHMAN FLX LAA closure device in patients with nonvalvular atrial fibrillation in whom oral anticoagulation is indicated, but who have an appropriate rationale to seek a nonpharmaceutical alternative. METHODS: This was a prospective, nonrandomized, multicenter US Food and Drug Administration study. The primary safety end point was the occurrence of one of the following events within 7 days after the procedure or by hospital discharge, whichever was later: death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring cardiac surgery. The primary effectiveness end point was the incidence of effective LAA closure (peri-device flow ≤5 mm), as assessed by the echocardiography core laboratory at 12-month follow-up. RESULTS: A total of 400 patients were enrolled. The mean age was 73.8±8.6 years and the mean CHA2DS2-VASc score was 4.2±1.5. The incidence of the primary safety end point was 0.5% with a 1-sided 95% upper CI of 1.6%, meeting the performance goal of 4.2% (P<0.0001). The incidence of the primary effectiveness end point was 100%, with a 1-sided 95% lower CI of 99.1%, again meeting the performance goal of 97.0% (P<0.0001). Device-related thrombus was reported in 7 patients, no patients experienced pericardial effusion requiring open cardiac surgery, and there were no device embolizations. CONCLUSIONS: LAA closure with this next-generation LAA closure device was associated with a low incidence of adverse events and a high incidence of anatomic closure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02702271.

A Loss-of-Function Mutation in the Integrin Alpha L (Itgal) Gene Contributes to Susceptibility to Salmonella enterica Serovar Typhimurium Infection in Collaborative Cross Strain CC042.

Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. Mouse models have been extensively used to model in vivo distinct aspects of human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection. In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J × CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.

Using Infant Mortality Data to Improve Maternal and Child Health Programs: An Application of Statistical Process Control Techniques for Rare Events.

Introduction The infant mortality rate (IMR) in the United States remains higher than most developed countries. To understand this public health issue and support state public health departments in displaying and analyzing data in ways that support learning, states participating in the Collaborative Improvement and Innovation Network to Reduce Infant Mortality (IM CoIIN) created statistical process control (SPC) charts for rare events. Methods State vital records data on live births and infant deaths was used to create U, T and G charts for Kansas and Alaska, two states participating in the IM CoIIN who sought methods to more effectively analyze IMR for subsets of their populations with infrequent number of deaths. The IMR and the number of days and number of births between infant deaths was charted for Kansas Non-Hispanic black population and six Alaska regions for the time periods 2013-2016 and 2011-2016, respectively. Established empirical patterns indicated points of special cause variation. Results The T and G charts for Kansas and G charts for Alaska depict points outside the upper control limit. These points indicate special cause variation and an increased number of days and/or births between deaths at these time periods. Discussion T and G charts offer value in examining rare events, and indicate special causes not detectable by U charts or other more traditional analytic methods. When small numbers make traditional analysis challenging, SPC has potential in the MCH field to better understand potential drivers of improvements in rare outcomes, inform decision making and take interventions to scale.

Gastroschisis Trends and Ecologic Link to Opioid Prescription Rates - United States, 2006-2015.

Prevalence of gastroschisis, a serious birth defect of the abdominal wall resulting in some of the abdominal contents extending outside the body at birth, has been increasing worldwide (1,2). Gastroschisis requires surgical repair after birth and is associated with digestive and feeding complications during infancy, which can affect development. Recent data from 14 U.S. states indicated an increasing prevalence of gastroschisis from 1995 to 2012 (1). Young maternal age has been strongly associated with gastroschisis, but research suggests that risk factors such as smoking, genitourinary infections, and prescription opioid use also might be associated (3-5). Data from 20 population-based state surveillance programs were pooled and analyzed to assess age-specific gastroschisis prevalence during two 5-year periods, 2006-2010 and 2011-2015, and an ecologic approach was used to compare annual gastroschisis prevalence by annual opioid prescription rate categories. Gastroschisis prevalence increased only slightly (10%) from 2006-2010 to 2011-2015 (prevalence ratio = 1.1, 95% confidence interval [CI] = 1.0-1.1), with the highest prevalence among mothers aged <20 years. During 2006-2015, the prevalence of gastroschisis was 1.6 times higher in counties with high opioid prescription rates (5.1 per 10,000 live births; CI = 4.9-5.3) and 1.4 times higher where opioid prescription rates were medium (4.6 per 10,000 live births; CI = 4.4-4.8) compared with areas with low prescription rates (3.2 per 10,000 live births; CI = 3.1-3.4). Public health research is needed to understand factors contributing to the association between young maternal age and gastroschisis and assess the effect of prescription opioid use during pregnancy on this pregnancy outcome.

A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8+ T cells.

Several previous studies outlined the importance of the histone H2A deubiquitinase MYSM1 in the regulation of stem cell quiescence and haematopoiesis. In this study we investigated the role of MYSM1 in T-cell development. Using mouse models that allow conditional Mysm1 ablation at late stages of thymic development, we found that MYSM1 is intricately involved in the maintenance, activation and survival of CD8+ T cells. Mysm1 ablation resulted in a twofold reduction in CD8+ T-cell numbers, and also led to a hyperactivated CD8+ T-cell state accompanied by impaired proliferation and increased pro-inflammatory cytokine production after ex vivo stimulation. These phenotypes coincided with an increased apoptosis and preferential up-regulation of p53 tumour suppressor protein in CD8+ T cells. Lastly, we examined a model of experimental cerebral malaria, in which pathology is critically dependent on CD8+ T cells. In the mice conditionally deleted for Mysm1 in the T-cell compartment, CD8+ T-cell numbers remained reduced following infection, both in the periphery and in the brain, and the mice displayed improved survival after parasite challenge. Collectively, our data identify MYSM1 as a novel factor for CD8+ T cells in the immune system, increasing our understanding of the role of histone H2A deubiquitinases in cytotoxic T-cell biology.

Three-dimensional Analysis of Normal Facial Morphologies of Asians and Whites: A Novel Method of Quantitative Analysis.

The purpose of this study is to compare 3-dimensional facial averages of Asians (Koreans and Chinese) and Houstonian white faces using a (3-dimensional) surface imaging system. METHODS: Three-dimensional images of Korean adults (Seoul, Korea) with class I malocclusion captured using the 3dMDface. The images of 138 Koreans were processed to generate average male and female facial shells using Rapidform 2006 plus pack 2 software and then superimposed and compared with the average shells of Chinese adults (Xi' An, China) and white adults (Houston, Tex.). RESULTS: The average Korean male and female faces were wider with prominent malar and zygomatic areas when compared with the white faces. The average white male and female faces showed more protrusion in the glabella, nasion, rhinion, and the soft-tissue pogonion than the Korean faces. The average Korean male face was retrusive at masseteric region while having more prominent lips, nasal tip, and supraglabella than the Chinese counterpart. The average Korean female face was narrower than the average Chinese female face, but there was more protrusion in the periorbital, nasal tip, and malar region seen in the Korean female face. CONCLUSIONS: Although the average faces of Chinese and Korean populations in this study showed remarkable similarities, there were distinct differences seen in the facial morphology of the 2 Asian groups. Three-dimensional imaging can be effectively used to establish population facial norms and to quantify the variations seen between different ethnicities. This information may be used in the clinical environment for plastic, oral, and maxillofacial surgery and orthodontics.

The impact of stent graft evolution on the results of endovascular abdominal aortic aneurysm repair.

OBJECTIVE: There have been four eras in the development of endovascular aneurysm repair (EVAR): physician-made grafts, early industry devices, intermediary commercial endografts, and modern stent grafts. This study analyzes differences in outcomes between these four groups and the impact of device evolution and increased physician experience. METHODS: From 1992 to 2012, 1380 patients underwent elective EVAR. Fourteen different devices were used during this time. The four generations were defined as follows: era 1, all physician-made devices; era 2, June 1994 to June 2003; era 3, June 2003 to January 2008; and era 4, January 2008 to July 2012. Grafts used in each era were the following: era 1, physician made; era 2, early industry, such as EVT, Talent, AneuRx, Excluder, Quantum LP, Vanguard, Ancure, and Teramed; era 3, Talent, Endologix, Excluder, AAAdvantage, Zenith, and Aptus; and era 4, Zenith, Endurant, and Excluder. RESULTS: Mean age was 75.2 years, and 84.5% were men. Adjunctive procedures decreased from era 1 to era 2 (P < .001) but rose again in eras 3 and 4 (P < .001). Procedure times (P < .001), blood loss (P < .001), and length of stay (P < .001) have decreased in eras 2, 3, and 4 compared with era 1. Major perioperative complications (era 1, 23%; era 2, 5.9%; era 3, 4.9%; and era 4, 4.7%; P < .001), abdominal aortic aneurysm-related perioperative mortality (era 1, 4.3%; era 2, 0.2%; era 3, 0.06%; and era 4, 0.5%; P < .001), and all-cause perioperative mortality (era 1, 7.7%; era 2, 1.9%; era 3, 1.5%; and era 4, 0.47%; P < .001) have also decreased in eras 2, 3, and 4 compared with era 1. Type I and type III endoleaks (P < .001) and the need for reintervention (P < .001) have decreased. Freedom from aneurysm-related mortality has significantly improved. CONCLUSIONS: EVAR has evolved during the last 20 years, resulting in an improvement in efficiency, outcomes, and procedural success. The most significant advance is seen in the transition from era 1 to the later eras.

Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin.

The mammalian target of rapamycin (mTOR) is centrally involved in cell growth, metabolism, and angiogenesis. While showing clinical efficacy in a subset of tumors, rapamycin and rapalogs are specific and allosteric inhibitors of mTOR complex 1 (mTORC1), but they do not directly inhibit mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report chemical structure and biological characterization of three pyrazolopyrimidine ATP-competitive mTOR inhibitors, WAY-600, WYE-687, and WYE-354 (IC(50), 5-9 nmol/L), with significant selectivity over phosphatidylinositol 3-kinase (PI3K) isofoms (>100-fold). Unlike the rapalogs, these inhibitors acutely blocked substrate phosphorylation by mTORC1 and mTORC2 in vitro and in cells in response to growth factor, amino acids, and hyperactive PI3K/AKT. Unlike the inhibitors of PI3K or dual-pan PI3K/mTOR, cellular inhibition of P-S6K1(T389) and P-AKT(S473) by the pyrazolopyrimidines occurred at significantly lower inhibitor concentrations than those of P-AKT(T308) (PI3K-PDK1 readout), showing mTOR selectivity in cellular setting. mTOR kinase inhibitors reduced AKT downstream function and inhibited proliferation of diverse cancer cell lines. These effects correlated with a strong G(1) cell cycle arrest in both the rapamycin-sensitive and rapamycin-resistant cells, selective induction of apoptosis, repression of global protein synthesis, and down-regulation of angiogenic factors. When injected into tumor-bearing mice, WYE-354 inhibited mTORC1 and mTORC2 and displayed robust antitumor activity in PTEN-null tumors. Together, our results highlight mechanistic differentiation between rapalogs and mTOR kinase inhibitors in targeting cancer cell growth and survival and provide support for clinical development of mTOR kinase inhibitors as new cancer therapy.