Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment.

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC50 = 0.024 µM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.

Nasogastric tube syndrome: A case of vocal cord paralysis due to a nasogastric tube.

Insertion of a nasogastric tube is one of the most common methods of administering nutrition, but can cause vocal cord paralysis.

Novel automated atrial pacemapping technique based on intracardiac pattern matching to identify the location of ectopic atrial activity.

Atrial ectopy from the pulmonary veins and non-pulmonary vein foci can trigger atrial fibrillation. In addition, the elimination of atrial ectopy is important to prevent recurrence. The intracardiac pattern matching technique has been reported as a useful method to manually visualize the location of triggers regardless of their frequency. We combined the original intracardiac pattern matching method with the automapping setting of CARTO CONFIDENCE and discovered the automated atrial pacemapping technique. We report two cases in which this technique was used to eliminate the atrial triggers. This technique achieved a time reduction and high-resolution mapping.

The Association Between the D-dimer Level at 1 Year After EVAR and Sac Diameter Change in Patients With Persistent Type 2 Endoleak.

PURPOSE: Recent studies suggested that continuous clotting renewal in thrombi plays a central role in sac enlargement after endovascular aneurysm repair (EVAR). We reviewed patients with persistent type 2 endoleak (T2EL) to estimate the impact of D-dimer level on sac enlargement. METHODS: A retrospective review of elective EVAR for infrarenal abdominal aortic aneurysm performed between June 2007 and February 2020. Persistent T2EL was defined as T2EL confirmed at both the 6 and 12 month contrast-enhanced computed tomography (CECT) follow-ups. "Isolated" T2EL was defined as T2EL without other types of endoleak within 12 months. Patients with >2 year follow-up, persistent isolated T2ELs, and D-dimer level data at 1 year (DD1Y) were included. Patients with any reintervention within 12 months were excluded. The association between DD1Y and aneurysm enlargement (AnE), defined as a ≥5 mm diameter increase, within 5 years was analyzed. Among 761 conventional EVAR, 515 patients had >2 years of follow-up. Thirty-three patients with any reintervention within 12 months and 127 patients without CECT at either 6 or 12 months were excluded. Among 131 patients with persistent isolated T2ELs, 74 patients with DD1Y data were enrolled. During a 37 month median follow-up [25-60, IQR], 24 AnEs were observed. In the AnE patients, the median DD1Y was significantly higher than that in the other patients (12.30 [6.88-21.90] vs 7.62 [4.41-13.00], P=0.024). ROC curve analysis indicated that the optimal cutoff point of DD1Y for AnE was 5.5 µg/mL (AUC=0.681). In univariate analysis, angulated neck, occlusion of the inferior mesenteric artery, and DD1Y≥5.5 µg/mL were significantly associated with AnE (P= 0.037, 0.038, and 0.010). Cox regression analysis revealed that DD1Y≥5.5 µg/mL was correlated with AnE (P=0.042, HR [95% CI] 4.520 [1.056-19.349]). CONCLUSION: A 1 year higher D-dimer level can potentially predict AnE within 5 years in persistent T2EL patients. AnE was considered improbable when the D-dimer level was low enough. CLINICAL IMPACT: The present study suggests that a 1-year higher D-dimer level could potentially predict aneurysm expansion within 5 years in patients with persistent type 2 endoleak (T2EL). On the other hand, aneurysm expansion was considered unlikely if the D-dimer level was low enough.As there are many patients with T2EL who require regular follow-up, any predictor of future aneurysm expansion could be of great help in conserving medical resources. In patients with a low likelihood of future expansion, we might consider delaying follow-up, similar to patients with sac shrinkage.

Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents.

Identification of structurally novel inhibitors of lysine methyltransferase G9a has been a subject of intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit rac-10a obtained from the chemical library of the University of Tokyo Drug Discovery Initiative, the structure-activity relationship of the unique substrate-competitive inhibitors was established with the help of X-ray crystallography and fragment molecular orbital (FMO) calculations for the ligand-protein interaction. Further optimization of the in vitro characteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of 26j (RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC50 = 27/53 nM). Compound 26j exhibited remarkable selectivity against other related methyltransferases, dose-dependent attenuation of cellular H3K9me2 levels, and tumor growth inhibition in MOLT-4 cells in vitro. Moreover, compound 26j showed inhibition of tumor initiation and growth in a carcinogen-induced hepatocellular carcinoma (HCC) in vivo mouse model without overt acute toxicity.

Evaluation of standardized uptake value on 131I-6ß-iodomethyl-19-norcholesterol scintigraphy for diagnosis of primary aldosteronism and correspondence with adrenal venous sampling.

PURPOSE: Adrenal venous sampling (AVS) is a reliable method for lateralization of adrenal hormone secretion, which is important for discriminating between aldosterone-producing adenoma and bilateral adrenal hyperplasia, both of which cause primary aldosteronism (PA). The aim of this study was to evaluate the diagnostic accuracy of the maximum and mean standardized uptake values (SUVmax and SUVmean, respectively) of 131I-6ß-iodomethyl-19-norcholesterol (NP-59) single-photon emission computed tomography (SPECT) for PA and its correspondence with AVS. METHODS: Adrenal NP-59 scintigraphy was performed in 14 patients with suspected PA, and AVS was also performed in 7 of them. SUVmax and SUVmean of the adrenal lesions on the dominant side and their ratios to the values on the non-dominant side (SUVRmax and SUVRmean, respectively) were calculated on SPECT images using ordered-subset conjugate gradient minimization (OSCGM) and three-dimensional ordered-subset expectation maximization (3D-OSEM) reconstruction algorithms. RESULTS: SUVmax and SUVmean on NP-59 SPECT images were significantly higher for aldosterone-producing adenoma than for bilateral adrenal hyperplasia or non-functioning adenoma and slightly superior to SUVRmax and SUVRmean (P = 0.0475 and P = 0.0447 vs. P = 0.124 and P = 0.132, respectively, with OSCGM). The respective areas under the receiver-operating characteristic curve for SUV and SUVR were 0.933 and 0.725 with OSCGM and 0.844 and 0.750 with 3D-OSEM, while SUVmax and SUVRmax had exactly the same diagnostic accuracy as SUVmean and SUVRmean. SUV and SUVR were associated with the diagnostic features on AVS and consistent with lateralization by AVS in most patients. CONCLUSION: In this study, SUV on NP-59 SPECT helped in the diagnosis of PA and was consistent with the results of AVS in nearly all cases.

One-year sac regression is associated with freedom from fatal adverse events after endovascular aneurysm repair.

OBJECTIVE: Although the predictors of long-term prognosis after endovascular aneurysm repair (EVAR) have been investigated, several reports have suggested that early sac shrinkage (ESS) is associated with superior long-term prognosis. However, it was not clear whether ESS was associated with aneurysm-related mortality. The aim of this study was to define fatal adverse events and to examine their association with ESS. METHODS: All consecutive patients who underwent EVAR for an abdominal aortic aneurysm at Nagoya University Hospital between June 2007 and August 2018 were identified. We defined ESS as an aneurysm diameter decrease of 10 mm or more at 1 year after EVAR, and we defined fatal adverse events as aneurysm-related death, aneurysm sac rupture, open conversion, secondary type Ia endoleak, or secondary type IIIa/b endoleak. Then, we evaluated the association between ESS and fatal adverse events and identified predictors of ESS. RESULTS: During the study period, 553 patients were identified and included. Fatal adverse events occurred in 42 patients (7.6%), and the details of the fatal adverse events were as follows: 13 aneurysm-related deaths, 17 aneurysm sac ruptures, 14 open conversions, 13 type Ia endoleaks, and 6 type III endoleaks. ESS occurred in 146 patients (26.4%). Kaplan-Meier curves showed that the ESS group had a significantly lower incidence of fatal adverse events (P < .001). Multivariate analysis showed that there were significant differences in terms of 5 or more preoperatively patent lumbar arteries (odds ratio [OR], 0.67; P = .049; 95% confidence interval [CI], 0.45-1.00), chronic kidney disease (OR, 0.49; P < .01; 95% CI, 0.29-0.84), and Zenith endograft use (OR, 1.76; P < .01; 95% CI, 1.16-2.67). Furthermore, the percentage of cases that achieved an aneurysm diameter of less than 40 mm was significantly higher in the ESS group (76.0% vs 15.5%; P < .01). The use of Zenith endografts showed a significantly higher rate of aneurysm disappearance than the use of Endurant endografts (P < .01) and Excluder endografts (P < .01). In addition, it was found that ESS was more likely to occur with the use of Zenith endografts, even when propensity score matching was performed for the neck morphology. CONCLUSIONS: ESS was associated with a lower rate of life-threatening adverse events after EVAR. The use of Zenith endografts was a predictor of ESS and was associated with increased rates of long-term sac shrinkage and aneurysm disappearance compared with the Endurant and Excluder endografts. Using the predictors of ESS identified in this study, we may be able to expand the indications for EVAR to patients with a longer life expectancy.

Factors Associated With Spontaneous Sac Shrinkage in Patients With Persistent Type 2 Endoleaks After EVAR.

PURPOSE: Despite controversy surrounding the management of type 2 endoleaks (T2ELs) after endovascular aortic aneurysm repair (EVAR), the current European guidelines recommend reintervention for T2ELs when the aneurysm expands by ≥10 mm. Meanwhile, sac shrinkage ≥10 mm can be considered low risk for failure even with T2ELs, and the guidelines suggest less frequent follow-up delayed until 5 years after EVAR. This study reviewed patients with persistent T2ELs to identify predictors of spontaneous sac shrinkage (SpS) within 5 years. METHODS: A retrospective review of elective EVAR for infrarenal aortic aneurysms between June 2007 and December 2017. Patients with >1 year follow-up and persistent T2ELs, defined as T2ELs confirmed at both the 6 and 12 month follow-up with contrast-enhanced computed tomography (CT), were included. Any reintervention or type 1 or 3 endoleaks within 12 months were excluded. SpS was defined as a ≥10 mm reduction in diameter without any reintervention. Aneurysm enlargement (AnE) was defined as a ≥5 mm increase in diameter. Factors associated with SpS within 5 years were analyzed. The clinical outcomes were reviewed. RESULTS: Among 726 patients, 162 patients had persistent isolated T2ELs. After excluding 21 patients, 141 patients were enrolled. During a median follow-up of 43 months (interquartile range [IQR], 26-60), 28 SpS and 39 AnE were observed, and 31 reinterventions were performed. The cumulative rates of SpS were 14.2%±2.9% and 25.6%±5.1% at 1 and 5 years. Cox regression analysis revealed that the presence of ≥6 patent lumbar arteries had a significant negative correlation with SpS (p=0.036). During further follow-up after SpS, 2 reinterventions for type 1a and 3b endoleaks were required at 49 and 45 months. CONCLUSIONS: Patients with fewer patent lumbar arteries were likely to experience SpS within 5 years, even in the presence of persistent T2ELs. Follow-up imaging studies were advisable earlier than 5 years, even after SpS.

Severe Tortuosity of the Distal Descending Thoracic Aorta Affects the Accuracy of Distal Deployment During a Thoracic Endovascular Aortic Repair.

PURPOSE: An accurate distal deployment is essential for successful thoracic endovascular aortic repair (TEVAR) of a paradiaphragmatic aortic aneurysm. This study aimed to investigate the anatomical and intraoperative factors that affect the accuracy of distal deployment during TEVAR. METHODS: We conducted a retrospective review of preoperative and postoperative computed tomography scans of 426 patients undergoing TEVAR at our institution between October 2008 and May 2021, of which the stent-graft was attempted to be deployed just above the celiac axis or the superior mesenteric artery in 56 patients. Based on the anatomical factors related to the malposition (deployed >10 mm away from the target vessel) and the greater curve to the straight-line ratio (G/S ratio), the patients were categorized as severe tortuosity (n=21) and mild tortuosity (n=35) groups to compare the operative and clinical outcomes. RESULT: Stent-graft malpositioning occurred in 21 cases. Among all anatomical variables, only the G/S ratio was significantly larger in the malpositioned cases (p=0.049). A cutoff G/S ratio value of 1.15 was determined using the receiver operating curve analysis. In the severe tortuosity group, the distal end of the stent-graft was significantly farther (median: 10.0 [interquartile range (IQR): 2.5-19.5] mm vs 3.0 [0-8.0] mm; p=0.015) from the target vessel, and the tilt angle of the stent-graft's distal edge was larger (median: 21.4 [IQR: 15.8-24.5] vs 9.5 [5.5-12.5] degree; p<0.01) than that in the mild tortuosity group. Both groups were comparable for the incidence of a primary type Ib endoleak (p=0.454), a secondary type Ib endoleak (p=1.0), and the rate of distal reintervention (p=0.276). CONCLUSION: Severe tortuosity in the distal descending thoracic aorta is associated with a malpositioned and tilted distal end of the stent-graft. CLINICAL IMPACT: Thoracic endovascular aortic repair (TEVAR) for paradiaphragmatic thoracic aortic aneurysms requires accurate distal landing. In this paper, a retrospective CT analysis revealed that the greater curve to the straight-line ratio (G/S ratio) was associated to affects the malposition of the stent graft, defined as being deployed more than 10 mm away from the target vessel. Further, a comparative analysis based on the G/S ratio demonstrated that severe aortic tortuosity was associated with a more distal and tilted deployment of the stent graft.

Selective Inhibitor Design for Kinase Homologs Using Multiobjective Monte Carlo Tree Search.

Designing highly selective molecules for a drug target protein is a challenging task in drug discovery. This task can be regarded as a multiobjective problem that simultaneously satisfies criteria for various objectives, such as selectivity for a target protein, pharmacokinetic endpoints, and drug-like indices. Recent breakthroughs in artificial intelligence have accelerated the development of molecular structure generation methods, and various researchers have applied them to computational drug designs and successfully proposed promising drug candidates. However, designing efficient selective inhibitors with releasing activities against various homologs of a target protein remains a difficult issue. In this study, we developed a de novo structure generator based on reinforcement learning that is capable of simultaneously optimizing multiobjective problems. Our structure generator successfully proposed selective inhibitors for tyrosine kinases while optimizing 18 objectives consisting of inhibitory activities against 9 tyrosine kinases, 3 pharmacokinetics endpoints, and 6 other important properties. These results show that our structure generator and optimization strategy for selective inhibitors will contribute to the further development of practical structure generators for drug designs.

Utilizing public and private sector data to build better machine learning models for the prediction of pharmacokinetic parameters.

One solution to compensate for the shortage of publicly available data is to collect more quality-controlled data from the private sector through public-private partnerships. However, several issues must be resolved before implementing such a system. Here, we review the technical aspects of public-private partnerships using our initiative in Japan as an example. In particular, we focus on the procedure for collecting data from multiple private sector companies and building prediction models and discuss how merging public and private sector datasets will help to improve the chemical space coverage and prediction performance. Teaser: Japan's first public-private consortium in pharmacokinetics has incorporated data from multiple pharmaceutical companies to create useful predictive models.

Predictors of infrapopliteal vein bypass graft revision in patients with chronic limb-threatening ischemia.

PURPOSE: Surgical revascularization is the standard treatment for chronic limb-threatening ischemia (CLTI). However, some patients may require reintervention. The Global Anatomic Staging System (GLASS), which evaluates the complexity of infrainguinal lesions, was proposed. This study aimed to identify predictors for graft revision and evaluate whether GLASS impacts vein graft revision. METHODS: Between 2011 and 2018, CLTI patients who underwent de novo infrapopliteal bypass using autogenous veins were retrospectively analyzed. To assess anatomic complexity with GLASS, femoropopliteal, infrapopliteal, and inframalleolar/pedal (IM) disease grades were determined. The outcomes of patients with or without graft revision were compared. Cox regression analysis was performed. RESULTS: Thirty-six of the 80 patients underwent reintervention for graft revision. Compared to the non-graft revision group, the graft revision group exhibited significantly higher rates of GLASS stage III (66% vs 81%, p = 0.046) and grade P2 IM disease (25% vs 58%, p = 0.009). Multivariate analysis revealed that IM grade P2 (hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.66-6.75; p = 0.001) and spliced vein grafts (HR, 3.18; 95% CI, 1.43-7.06; p = 0.005) were significantly associated with graft revision. CONCLUSIONS: This study demonstrated that IM grade P2 and spliced vein grafts were predictors of graft revision. The GLASS stratification of IM disease grade may be useful in optimizing treatment for CLTI.

Cardiopulmonary arrest caused by nafamostat mesylate during hemodialysis.

Dialysis-related adverse reactions can be serious and difficult to predict. In our case, nafamostat mesylate (NM) was thought to be the cause of cardiopulmonary arrest (CPA) due to NM-induced anaphylaxis but was not reflected in the allergy tests. Rare but life-threatening drawbacks occur immediately after hemodialysis initiation.

Epicardial adipose tissue volume is associated with abdominal aortic aneurysm expansion.

BACKGROUND: The epicardial adipose tissue volume (EATV) is associated with cardiovascular diseases such as coronary artery disease. However, no information is available regarding the relationship between the EATV and abdominal aortic aneurysm (AAA) expansion. In the present study, we evaluated the association between the EATV and AAA growth and sought to identify the predictors of AAA expansion. METHODS: Between June 2009 and December 2019, 906 patients had undergone endovascular or open repair of AAAs at our institution. Patients with previous cardiac surgery, previous ascending thoracic aortic surgery, a ruptured AAA, an infected AAA, an inflammatory AAA, a saccular aneurysm, a solitary iliac aneurysm, or reintervention after treatment of the AAA were excluded. A total of 237 patients with at least two preoperative computed tomography (CT) scans performed >180 days apart were included in the present study. The EATV within the pericardium was retrospectively quantified from the preoperative non-contrast-enhanced CT images using a three-dimensional workstation. The EATV index was defined as the EATV divided by the body surface area. The AAA expansion rate was defined as an increase in the AAA diameter annually, and the patients were divided into the slow-expansion group (expansion rate, <5 mm/y) and the fast-expansion group (expansion rate, ≥5 mm/y). The correlation between the expansion rate and the EATV index was analyzed, and the cutoff value for the EATV index was determined using a receiver operating characteristics curve. Multivariate analysis was used to assess the predictors of the AAA expansion rate. RESULTS: The expansion rate of AAA correlated positively with the EATV index (R = 0.237; P < .001). The initial aneurysm diameter (P < .001) and EATV index (P = .009) differed significantly between the two groups. The cutoff for the EATV index was 60.3 cm3/m2 (area under the curve, 0.658; 95% confidence interval [CI], 0.568-0.749; sensitivity, 1.000; specificity, 0.309). Multivariate analysis revealed that the initial aneurysm diameter and an EATV index of >60.3 cm3/m2 were significantly associated with the AAA expansion rate. CONCLUSIONS: The results of the present study have demonstrated that the EATV index is associated with AAA expansion.

Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles.

Lysine-specific demethylase 1 (LSD1/KDM1A) is a promising therapeutic target for the treatment of cancers. Several derivatives of tranylcypromine (trans-2-phenylcyclopropylamine) have been developed as LSD1 inhibitors. One such derivative is S2157; however, this compound has a high hERG channel inhibitory activity and a low microsomal stability, making it unsuitable as a drug candidate. Here, using an in silico hERG inhibition prediction model, we designed, synthesized, and evaluated a novel series of S2157 derivatives characterized by modifications of the benzyloxy and piperazine groups. Among the synthesized derivatives, a compound possessing 2-fluoropyridine and 2,8-diaza-spiro[4.5]decane groups (compound 10) showed the most desirable activities, and its eutomer, S1427, was isolated by the optical resolution of 10. In addition to potent LSD1 inhibitory activity, S1427 exhibited desirable hERG channel inhibition and microsomal stability profiles.

Physiological background parenchymal uptake of 18F-FDG in normal breast tissues using dedicated breast PET: correlation with mammographic breast composition, menopausal status, and menstrual cycle.

OBJECTIVE: This study aimed to quantitatively evaluate the effects of age, mammographic density, menopausal status, and menstrual cycle on background parenchymal uptake (BPU) using ring-shaped dedicated breast positron emission tomography (dbPET). METHODS: This study included 186 adult women who underwent mammography and dbPET on the same day and had no abnormalities classified as Breast Imaging Reporting and Data System (BI-RADS) category 1 on both examinations. The volume of interest (VOI) was placed in the glandular tissue of both breasts, and the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and metabolic breast volume (MBV) were measured as indicators of BPU. We analyzed the correlation between BPU and age, mammographic density, menopausal status, and menstrual cycle. RESULTS: The SUVmax and SUVmean for normal breast tissue were inversely correlated with age (both p < 0.001). The SUVmax, SUVmean, and MBV of mammographically dense breast tissues were significantly higher than those of non-dense breast tissues (all p < 0.001). The SUVmax, SUVmean, and MBV of normal breast tissue in premenopausal women were significantly higher than those in postmenopausal women (p < 0.001, p < 0.001, p = 0.002, respectively). In the study, 59 premenopausal women, the SUVmax of normal breast tissue in the menstrual-follicular phase was significantly lower than that in the periovulatory-luteal phase (p = 0.02). When we sorted the premenopausal women by mammographic breast composition, the SUVmax and SUVmean of normal breast tissues in the menstrual-follicular phase were significantly lower than those in the periovulatory-luteal phase in the 44 premenopausal women with dense breasts (p = 0.007, and p = 0.038, respectively), whereas no statistically significant difference was found between the menstrual-follicular phase and the periovulatory-luteal phase in the 15 premenopausal women with non-dense breasts. CONCLUSIONS: BPU in normal breast tissues assessed using ring-shaped dbPET was associated with mammographic density, menopausal status, and women's menstrual cycle. The menstrual cycle was significantly associated with BPU in premenopausal women with dense breasts but not in women with non-dense breasts.

Impact of Serum Zinc Level and Oral Zinc Supplementation on Clinical Outcomes in Patients Undergoing Infrainguinal Bypass for Chronic Limb-Threatening Ischemia.

BACKGROUND: Zinc (Zn) has been reported to play an important role in wound healing (WH). Nevertheless, the effect of Zn in chronic limb-threatening ischemia (CLTI) patients is unclear. This study investigated the effect of Zn on the clinical outcomes of CLTI patients undergoing bypass surgery.Methods and Results: This study reviewed 111 consecutive patients who underwent an infrainguinal bypass from 2012 to 2020. Patients with Zn deficiency (serum Zn level <60 µg/dL) received oral Zn supplementation and maintained a normal level until WH. This study aimed to explore: (1) the effect of Zn deficiency; and (2) Zn supplementation in Zn-deficient patients on the clinical outcomes of this cohort. Patients with Zn deficiency, Zn supplementation, and no Zn supplementation despite Zn deficiency accounted for 48, 21, and 42 patients, respectively. (1) Zn deficiency was associated with WH (HR, 0.47; 95% CI, 0.29-0.78: P=0.003), major adverse limb events (MALE) (HR, 2.53; 95% CI, 1.26-5.09: P=0.009), and major amputation or death (HR, 3.17; 95% CI, 1.51-6.63: P=0.002). (2) Zn supplementation was positively related to WH (HR, 2.30; 95% CI, 1.21-4.34: P=0.011). This result was confirmed using propensity score matching (HR, 2.24; 95% CI, 1.02-4.87: P=0.043). CONCLUSIONS: The current study revealed that Zn level was associated with clinical outcomes in CLTI patients after bypass surgery. Oral Zn supplementation could improve WH in these patients.

New Morphological Factor for Predicting Late Proximal Type I Endoleak after Endovascular Aneurysm Repair.

BACKGROUND: Although we have witnessed several cases of late proximal type I endoleak (T1AEL) after endovascular aneurysm repair (EVAR), most patients did not have "hostile neck" preoperatively. We hypothesized that the distance between the lowest renal artery and the neck angulation point and neck length are the 2 most important factors for maintaining long-term proximal sealing. This study evaluated "neck hostility," which is the product of the distance to the angulation point and the neck length, as a preoperative morphological risk factor for the development of late T1AEL after EVAR. METHODS: A retrospective review of a prospectively assembled database was performed for all patients who had undergone EVAR at a single institution from June 2007 to May 2017. Patient demographics and preoperative imaging data were collected, and Cox regression analysis was performed to identify the risk factors for late T1AEL. RESULTS: Of the 655 patients who underwent EVAR during the study period, 115 were excluded due to complex EVAR (n = 14), primary indications for iliac aneurysms (n = 86), primary T1AEL (n = 3), or other reasons (n = 15). Of the remaining 537 patients, twelve patients (2.2%) developed late T1AEL a median of 3.2 (interquartile range [IQR]; 3.0, 5.4) years after EVAR. Receiver operating characteristic (ROC) curve analysis revealed a neck hostility cutoff value of 8. Cox regression analysis revealed that a neck hostility value ≤8 and conical neck anatomy were risk factors for the development of late T1AEL after EVAR. Well-known hostile neck factors such as short neck, severe angulated neck, and severe calcification/thrombus in the proximal neck were not significantly different. CONCLUSIONS: The present study demonstrated a correlation between late T1AEL and the product of the angulation distance and the neck length. This factor may be useful for predicting poor late proximal outcomes after EVAR.

Versatile Post-Doping toward Two-Dimensional Semiconductors.

We have developed a simple and straightforward way to realize controlled postdoping toward 2D transition metal dichalcogenides (TMDs). The key idea is to use low-kinetic-energy dopant beams and a high-flux chalcogen beam simultaneously, leading to substitutional doping with controlled dopant densities. Atomic-resolution transmission electron microscopy has revealed that dopant atoms injected toward TMDs are incorporated substitutionally into the hexagonal framework of TMDs. The electronic properties of doped TMDs (Nb-doped WSe2) have shown drastic change and p-type action with more than 2 orders of magnitude increase in current. Position-selective doping has also been demonstrated by the postdoping toward TMDs with a patterned mask on the surface. The postdoping method developed in this work can be a versatile tool for 2D-based next-generation electronics in the future.