Polygenic risk and rare variant gene clustering enhance cancer risk stratification for breast and prostate cancers.

Polygenic risk score (PRS) and rare monogenic variant screening are valuable tools for predicting cancer risk and identifying individuals at high risk. Integrating both common and rare genetic variants is crucial for accurate risk assessment. However, estimating the impacts of rare variants on cancer and combining them with PRS remains challenging. Here, we analyze 454,711 exome sequencing and 487,409 array UK Biobank samples, focusing on breast and prostate cancers. We introduce an expanded PRS (EPRS) approach, yielding a systematic model for more effective risk stratification. By prioritizing and clustering genes with cancer-specific rare variants based on odds ratios and population-attributable fraction, we refine risk stratification by combining both monogenic and polygenic effects. Individuals in high-PRS groups with rare high-impact gene variants show up to 15- and 22-fold higher risk for breast and prostate cancers, respectively, compared to those in the intermediate-PRS groups without rare variants. Combined risk profiles vary across distinct rare variant clusters within the same PRS group for both cancers. Our EPRS approach enhances risk stratification for breast and prostate cancers, offering important insights for future research and potential applications to other cancer types.

Single-Center Experience With Dynamic Contrast-Enhanced Magnetic Resonance Lymphangiography for Diagnosing Lymphatic Disorders and Guiding Percutaneous Embolization.

BACKGROUND: The pragmatic role of dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) needs to be evaluated and compared across distinct lymphatic disorders. We aimed to evaluate the performance of DCMRL for identifying the underlying causes of lymphatic disorders and to define the potential benefit of DCMRL for planning lymphatic interventions. METHODS: Patients who underwent DCMRL between August 2017 and July 2022 were included in this retrospective analysis. DCMRL was performed with intranodal injection of a gadolinium-based contrast medium through inguinal lymph nodes under local anesthesia. Technical success of DCMRL and feasibility of percutaneous embolization were assessed based on the lymphatic anatomy visualized by DCMRL. Based on the underlying causes, clinical outcomes were evaluated and compared. RESULTS: Seventy consecutive patients were included. The indications were traumatic chylothorax (n = 42), traumatic chylous ascites (n = 11), and nontraumatic lymphatic leak (n = 17). The technical success rate of DCMRL was the highest in association with nontraumatic lymphatic disorders (94.1% [16/17]), followed by traumatic chylothorax (92.9% [39/42]) and traumatic chylous ascites (81.8% [9/11]). Thirty-one (47.7%) patients among 65 patients who underwent technically successful DCMRL had feasible anatomy for intervention. Clinical success was achieved in 90.3% (28/31) of patients with feasible anatomy for radiologic intervention, while 62.5% (10/16) of patients with anatomical challenges showed improvement. Most patients with traumatic chylothorax showed improvement (92.9% [39/42]), whereas only 23.5% (4/17) of patients with nontraumatic lymphatic disorders showed clinical improvement. CONCLUSION: DCMRL can help identify the underlying causes of lymphatic disorders. The performance of DCMRL and clinical outcomes vary based on the underlying cause. The feasibility of lymphatic intervention can be determined using DCMRL, which can help in predicting clinical outcomes.

Native Sinus Hemodynamics and Thrombosis in Transcatheter Heart Valve: Effect of Implant Depth and Coronary Flow.

BACKGROUND: This study aimed to investigate the hemodynamic and anatomic factors associated with sinus thrombosis following transcatheter aortic valve replacement (TAVR), integrating in vivo patient data analysis and in vitro experiments. METHODS AND RESULTS: Postprocedural, 4-dimensional, multiphase computed tomography data from 211 patients enrolled in the ADAPT-TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) study were analyzed. The prevalence of native sinus thrombosis was examined in relation to valve type, implant depth, and anatomic features. In vitro experiments used particle image velocimetry to observe changes in sinus flow based on the transcatheter heart valves (23-mm SAPIEN3, Edwards Lifesciences; and 29-mm CoreValve, Medtronic) height and coronary artery flow. Native sinus thrombosis was more common in self-expanding valves (39.1% versus 14.9%, P=0.004). In per-cusp analysis of in vivo patient data, adjusted transcatheter heart valve implant depth (odds ratio, 1.2 [95% CI, 1.1-1.3]; P<0.001), noncoronary sinus of Valsalva (odds ratio, 4.0 [95% CI, 2.0-7.8]; P<0.001), sinus inflow diameter (odds ratio, 0.8 [95% CI, 0.6-0.9]; P=0.008), and implanted valve size (odds ratio, 0.8 [95% CI, 0.7-1.0]; P=0.025) were significant factors associated with native sinus thrombosis. In the in vitro experiments, CoreValve showed noticeable flow stasis compared with SAPIEN3. High-positioned SAPIEN3 was linked to reduced velocity within the native sinus of Valsalva. Coronary artery flow led to higher sinus velocity and improved particle washout, reducing sinus thrombosis risk. CONCLUSIONS: This study provides insights into the relationship between transcatheter heart valve deployment and native sinus thrombosis, emphasizing the role of anatomic factors in relation to the risk of sinus thrombosis.

CT-derived myocardial strain measurement in patients with chronic constrictive pericarditis.

BACKGROUND: We aimed to compare computed tomography (CT)-derived myocardial strain between patients with constrictive pericarditis (CP) and a matched healthy control group and to identify factors associated with clinical outcomes after pericardiectomy. METHODS: This retrospective study included 65 patients with CP (mean age: 58.9 â€‹± â€‹8.0 years) and 65 healthy individuals (mean age: 58.0 â€‹± â€‹6.5 years) who underwent multiphase cardiac CT. The type of CP was classified as calcified CP or fibrotic CP. CT-derived strains from four cardiac chambers were compared between the CP and control groups, as well as between different types of CP. Clinical and CT-derived factors associated with adverse outcomes were identified using Cox regression analysis. RESULTS: Compared with the control group, the CP group showed significantly lower values of left atrium (LA) reservoir strain (15.7 â€‹% vs. 27.4 â€‹%), right atrium (RA) reservoir strain (15.1 â€‹% vs. 27.0 â€‹%), left ventricle (LV) global longitudinal strain (GLS) (-17.0 â€‹% vs. -19.5 â€‹%), and right ventricle free wall longitudinal strain (-21.1 â€‹% vs. -25.9 â€‹%) (all p â€‹< â€‹0.001). Biatrial reservoir strains and LV GLS were significantly lower in those with calcified CP compared to those with fibrotic CP. LA reservoir strain (hazard ratio, 0.91-95 â€‹% confidence interval, 0.86-0.96- p â€‹= â€‹0.001) was an independent prognostic factor for adverse events in patients with CP. CONCLUSION: Cardiac strain differences in CP were predominantly observed in the LA and RA compared to the healthy control group. Biatrial reservoir strains were specifically impaired in those with calcified CP than in those with fibrotic CP. LA reservoir strain was associated with prognosis in patients with CP following pericardiectomy.

Integrated electrochemical-adsorption for simultaneous removal of pharmaceuticals from water: Process optimization and synergistic insights.

Water contamination with pharmaceuticals has become an evident environmental challenge. Treatment processes such as electrochemical oxidation (EO) and adsorption have limitations in the simultaneous removal of pharmaceuticals from water. Therefore, this study examined the potential of coupled process (EO followed by adsorption) in binary pharmaceuticals (acetaminophen (ACM) + ciprofloxacin (CIP)) removal from water, with an emphasis on coupled process optimization. Consequently, optimized coupled process conditions including current density (22 mA/cm2), pH (5.5), EO time (40 min), adsorbent dose (0.1 g/L) and adsorption time (60 min) were obtained. Under optimal conditions, removal efficiencies of 94.6% (ACM)+92% (CIP), 94.07% (ACM)+91.15% (CIP), and > 99.8% (ACM + CIP) were recorded for 20 mg/L (ACM + CIP) removal in EO, adsorption and EO + adsorption, respectively. Further, the coupled process was employed in multiple pharmaceuticals (20 mg/L of ACM + CIP + ATN (atenolol) + AMX (amoxicillin)) removal from water and removal of > 97.56% (ACM + CIP + ATN + AMX) was achieved. Removal efficiencies of ACM (83.35%) + CIP (73.1%) + ATN (68.52%) + AMX (63.05%) and ACM (80.37%) + CIP (66.5%) + ATN (73.07%) + AMX (60.5%) were obtained in EO and adsorption, respectively. The noted lower removal efficiencies in EO and adsorption are associated with the diverse nature of the pharmaceuticals, limited adsorbent active sites, and the shared utilization of reactive oxygen species (ROS) among the pharmaceuticals in EO. The total organic carbon (TOC) removal of 40.24%, and 99% and chemical oxygen demand (COD) removal of 72.45%, and 99.6% were obtained under optimal conditions of EO, and coupled process, respectively. These findings indicate that the pharmaceuticals are only partially mineralized in EO and the subsequent adsorption effectively eliminated the remaining target pharmaceuticals, and degradation by-products from water. Additionally, integrating EO with adsorption reduced the electrical energy consumption of the EO process from 31.6 kWh/m³ to 6 kWh/m³ under optimal conditions. Overall, coupling EO with adsorption offers the utmost advantages when removing multiple pharmaceuticals from complex water matrices.

Architectural organization and in situ fusion protein structure of lymphocytic choriomeningitis virus.

Arenaviruses exist globally and can cause hemorrhagic fever and neurological diseases, exemplified by the zoonotic pathogen lymphocytic choriomeningitis virus (LCMV). The structures of individual LCMV proteins or their fragments have been reported, but the architectural organization and the nucleocapsid assembly mechanism remain elusive. Importantly, the in situ structure of the arenavirus fusion protein complex (glycoprotein complex, GPC) as present on the virion prior to fusion, particularly with its integral stable signal peptide (SSP), has not been shown, hindering efforts such as structure-based vaccine design. Here, we have determined the in situ structure of LCMV proteins and their architectural organization in the virion by cryogenic electron tomography. The tomograms reveal the global distribution of GPC, matrix protein Z, and the contact points between the viral envelope and nucleocapsid. Subtomogram averaging yielded the in situ structure of the mature GPC with its transmembrane domain intact, revealing the GP2-SSP interface and the endodomain of GP2. The number of RNA-dependent RNA polymerase L molecules packaged within each virion varies, adding new perspectives to the infection mechanism. Together, these results delineate the structural organization of LCMV and offer new insights into its mechanism of LCMV maturation, egress, and cell entry. IMPORTANCE: The impact of COVID-19 on public health has highlighted the importance of understanding zoonotic pathogens. Lymphocytic choriomeningitis virus (LCMV) is a rodent-borne human pathogen that causes hemorrhagic fever. Herein, we describe the in situ structure of LCMV proteins and their architectural organization on the viral envelope and around the nucleocapsid. The virion structure reveals the distribution of the surface glycoprotein complex (GPC) and the contact points between the viral envelope and the underlying matrix protein, as well as the association with the nucleocapsid. The morphology and sizes of virions, as well as the number of RNA polymerase L inside each virion vary greatly, highlighting the fast-changing nature of LCMV. A comparison between the in situ GPC trimeric structure and prior ectodomain structures identifies the transmembrane and endo domains of GPC and key interactions among its subunits. The work provides new insights into LCMV assembly and informs future structure-guided vaccine design.

Virtual stimulation of the interictal EEG network localizes the EZ as a measure of cortical excitability.

Introduction: For patients with drug-resistant epilepsy, successful localization and surgical treatment of the epileptogenic zone (EZ) can bring seizure freedom. However, surgical success rates vary widely because there are currently no clinically validated biomarkers of the EZ. Highly epileptogenic regions often display increased levels of cortical excitability, which can be probed using single-pulse electrical stimulation (SPES), where brief pulses of electrical current are delivered to brain tissue. It has been shown that high-amplitude responses to SPES can localize EZ regions, indicating a decreased threshold of excitability. However, performing extensive SPES in the epilepsy monitoring unit (EMU) is time-consuming. Thus, we built patient-specific in silico dynamical network models from interictal intracranial EEG (iEEG) to test whether virtual stimulation could reveal information about the underlying network to identify highly excitable brain regions similar to physical stimulation of the brain. Methods: We performed virtual stimulation in 69 patients that were evaluated at five centers and assessed for clinical outcome 1 year post surgery. We further investigated differences in observed SPES iEEG responses of 14 patients stratified by surgical outcome. Results: Clinically-labeled EZ cortical regions exhibited higher excitability from virtual stimulation than non-EZ regions with most significant differences in successful patients and little difference in failure patients. These trends were also observed in responses to extensive SPES performed in the EMU. Finally, when excitability was used to predict whether a channel is in the EZ or not, the classifier achieved an accuracy of 91%. Discussion: This study demonstrates how excitability determined via virtual stimulation can capture valuable information about the EZ from interictal intracranial EEG.

Network excitability of stimulation-induced spectral responses helps localize the seizure onset zone.

OBJECTIVE: While evoked potentials elicited by single pulse electrical stimulation (SPES) may assist seizure onset zone (SOZ) localization during intracranial EEG (iEEG) monitoring, induced high frequency activity has also shown promising utility. We aimed to predict SOZ sites using induced cortico-cortical spectral responses (CCSRs) as an index of excitability within epileptogenic networks. METHODS: SPES was conducted in 27 epilepsy patients undergoing iEEG monitoring and CCSRs were quantified by significant early (10-200 ms) increases in power from 10 to 250 Hz. Using response power as CCSR network connection strengths, graph centrality measures (metrics quantifying each site's influence within the network) were used to predict whether sites were within the SOZ. RESULTS: Across patients with successful surgical outcomes, greater CCSR centrality predicted SOZ sites and SOZ sites targeted for surgical treatment with median AUCs of 0.85 and 0.91, respectively. We found that the alignment between predicted and targeted SOZ sites predicted surgical outcome with an AUC of 0.79. CONCLUSIONS: These findings indicate that network analysis of CCSRs can be used to identify increased excitability of SOZ sites and discriminate important surgical targets within the SOZ. SIGNIFICANCE: CCSRs may supplement traditional passive iEEG monitoring in seizure localization, potentially reducing the need for recording numerous seizures.

Deep Learning Based Automatic Segmentation of the Thoracic Aorta from Chest Computed Tomography in Healthy Korean Adults.

OBJECTIVE: Segmenting the aorta into zones based on anatomical landmarks is a current trend to better understand interventions for aortic dissection or aneurysm. However, comprehensive reference values for aortic zones are lacking. The aim of this study was to establish reference values for aortic size using a fully automated deep learning based segmentation method. METHODS: This retrospective study included 704 healthy adults (mean age 50.6 ± 7.5 years; 407;57.8%] males) who underwent contrast enhanced chest computed tomography (CT) for health screening. A convolutional neural network (CNN) was trained and applied on 3D CT images for automatic segmentation of the aorta based on the Society for Vascular Surgery and Society of Thoracic Surgeons classification. The CNN generated masks were reviewed and corrected by expert cardiac radiologists. RESULTS: Aortic size was significantly larger in males than in females across all zones (zones 0 - 8, all p < .001). The aortic size in each zone increased with age, by approximately 1 mm per 10 years of age, e.g., 25.4, 26.7, 27.5, 28.8, and 29.8 mm at zone 2 in men in the age ranges of 30 - 39, 40 - 49, 50 - 59, 60 - 69, and ≥ 70 years, respectively (all p < .001). CONCLUSION: The deep learning algorithm provided reliable values for aortic size in each zone, with automatic masks comparable to manually corrected ones. Aortic size was larger in males and increased with age. These findings have clinical implications for the detection of aortic aneurysms and other aortic diseases.

Reference ranges of computed tomography-derived strains in four cardiac chambers.

Research on cardiovascular diseases using CT-derived strain is gaining momentum, yet there is a paucity of information regarding reference standard values beyond echocardiography, particularly in cardiac chambers other than the left ventricle (LV). We aimed to compile CT-derived strain values from the four cardiac chambers in healthy adults and assess the impact of age and sex on myocardial strains. This study included 101 (mean age: 55.2 ± 9.0 years, 55.4% men) consecutive healthy individuals who underwent multiphase cardiac CT. CT-derived cardiac strains, including LV global and segmental longitudinal, circumferential, and transverse strains, left atrial (LA), right atrial (RA), and right ventricle (RV) strains were measured by the commercially available software. Strain values were classified and compared by their age and sex. The normal range of CT-derived LV global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were -20.2 ± 2.7%, -27.9 ± 4.1%, and 49.4 ± 12.1%, respectively. For LA, reservoir strain, pump strain, and conduit strain were 28.6 ± 8.5%, 13.2 ± 6.4%, and 15.5 ± 8.6%, respectively. The GLS of RA and RV were 27.9 ± 10.9% and -22.0 ± 5.7%, respectively. The absolute values of GLS of RA and RV of women were higher than that in men (32.4 ± 11.4 vs. 24.3 ± 9.1 and -25.2 ± 4.7 vs. -19.4 ± 5.0, respectively; p<0.001, both). Measurement of CT-derived strain in four cardiac chambers is feasible. The reference ranges of CT strains in four cardiac chambers can be used for future studies of various cardiac diseases using the cardiac strains.

Stacked neural network for predicting polygenic risk score.

In recent years, the utility of polygenic risk scores (PRS) in forecasting disease susceptibility from genome-wide association studies (GWAS) results has been widely recognised. Yet, these models face limitations due to overfitting and the potential overestimation of effect sizes in correlated variants. To surmount these obstacles, we devised the Stacked Neural Network Polygenic Risk Score (SNPRS). This novel approach synthesises outputs from multiple neural network models, each calibrated using genetic variants chosen based on diverse p-value thresholds. By doing so, SNPRS captures a broader array of genetic variants, enabling a more nuanced interpretation of the combined effects of these variants. We assessed the efficacy of SNPRS using the UK Biobank data, focusing on the genetic risks associated with breast and prostate cancers, as well as quantitative traits like height and BMI. We also extended our analysis to the Korea Genome and Epidemiology Study (KoGES) dataset. Impressively, our results indicate that SNPRS surpasses traditional PRS models and an isolated deep neural network in terms of accuracy, highlighting its promise in refining the efficacy and relevance of PRS in genetic studies.

Predictors of Late Adverse Events in Patients with Surgically Treated Type I Aortic Dissection.

OBJECTIVE: Residual aortic dissection (AD) following DeBakey type I AD repair is associated with a high rate of adverse events that need additional intervention or surgery. This study aimed to identify clinical and early post-operative computed tomography angiography (CTA) imaging factors associated with adverse events in patients with type I AD after ascending aorta replacement. METHODS: This single centre, retrospective cohort study included consecutive patients with type I AD who underwent ascending aorta replacement from January 2011 to December 2017 and post-operative CTA within three months. The primary outcome was AD related adverse events, defined as AD related death and re-operation due to aortic aneurysm or impending rupture. The location and size of the primary intimal tears, aortic diameter, and false lumen status were evaluated. Regression analyses were performed to identify factors associated with AD related adverse events. A decision tree model was used to classify patients as high or low risk. RESULTS: Of 103 participants (55.43 ± 13.94 years; 49.5% male), 24 (23.3%) experienced AD related adverse events. In multivariable Cox regression analysis, connective tissue disease (hazard ratio [HR] 15.33; p < .001), maximum aortic diameter ≥ 40 mm (HR 4.90; p < .001), and multiple (three or more) intimal tears (HR 7.12; p < .001) were associated with AD related adverse events. The three year cumulative survival free from AD related events was lower in the high risk group with aortic diameter ≥ 40 mm and multiple intimal tears (41.7% vs. 90.9%; p < .001). CONCLUSION: Early post-operative CTA findings indicating a maximum aortic diameter ≥ 40 mm and multiple intimal tears may predict a higher risk of adverse events. These findings suggest the need for careful monitoring and more vigilant management approaches in these cases.

Comparison of Audience Behavior between eSports and Authentic Sports Fans.

This study analyzed how the behavioral patterns of esports and authentic sports viewers differ, adopting user and gratification theory and media transportation theory. In particular, it was investigated whether there was a difference in behavioral patterns according to the experience of playing the sport even among authentic sports viewers. As a result of analyzing the relationship between viewers' motivation and media transportation outcomes through structural equation modeling and multigroup structural equation modeling, it was observed that cognitive motivation was more important for esports viewers than for authentic sports viewers. A second analysis of comparisons among fans of authentic sports showed that viewers with sports experience had greater cognitive needs. This result shows that there is a difference between the viewer behaviors of esports and traditional sports, but it is concluded that the presence or absence of sports participation experience rather than content is the factor that separates the difference.

Preoperative Hindfoot Alignment and Outcomes After High Tibial Osteotomy for Varus Knee Osteoarthritis: We Walk on Our Heel, Not Our Ankle.

UPDATE: This article was updated on May 15, 2024 because of previous errors, which were discovered after the preliminary version of the article was posted online. On page 898, in the section entitled "Materials and Methods," the sentence that had read "The WBL ratio of the knee joint was defined as the point where the GA or MA passed through the width of the tibia and intersected a line from the center of the femoral head to the center of the calcaneus (for the GA) or talus (for the MA), with the medial edge defined as 0% and the lateral edge as 100%." now reads "The WBL ratio of the knee joint was defined as the point where the GA or MA passed through the width of the tibia and intersected a line from the center of the femoral head to the lowest point of the calcaneus (for the GA) or the center of the talus (for the MA), with the medial edge defined as 0% and the lateral edge as 100%." Likewise, in the legend for Figure 3 on page 899, the sentence that had read "Depiction of the ground mechanical axis (GA), defined as the line (represented by the solid red line) from the center of the femoral head to the ground reaction point at the center of the calcaneus, passing lateral to the traditional mechanical axis (MA; represented by the dashed red line)." now reads "Depiction of the ground mechanical axis (GA), defined as the line (represented by the solid red line) from the center of the femoral head to the ground reaction point at the lowest point of the calcaneus, passing lateral to the traditional mechanical axis (MA; represented by the dashed red line)." Finally, on page 903, "HKA" was changed to "HKA angle" in Table III. BACKGROUND: The hip-to-calcaneus axis, previously known as the ground mechanical axis (GA), ideally passes through the center of the knee joint in the native knee. The aim of this study was to elucidate, with use of hip-to-calcaneus radiographs, changes in knee and hindfoot alignment and changes in outcomes following high tibial osteotomy (HTO). METHODS: We reviewed the records for 128 patients who underwent HTO between 2018 and 2020. Patients were stratified into 2 groups, a hindfoot valgus group (n = 94) and a hindfoot varus group (n = 34), on the basis of their preoperative hindfoot alignment. The hindfoot alignment was evaluated with use of the hindfoot alignment angle (HAA). To evaluate lower-limb alignment, full-length standing posteroanterior hip-to-calcaneus radiographs were utilized to measure 4 radiographic parameters preoperatively and 2 years postoperatively: the hip-knee-ankle (HKA) angle, hip-knee-calcaneus (HKC) angle, and the weight-bearing line (WBL) ratios of the mechanical axis (MA) and GA. RESULTS: The mean HAA improved significantly from 5.1° valgus preoperatively to 1.9° valgus postoperatively in the hindfoot valgus group (p < 0.001). In contrast, in the hindfoot varus group, the HAA showed no meaningful improvement in the coronal alignment of the hindfoot following HTO (p = 0.236). The postoperative mean HKC angle in the hindfoot varus group was 2° more varus than that in the hindfoot valgus group (1.0° versus 3.0°; p = 0.001), and the GA in the hindfoot varus group passed across the knee 8.0% more medially than that in the hindfoot valgus group (55% versus 63% from the most medial to the most lateral part of the tibial plateau). The hindfoot varus group had worse postoperative clinical outcomes than the hindfoot valgus group in terms of the mean Knee injury and Osteoarthritis Outcome Score for pain and American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Score. CONCLUSIONS: Although our findings did not provide sufficient evidence to establish clinically relevant differences between the groups, they indicated that the group with a preoperative fixed hindfoot varus deformity had a higher rate of undercorrection and worse clinical outcomes, especially pain, following HTO. Therefore, modification of the procedure to shift the GA more laterally may be required for these patients. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

A Thrombus within an Interventricular Membranous Septal Aneurysm Leading to Cerebral Infarction: A Case Report.

Interventricular membranous septal aneurysms are rare. Since these aneurysms can lead to complications such as obstruction of right ventricular outflow and thromboembolism, the detection of this aneurysm has clinical significance. Herein, we report a case of an interventricular membranous septal aneurysm with an internal thrombus thought to be the cause of a cerebral infarction.

The Temporal Lobe Club: Newer Approaches to Treat Temporal Lobe Epilepsy.

This brief review summarizes presentations at the Temporal Lobe Club Special Interest Group session held in December 2022 at the American Epilepsy Society meeting. The session addressed newer methods to treat temporal epilepsy, including methods currently in clinical use and techniques under investigation. Brief summaries are provided for each of 4 lectures. Dr Chengyuan Wu discussed ablative techniques such as laser interstitial thermal ablation, radiofrequency ablation, focused ultrasound; Dr Joon Kang reviewed neuromodulation techniques including electrical stimulation and focused ultrasound; Dr Julia Makhalova discussed network effects of the aforementioned techniques; and Dr Derek Southwell reviewed inhibitory interneuron transplantation. These summaries are intended to provide a brief overview and references are provided for the reader to learn more about each topic.

Low- or standard-dose edoxaban versus antiplatelet therapy for leaflet thrombus and cerebral thromboembolism after TAVR: A prespecified analysis of randomized ADAPT-TAVR trial.

BACKGROUND: The risks of leaflet thrombosis and the associated cerebral thromboembolism are unknown according to different anticoagulation dosing after transcatheter aortic valve replacement (TAVR). The aim was to evaluate the incidence of leaflet thrombosis and cerebral thromboembolism between low-dose (30 mg) or standard-dose (60 mg) edoxaban and dual antiplatelet therapy (DAPT) after TAVR. METHODS: In this prespecified subgroup analysis of the ADAPT-TAVR trial, the primary endpoint was the incidence of leaflet thrombosis on 4-dimensional computed tomography at 6-months. Key secondary endpoints were new cerebral lesions on brain magnetic resonance imaging and neurological and neurocognitive dysfunction. RESULTS: Of 229 patients enrolled in this study, 118 patients were DAPT group and 111 were edoxaban group (43 [39.1%] 60 mg vs 68 [61.3%] 30 mg). There was a significantly lower incidence of leaflet thrombosis in the standard-dose edoxaban group than in the DAPT group (2.4% vs 18.3%; odds ratio [OR] 0.11; 95% confidence interval [CI], 0.01-0.55; P = .03). However, no significant difference was observed between low-dose edoxaban and DAPT (15.0% vs 18.3%; OR 0.79; 95% CI, 0.32-1.81; P = .58). Irrespective of different antithrombotic regiments, the percentages of patients with new cerebral lesions on brain MRI and worsening neurological or neurocognitive function were not significantly different. CONCLUSIONS: In patients without an indication for anticoagulation after TAVR, the incidence of leaflet thrombosis was significantly lower with standard-dose edoxaban but not with low-dose edoxaban, as compared with DAPT. However, this differential effect of edoxaban on leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and neurological dysfunction.

Tailored Planning of Surgical Myectomy in Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disease characterized by abnormal thickening of the myocardium caused by myocardial disarray and interstitial fibrosis. HCM is associated with sudden cardiac-related events, such as ventricular fibrillation, tachycardia, and syncope. Moreover, left ventricular or midcavity obstruction due to the thickened myocardium can result in severe heart failure and mortality in patients with HCM. Surgical myectomy is a standard treatment option for patients with symptomatic obstructive HCM; however, it is a complex procedure that requires careful planning and execution to avoid complications, such as residual flow obstruction, persistent obliteration of the left ventricular cavity in systole, or iatrogenic ventricular septal defects. Therefore, a thorough understanding of the mechanics of HCM and precise evaluation of the location and extent of the hypertrophic myocardium to be removed are crucial for preoperative planning. Multiphase cardiac CT postprocessing is important for preoperative evaluation and planning of surgical myectomy in patients with HCM. In this review, the authors highlight use of multiphase cardiac CT with step-by-step postprocessing methods to simulate successful surgical myectomy. The transaortic surgeon's view on end-diastolic phase images accurately represents the surgical field. Moreover, myocardial segmentation can be used to generate volume-rendered images and three-dimensional printing. CT evaluation can also assist in identifying concurrent abnormalities, such as mitral valve or papillary muscle abnormalities. In addition to CT, other imaging modalities for preoperative evaluation of HCM and postmyectomy evaluation methods are presented. ©RSNA, 2023 Test Your Knowledge questions in the supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.

Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma.

Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the ß-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the ß-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.

Evaluation of optimal methods and ancestries for calculating polygenic risk scores in East Asian population.

Polygenic risk scores (PRSs) have been studied for predicting human diseases, and various methods for PRS calculation have been developed. Most PRS studies to date have focused on European ancestry, and the performance of PRS has not been sufficiently assessed in East Asia. Herein, we evaluated the predictive performance of PRSs for East Asian populations under various conditions. Simulation studies using data from the Korean cohort, Health Examinees (HEXA), demonstrated that SBayesRC and PRS-CS outperformed other PRS methods (lassosum, LDpred-funct, and PRSice) in high fixed heritability (0.3 and 0.7). In addition, we generated PRSs using real-world data from HEXA for ten diseases: asthma, breast cancer, cataract, coronary artery disease, gastric cancer, glaucoma, hyperthyroidism, hypothyroidism, osteoporosis, and type 2 diabetes (T2D). We utilized the five previous PRS methods and genome-wide association study (GWAS) data from two biobank-scale datasets [European (UK Biobank) and East Asian (BioBank Japan) ancestry]. Additionally, we employed PRS-CSx, a PRS method that combines GWAS data from both ancestries, to generate a total of 110 PRS for ten diseases. Similar to the simulation results, SBayesRC showed better predictive performance for disease risk than the other methods. Furthermore, the East Asian GWAS data outperformed those from European ancestry for breast cancer, cataract, gastric cancer, and T2D, but neither of the two GWAS ancestries showed a significant advantage on PRS performance for the remaining six diseases. Based on simulation data and real data studies, it is expected that SBayesRC will offer superior performance for East Asian populations, and PRS generated using GWAS from non-East Asian may also yield good results.