Flat-surface-assisted and self-regulated oxidation resistance of Cu(111).

Oxidation can deteriorate the properties of copper that are critical for its use, particularly in the semiconductor industry and electro-optics applications1-7. This has prompted numerous studies exploring copper oxidation and possible passivation strategies8. In situ observations have, for example, shown that oxidation involves stepped surfaces: Cu2O growth occurs on flat surfaces as a result of Cu adatoms detaching from steps and diffusing across terraces9-11. But even though this mechanism explains why single-crystalline copper is more resistant to oxidation than polycrystalline copper, the fact that flat copper surfaces can be free of oxidation has not been explored further. Here we report the fabrication of copper thin films that are semi-permanently oxidation resistant because they consist of flat surfaces with only occasional mono-atomic steps. First-principles calculations confirm that mono-atomic step edges are as impervious to oxygen as flat surfaces and that surface adsorption of O atoms is suppressed once an oxygen face-centred cubic (fcc) surface site coverage of 50% has been reached. These combined effects explain the exceptional oxidation resistance of ultraflat Cu surfaces.

Sniper2L is a high-fidelity Cas9 variant with high activity.

Although several high-fidelity SpCas9 variants have been reported, it has been observed that this increased specificity is associated with reduced on-target activity, limiting the applications of the high-fidelity variants when efficient genome editing is required. Here, we developed an improved version of Sniper-Cas9, Sniper2L, which represents an exception to this trade-off trend as it showed higher specificity with retained high activity. We evaluated Sniper2L activities at a large number of target sequences and developed DeepSniper, a deep learning model that can predict the activity of Sniper2L. We also confirmed that Sniper2L can induce highly efficient and specific editing at a large number of target sequences when it is delivered as a ribonucleoprotein complex. Mechanically, the high specificity of Sniper2L originates from its superior ability to avoid unwinding a target DNA containing even a single mismatch. We envision that Sniper2L will be useful when efficient and specific genome editing is required.

Structural Asymmetry and Chiral-Induced Spin Selectivity in Chiral Palladium-Halide Semiconductors.

Chiral Pb-free metal-halide semiconductors (MHSs) have attracted considerable attention in the field of spintronics due to various interesting spin-related properties and chiral-induced spin selectivity (CISS) effect. Despite their excellent chemical and structural tunability, the material scope and crystal structure of Pb-free chiral MHSs exhibiting the CISS effect are still limited; chiral MHSs that have metal-halide structures of octahedra and tetrahedra are only reported. Here, we report a new class of chiral MHSs, of which palladium (Pd)-halides are formed in 1D square-pyramidal structures or 0D square-planar structures, with a general formula of ((R/S-MBA)2PdBr4)1-x((R/S-MBA)2PdCl4)x (MBA = methylbenzylammonium; x = 0, 0.25, 0.5, 0.75, and 1) for the first time. The crystals adopt the 1D helical chain of Pd-halide square-pyramid (for x = 0, 0.25, 0.5, and 0.75) and 0D structure of Pd-halide square-plane (for x = 1). All the Pd-halides are distorted by the interaction between the halide and the chiral organic ammonium and arranged in a noncentrosymmetric position. Circular dichroism (CD) for ((R/S-MBA)2PdBr4)1-x((R/S-MBA)2PdCl4)x indicates that chirality was transferred from chiral organic ammonium to Pd-halide inorganics. ((R-MBA)2PdBr4)1-x((R-MBA)2PdCl4)x (x = 0, 0.25, 0.5, and 0.75) shows a distortion index of 0.127-0.128, which is the highest value among the previously reported chiral MHSs to the best of our knowledge. We also find that (R/S-MBA)2Pd(Br1-xClx)4 crystals grow along the out-of-plane direction during spin coating and have high c-axis orientation and crystallinity, and (R/S-MBA)2Pd(Br1-xClx)4 (x = 0 and 0.5) crystals exhibit a CISS effect in polycrystalline bulk films. These results demonstrate the possibility of a new metal-halide series with square-planar structures or square-pyramidal structures for future spintronic applications.

Regional disparities and risk factors of mortality among patients at high risk of sudden cardiac death in emerging countries: a nonrandomized controlled trial.

BACKGROUND: Comprehensive data on patients at high risk of sudden cardiac death (SCD) in emerging countries are lacking. The aim was to deepen our understanding of the SCD phenotype and identify risk factors for death among patients at high risk of SCD in emerging countries. METHODS: Patients who met the class I indication for implantable cardioverter-defibrillator (ICD) implantation according to guideline recommendations in 17 countries and regions underrepresented in previous trials were enrolled. Countries were stratified by the WHO regional classification. Patients were or were not implanted with an ICD at their discretion. The outcomes were all-cause mortality and SCD. RESULTS: We enrolled 4222 patients, and 3889 patients were included in the analysis. The mean follow-up period was 21.6 ± 10.2 months. There were 433 (11.1%) instances of all-cause mortality and 117 (3.0%) cases of SCD. All-cause mortality was highest in primary prevention (PP) patients from Southeast Asia and secondary prevention (SP) patients from the Middle East and Africa. The SCD rates among PP and SP patients were both highest in South Asia. Multivariate Cox regression modelling demonstrated that in addition to the independent predictors identified in previous studies, both geographic region and ICD use were associated with all-cause mortality in patients with high SCD risk. Primary prophylactic ICD implantation was associated with a 36% (HR = 0.64, 95% CI 0.531-0.802, p < 0.0001) lower all-cause mortality risk and an 80% (HR = 0.20, 95% CI = 0.116-0.343, p < 0.0001) lower SCD risk. CONCLUSIONS: There was significant heterogeneity among patients with high SCD risk in emerging countries. The influences of geographic regions on patient characteristics and outcomes were significant. Improvement in increasing ICD utilization and uptake of guideline-directed medical therapy in emerging countries is urgent. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02099721.

Suppression of Thermally Induced Surface Traps in Colloidal Quantum Dot Solids via Ultrafast Pulsed Light.

Thermal annealing (TA) of colloidal quantum dot (CQD) films is considered an important process for recent high-performing CQD solar cells (SCs) due to its beneficial effects on CQD solids, including enhanced electrical conductivity, denser packing of CQD films, and the removal of organic residues and solvents. However, the conventional TA for CQDs, which requires several  minutes, leads to hydroxylation and oxidation on the CQD surface, resulting in the formation of trap states and a subsequent decline in SC performance. To address these challenges, this study introduces a flashlight annealing (FLA) technique that significantly reduces the annealing time to the millisecond scale. Through the FLA approach, it successfully suppressed hydroxylation and oxidation, resulting in decreased trap states within the CQD solids while simultaneously preserving their charge transport properties. As a result, CQD SCs treated with FLA exhibited a notable improvement, achieving an open-circuit voltage of 0.66 V compared to 0.63 V in TA-treated devices, leading to an increase in power conversion efficiency from 12.71% to 13.50%.

Interfacial Triboelectricity Lights Up Phosphor-Polymer Elastic Composites: Unraveling the Mechanism of Mechanoluminescence in Zinc Sulfide Microparticle-Embedded Polydimethylsiloxane Films.

Composites comprising copper-doped zinc sulfide phosphor microparticles embedded in polydimethylsiloxane (ZnS:Cu-PDMS) have received significant attention over the past decade because of their bright and durable mechanoluminescence (ML); however, the underlying mechanism of this unique ML remains unclear. This study reports empirical and theoretical findings that confirm this ML is an electroluminescence (EL) of the ZnS:Cu phosphor induced by the triboelectricity generated at the ZnS:Cu microparticle-PDMS matrix interface. ZnS:Cu microparticles that exhibit bright ML are coated with alumina, an oxide with strong positive triboelectric properties; the contact separation between this oxide coating and PDMS, a polymer with strong negative triboelectric properties, produces sufficient interfacial triboelectricity to induce EL in ZnS:Cu microparticles. The ML of ZnS:Cu-PDMS composites varies on changing the coating material, exhibiting an intensity that is proportional to the amount of interfacial triboelectricity generated in the system. Finally, based on these findings, a mechanism that explains the ML of phosphor-polymer elastic composites (interfacial triboelectric field-driven alternating-current EL model) is proposed in this study. It is believed that understanding this mechanism will enable the development of new materials (beyond ZnS:Cu-PDMS systems) with bright and durable ML.

Association of temporal change in body mass index with sudden cardiac arrest in diabetes mellitus.

BACKGROUND: Underweight imposes significant burden on cardiovascular outcomes in patients with diabetes mellitus. However, less is known about the impact of serial change in body weight status measured as body mass index (BMI) on the risk of sudden cardiac arrest (SCA). This study investigated the association between SCA and temporal change in BMI among patients with diabetes mellitus. METHODS: Based on Korean National Health Insurance Service database, participants with diabetes mellitus who underwent health examination between 2009 and 2012 and had prior health examination data (four years ago, 2005-2008) were retrospectively analyzed. BMI was measured at baseline (2005-2008) and 4-year follow-up health examination (2009-2012). Patients were classified in four groups according to the body weight status and its temporal change: sustained non-underweight, sustained underweight, previous underweight, and newly developed underweight. Primary outcome was defined as occurrence of SCA. RESULTS: A total of 1,355,746 patients with diabetes mellitus were included for analysis, and SCA occurred in 12,554 cases. SCA was most common in newly developed underweight (incidence rate = 4.45 per 1,000 person-years), followed by sustained underweight (incidence rate = 3.90), previous underweight (incidence rate = 3.03), and sustained non-underweight (incidence rate = 1.34). Adjustment of covariates resulted highest risk of SCA in sustained underweight (adjusted hazard ratio = 2.60, 95% confidence interval [2.25-3.00], sustained non-underweight as a reference), followed by newly developed underweight (2.42, [2.15-2.74]), and previous underweight (2.12, [1.77-2.53]). CONCLUSIONS: In diabetes mellitus, sustained underweight as well as decrease in body weight during 4-year follow-up imposes substantial risk on SCA. Recovery from underweight over time had relatively lower, but yet increased risk of SCA. Both underweight and dynamic decrease in BMI can be associated with increased risk of SCA.

Assessment of imaging risks for recurrence after stereotactic radiosurgery for brain metastases (IRRaS-BM).

BACKGROUND: The identification of viable tumors and radiation necrosis after stereotactic radiosurgery (SRS) is crucial for patient management. Tumor habitat analysis involving the grouping of similar voxels can identify subregions that share common biology and enable the depiction of areas of tumor recurrence and treatment-induced change. This study aims to validate an imaging biomarker for tumor recurrence after SRS for brain metastasis by conducting tumor habitat analysis using multi-parametric MRI. METHODS: In this prospective study (NCT05868928), patients with brain metastases will undergo multi-parametric MRI before SRS, and then follow-up MRIs will be conducted every 3 months until 24 months after SRS. The multi-parametric MRI protocol will include T2-weighted and contrast-enhanced T1-weighted imaging, diffusion-weighted imaging, and dynamic susceptibility contrast imaging. Using k-means voxel-wise clustering, this study will define three structural MRI habitats (enhancing, solid low-enhancing, and nonviable) on T1- and T2-weighted images and three physiologic MRI habitats (hypervascular cellular, hypovascular cellular, and nonviable) on apparent diffusion coefficient maps and cerebral blood volume maps. Using RANO-BM criteria as the reference standard, via Cox proportional hazards analysis, the study will prospectively evaluate associations between parameters of the tumor habitats and the time to recurrence. The DICE similarity coefficients between the recurrence site and tumor habitats will be calculated. DISCUSSION: The tumor habitat analysis will provide an objective and reliable measure for assessing tumor recurrence from brain metastasis following SRS. By identifying subregions for local recurrence, our study could guide the next therapeutic targets for patients after SRS. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT05868928).

Atrial Fibrillation and Risk of Sudden Cardiac Arrest in Young Adults.

BACKGROUND AND AIMS: Evidence of an association between atrial fibrillation (AF) and sudden cardiac arrest (SCA) in young adults is limited. We aimed to evaluate this association in a general population aged between 20-39 years. METHODS: Young adults who underwent health check-ups between 2009 and 2012 were screened from a nationwide healthcare database in South Korea. A history of AF diagnosis before the health check-ups was identified based on the relevant International Classification of Diseases, 10th edition codes reported in the database. Associations between an established diagnosis of AF and the risk of SCA during follow-up were examined. RESULTS: A total of 6,345,162 young people were analyzed with a mean follow-up duration of 9.4 years. The mean age was 30.9 ± 5.0 years, and 5,875 (0.09%) individuals were diagnosed with AF. During follow-up, SCA occurred in 5,352 (0.08%) individuals, and the crude incidence was 0.56 and 0.09 events per 1,000 person-years for participants with and without AF, respectively. Individuals with AF had a 3.0-fold higher risk in a multivariate model adjusted for age, sex, lifestyle, anthropometric data, and medical comorbidities (adjusted hazard ratio 2.96, 95% confidence interval 1.99-4.41, p<0.001). Both incident and prevalent AF were associated with an increased risk of SCA, with no significant differences between the two groups. CONCLUSION: Atrial fibrillation was associated with a significantly higher risk of developing SCA in healthy young adults. Whether the rate or rhythm affects the risk of SCA in young patients with AF remains to be examined.

2024 European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society expert consensus statement on catheter and surgical ablation of atrial fibrillation.

In the last three decades, ablation of atrial fibrillation (AF) has become an evidence-based safe and efficacious treatment for managing the most common cardiac arrhythmia. In 2007, the first joint expert consensus document was issued, guiding healthcare professionals involved in catheter or surgical AF ablation. Mounting research evidence and technological advances have resulted in a rapidly changing landscape in the field of catheter and surgical AF ablation, thus stressing the need for regularly updated versions of this partnership which were issued in 2012 and 2017. Seven years after the last consensus, an updated document was considered necessary to define a contemporary framework for selection and management of patients considered for or undergoing catheter or surgical AF ablation. This consensus is a joint effort from collaborating cardiac electrophysiology societies, namely the European Heart Rhythm Association, the Heart Rhythm Society, the Asia Pacific Heart Rhythm Society, and the Latin American Heart Rhythm Society .

RNA Remodeling Activity of DEAD Box Proteins Tuned by Protein Concentration, RNA Length, and ATP.

DEAD box RNA helicases play central roles in RNP biogenesis. We reported earlier that LAF-1, a DEAD box RNA helicase in C. elegans, dynamically interacts with RNA and that the interaction likely contributes to the fluidity of RNP droplets. Here we investigate the molecular basis of the interaction of RNA with LAF-1 and its human homolog, DDX3X. We show that both LAF-1 and DDX3X, at low concentrations, are monomers that induce tight compaction of single-stranded RNA. At high concentrations, the proteins are multimeric and dynamically interact with RNA in an RNA length-dependent manner. The dynamic LAF-1-RNA interaction stimulates RNA annealing activity. ATP adversely affects the RNA remodeling ability of LAF-1 by suppressing the affinity, dynamics, and annealing activity of LAF-1, suggesting that ATP may promote disassembly of the RNP complex. Based on our results, we postulate a plausible molecular mechanism underlying the dynamic equilibrium of the LAF-1 RNP complex.

Endoscopic decompression of severe post-tuberculosis kyphosis related ossification of the ligamentum flavum: case report and literature review.

PURPOSE: Spinal tuberculosis, if not promptly treated, can lead to kyphotic deformity, causing persistent neurological abnormalities and discomfort. Spinal cord compression can occur due to ossification of the ligamentum flavum (OLF) at the apex of kyphosis. Traditional surgical interventions, including osteotomy and fixation, pose challenges and risks. We present a case of thoracic myelopathy in a patient with post-tuberculosis kyphosis, successfully treated with biportal endoscopic spinal surgery (BESS). METHOD: A 73-year-old female with a history of untreated kyphosis presented with walking difficulties and lower limb pain. Imaging revealed a kyphotic deformity of 120° and OLF-induced cord compression at T8-9. UBE was performed under spinal anesthesia. Using the BESS technique, OLF was successfully removed with minimal damage to the stabilizing structures. RESULTS: The patient exhibited neurological improvement after surgery, walking on the first day without gait instability. Follow-up at 1 year showed no kyphosis progression or recurrence of symptoms. BESS successfully resolved the cord compression lesion with minimal blood loss and damage. CONCLUSION: In spinal tuberculosis-related OLF, conventional open surgery poses challenges. BESS emerges as an excellent alternative, providing effective decompression with reduced instrumentation needs, minimal blood loss, and preservation of surrounding structures. Careful patient selection and surgical planning are crucial for optimal outcomes in endoscopic procedures.

Risk factors for mechanical complications after fusion extension surgery for lumbar adjacent segment disease.

PURPOSE: Adjacent segment disease (ASD) is a common complication in fusion surgery. In the event of solid segmental fusion, previous implants can be removed or preserved during fusion extension for ASD. To compare the surgical outcomes of patients with and without implants and analyzes the risk factors for postoperative mechanical complications. METHODS: Patients who underwent fusion extension for lumbar ASD from 2011 to 2019 with a minimum 2 year follow-up were retrospectively reviewed. Spinopelvic parameters were measured preoperatively and postoperatively. Clinical outcomes and surgical complications were compared between groups with implants preserved and removed. Risk factors for mechanical complications, including clinical, surgical, and radiographic factors were analyzed. RESULTS: Sixty-nine patients (mean age, 69.9 ± 6.9 years) were included. The mean numbers of initial and extended fused segments were 2.8 ± 0.7 and 2.7 ± 0.7, respectively. Previous implants were removed in 43 patients (R group) and preserved in 26 patients (P group). Both groups showed an improvement in clinical outcomes without between-group differences. The operation time was significantly longer in R group (260 vs 207 min, p < 0.001). Mechanical complications occurred in 13 patients (12 in R group and 1 in P group) and reoperation was needed in 3 patients (R group). Implant removal, index fusion surgery including L5-S1, and postoperative sagittal malalignment were risk factors for mechanical complications. CONCLUSION: Implant removal was a risk factor for mechanical complications. Index fusion surgery including L5-S1 and postoperative sagittal malalignment were also risk factors for mechanical complications.

Autophagy in an extruded disc compared to the remaining disc after lumbar disc herniation in the same patient.

PURPOSE: The purpose of this study was to investigate autophagy in an extruded disc and to compare this activity with the activity in the remaining disc after lumbar disc herniation in the same patient. METHODS: In total, 12 patients (females 4, males 8) with the extruded type of lumbar disc herniation (LDH) were surgically treated. Their mean age was 54.3 ± 15.8 years (range: 29 ~ 78 years). The mean interval from the occurrence of symptoms to the operation was 9.8 ± 9.4 weeks (range: 2 ~ 24 weeks). The extruded discs were excised, and the remaining disc material removed, to prevent recurrence of herniation. Immediately after specimen collection, all tissues were stored at -70 °C prior to analysis. Autophagy was assessed immunohistochemically and via Western blotting for Atg5, Atg7, Atg12, Atg12L1, and Beclin-1. And the relationship between autophagy and apoptosis was investigated by correlation analysis of caspase-3 with autophagy proteins. RESULTS: The expression levels of autophagic markers were significantly increased in the extruded discs compared to the remaining discs within the same patients. The mean expression levels of Atg5, Atg7, Atg12, and Beclin-1 in extruded discs were statistically significantly higher than those in the remaining discs (P < 0.01, P < 0.001, P < 0.01, and P < 0.001 respectively). CONCLUSIONS: The autophagic pathway was more active in extruded disc material than in remaining disc material within the same patient. This may explain spontaneous resorption of the extruded disc after LDH.

Coronal vertical fracture of vertebral body following minimally invasive lateral lumbar interbody fusion: risk factor analysis in consecutive case series.

BACKGROUND: To investigate the incidence and risk factors of coronal vertical vertebral body fracture (CV-VBF) during lateral lumbar interbody fusion (LLIF) for degenerative lumbar disease. METHODS: Clinical data, including age, sex, body mass index, and bone mineral density, were reviewed. Radiological assessments, such as facet joint arthrosis, intervertebral disc motion, index disc height, and cage profiles, were conducted. Posterior instrumentation was performed using either a single or staged procedure after LLIF. Demographic and surgical data were compared between patients with and without VBF. RESULTS: Out of 273 patients (552 levels), 7 (2.6%) experienced CV-VBF. Among the 552 levels, VBF occured in 7 levels (1.3%). All VBF cases developed intraoperatively during LLIF, with no instances caused by cage subsidence during the follow-up period. Sagittal motion in segments adjacent to VBF was smaller than in others (4.6° ± 2.6° versus 6.5° ± 3.9°, P = 0.031). The average grade of facet arthrosis was 2.5 ± 0.7, indicating severe facet arthrosis. All fractures developed due to oblique placement of a trial or cage into the index disc space, leading to a nutcracker effect. These factors were not related to bone quality. CONCLUSIONS: CV-VBF after LLIF occurred in 2.6% of patients, accounting for 1.3% of all LLIF levels. A potential risk factor for VBF involves the nutcracker-impinging effect due to the oblique placement of a cage. Thorough preoperative evaluations and surgical procedures are needed to avoid VBF when considering LLIF in patients with less mobile spine.

Deep learning based prediction of urban air mobility noise propagation in urban environment.

A deep learning based method is proposed to predict the urban air mobility (UAM) noise propagation in the urban environment. This method aims to efficiently estimate the noise impact of UAM flights on the complex urban area. The noise hemisphere was created via the comprehensive multirotor noise assessment framework to determine the noise level of UAM. The noise propagation to a randomly generated three-dimensional (3D) urban area was then calculated using the ray tracing method, including atmospheric attenuation and multiple reflections. 45 000 two-dimensional noise maps were used to train and evaluate the modified convolutional neural network. The results demonstrated high accuracy, with a root mean square error of only 2.56 dB compared to the ray tracing method, while reducing computation time by more than 1800 times. This model was applied to analyze the noise impact of various UAM flight conditions and landing scenarios at a vertiport. This deep learning approach is a fast method with adequate accuracy for predicting UAM noise impact in 3D urban environments. Also, it can inform the development of noise based strategies for UAM operations.

The Effects of Longer Use of Teriparatide on Clinical and Radiographic Outcomes after Spinal Fusion in Geriatric Patients.

Background: Teriparatide is an anabolic agent for osteoporosis and is believed to improve the bone healing process. Previous studies showed that teriparatide could enhance not only fracture healing but also spine fusion. It has been reported that use of teriparatide could promote the spine fusion process and decrease mechanical complications. However, there was no consensus regarding optimal treatment duration. The purpose of this study was to compare surgical outcomes between short-duration and long-duration teriparatide treatment after lumbar fusion surgery in elderly patients. Materials and Methods: All consecutive patients older than 60 years who underwent 1-level lumbar fusion surgery for degenerative diseases between January 2015 and December 2019 were retrospectively reviewed. Based on the duration of teriparatide treatment (daily subcutaneous injection of 20 µg teriparatide), patients were subdivided into two groups: a short-duration (SD) group (<6 months) and a long-duration (LD) group (≥6 months). Mechanical complications, such as screw loosening, cage subsidence, and adjacent vertebral fractures, were investigated. Postoperative 1-year union rate was also evaluated on computed tomography. Clinical outcomes were recorded using visual analog scale (VAS) and Oswestry Disability Index (ODI). Between-group differences for these radiographic and clinical outcomes were analyzed. Results: Ninety-one patients were reviewed in this study, including sixty patients in the SD group and thirty-one patients in the LD group. Their mean age was 72.3 ± 6.2 years, and 79 patients were female. Mean T-score was -3.3 ± 0.8. Cage subsidence (6.7% vs. 3.2%), screw loosening (28.3% vs. 35.5%), and adjacent vertebral fracture (6.7% vs. 9.7%) were not significantly different between the SD and LD groups. Union rate at 1-year postoperative was 65.0% in the SD group and 87.1% in the LD group (p = 0.028). Both groups showed improvement in VAS and ODI after surgery. However, the differences of VAS from preoperative to 6 months and 1 year postoperative were significantly higher in the LD group. Conclusions: Longer teriparatide treatment after lumbar fusion surgery resulted in a higher union rate at 1-year postoperative than the shorter treatment. Also, it could be more beneficial for clinical outcomes.

First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent With Defibrillator Implantation: The PAUSE-SCD Randomized Trial.

BACKGROUND: Catheter ablation as first-line therapy for ventricular tachycardia (VT) at the time of implantable cardioverter defibrillator (ICD) implantation has not been adopted into clinical guidelines. Also, there is an unmet clinical need to prospectively examine the role of VT ablation in patients with nonischemic cardiomyopathy, an increasingly prevalent population that is referred for advanced therapies globally. METHODS: We conducted an international, multicenter, randomized controlled trial enrolling 180 patients with cardiomyopathy and monomorphic VT with an indication for ICD implantation to assess the role of early, first-line ablation therapy. A total of 121 patients were randomly assigned (1:1) to ablation plus an ICD versus conventional medical therapy plus an ICD. Patients who refused ICD (n=47) were followed in a prospective registry after stand-alone ablation treatment. The primary outcome was a composite end point of VT recurrence, cardiovascular hospitalization, or death. RESULTS: Randomly assigned patients had a mean age of 55 years (interquartile range, 46-64) and left ventricular ejection fraction of 40% (interquartile range, 30%-49%); 81% were male. The underlying heart disease was ischemic cardiomyopathy in 35%, nonischemic cardiomyopathy in 30%, and arrhythmogenic cardiomyopathy in 35%. Ablation was performed a median of 2 days before ICD implantation (interquartile range, 5 days before to 14 days after). At 31 months, the primary outcome occurred in 49.3% of the ablation group and 65.5% in the control group (hazard ratio, 0.58 [95% CI, 0.35-0.96]; P=0.04). The observed difference was driven by a reduction in VT recurrence in the ablation arm (hazard ratio, 0.51 [95%CI, 0.29-0.90]; P=0.02). A statistically significant reduction in both ICD shocks (10.0% versus 24.6%; P=0.03) and antitachycardia pacing (16.2% versus 32.8%; P=0.04) was observed in patients who underwent ablation compared with control. No differences in cardiovascular hospitalization (32.0% versus. 33.7%; hazard ratio, 0.82 [95% CI, 0.43-1.56]; P=0.55) or mortality (8.9% versus 8.8%; hazard ratio, 1.40 [95% CI, 0.38-5.22]; P=0.62]) were observed. Ablation-related complications occurred in 8.3% of patients. CONCLUSIONS: Among patients with cardiomyopathy of varied causes, early catheter ablation performed at the time of ICD implantation significantly reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. These findings were driven by a reduction in ICD therapies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02848781.

LIN28A loss of function is associated with Parkinson's disease pathogenesis.

Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.

Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma.

BACKGROUND: Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. METHODS: We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC-MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC-MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. RESULTS: In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. CONCLUSIONS: The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.