Diradical B/N-Doped Polycyclic Hydrocarbons.

Heterocyclic diradicaloids with atom-precise control over open-shell nature are promising materials for organic electronics and spintronics. Herein, we disclose quinoidal π-extension of a B/N-heterocycle for generating B/N-type organic diradicaloids. Two quinoidal π-extended B/N-doped polycyclic hydrocarbons that feature fusion of the B/N-heterocycle motif with the antiaromatic s-indacene or dicyclopenta[b,g]naphthalene core were synthesized. This quinoidal π-extension and B/N-heterocycle leads to their open-shell electronic nature, which stands in contrast to the multiple-resonance effect of conventional B/N-type emitters. These B/N-type diradicaloids have modulated (anti)aromaticity and enhanced diradical characters comparing with the all-carbon analogues, as well as intriguing properties, such as magnetic activities, narrow energy gaps and highly red-shifted absorptions. This study thus opens the new space for both of B/N-doped polycyclic π-systems and heterocyclic diradicaloids.

Implantable device measured objective daily physical activity as a predictor of long-term all-cause mortality and cardiac death in patients with age > 75 years and high risk of sudden cardiac death: a cohort study : Physical activity and patients over 75 years old.

BACKGROUND: To study the relationship between objective daily physical activity (PA), as measured by implantable cardioverter defibrillators (ICDs)/cardiac resynchronization therapy defibrillators (CRTDs), and long-term prognoses in patients with age > 75 years at high risk of sudden cardiac death (SCD). METHODS: In total, 133 patients with age > 75 years old (age 79.52 ± 3.68 years) in the SUMMIT study were retrospectively analysed. The major endpoint was all-cause mortality, and the minor endpoint was cardiac death. RESULTS: The mean follow-up time was 57.1 ± 24.2 months (range: from 4 to 96 months). In total, 46 all-cause mortality and 23 cardiac death events occurred. The receiver operating characteristic curve indicated a baseline PA cut-off value of 6.47% (93 min/day) can predict all-cause mortality in patients with age > 75 years, with an area under the curve of 0.670 (95% confidence interval (CI): 0.573-0.767, P = 0.001). The sensitivity was 67.4%, and the specificity was 66.7%. Patients with baseline PA ≤ 6.47% had higher rates of all-cause mortality (51.7% vs 20.5%, P < 0.001) and cardiac death (25.0% vs 11.0%, P = 0.040). The estimated Kaplan-Meier survival curves showed that patients with PA ≤ 6.47% had an increased cumulative incidence of all-cause mortality (Log-rank P < 0.0001) and cardiac death (Log-rank P = 0.0067). Multivariate Cox regression analysis showed that PA ≤ 6.47% was an independent predictor of all-cause mortality (hazard ratio (HR) 3.137, 95% CI: 1.667-5.904, P < 0.001) and cardiac death (HR value 3.345, 95% CI: 1.394-8.028, P = 0.007). CONCLUSIONS: Daily PA of about 1.5 h was associated with lower all-cause mortality and cardiac death risk in patients with age > 75 years and high risk of SCD with ICDs/CRTDs. PA monitoring may aid in long-term management of older patients at high risk of SCD.

Pretarsal orbicularis oculi muscle tightening with skin flap excision in the treatment of lower eyelid involutional entropion.

BACKGROUND: To evaluate a modified technique for involutional entropion correction in a retrospective cohort study. METHODS: The patients with involutional entropion eyelid were corrected by tightening the pretarsal orbicularis oculi muscle and excising the excess skin of the lower eyelid. The patients received correction surgery from April 2013 to March 2019 were followed up for more than 6 months postoperatively. The outcome measures included the complications and the recurrence rates. RESULTS: Total 152 patients (169 eyes) were included. The mean follow-up period was 29.6 months (range: 6-36 months). Postoperative ectropion (over-correction) was observed in 1 patient with 1 eyelid (0.59%); yet, no further surgery was needed for this patient. Recurrence of entropion was found in 1 patient (0.59%). The patient with recurrent entropion received repeated surgery with the same method and achieved a good eyelid position. CONCLUSIONS: This study demonstrated that tightening the pretarsal orbicularis oculi muscle and excising the excess skin of the lower eyelid could be an effective surgical method to correct lower eyelid involutional entropion. This method is technically easy with a low recurrence rate and not associated with significant complications in Asians.

More significance of TB-IGRA except for the diagnose of tuberculosis.

OBJECTIVE: Tuberculosis (TB)-interferon gamma release assay (IGRA) test has the characteristics of short time, high specificity, and high sensitivity, but it lacks the correlation research between TB-IGRA test results and body's immune cells, disease progression and prognosis, which is explored in this study. DESIGN: A retrospective study was carried out on positive TB-IGRA patients who were infected with TB and diagnosed at our hospital from January 2014 to June 2015. The TB-IGRA, routine blood test, T-cell subgroup data were collected for statistical analysis. RESULTS: TB-IGRA results were in positive proportion to the lymphocytes, CD4+ T cells and CD4+ CD28+ T cells, whereas negative to the Treg cells. Patient with unilateral pulmonary lesion had higher TB-IGRA than those with bilateral pulmonary lesions. After the stimulation of TB-specific antigen, the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T Tcells were both increased and the CD4+ IFN-γ+ T had positive correlation with the value of TB-IGRA. CONCLUSIONS: IFN-γ was tested with TB-IGRA in patients with TB by the specific TB T cells and correlated with the lymphocytes, while the lymphocytes also closely related to the host's anti-TB immunity and disease outcome. Hence the result of TB-IGRA could reflect the specific anti-TB immunity ability of the host, disease progression and prognosis. This study further expands the application scope of TB-IGRA technology in the diagnosis of TB and lays a foundation for clinical practice to understand the immunity state of the patients with TB and the application of auxiliary clinical immunity regulators.

Prognostic significance of frequent premature ventricular complex early after implantation among patients with implantable cardioverter defibrillator.

BACKGROUND: Premature ventricular complex (PVC) was mainly studied by 24-hour Holter in previous studies. However, the value of long-term Home Monitoring of PVC burden early after ICD implantation is unknown. METHODS: The data of 416 patients with ICD were analyzed. The percentage of days with frequent PVC (≥10/h) within 30th-90th days was calculated as the continuous frequent PVC (CfPVC) percentage. ROC curve of CfPVC percentages was plotted. Kaplan-Meier survival and Cox regression were used to assess the cumulative risks. RESULTS: Based on ROC curves, the cut-off value for the CfPVC percentage was 40%. According to Kaplan-Meier analysis and multivariate Cox regression analysis, CfPVC percentage ≥40% was an independent predictor of higher incidences of VAEs, appropriate ATP, appropriate shocks, and cardiac death. CONCLUSION: A long-term continuous burden of frequent PVC with CfPVC percentage ≥40% can be a predictor of future VAEs, appropriate ATP, appropriate shocks and cardiac death in ICD recipients.

The role of variability in night-time mean heart rate on the prediction of ventricular arrhythmias and all-cause mortality in implantable cardioverter defibrillator patients.

AIMS: This study was to use implantable cardioverter defibrillator (ICD) home monitoring (HM) feature to evaluate the role of mean night-time heart rate (MNHR) in the occurrence of ventricular arrhythmias (VAs) and mortality. METHODS AND RESULTS: This study retrospectively analysed clinical and ICD device data in 318 ICD patients. Data of the first 30-day MNHR (recorded 02:00-06:00 am) by HM were collected. The average and standard deviation of 30-day MNHR (AVHR and SDHR, respectively) were then determined in each patient. The primary endpoint was appropriate ICD treatment of VAs. The secondary endpoint was all-cause mortality. During a mean follow-up period of 32 ± 10 months, 179 of the 318 patients (56.3%) experienced VAs, 123 patients (38.7%) were treated by ICD shocks, and 37 patients (11.6%) died. The overall SDHR in this study cohort was 4.5 ± 3.0 bpm. Based on the receiver operating characteristic curve, the cut-off value of SDHR = 3.685 bpm was identified to predict VAs. In the Kaplan-Meier survival, SDHR ≥ 3.685 bpm was associated with increased VAs [hazard ratio (HR) = 1.885; 95% confidence interval (CI) = 1.362-2.609; P < 0.001], shock events (HR = 1.637; 95% CI = 1.11-2.414; P = 0.013), all-cause mortality (HR = 2.42; 95% CI = 1.266-4.627; P = 0.008), and the combined endpoints (HR = 1.872; 95% CI = 1.365-2.567; P < 0.001). In univariate and multivariate Cox models (adjusting for clinical factors), SDHR ≥ 3.685 bpm was still an independent predictor for all endpoints. CONCLUSION: In ICD population, SDHR ≥ 3.685 bpm was an independent predictor for VAs and all-cause mortality.

Canalicular laceration repair using a novel bicanalicular silicone stent versus traditional bicanalicular stent with nasal fixation.

PURPOSE: To compare the clinical effects of two types of lacrimal stents in the repair of canalicular lacerations. METHODS: A retrospective analysis was conducted on patients with canalicular lacerations between January 2017 and December 2022. The canalicular reconstruction was performed using either the Runshi-RS bicanalicular silicone stent or the traditional bicanalicular silicone stent with nasal fixation, under a surgical microscope. The stent was placed for 3 months, and patients were followed up for more than 3 months after extubation. The anatomical and functional success rates were compared between the two groups. Anatomical success was assessed through diagnostic probing and irrigation of lacrimal passage, while functional success was determined by the patient's subjective symptoms of epiphora. RESULTS: The study included 315 patients (315 eyes) undergoing canalicular laceration repair. The Runshi-RS stent was utilized in 147 patients (46.7%), while the traditional stent with nasal fixation was employed in 168 patients (53.3%). The anatomical success rates (99.3% vs 98.8%, P = 0.642) and functional success rates (87.2% vs 88.1%, P = 0.926) were similar between the RS group and the traditional stent group. Postoperative complications were fewer (4.1% vs 10.1%, P = 0.04) and the operation time was shorter (67.1 ± 35.3 min vs 86.1 ± 43.4 min, P < 0.001) in the RS group. CONCLUSION: The Runshi-RS tube demonstrates favorable surgical outcomes for the repair of canalicular lacerations. Compared to the traditional stent with nasal fixation, the RS stent allows for shorter operation times and fewer postoperative complications in the repair of canalicular lacerations.

Machine learning predictors of risk of death within 7 days in patients with non-traumatic subarachnoid hemorrhage in the intensive care unit: A multicenter retrospective study.

Non-traumatic subarachnoid hemorrhage (SAH) is a critical neurosurgical emergency with a high mortality rate, imposing a significant burden on both society and families. Accurate prediction of the risk of death within 7 days in SAH patients can provide valuable information for clinicians, enabling them to make better-informed medical decisions. In this study, we developed six machine learning models using the MIMIC III database and data collected at our institution. These models include Logistic Regression (LR), AdaBoosting (AB), Multilayer Perceptron (MLP), Bagging (BAG), Gradient Boosting Machines (GBM), and Extreme Gradient Boosting (XGB). The primary objective was to identify predictors of death within 7 days in SAH patients admitted to intensive care units. We employed univariate and multivariate logistic regression as well as Pearson correlation analysis to screen the clinical variables of the patients. The initially screened variables were then incorporated into the machine learning models, and the performance of these models was evaluated. Furthermore, we compared the performance differences among the six models and found that the MLP model exhibited the highest performance with an AUC of 0.913. In this study, we conducted risk factor analysis using Shapley values to identify the factors associated with death within 7 days in patients with SAH. The risk factors we identified include Gcsmotor, bicarbonate, wbc, spo2, heartrate, age, nely, glucose, aniongap, GCS, rbc, sysbp, sodium, and gcseys. To provide clinicians with a useful tool for assessing the risk of death within 7 days in SAH patients, we developed a web calculator based on the MLP machine learning model.

Helical-caging enables single-emitted large asymmetric full-color circularly polarized luminescence.

Colorful circularly polarized luminescence materials are desired for 3D displays, information security and asymmetric synthesis, in which single-emitted materials are ideal owing to self-absorption avoidance, evenly entire-visible-spectrum-covered photon emission and facile device fabrication. However, restricted by the synthesis of chiral broad-luminescent emitters, the realization and application of high-performing single-emitted full-color circularly polarized luminescence is in its infancy. Here, we disclose a single-emitted full-color circularly polarized luminescence system (spiral full-color emission generator), composed of whole-vis-spectrum emissive quantum dots and chiral liquid crystals. The system achieves a maximum luminescence dissymmetry factor of 0.8 and remains an order of 10-1 in visible region by tuning its photonic bandgap. We then expand it to a series of desired customized-color circularly polarized luminescence, build chiral devices and further demonstrate the working scenario in the photoinduced enantioselective polymerization. This work contributes to the design and synthesis of efficient chiroptical materials, device fabrication and photoinduced asymmetric synthesis.

Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.

Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.

Morphological characterization of nevi on the caruncle conjunctiva under in vivo confocal microscopy.

Objective: This study aimed to investigate the microscopic structure and characteristics of nevi on the conjunctiva of the lacrimal caruncle by in vivo confocal microscopy. Methods: In total, four patients with nevi growing on the lacrimal caruncle conjunctiva were recruited. The morphological characteristics of the nevi were evaluated by in vivo confocal microscopy before excision surgery; the results were compared with histopathological analyses of the surgical specimens. Results: The nevi of the four patients were all located at the conjunctiva of the lacrimal caruncle, with a slightly nodular surface, mixed black and brown color, and clear boundary. The nevi were round and highly protruded on the surface of the lacrimal caruncle, with an average diameter of 4.5 ± 1.29 mm. Under in vivo confocal microscopy, the pigmented nevus cells on the conjunctiva of the lacrimal caruncle were observed to be clustered in nests with irregular boundaries. The cells were round or irregular, with clear cell boundaries, hyper-reflective at the periphery, with low reflectivity in the center. Vascular crawling was observed in some regions. Histopathological analysis showed that nevus cells were roughly equal in size and distributed in a nodular pattern. Melanin granules were observed in the cytoplasm. No atypia or mitotic figures of the cells were found. Conclusion: This study revealed that the microstructure of nevi growing on the conjunctiva of the lacrimal caruncle can be identified by in vivo confocal microscopy.

Distorted B/O-containing nanographenes with tunable optical properties.

We report the synthesis of two B/O-containing nanographenes, which feature the fusion of three or six planar B/O-heterocycles onto one hexa-peri-hexabenzocoronene π-framework. Incorporation of the B/O-heterocycles not only leads to distorted geometries, but also modulates the electronic structures and results in gradually red-shifted absorptions and fluorescence.

Nitrogen-doped carbon dots/Fe3+-based fluorescent probe for the "off-on" sensing of As(V) in seafood.

To better satisfy the application of rapid detection methods in the detection of As(V) in complex food substrates, we developed an "off-on" fluorescence assay to detect As(V) based on the competition between the electron transfer effect of nitrogen-doped carbon dots (N-CDs)/Fe3+ and the complexation reaction of As(V)/Fe3+, using N-CDs/Fe3+ as a fluorescence probe. Solid-phase extraction (SPE) was used to eliminate matrix interference during sample pretreatment. The detection limit was 7.6 ng g-1, with a linear range of 10-100 ng g-1. The method was further used to determine As(V) in different seafood products including snapper, shrimp, clams, and kelp. At the same time, the recovery of the method was validated by high-performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP/MS), indicating that the developed method had good recoveries from 86% to 117% and met the needs for accurate determination of As(V). This approach has shown excellent application potential in the field of As(V) detection in various seafood products.

Machine learning-based prediction of cerebral hemorrhage in patients with hemodialysis: A multicenter, retrospective study.

Background: Intracerebral hemorrhage (ICH) is one of the most serious complications in patients with chronic kidney disease undergoing long-term hemodialysis. It has high mortality and disability rates and imposes a serious economic burden on the patient's family and society. An early prediction of ICH is essential for timely intervention and improving prognosis. This study aims to build an interpretable machine learning-based model to predict the risk of ICH in patients undergoing hemodialysis. Methods: The clinical data of 393 patients with end-stage kidney disease undergoing hemodialysis at three different centers between August 2014 and August 2022 were retrospectively analyzed. A total of 70% of the samples were randomly selected as the training set, and the remaining 30% were used as the validation set. Five machine learning (ML) algorithms, namely, support vector machine (SVM), extreme gradient boosting (XGB), complement Naïve Bayes (CNB), K-nearest neighbor (KNN), and logistic regression (LR), were used to develop a model to predict the risk of ICH in patients with uremia undergoing long-term hemodialysis. In addition, the area under the curve (AUC) values were evaluated to compare the performance of each algorithmic model. Global and individual interpretive analyses of the model were performed using importance ranking and Shapley additive explanations (SHAP) in the training set. Results: A total of 73 patients undergoing hemodialysis developed spontaneous ICH among the 393 patients included in the study. The AUC of SVM, CNB, KNN, LR, and XGB models in the validation dataset were 0.725 (95% CI: 0.610 ~ 0.841), 0.797 (95% CI: 0.690 ~ 0.905), 0.675 (95% CI: 0.560 ~ 0.789), 0.922 (95% CI: 0.862 ~ 0.981), and 0.979 (95% CI: 0.953 ~ 1.000), respectively. Therefore, the XGBoost model had the best performance among the five algorithms. SHAP analysis revealed that the levels of LDL, HDL, CRP, and HGB and pre-hemodialysis blood pressure were the most important factors. Conclusion: The XGB model developed in this study can efficiently predict the risk of a cerebral hemorrhage in patients with uremia undergoing long-term hemodialysis and can help clinicians to make more individualized and rational clinical decisions. ICH events in patients undergoing maintenance hemodialysis (MHD) are associated with serum LDL, HDL, CRP, HGB, and pre-hemodialysis SBP levels.

DB-DCAFN: dual-branch deformable cross-attention fusion network for bacterial segmentation.

Sputum smear tests are critical for the diagnosis of respiratory diseases. Automatic segmentation of bacteria from sputum smear images is important for improving diagnostic efficiency. However, this remains a challenging task owing to the high interclass similarity among different categories of bacteria and the low contrast of the bacterial edges. To explore more levels of global pattern features to promote the distinguishing ability of bacterial categories and maintain sufficient local fine-grained features to ensure accurate localization of ambiguous bacteria simultaneously, we propose a novel dual-branch deformable cross-attention fusion network (DB-DCAFN) for accurate bacterial segmentation. Specifically, we first designed a dual-branch encoder consisting of multiple convolution and transformer blocks in parallel to simultaneously extract multilevel local and global features. We then designed a sparse and deformable cross-attention module to capture the semantic dependencies between local and global features, which can bridge the semantic gap and fuse features effectively. Furthermore, we designed a feature assignment fusion module to enhance meaningful features using an adaptive feature weighting strategy to obtain more accurate segmentation. We conducted extensive experiments to evaluate the effectiveness of DB-DCAFN on a clinical dataset comprising three bacterial categories: Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The experimental results demonstrate that the proposed DB-DCAFN outperforms other state-of-the-art methods and is effective at segmenting bacteria from sputum smear images.

Processable circularly polarized luminescence material enables flexible stereoscopic 3D imaging.

Endowing three-dimensional (3D) displays with flexibility drives innovation in the next-generation wearable and smart electronic technology. Printing circularly polarized luminescence (CPL) materials on stretchable panels gives the chance to build desired flexible stereoscopic displays: CPL provides unusual optical rotation characteristics to achieve the considerable contrast ratio and wide viewing angle. However, the lack of printable, intense circularly polarized optical materials suitable for flexible processing hinders the implementation of flexible 3D devices. Here, we report a controllable and macroscopic production of printable CPL-active photonic paints using a designed confining helical co-assembly strategy, achieving a maximum luminescence dissymmetry factor (glum) value of 1.6. We print customized graphics and meter-long luminous coatings with these paints on a range of substates such as polypropylene, cotton fabric, and polyester fabric. We then demonstrate a flexible textile 3D display panel with two printed sets of pixel arrays based on the orthogonal CPL emission, which lays an efficient framework for future intelligent displays and clothing.

Canalicular laceration repair with a novel bicanalicular silicone tube.

PURPOSE: This study aimed to investigate the efficacy and safety of canalicular laceration repair using a novel bicanalicular silicone tube. METHODS: Retrospective and consecutive patients who underwent canalicular laceration repair using novel Runshi-RS bicanalicular silicone stents from January 2020 to February 2021 were included. The stent was placed for 3 months, and patients were followed up for more than 3 months after extubation. Demographics, causes of eyelid injuries, placement time and position of stent, and surgical outcomes at follow-up were recorded. Anatomical success was evaluated by diagnostic probing and irrigation of lacrimal passage, while functional success was evaluated by the patient's subjective symptoms of epiphora. RESULTS: This study included 43 patients with canalicular laceration. The median age was 43 years (3-75 years). The average duration of stent implantation was 12.9 weeks, and the follow-up time was 8.8 months. No complications were observed in any patients during operation and follow-up. After extubation, irrigation of the lacrimal passage in 43 eyes showed no obstruction, and the anatomical success rate was 100%. Overall, 39 patients (90.7%) had no subjective symptoms of epiphora. All patients got good cosmetic results. Furthermore, subgroup classification showed deep laceration group (distance from laceration to punctum>5 mm) accounted for 51.2%, and the functional success rate of the deep laceration group was lower than that of the shallow laceration group. CONCLUSION: Runshi-RS bicanalicular silicone stent achieved good anatomical (100%) as well as functional (90.7%) success and good cosmetic results (100%) in patients with canalicular laceration repair.

Interaction between electrical storm and left ventricular ejection fraction as predictors of mortality in patients with implantable cardioverter defibrillator: A Chinese cohort study.

Aims: To determine the interaction of electrical storm (ES) and impaired left ventircular ejection fraction (LVEF) on the mortality risk of patients with implantable cardioverter defibrillator (ICD). Methods and results: A total of 554 Chinese ICD recipients from 2010 to 2014 were retrospectively included and the mean follow-up was 58 months. The proportions of dilated cardiomyopathy and the hypertrophic cardiomyopathy were 26.0% (144/554) and 5.6% (31/554), respectively. There were 8 cases with long QT syndrome, 6 with arrhythmogenic right ventricular cardiomyopathy and 2 with Brugada syndrome. Patients with prior MI accounted for 15.5% (86/554) and pre-implantation syncope accounted for 23.3% (129/554). A total of 199 (35.9%) patients had primary prevention indications for ICD therapy. Both ES and impaired LVEF (<40%) were independent predictors for all-cause mortality [hazard ratio (HR) 2.40, 95% CI 1.57-3.68, P < 0.001; HR 1.94, 95% CI 1.30-2.90, P = 0.001, respectively] and cardiovascular mortality (HR 4.63, 95% CI 2.68-7.98, P < 0.001; HR 2.56, 95% CI 1.47-4.44, p = 0.001, respectively). Compared with patients with preserved LVEF (≥40%) and without ES, patients with impaired LVEF and ES had highest all-cause and cardiovascular mortality risks (HR 4.17, 95% CI 2.16-8.06, P < 0.001; HR 11.91, 95% CI 5.55-25.56, P < 0.001, respectively). In patients with impaired LVEF, ES increased the all-cause and cardiovascular mortality risks (HR 1.84, 95% CI 1.00-3.37, P = 0.034; HR 4.86, 95% CI 2.39-9.86, P < 0.001, respectively). In patients with ES, the deleterious effects of impaired LVEF seemed confined to cardiovascular mortality (HR 2.54, 95% CI 1.25-5.14, p = 0.038), and the HR for all-cause mortality was not significant statistically (HR 1.14, 95% CI 0.54-2.38, P = 0.735). Conclusion: Both ES and impaired LVEF are independent predictors of mortality risk in this Chinese cohort of ICD recipients. The interaction of ES and impaired LVEF in patients significantly amplifies the deleterious effects of each other as distinct disease.

Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia.

PURPOSE: The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions. EXPERIMENTAL DESIGN: We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed. RESULTS: A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling. CONCLUSIONS: Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.