De novo protein design by citizen scientists.

Online citizen science projects such as GalaxyZoo1, Eyewire2 and Phylo3 have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity. An exception is the game EteRNA4, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of Watson-Crick base pairing possibilities. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. We posed the challenge of de novo protein design in the online protein-folding game Foldit5. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can now-starting from an extended polypeptide chain-generate a diversity of protein structures and sequences that encode them in silico. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. The diversity of these structures is unprecedented in de novo protein design, representing 20 different folds-including a new fold not observed in natural proteins. High-resolution structures were determined for four of the designs, and are nearly identical to the player models. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem.

Cyclin A2 Expression as Predictive Biomarker in Muscle-Invasive Upper Tract Urothelial Carcinoma.

INTRODUCTION: The aim was to evaluate the prognostic value of altered Cyclin A2 (CCNA2) gene expression in upper tract urothelial carcinoma (UTUC) and to assess its predictive potential as a prognostic factor for overall survival (OS) and disease-free survival. METHODS: 62 patients who underwent surgical treatment for UTUC were included. Gene expression of CCNA2, MKI67, and p53 was analyzed by quantitative reverse transcriptase polymerase chain reaction. Survival analyses were performed using the Kaplan-Meier method and the log-rank test. For Cox regression analyses, uni- and multivariable hazard ratios were calculated. Spearman correlation was used to analyze correlation of CCNA2 expression with MKI67 and p53. RESULTS: The median age of the cohort was 73 years, and it consisted of 48 males (77.4%) and 14 females (22.6%). Patients with high CCNA2 expression levels showed longer OS (HR 0.33; 95% CI: 0.15-0.74; p = 0.0073). Multivariable Cox regression analyses identified CCNA2 overexpression (HR 0.37; 95% CI: 0.16-0.85; p = 0.0189) and grading G2 (vs. G3) (HR 0.39; 95% CI: 0.17-0.87; p = 0.0168) to be independent predictors for longer OS. CCNA2 expression correlated positively with MKI67 expression (Rho = 0.4376, p = 0.0005). CONCLUSION: Low CCNA2 expression is significantly associated with worse OS. Thus, CCNA2 might serve as a potential biomarker in muscle-invasive UTUC and may be used to characterize a subset of patients having an unfavorable outcome and for future risk assessment scores.

Clinical and echocardiographic outcomes with new-onset left bundle branch block after SAPIEN-3 transcatheter aortic valve replacement.

BACKGROUND: New-onset left bundle branch block (LBBB) can develop after transcatheter aortic valve replacement (TAVR) resulting in worse outcomes. AIMS: Describe clinical and echocardiographic outcomes with new-onset LBBB after TAVR. METHODS: We included consecutive patients who underwent transfemoral-TAVR with SAPIEN-3 (S3) valve between April 2015 and December 2018. Exclusion criteria included pre-existing LBBB, right BBB, left anterior hemiblock, left posterior hemiblock, wide QRS ≥ 120ms, prior permanent pacemaker (PPM), and nontransfemoral access. RESULTS: Among 612 patients, 11.4% developed new-onset LBBB upon discharge. The length of stay was longer with new-onset LBBB compared with no LBBB [3 (2-5) days versus 2 (1-3) days; p < 0.001]. New-onset LBBB was associated with higher rates of 30-day PPM requirement (18.6% vs. 5.4%; p < 0.001) and 1-year heart failure hospitalizations (10.7% vs. 4.4%; p = 0.033). There was no difference in 3-year mortality between both groups (30.9% vs. 30.6%; p = 0.829). Further, new-onset LBBB was associated with lower left ventricular ejection fraction (LVEF) at both 30 days (55.9 ± 11.4% vs. 59.3 ± 9%; p = 0.026) and 1 year (55 ± 12% vs. 60.1 ± 8.9%; p = 0.002). These changes were still present when we stratified patients according to baseline LVEF (≥50% or <50%). New-onset LBBBs were associated with a higher 1-year LV end-diastolic volume index (51.4 ± 18.6 vs. 46.4 ± 15.1 ml/m2 ; p = 0.036), and LV end-systolic volume index (23.2 ± 14.1 vs. 18.9 ± 9.7 ml/m2 ; p = 0.009). Compared with resolved new-onset LBBB, persistent new-onset LBBB was associated with worse LVEF and higher PPM at 1 year. CONCLUSIONS: New-onset LBBB after S3 TAVR was associated with higher PPM requirement, worse LVEF, higher LV volumes, and increased heart failure hospitalizations, with no difference in mortality.

A self-supervised vision transformer to predict survival from histopathology in renal cell carcinoma.

PURPOSE: To develop and validate an interpretable deep learning model to predict overall and disease-specific survival (OS/DSS) in clear cell renal cell carcinoma (ccRCC). METHODS: Digitised haematoxylin and eosin-stained slides from The Cancer Genome Atlas were used as a training set for a vision transformer (ViT) to extract image features with a self-supervised model called DINO (self-distillation with no labels). Extracted features were used in Cox regression models to prognosticate OS and DSS. Kaplan-Meier for univariable evaluation and Cox regression analyses for multivariable evaluation of the DINO-ViT risk groups were performed for prediction of OS and DSS. For validation, a cohort from a tertiary care centre was used. RESULTS: A significant risk stratification was achieved in univariable analysis for OS and DSS in the training (n = 443, log rank test, p < 0.01) and validation set (n = 266, p < 0.01). In multivariable analysis, including age, metastatic status, tumour size and grading, the DINO-ViT risk stratification was a significant predictor for OS (hazard ratio [HR] 3.03; 95%-confidence interval [95%-CI] 2.11-4.35; p < 0.01) and DSS (HR 4.90; 95%-CI 2.78-8.64; p < 0.01) in the training set but only for DSS in the validation set (HR 2.31; 95%-CI 1.15-4.65; p = 0.02). DINO-ViT visualisation showed that features were mainly extracted from nuclei, cytoplasm, and peritumoural stroma, demonstrating good interpretability. CONCLUSION: The DINO-ViT can identify high-risk patients using histological images of ccRCC. This model might improve individual risk-adapted renal cancer therapy in the future.

Prognostic impact of left ventricular systolic dysfunction in patients with mixed aortic valve disease undergoing aortic valve replacement.

BACKGROUND: The implications of left ventricular remodeling and dysfunction before and after aortic valve replacement (AVR) for mixed aortic valve disease (MAVD) are not well understood. This study aims to evaluate the impact of AVR on left ventricular (LV) systolic function in MAVD, and determine the prognostic value of postoperative LV global longitudinal strain (LV-GLS) and LV ejection fraction (LVEF). METHODS: We retrospectively assessed 489 consecutive patients with MAVD (defined as at least moderate aortic stenosis and at least moderate aortic regurgitation) and baseline LVEF ≥50%, who underwent AVR between February 2003 and August 2018. All patients had baseline echocardiography, whereas 192 patients underwent postoperative echocardiography between 3 and 18 months after AVR. The primary endpoint was all-cause mortality. RESULTS: Mean age was 65 ± 15 years, and 65% were male. AVR in MAVD patients has a neutral effect on LV systolic function quantitated by LVEF and LV-GLS. During a median follow-up period of 5.8 years, 65 patients (34%) of 192 patients with follow-up echocardiography died. The patients with postoperative LVEF ≥50% had better survival than those with postoperative LVEF <50% (P < .001). Furthermore, among patients with postoperative LVEF ≥50%, mortality differed between patients with postoperative LV-GLS worse than -15% and those with postoperative LV-GLS better than -15% (P < .001). CONCLUSIONS: In patients with MAVD who underwent AVR, the mean postoperative LV-GLS and LVEF remain at a similar value to baseline. However, worse postoperative LV-GLS and LVEF were both independently associated with higher mortality in this population.

Physical and physiological effects of dobutamine stress echocardiography in low-gradient aortic stenosis.

Dobutamine stress echocardiography (DSE) is a useful tool for assessing low-gradient significant aortic stenosis (AS) and contractile reserve (CR), but its prognostic utility has become controversial in recent studies. We evaluated the impact of DSE on aortic valve physiological, structural, and left ventricular parameters in low-gradient AS. Consecutive patients undergoing DSE for low-gradient AS evaluation from September 2010 to July 2016 were retrospectively studied, and DSE findings were divided into four groups: with and without severe AS and/or CR. Relationships between left ventricular chamber quantification, CR, aortic valve Doppler during DSE, and calcium score [by computerized tomography (CT)] were analyzed. There were 258 DSE studies performed on 243 patients, mean age 77.6 ± 10.8 yr and 183 (70.1%) were males. With increasing dobutamine dose, apart from systolic blood pressure, left ventricular ejection fraction, flow, cardiac power output, and longitudinal strain magnitude, along with aortic valve area and mean aortic gradient were all significantly increased (P < 0.05). Flow and mean gradient increased in both the presence and absence of CR, whereas stroke volume and aortic valve area increased mainly in those with CR only. The aortic valve area increased in both patients with low and high calcium scores; however, the baseline area was lower in those with a higher calcium score. During DSE, aortic valve area increases with increase in aortic valve gradient. Higher calcium score is associated with lower baseline aortic valve area, but the aortic valve area still increases with dobutamine even in presence of a high calcium score.NEW & NOTEWORTHY We show that even in most severe aortic stenosis, there is some residual valve pliability. This suggests that a complete loss of pliability is not compatible with survival.

Two-year outcomes after transcatheter aortic valve-in-valve implantation in degenerated surgical valves.

BACKGROUND: Transcatheter aortic valve-in-valve implantation (ViV-TAVI) has emerged in recent years as a safe alternative to redo surgery in high-risk patients. Although early results are encouraging, data beyond short-term outcomes are lacking. Herein, we aimed to assess the 2-year outcomes after ViV-TAVI. METHODS: Patients undergoing ViV-TAVI for degenerated surgical valves between 2013 and 2019 at the Cleveland Clinic were reviewed. The coprimary endpoints were all-cause mortality and congestive heart failure (CHF) hospitalizations. We used time-to-event analyses to assess the primary outcomes. Further, we measured the changes in transvalvular gradients and the incidence of structural valve deterioration (SVD). RESULTS: One hundred and eighty-eight patients were studied (mean age = 76 years; 65% males). At 2 years of follow-up, all-cause mortality and CHF hospitalizations occurred in 15 (8%) and 28 (14.9%) patients, respectively. On multivariable analysis, the postprocedural length of stay was a significant predictor for both all-cause mortality (hazard ratio [HR] = 1.1; 95% confidence interval [CI]: 1.01, 1.19) and CHF hospitalization (HR = 1.16; 95% CI: 1.07, 1.27). However, the internal diameter of the surgical valve was not associated with significant differences in both primary endpoints. For hemodynamic outcomes, nine patients (4.8%) developed SVD. The mean and peak transvalvular pressure gradients remained stable over the follow-up period. CONCLUSION: ViV-TAVI for degenerated surgical valves was associated with favorable 2-year clinical and hemodynamic outcomes. Further studies are needed to better understand the role of ViV-TAVI as a treatment option in the life management of aortic valve disease.

Cerebral embolic protection and severity of stroke following transcatheter aortic valve replacement.

BACKGROUND: The cerebral embolic protection (CEP) device captures embolic debris during transcatheter aortic valve replacement (TAVR). However, the impact of CEP on stroke severity following TAVR remains unclear. Therefore, we aimed to examine whether CEP was associated with reduced severity of stroke following TAVR. METHODS: This was a retrospective cohort study of 2839 consecutive patients (mean age: 79.2 ± 9.5 years, females: 41.5%) who underwent transfemoral TAVR at our institution between 2013 and 2020. We categorized patients into Sentinel CEP users and nonusers. Neuroimaging data were reviewed and the final diagnosis of a cerebrovascular event was adjudicated by a neurologist blinded to the CEP use or nonuse. We compared the incidence and severity (assessed by the National Institutes of Health Stroke Scale [NIHSS]) of stroke through 72 h post-TAVR or discharge between the two groups using stabilized inverse probability of treatment weighting (IPTW) of propensity scores. RESULTS: Of the eligible patients, 1802 (63.5%) received CEP during TAVR and 1037 (36.5%) did not. After adjustment for patient characteristics by stabilized IPTW, the rate of overall stroke was numerically lower in CEP users than in CEP nonusers, but the difference did not reach statistical significance (0.49% vs. 1.18%, p = 0.064). However, CEP users had significantly lower rates of moderate-or-severe stroke (NIHSS ≥ 6: 0.11% vs. 0.69%, p = 0.013) and severe stroke (NIHSS ≥ 15: 0% vs. 0.29%, p = 0.046). Stroke following CEP use (n = 8), compared with stroke following CEP nonuse (n = 15), tended to carry a lower NIHSS (median [IQR], 4.0 [2.0-7.0] vs. 7.0 [4.5-19.0], p = 0.087). Four (26.7%) out of 15 patients with stroke following CEP nonuse died within 30 days, with no death after stroke following CEP use. CONCLUSIONS: CEP use may be associated with attenuated severity of stroke despite no significant difference in overall stroke incidence compared with CEP nonuse. This finding is considered hypothesis-generating and needs to be confirmed in large prospective studies.

Building de novo cryo-electron microscopy structures collaboratively with citizen scientists.

With the rapid improvement of cryo-electron microscopy (cryo-EM) resolution, new computational tools are needed to assist and improve upon atomic model building and refinement options. This communication demonstrates that microscopists can now collaborate with the players of the computer game Foldit to generate high-quality de novo structural models. This development could greatly speed the generation of excellent cryo-EM structures when used in addition to current methods.

Sex-based differences in left ventricular remodeling in patients with chronic aortic regurgitation: a multi-modality study.

BACKGROUND: Significant aortic regurgitation (AR) leads to left ventricular (LV) remodeling; however, little data exist regarding sex-based differences in LV remodeling in this setting. We sought to compare LV remodeling and AR severity, assessed by echocardiography and cardiovascular magnetic resonance (CMR), to discern sex-based differences. METHODS: Patients with ≥ moderate chronic AR by echocardiography who underwent CMR within 90 days between December 2005 and October 2015 were included. Nonlinear regression models were built to assess the effect of AR regurgitant fraction (RF) on LV remodeling. A generalized linear model and Bland Altman analyses were constructed to evaluate differences between CMR and echocardiography. Referral for surgical intervention based on symptoms and LV remodeling was evaluated. RESULTS: Of the 243 patients (48.3 ± 16.6 years, 58 (24%) female), 119 (49%) underwent surgical intervention with a primary indication of severe AR, 97 (82%) men, 22 (18%) women. Significant sex differences in LV remodeling emerged on CMR. Women demonstrated significantly smaller LV end-diastolic volume index (LVEDVI) (96.8 ml/m2 vs 125.6 ml/m2, p < 0.001), LV end-systolic volume index (LVESVI) (41.1 vs 54.5 ml/m2, p < 0.001), blunted LV dilation in the setting of increasing AR severity (LVEDVI p value < 0.001, LVESVI p value 0.011), and LV length indexed (8.32 vs 9.69 cm, p < 0.001). On Bland Altman analysis, a significant interaction with sex and LV diameters was evident, demonstrating a significant increase in the difference between CMR and echocardiography measurements as the LV enlarged in women: LVEDVI (p = 0.006), LVESVI (p < 0.001), such that echocardiographic measurements increasingly underestimated LV diameters in women as the LV enlarged. LV length was higher for males with a linear effect from RF (p < 0.001), with LV length increasing at a higher rate with increasing RF for males compared to females (two-way interaction with sex p = 0.005). Sphericity volume index was higher for men after adjusting for a relative wall thickness (p = 0.033). CONCLUSIONS: CMR assessment of chronic AR revealed significant sex differences in LV remodeling and significant echocardiographic underestimation of LV dilation, particularly in women. Defining optimal sex-based CMR thresholds for surgical referral should be further developed. TRIAL REGISTRATION: NA.

Suppression of Superconductivity and Nematic Order in Fe1-ySe1-xSx (0 ≤ x ≤ 1; y ≤ 0.1) Crystals by Anion Height Disorder.

Connections between crystal chemistry and critical temperature Tc have been in the focus of superconductivity, one of the most widely studied phenomena in physics, chemistry, and materials science alike. In most Fe-based superconductors, materials chemistry and physics conspire so that Tc correlates with the average anion height above the Fe plane, i.e., with the geometry of the FeAs4 or FeCh4 (Ch = Te, Se, or S) tetrahedron. By synthesizing Fe1-ySe1-xSx (0 ≤ x ≤ 1; y ≤ 0.1), we find that in alloyed crystals Tc is not correlated with the anion height like it is for most other Fe superconductors. Instead, changes in Tc(x) and tetragonal-to-orthorhombic (nematic) transition Ts(x) upon cooling are correlated with disorder in Fe vibrations in the direction orthogonal to Fe planes, along the crystallographic c-axis. The disorder stems from the random nature of S substitution, causing deformed Fe(Se,S)4 tetrahedra with different Fe-Se and Fe-S bond distances. Our results provide evidence of Tc and Ts suppression by disorder in anion height. The connection to local crystal chemistry may be exploited in computational prediction of new superconducting materials with FeSe/S building blocks.

Upper Tract Urinary Cancer Recurrence after Radical Cystectomy: Risk Assessment of Intraoperative Frozen Section.

INTRODUCTION: Upper tract urinary cancer recurrence (UTUCR) after radical cystectomy (RC) is outcome-limiting. Surgical recommendations on intraoperative performance of frozen section analysis (FSA) and management of positive ureteral margin (PUM) are lacking. METHODS: 634 RC cases were identified (2010-2018). In patients with PUM, sequential ureteral resections up to a negative margin were performed. We investigated the accuracy of FSA, significance of PUM, and identified risk factors (RFs) to stratify patients for UTUCR. RESULTS: FSA was performed in 355 patients, including a total of 693 ureters. FSA sensitivity was 0.93 and specificity 0.99. PUM conversion was possible in 52 (91.2%) cases. UTUCR occurred in 17 (4.8%) patients. Identified UTUCR RFs are non-muscle invasive bladder carcinoma (NMIBC) (OR 3.8, 95% confidence intervals [CI] 1.4-10.2, p = 0.008), multifocal bladder cancer in cystectomy specimen (OR 4.7, CI 1.1-20.8, p = 0.042), and recurrent NMIBC (OR 4.1, CI 1.5-10.9, p = 0.006). Risk-group stratification showed a six-fold increase in UTUCR risk (low-to high-risk). CONCLUSION: FSA is a sensitive and specific method to identify PUM. UTUCR occurs significantly more often in patients with recurrent, multifocal NMIBC at the time of RC. Patients can be risk stratified for UTUCR. In case of NMIBC-PUM, surgeons can safely opt for a kidney preserving strategy.

Incremental Value of Global Longitudinal Strain to Michigan Risk Score and Pulmonary Artery Pulsatility Index in Predicting Right Ventricular Failure Following Left Ventricular Assist Devices.

BACKGROUND: The incremental utility of right ventricular (RV) strain on predicting right ventricular failure (RVF) following left ventricular assist device (LVAD) implantation, beyond clinical and haemodynamic indices, is not clear. METHODS: Two hundred and forty-six (246) patients undergoing LVAD implantation, who had transthoracic echocardiograms pre and post LVAD, pulmonary artery pulsatility index (PAPI) measurements and Michigan risk score, were included. We analysed RV global longitudinal strain (GLS) using speckle tracking echocardiography. RVF following LVAD implantation was defined as the need for medical support for >14 days, or unplanned RV assist device insertion after LVAD implantation. RESULTS: Mean preoperative RV-GLS was -7.8±2.8%. Among all, 27% developed postoperative RVF. A classification and regression tree analysis identified preoperative Michigan risk score, PAPI and RV-GLS as important parameters in predicting postoperative RVF. Eighty per cent (80%) of patients with PAPI <2.1 developed postoperative RVF, while only 4% of patients with PAPI >6.8 developed RVF. For patients with a PAPI of 2.1-3.2, having baseline Michigan risk score >2 points conferred an 81% probability of subsequent RVF. For patients with a PAPI of 3.3-6.8, having baseline RV-GLS of -4.9% or better conferred an 86% probability of no subsequent RVF. The sensitivity and specificity of this algorithm for predicting postoperative RVF were 67% and 93%, respectively, with an area under the curve of 0.87. CONCLUSION: RV-GLS has an incremental role in predicting the development of RVF post-LVAD implantation, even after controlling for clinical and haemodynamic parameters.

[Differential diagnosis of intraorbital masses - a narrative review]. / Differentialdiagnostik intraorbitaler Raumforderungen ­ eine Übersicht.

OBJECTIVE: Intraorbital masses represent a condition that is frequently threatening for the visual system. A rigorous differential diagnosis is essential to promptly initiate appropriate therapy and optimize prognosis. MATERIALS/METHODS: Narrative review of current literature and expert recommendations. For further illustration we describe the case of a 71-year-old male admitted to our department three months after sinus surgery. Postoperative intraorbital hematoma of the right orbit had been treated conservatively with antibiotics/corticosteroids, leading to a near-complete unilateral visual loss. The immediate surgical intervention aimed at decompression of the orbit and the optical nerve. Due to the delay, the intervention could not prevent formation of a lipogranuloma. Inflammatory phases associated with the lipogranuloma are successfully managed by conservative treatment based on multidisciplinary recommendations. RESULTS: In the case reported, delay of surgical therapy acted as a cause of intraorbital lipogranuloma formation. Literature supports our recommendation of immediate surgical intervention in case of acute retrobulbar hematoma. Besides acute conditions, intraorbital masses can be a sign of systemic disease. In every case, a multidisciplinary therapeutic approach is required for adequate management. CONCLUSIONS: Intraorbital masses can occur as a complication of trauma or e.g. sinus surgery. On the other hand they can be a sign of systemic disease. Timely diagnosis and treatment prevents from visual loss. That is why rigorous differential diagnosis is essential for every discipline managing intraorbital lesions.

Cardiac risk stratification in cancer patients: A longitudinal patient-patient network analysis.

BACKGROUND: Cardiovascular disease is a leading cause of death in general population and the second leading cause of mortality and morbidity in cancer survivors after recurrent malignancy in the United States. The growing awareness of cancer therapy-related cardiac dysfunction (CTRCD) has led to an emerging field of cardio-oncology; yet, there is limited knowledge on how to predict which patients will experience adverse cardiac outcomes. We aimed to perform unbiased cardiac risk stratification for cancer patients using our large-scale, institutional electronic medical records. METHODS AND FINDINGS: We built a large longitudinal (up to 22 years' follow-up from March 1997 to January 2019) cardio-oncology cohort having 4,632 cancer patients in Cleveland Clinic with 5 diagnosed cardiac outcomes: atrial fibrillation, coronary artery disease, heart failure, myocardial infarction, and stroke. The entire population includes 84% white Americans and 11% black Americans, and 59% females versus 41% males, with median age of 63 (interquartile range [IQR]: 54 to 71) years old. We utilized a topology-based K-means clustering approach for unbiased patient-patient network analyses of data from general demographics, echocardiogram (over 25,000), lab testing, and cardiac factors (cardiac). We performed hazard ratio (HR) and Kaplan-Meier analyses to identify clinically actionable variables. All confounding factors were adjusted by Cox regression models. We performed random-split and time-split training-test validation for our model. We identified 4 clinically relevant subgroups that are significantly correlated with incidence of cardiac outcomes and mortality. Among the 4 subgroups, subgroup I (n = 625) has the highest risk of de novo CTRCD (28%) with an HR of 3.05 (95% confidence interval (CI) 2.51 to 3.72). Patients in subgroup IV (n = 1,250) had the worst survival probability (HR 4.32, 95% CI 3.82 to 4.88). From longitudinal patient-patient network analyses, the patients in subgroup I had a higher percentage of de novo CTRCD and a worse mortality within 5 years after the initiation of cancer therapies compared to long-time exposure (6 to 20 years). Using clinical variable network analyses, we identified that serum levels of NT-proB-type Natriuretic Peptide (NT-proBNP) and Troponin T are significantly correlated with patient's mortality (NT-proBNP > 900 pg/mL versus NT-proBNP = 0 to 125 pg/mL, HR = 2.95, 95% CI 2.28 to 3.82, p < 0.001; Troponin T > 0.05 µg/L versus Troponin T ≤ 0.01 µg/L, HR = 2.08, 95% CI 1.83 to 2.34, p < 0.001). Study limitations include lack of independent cardio-oncology cohorts from different healthcare systems to evaluate the generalizability of the models. Meanwhile, the confounding factors, such as multiple medication usages, may influence the findings. CONCLUSIONS: In this study, we demonstrated that the patient-patient network clustering methodology is clinically intuitive, and it allows more rapid identification of cancer survivors that are at greater risk of cardiac dysfunction. We believed that this study holds great promise for identifying novel cardiac risk subgroups and clinically actionable variables for the development of precision cardio-oncology.

Correction of static and non-common path aberrations in an adaptive optics system using inherent calibration data.

For low-order adaptive optics systems, a method that is able to correct for system aberrations in the final focal plane is presented. The paper presents a novel figure of merit, corresponding to the integrated non-normalized tip-tilt-free optical transfer function. The inherent singular value decomposition modal content of the interaction matrix is used to optimize this figure of merit. The method has proven to be stable and robust, providing a simple mean to facilitate diffraction limited imaging in an experimental setup for ophthalmic applications.

Reference Ranges, Diagnostic and Prognostic Utility of Native T1 Mapping and Extracellular Volume for Cardiac Amyloidosis: A Meta-Analysis.

BACKGROUND: Cardiac MRI is central to the evaluation of cardiac amyloidosis (CA). Native T1 mapping and extracellular volume (ECV) are novel MR techniques with evolving utility in cardiovascular diseases, including CA. PURPOSE: To perform a meta-analysis of the diagnostic and prognostic data of native T1 mapping and ECV techniques for assessing CA. STUDY TYPE: Systematic review and meta-analysis. POPULATION: In all, 3520 patients including 1539 with CA from 22 studies retrieved following systematic search of Pubmed, Cochrane, and Embase. FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T/modified Look-Locker inversion recovery (MOLLI) or shortened MOLLI (shMOLLI) sequences. ASSESSMENT: Meta-analysis was performed for all CA and for light-chain (AL) and transthyretin (ATTR) subtypes. Thresholds were calculated to classify native T1 and ECV values as not suggestive, indeterminate, or suggestive of CA. STATISTICAL ANALYSIS: Area under the receiver-operating characteristic curves (AUCs) and hazards ratios (HRs) with 95% confidence intervals (95% CI) were pooled using random-effects models and Open-Meta(Analyst) software. RESULTS: Six studies were diagnostic, 16 studies reported T1 and ECV values to determine reference range, and six were prognostic. Pooled AUCs (95% CI) for diagnosing CA were 0.92 (0.89-0.96) for native T1 mapping and 0.96 (0.93-1.00) for ECV, with similarly high detection rates for AL- and ATTR-CA. Based on the pooled values of native T1 and ECV in CA and control subjects, the thresholds that suggested the absence, indeterminate, or presence of CA were identified as <994 msec, 994-1073 msec, and >1073 msec, respectively, for native T1 at 1.5T. Pooled HRs (95% CI) for predicting all-cause mortality were 1.15 (1.08-1.22) for native T1 mapping as a continuous parameter, 1.19 (1.01-1.40) for ECV as a continuous parameter, and 4.93 (2.64-9.20) for ECV as a binary threshold. DATA CONCLUSION: Native T1 mapping and ECV had high diagnostic performance and predicted all-cause mortality in CA. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Impact of baseline conduction abnormalities on outcomes after transcatheter aortic valve replacement with SAPIEN-3.

BACKGROUND: Baseline conduction abnormalities are known risk factors for permanent pacemaker (PPM) implantation after transcatheter aortic valve replacement (TAVR). We sought to determine the impact of baseline right bundle branch block (RBBB), left bundle branch block (LBBB), left anterior hemiblock (LAHB), first-degree atrioventricular block (AVB) and atrial fibrillation/flutter (AF) on TAVR outcomes. METHODS: Consecutive patients who underwent transfemoral TAVR with SAPIEN-3 (S3) were included. We excluded patients with prior PPM, nontransfemoral access or valve-in-valve. RESULTS: Among 886 patients, baseline RBBB was seen in 15.9%, LBBB in 6.3%, LAHB in 6.2%, first-degree AVB in 26.3% and AF in 37.5%. The rate of 30-day PPM was 10.1%. Baseline RBBB (OR 4.005; 95% CI 2.386-6.723; p < .001) and first-degree AVB (OR 1.847; 95% CI 1.133-3.009; p = .014) were independent predictors of 30 day PPM. LAHB also resulted in higher PPM rates but only in unadjusted analysis (21.8% vs. 9.4%; p = .003). Baseline LBBB and AF were associated with lower left ventricular ejection fraction (LVEF) at both baseline and 1 year after TAVR. However, Δ LVEF over time were noted to be similar with baseline LBBB (1.8% vs. 1.4%; p = .809) and AF (1.1% vs. 1.7%; p = .458). Moreover, baseline AF was also associated with higher stroke/transient ischemic attack (TIA) at 1 year (4.4% vs. 1.8%; p = .019), 1-year major adverse cardiac and cerebrovascular events (MACCE) (19.5% vs. 13.3%; p = .012) and 2 year mortality (23.5% vs. 15.2%; p = .016). None of the other baseline conduction defects affected long-term mortality or MACCE. CONCLUSION: In our S3 TAVR population, baseline RBBB and first-degree AVB predicted higher PPM risk. Prior LBBB and AF were associated with lower LVEF at both baseline and 1 year. Lastly, preexisting AF was associated with higher rates of mortality, stroke/TIA, and MACCE.

Defining the Reference Range for Left Ventricular Strain in Healthy Patients by Cardiac MRI Measurement Techniques: Systematic Review and Meta-Analysis.

BACKGROUND. Echocardiography is the primary noninvasive technique for left ventricular (LV) strain measurement. MRI has potential advantages, although reference ranges and thresholds to differentiate normal from abnormal left ventricular global longitudinal strain (LVGLS), left ventricular global circumferential strain (LVGCS), and left ventricular global radial strain (LVGRS) are not yet established. OBJECTIVE. The purpose of our study was to determine the mean and lower limit of normal (LLN) of MRI-derived LV strain measurements in healthy patients and explore factors potentially influencing these measurements. EVIDENCE ACQUISITION. PubMed, Embase, and Cochrane Library databases were searched for studies published through January 1, 2020, that reported MRI-derived LV strain measurements in at least 30 healthy individuals. Mean and LLN measurements of LV strain were pooled using random-effects models overall and for studies stratified by measurement method (feature tracking [FT] or tagging). Additional subgroup and meta-regression analyses were performed. EVIDENCE SYNTHESIS. Twenty-three studies with a total of 1782 healthy subjects were included. Pooled means and LLNs for all studies were -18.6% (95% CI, -19.5% to -17.6%) and -13.3% (-13.9% to 12.7%) for LVGLS, -21.0% (-22.4% to -19.6%) and -15.6% (-17.0% to -14.3%) for LVGCS, and 38.7% (30.5-46.9%) and 20.6% (15.1-26.1%) for LVGRS. Pooled means and LLNs for LVGLS by strain measurement method were -19.4% (95% CI, -20.6% to -18.1%) and -13.1% (-14.2% to -12.0%) for FT and -15.6% (-16.2% to -15.1%) and -13.1% (-14.1% to -12.2%) for tagging. A later year of study publication, increasing patient age, and increasing body mass index were associated with more negative mean LVGLS values. An increasing LV end-diastolic volume index was associated with less negative mean LVGLS values. No factor was associated with LLN of LVGLS. CONCLUSION. We determined the pooled means and LLNs, with associated 95% CIs, for LV strain by cardiac MRI to define thresholds for normal, abnormal, and borderline strain in healthy patients. The method of strain measurement by MRI affected the mean LVGLS. No factor affected the LLN of LVGLS. CLINICAL IMPACT. This meta-analysis lays a foundation for clinical adoption of MRI-derived LV strain measurements, with management implications in both healthy patients and patients with various disease states.

CD73 Overexpression in Podocytes: A Novel Marker of Podocyte Injury in Human Kidney Disease.

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001-p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = -0.5068, p = 0.0031; Pearson r = -0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.