Development of novel machine learning model for right ventricular quantification on echocardiography-A multimodality validation study.

PURPOSE: Echocardiography (echo) is widely used for right ventricular (RV) assessment. Current techniques for RV evaluation require additional imaging and manual analysis; machine learning (ML) approaches have the potential to provide efficient, fully automated quantification of RV function. METHODS: An automated ML model was developed to track the tricuspid annulus on echo using a convolutional neural network approach. The model was trained using 7791 image frames, and automated linear and circumferential indices quantifying annular displacement were generated. Automated indices were compared to an independent reference of cardiac magnetic resonance (CMR) defined RV dysfunction (RVEF < 50%). RESULTS: A total of 101 patients prospectively underwent echo and CMR: Fully automated annular tracking was uniformly successful; analyses entailed minimal processing time (<1 second for all) and no user editing. Findings demonstrate all automated annular shortening indices to be lower among patients with CMR-quantified RV dysfunction (all P < .001). Magnitude of ML annular displacement decreased stepwise in relation to population-based tertiles of TAPSE, with similar results when ML analyses were localized to the septal or lateral annulus (all P ≤ .001). Automated segmentation techniques provided good diagnostic performance (AUC 0.69-0.73) in relation to CMR reference and compared to conventional RV indices (TAPSE and S') with high negative predictive value (NPV 84%-87% vs 83%-88%). Reproducibility was higher for ML algorithm as compared to manual segmentation with zero inter- and intra-observer variability and ICC 1.0 (manual ICC: 0.87-0.91). CONCLUSIONS: This study provides an initial validation of a deep learning system for RV assessment using automated tracking of the tricuspid annulus.

Transcatheter MitraClip repair alters mitral annular geometry - device induced annular remodeling on three-dimensional echocardiography predicts therapeutic response.

BACKGROUND: Echocardiography (echo) is widely used to guide therapeutic decision-making for patients being considered for MitraClip. Relative utility of two- (2D) and three-dimensional (3D) echo predictors of MitraClip response, and impact of MitraClip on mitral annular geometry, are uncertain. METHODS: The study population comprised patients with advanced (> moderate) MR undergoing MitraClip. Mitral annular geometry was quantified on pre-procedural 2D transthoracic echocardiography (TTE) and intra-procedural 3D transesophageal echocardiography (TEE); 3D TEE was used to measure MitraClip induced changes in annular geometry. Optimal MitraClip response was defined as ≤mild MR on follow-up (mean 2.7 ± 2.5 months) post-procedure TTE. RESULTS: Eighty patients with advanced MR underwent MitraClip; 41% had optimal response (≤mild MR). Responders had smaller pre-procedural global left ventricular (LV) end-diastolic size and mitral annular diameter on 2D TTE (both p ≤ 0.01), paralleling smaller annular area and circumference on 3D TEE (both p = 0.001). Mitral annular size yielded good diagnostic performance for optimal MitraClip response (AUC 0.72, p < 0.01). In multivariate analysis, sub-optimal MitraClip response was independently associated with larger pre-procedural mitral annular area on 3D TEE (OR 1.93 per cm2/m2 [CI 1.19-3.13], p = 0.007) and global LV end-diastolic volume on 2D TTE (OR 1.29 per 10 ml/m2 [CI 1.02-1.63], p = 0.03). Substitution of 2D TTE derived mitral annular diameter for 3D TEE data demonstrated a lesser association between pre-procedural annular size (OR 5.36 per cm/m2 [CI 0.95-30.19], p = 0.06) and sub-optimal MitraClip response. Matched pre- and post-procedural TEE analyses demonstrated MitraClip to acutely decrease mitral annular area and circumference (all p < 0.001) as well as mitral tenting height, area, and volume (all p < 0.05): Magnitude of MitraClip induced reductions in mitral annular circumference on intra-procedural 3D TEE was greater among patients with, compared to those without, sub-optimal MitraClip response (>mild MR) on followup TTE (p = 0.017); greater magnitude of device-induced annular reduction remained associated with sub-optimal MitraClip response even when normalized for pre-procedure annular circumference (p = 0.028). CONCLUSIONS: MitraClip alters mitral annular geometry as quantified by intra-procedural 3D TEE. Pre-procedural mitral annular dilation and magnitude of device-induced reduction in mitral annular size on 3D TEE are each associated with sub-optimal therapeutic response to MitraClip.

Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres.

Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC) is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus. However, little is known about the role of the FPC at other natural impediments including telomeres. Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatory mechanism that ensures telomere replication is not fully understood. Here, we report the role of the fission yeast Swi1(Timeless), a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomere shortening in a telomerase-independent manner. Our epistasis analyses suggest that heterochromatin and telomere-binding proteins are not major impediments for telomere replication in the absence of Swi1. Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss of repeat DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also be relevant in understanding the potential role of Swi1(Timeless) in regulation of telomere stability in cancer cells.

Complete Myocardial Function Recovery with ECMO in a Woman Presenting with Cardiogenic Shock during Peripartum Period.

Peripartum cardiomyopathy is a potentially life-threatening cause of heart failure (HF) that affects women toward the end of pregnancy or in months after delivery. Treatment is similar to the treatment for HF with reduced ejection fraction (EF). Most women make full myocardial function recovery within 6 months on conventional HF therapy. In rare instances, catastrophic presentations may occur with hemodynamic instability requiring the use of mechanical support. Because of the small patient population, limited information is available regarding the recovery of myocardial function in women who received mechanical support. We present a case of a woman in her peripartum period who presented with cardiogenic shock and made complete myocardial function recovery after 4 days of extracorporeal membrane oxygenation (ECMO). Our patient's EF at the time of catastrophe was 5-10%, which improved to 60% on day 4 on ECMO.

Left Ventricular Outflow Tract Obstruction From Preserved Leaflet After Mitral Valve Replacement.

Left ventricular outflow tract obstruction (LVOTO) can be caused by multiple factors. One of the rare causes of LVOTO is preserved anterior mitral valve leaflet and chordal apparatus after mitral valve replacement. We describe a case of a patient with worsening chronic congestive heart failure secondary to LVOTO from systolic anterior motion of residual native anterior mitral leaflet. In this patient, LVOTO was surgically corrected by excision of anterior leaflet and chordal apparatus through the aortic root.

Shock Index as a Marker for Mortality Rates in Those Admitted to the Medical Intensive Care Unit from the Emergency Department.

Objective Shock index (SI) is defined as the heart rate divided by systolic blood pressure. Studies have shown a correlation between the shock index and mortality in trauma patients in prehospital settings and in the emergency department (ED). The objective of this study was to identify the utility of SI in predicting mortality in the medical intensive care unit (MICU) patients admitted from the ED and transfers from the floor to MICU.  Design We performed a retrospective analysis of adult patients admitted to the MICU at our urban trauma hospital between January 2015 through August 2015 using ED vital signs to calculate the shock index and identify inpatient deaths. Similar data were examined for inpatient transfers to the MICU. Results Nine hundred and fifty patients were included in the study; 743 had an SI ≤ 0.99 with a mortality rate of 15.9%. Two hundred and seven patients had a SI ≥ 1.00 with a mortality rate of 22.7%. A higher SI was significant for mortality. There was no statistical significance in SI and mortality rate for patients transferred from the medical floor to the ICU. Conclusions Patients with an SI ≥ 1.00 from initial ED vital signs correlated with a higher mortality rate. In patients transferred from the floor to MICU, SI ≥ 1.00 did not correlate with a higher mortality rate.

Left Atrial Strain Impairment Precedes Geometric Remodeling as a Marker of Post-Myocardial Infarction Diastolic Dysfunction.

OBJECTIVES: The aims of this study were to test the magnitude of agreement between echocardiography (echo)- and cardiac magnetic resonance (CMR)-derived left atrial (LA) strain and to study their relative diagnostic performance in discriminating diastolic dysfunction (DD) and predicting atrial fibrillation (AF). BACKGROUNDS: Peak atrial longitudinal strain (PALS) is a novel performance index. Utility of echo-quantified LA strain has yet to be prospectively tested in relation to current DD guidelines or compared to CMR. METHODS: The study population comprised 257 post-myocardial infarction (MI) patients undergoing echo and CMR, including prospective derivation (n = 157) and clinical validation (n = 100) cohorts. DD was graded on echo using established consensus guidelines blinded to strain results. RESULTS: PALS on both echo and CMR was nearly 2-fold lower among patients with versus no DD (p < 0.001) and was significantly different in those with mild versus no DD (p < 0.01). In contrast, LA geometric parameters including echo- and CMR-derived volumes were significantly different between advanced versus no DD groups (p < 0.001) but not between groups with mild versus no DD (all p > 0.05). Echo and CMR PALS yielded small differences irrespective of orientation and similar diagnostic performance for DD in the derivation (area under the curve [AUC]: 0.70 to 0.78) and validation (AUC: 0.75 to 0.78) cohorts. Impaired PALS on both modalities was independently associated with MI size (p < 0.001). During 4.4 ± 3.8 years of follow-up in the derivation cohort, 8% developed AF. Both 2-chamber echo- and CMR-derived PALS stratified arrhythmic risk (p = 0.004 and p = 0.02, respectively), including a 4-fold difference among patients in the lowest versus remainder of quartiles of echo-derived PALS (24% vs. 6%). Similarly, echo and CMR PALS were lower (both p < 0.05) among patients with subsequent heart failure hospitalizations. CONCLUSIONS: Echo-derived PALS parallels results of CMR, yields incremental diagnostic utility versus LA geometry for stratifying presence and severity of DD, and improves prediction of AF and congestive heart failure after MI.

Oxygen-Dependent Patient with Antisynthetase Syndrome Associated Interstitial Lung Disease Responds Promptly to Rituximab with Rapid Pulmonary Function Improvement.

Antisynthetase syndrome (anti-SS) is a rare systemic autoimmune disorder characterized by myositis, Raynaud's phenomenon, fever, interstitial lung disease (ILD), polyarthralgia, and presence of antibodies against tRNA synthetase, especially anti-Jo-1. Rarely, anti-SS can present as isolated ILD, with clinical features very similar to atypical pneumonia, making diagnosis extremely challenging. We report a patient originally diagnosed with atypical pneumonia, requiring oxygen supplementation, who failed treatment with antibiotics. Radiological findings were suspicious for ILD and a comprehensive rheumatological work-up revealed the diagnosis of anti-SS associated ILD. Prompt treatment was initiated with steroids and rituximab. Follow up pulmonary function tests showed an improvement in her diffusing capacity of the lung for carbon monoxide and forced vital capacity allowing her to resume her daily life without supplemental oxygen.

Timeless preserves telomere length by promoting efficient DNA replication through human telomeres.

A variety of telomere protection programs are utilized to preserve telomere structure. However, the complex nature of telomere maintenance remains elusive. The Timeless protein associates with the replication fork and is thought to support efficient progression of the replication fork through natural impediments, including replication fork block sites. However, the mechanism by which Timeless regulates such genomic regions is not understood. Here, we report the role of Timeless in telomere length maintenance. We demonstrate that Timeless depletion leads to telomere shortening in human cells. This length maintenance is independent of telomerase, and Timeless depletion causes increased levels of DNA damage, leading to telomere aberrations. We also show that Timeless is associated with Shelterin components TRF1 and TRF2. Timeless depletion slows telomere replication in vitro, and Timeless-depleted cells fail to maintain TRF1-mediated accumulation of replisome components at telomeric regions. Furthermore, telomere replication undergoes a dramatic delay in Timeless-depleted cells. These results suggest that Timeless functions together with TRF1 to prevent fork collapse at telomere repeat DNA and ensure stable maintenance of telomere length and integrity.

The double-bromodomain proteins Bdf1 and Bdf2 modulate chromatin structure to regulate S-phase stress response in Schizosaccharomyces pombe.

Bromodomain proteins bind acetylated histones to regulate transcription. Emerging evidence suggests that histone acetylation plays an important role in DNA replication and repair, although its precise mechanisms are not well understood. Here we report studies of two double bromodomain-containing proteins, Bdf1 and Bdf2, in fission yeast. Loss of Bdf1 or Bdf2 led to a reduction in the level of histone H4 acetylation. Both bdf1Δ and bdf2Δ cells showed sensitivity to DNA damaging agents, including camptothecin, that cause replication fork breakage. Consistently, Bdf1 and Bdf2 were important for recovery of broken replication forks and suppression of DNA damage. Surprisingly, deletion of bdf1 or bdf2 partially suppressed sensitivity of various checkpoint mutants including swi1Δ, mrc1Δ, cds1Δ, crb2Δ, chk1Δ, and rad3Δ, to hydroxyurea, a compound that stalls replication forks and activates the Cds1-dependent S-phase checkpoint. This suppression was not due to reactivation of Cds1. Instead, we found that bdf2 deletion alleviates DNA damage accumulation caused by defects in the DNA replication checkpoint. We also show that hydroxyurea sensitivity of mrc1Δ and swi1Δ was suppressed by mutations in histone H4 acetyltransferase subunits or histone H4. These results suggest that the double bromodomain-containing proteins modulate chromatin structure to coordinate DNA replication and S-phase stress response.

Genetic evidence that polysumoylation bypasses the need for a SUMO-targeted Ub ligase.

Saccharomyces cerevisiae cells lacking the Slx5-Slx8 SUMO-targeted Ub ligase display increased levels of sumoylated and polysumoylated proteins, and they are inviable in the absence of the Sgs1 DNA helicase. One explanation for this inviability is that one or more sumoylated proteins accumulate to toxic levels in sgs1Δ slx5Δ cells. To address this possibility, we isolated a second-site suppressor of sgs1Δ slx5Δ synthetic lethality and identified it as an allele of the ULP2 SUMO isopeptidase. The suppressor, ulp2-D623H, behaved like the ulp2Δ allele in its sensitivity to heat, DNA replication stress, and DNA damage. Surprisingly, deletion of ULP2, which is known to promote the accumulation of poly-SUMO chains, suppressed sgs1Δ slx5Δ synthetic lethality and the slx5Δ sporulation defect. Further, ulp2Δ's growth sensitivities were found to be suppressed in ulp2Δ slx5Δ double mutants. This mutual suppression indicates that SLX5-SLX8 and ULP2 interact antagonistically. However, the suppressed strain sgs1Δ slx5Δ ulp2-D623H displayed even higher levels of sumoylated proteins than the corresponding double mutants. Thus, sgs1Δ slx5Δ synthetic lethality cannot be due simply to high levels of bulk sumoylated proteins. We speculate that the loss of ULP2 suppresses the toxicity of the sumoylated proteins that accumulate in slx5Δ-slx8Δ cells by permitting the extension of poly-SUMO chains on specific target proteins. This additional modification might attenuate the activity of the target proteins or channel them into alternative pathways for proteolytic degradation. In support of this latter possibility we find that the WSS1 isopeptidase is required for suppression by ulp2Δ.

Checkpoint-dependent and -independent roles of Swi3 in replication fork recovery and sister chromatid cohesion in fission yeast.

Multiple genome maintenance processes are coordinated at the replication fork to preserve genomic integrity. How eukaryotic cells accomplish such a coordination is unknown. Swi1 and Swi3 form the replication fork protection complex and are involved in various processes including stabilization of replication forks, activation of the Cds1 checkpoint kinase and establishment of sister chromatid cohesion in fission yeast. However, the mechanisms by which the Swi1-Swi3 complex achieves and coordinates these tasks are not well understood. Here, we describe the identification of separation-of-function mutants of Swi3, aimed at dissecting the molecular pathways that require Swi1-Swi3. Unlike swi3 deletion mutants, the separation-of-function mutants were not sensitive to agents that stall replication forks. However, they were highly sensitive to camptothecin that induces replication fork breakage. In addition, these mutants were defective in replication fork regeneration and sister chromatid cohesion. Interestingly, unlike swi3-deleted cell, the separation-of-functions mutants were proficient in the activation of the replication checkpoint, but their fork regeneration defects were more severe than those of checkpoint mutants including cds1Δ, chk1Δ and rad3Δ. These results suggest that, while Swi3 mediates full activation of the replication checkpoint in response to stalled replication forks, Swi3 activates a checkpoint-independent pathway to facilitate recovery of collapsed replication forks and the establishment of sister chromatid cohesion. Thus, our separation-of-function alleles provide new insight into understanding the multiple roles of Swi1-Swi3 in fork protection during DNA replication, and into understanding how replication forks are maintained in response to different genotoxic agents.