Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia.

Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 µg once daily (QD) for week 1 and 500 µg three times weekly (TIW) thereafter (250 µg/500 µg) or (2) 500 µg QD for week 1 and 1000 µg TIW thereafter (500 µg/1000 µg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 µg/500 µg dose and 13 at 500 µg/1000 µg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 µg/500 µg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10-4 leukemic blasts). At the 500 µg/1000 µg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.

Oxford nanopore sequencing in clinical microbiology and infection diagnostics.

Extended turnaround times and large economic costs hinder the usage of currently applied screening methods for bacterial pathogen identification (ID) and antimicrobial susceptibility testing. This review provides an overview of current detection methods and their usage in a clinical setting. Issues of timeliness and cost could soon be circumvented, however, with the emergence of detection methods involving single molecule sequencing technology. In the context of bringing diagnostics closer to the point of care, we examine the current state of Oxford Nanopore Technologies (ONT) products and their interaction with third-party software/databases to assess their capabilities for ID and antimicrobial resistance (AMR) prediction. We outline and discuss a potential diagnostic workflow, enumerating (1) rapid sample prep kits, (2) ONT hardware/software and (3) third-party software and databases to improve the cost, accuracy and turnaround times for ID and AMR. Multiple studies across a range of infection types support that the speed and accuracy of ONT sequencing is now such that established ID and AMR prediction tools can be used on its outputs, and so it can be harnessed for near real time, close to the point-of-care diagnostics in common clinical circumstances.

Transcatheter Aortic Valve Replacement in Special Populations.

Since its food and drug administration (FDA) approval in 2011, transcatheter aortic valve replacement (TAVR) has revolutionized the highly prevalent disease of aortic stenosis. In this review, we present a comprehensive overview of the data and considerations for utilization of TAVR in special populations who were either excluded from or not adequately represented in the seminal TAVR trials, due to high-risk valvular and/or systemic factors. These include nonagenarians, patients with renal dysfunction, chronic thrombocytopenia, bicuspid aortic valve, rheumatic valve disease, patients with failed aortic valve bioprosthesis requiring valve-in-valve intervention and patients with mixed aortic valve disease. In short, TAVR is a feasible therapeutic strategy in high-risk and special populations with mortality benefit and improvement in quality of life. Randomized controlled trials in high-risk populations are recommended to confirm results from observational studies.

Transcatheter Edge-to-Edge Repair of Mitral Valve Regurgitation: Closing the Gap to Broaden the Coverage.

Background: Transcatheter edge-to-edge repair of mitral valve (M-TEER) is reasonable consideration in symptomatic patients with severe degenerative mitral regurgitation (MR) who are at high or prohibitive risk of surgical repair or replacement. In symptomatic patients on maximally tolerated medical therapy with severe secondary MR from left ventricular systolic dysfunction, M-TEER is reasonable therapeutic option. Methods: In this review, we present a comprehensive overview of the most recent literature and considerations for M-TEER in patients excluded from key trials. These include patients with cardiogenic shock, acute ischemic MR, atrial functional MR, failed surgical mitral valve prosthesis and pulmonary hypertension. Conclusions: M-TEER is feasible and a reasonable alternative option for these patient populations with a significant clinical benefit. However, randomized clinical trials are needed to ascertain findings from these observational studies.

Sex-related differences in the trends and outcomes of trans-septal transcatheter mitral valve replacement: Insights from the National Readmissions Database.

BACKGROUND: There is a paucity of data regarding the sex-related differences in the trends and outcomes of trans-septal transcatheter mitral valve replacement (TS-TMVR). METHODS: The Nationwide Readmissions Database (2015-2018) was queried for admissions for TS-TMVR. Propensity matched analysis was conducted to compare outcomes with hospitalizations for TS-TMVR among women versus men. The main study outcome was in-hospital mortality. RESULTS: Our final analysis included 2063 hospitalizations for TS-TMVR; of whom, 58.1% were women. The proportion of women among those undergoing TS-TMVR increased from 50% in 2015 to 60.2% in 2018 (Ptrend = 0.04). Compared with men, women undergoing TS-TMVR were slightly younger, and had a distinct profile of comorbidities. After matching, there was no significant difference in in-hospital mortality among women versus men undergoing TS-TMVR (7.8% vs. 6.1%, OR = 1.30; 95% CI: 0.79-2.13). Subgroup analyzes showed an interaction toward higher mortality with women versus men among patients with CKD (Pinteraction = 0.07). There were no significant differences between women and men in in-hospital complications or length of stay after TS-TMVR. Compared with men, women undergoing TS-TMVR were more likely to be discharged to a nursing facility (17.7% vs. 11.5%, p = 0.01) and had higher rates of 30-day readmissions (22.4% vs. 13.6%, p = 0.01). CONCLUSION: This nationwide analysis showed an increase in the proportion of women among patients undergoing TS-TMVR during the study years. There were no differences in in-hospital mortality, in-hospital complications, or length of stay between both sexes following TS-TMVR. Women were more likely to be discharged to nursing facilities and had higher rates of readmission at 30 days even after propensity matching.

Prosthetic valve endocarditis after transcatheter aortic valve replacement in low-risk patients.

OBJECTIVES: We sought to report details of the incidence, organisms, clinical course, and outcomes of prosthetic valve endocarditis (PVE) after transcatheter aortic valve replacement (TAVR) in low-risk patients. BACKGROUND: PVE remains a rare but devastating complication of aortic valve replacement. Data regarding PVE after TAVR in low-risk patients are lacking. METHODS: We performed a detailed review of all patients in the low-risk TAVR trials who underwent TAVR from 2016 to 2020 and were adjudicated to have definitive PVE by the independent Clinical Events Committee. RESULTS: We analyzed 396 low-risk patients who underwent TAVR (including 72 with bicuspid valves). PVE occurred in 11 patients at a median 379 days (210, 528) from TAVR. The incidence within the first 30 days was 0%; days 31-365, 1.5%; and after day 365, 2.8%. The most common organism identified was Streptococcus (n = 4/11). Early PVE (≤ 365 days) occurred in five patients, of whom three demonstrated evidence of embolic stroke and two underwent surgical aortic valve re-intervention. Late PVE (> 365 days) occurred in six patients, of whom thee demonstrated evidence of embolic stroke and only one underwent surgical aortic valve re-intervention. Of the six patients with evidence of embolic stroke, two died, two were discharged to rehabilitation, and two were discharged home with home care. CONCLUSIONS: PVE was infrequent following TAVR in low-risk patients but was associated with substantial morbidity and mortality. Embolic stroke complicated the majority of PVE cases, contributing to worse outcomes in these patients. Efforts must be undertaken to minimize PVE in TAVR.

Evaluating the effectiveness of ensemble voting in improving the accuracy of consensus signals produced by various DTWA algorithms from step-current signals generated during nanopore sequencing.

Nanopore sequencing device analysis systems simultaneously generate multiple picoamperage current signals representing the passage of DNA or RNA nucleotides ratcheted through a biomolecule nanopore array by motor proteins. Squiggles are a noisy and time-distorted representation of an underlying nucleotide sequence, "gold standard model", due to experimental and algorithmic artefacts. Other research fields use dynamic time warped-space averaging (DTWA) algorithms to produce a consensus signal from multiple time-warped sources while preserving key features distorted by standard, linear-averaging approaches. We compared the ability of DTW Barycentre averaging (DBA), minimize mean (MM) and stochastic sub-gradient descent (SSG) DTWA algorithms to generate a consensus signal from squiggle-space ensembles of RNA molecules Enolase, Sequin R1-71-1 and Sequin R2-55-3 without knowledge of their associated gold standard model. We propose techniques to identify the leader and distorted squiggle features prior to DTWA consensus generation. New visualization and warping-path metrics are introduced to compare consensus signals and the best estimate of the "true" consensus, the study's gold standard model. The DBA consensus was the best match to the gold standard for both Sequin studies but was outperformed in the Enolase study. Given an underlying common characteristic across a squiggle ensemble, we objectively evaluate a novel "voting scheme" that improves the local similarity between the consensus signal and a given fraction of the squiggle ensemble. While the gold standard is not used during voting, the increase in the match of the final voted-on consensus to the underlying Enolase and Sequin gold standard sequences provides an indirect success measure for the proposed voting procedure in two ways: First is the decreased least squares warped distance between the final consensus and the gold model, and second, the voting generates a final consensus length closer to the known underlying RNA biomolecule length. The results suggest considerable potential in marrying squiggle analysis and voted-on DTWA consensus signals to provide low-noise, low-distortion signals. This will lead to improved accuracy in detecting nucleotides and their deviation model due to chemical modifications (a.k.a. epigenetic information). The proposed combination of ensemble voting and DTWA has application in other research fields involving time-distorted, high entropy signals.

Transcatheter aortic valve replacement in low-risk patients: 2-year results from the LRT trial.

BACKGROUND: Previous studies from the Low Risk TAVR (LRT) trial demonstrated that transcatheter aortic valve replacement (TAVR) is safe and feasible in low-risk patients, with excellent 30-day and 1-year outcomes. The objective of this study was to report clinical outcomes and the impact of 30-day hypoattenuated leaflet thickening (HALT) on structural valve deterioration (SVD) 2 years after TAVR. METHODS: The LRT trial was the first Food and Drug Administration-approved Investigational Device Exemption trial in the United States to evaluate the safety and feasibility of TAVR in low-risk patients with symptomatic severe tricuspid aortic stenosis (AS). Valve hemodynamics and SVD by echo were recorded 30 days, 1 year, and 2 years post-TAVR. RESULTS: The LRT trial enrolled 200 low-risk patients to receive TAVR. Their mean age was 73.6 years and 61.5% were men. At 2-year follow-up, the mortality rate was 4.2%; the cardiovascular death rate was 1.6%. The disabling stroke rate was 1.1%, permanent pacemaker implantation rate was 8.6%, and 4 patients (2.2%) presented with endocarditis (2 between years 1 and 2). Of the 14% of TAVR subjects who had evidence of HALT at 30 days, there was no impact on valve hemodynamics, endocarditis or stroke at 2 years. CONCLUSIONS: TAVR for low-risk patients with symptomatic severe tricuspid AS is safe at 2 years. The presence of HALT at 30 days did not impact the early hemodynamic improvements nor the durability of the valve structure.

Benzene Derivatives Analysis Using Aluminum Nitride Waveguide Raman Sensors.

Raman spectroscopy using aluminum nitride (AlN) optical waveguides was demonstrated for organic compound analysis. The AlN waveguide device was prepared by reactive sputtering deposition and complementary-metal-oxide semiconductor (CMOS) processes. A fundamental waveguide mode was observed over a broad visible spectrum and the waveguide evanescent wave was used to excite the Raman signals of the test analytes. The performance of the waveguide sensor was characterized by measuring the Raman spectra of the benzene derivative mixtures consisting of benzene, anisole, and toluene. The compositions and concentrations were resolved by correlating the obtained Raman spectrum with the characteristic Raman peaks associated with C-C, C-H, and C-O functional groups. With the advantages of real-time detection and enhanced Raman signal intensity, the AlN waveguides provided a sensor platform for nondestructive and online chemical compound monitoring.

PRESM: personalized reference editor for somatic mutation discovery in cancer genomics.

MOTIVATION: Accurate detection of somatic mutations is a crucial step toward understanding cancer. Various tools have been developed to detect somatic mutations from cancer genome sequencing data by mapping reads to a universal reference genome and inferring likelihoods from complex statistical models. However, read mapping is frequently obstructed by mismatches between germline and somatic mutations on a read and the reference genome. Previous attempts to develop personalized genome tools are not compatible with downstream statistical models for somatic mutation detection. RESULTS: We present PRESM, a tool that builds personalized reference genomes by integrating germline mutations into the reference genome. The aforementioned obstacle is circumvented by using a two-step germline substitution procedure, maintaining positional fidelity using an innovative workaround. Reads derived from tumor tissue can be positioned more accurately along a personalized reference than a universal reference due to the reduced genetic distance between the subject (tumor genome) and the target (the personalized genome). Application of PRESM's personalized genome reduced false-positive (FP) somatic mutation calls by as much as 55.5%, and facilitated the discovery of a novel somatic point mutation on a germline insertion in PDE1A, a phosphodiesterase associated with melanoma. Moreover, all improvements in calling accuracy were achieved without parameter optimization, as PRESM itself is parameter-free. Hence, similar increases in read mapping and decreases in the FP rate will persist when PRESM-built genomes are applied to any user-provided dataset. AVAILABILITY AND IMPLEMENTATION: The software is available at https://github.com/precisionomics/PRESM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cardiac implantable electronic device placement following alcohol septal ablation for hypertrophic cardiomyopathy in the United States.

BACKGROUND: Cardiac implantable electronic devices (CIED) are sometimes required after alcohol septal ablation (ASA) for hypertrophic cardiomyopathy (HCM). The primary objectives of this study were to characterize the incidence, timing, and predictors of CIED placement after ASA for HCM. METHODS: Patients were identified from the 2010-2015 Nationwide Readmissions Databases. Incidence, timing and independent predictors of CIED placement, as well as 30-day readmission rates were examined. RESULTS: There were 1296 patients (national estimate = 2864) with HCM who underwent ASA. CIED were implanted in 322 (25% overall; 14% permanent pacemaker, 11% implantable cardioverter defibrillator) during the index hospitalization. Of these, 21%, 23%, 21%, and 18% occurred on postprocedure day 0, 1, 2, and 3, respectively. Only 17 (1.3%) patients underwent CIED implantation between discharge and 30-day follow up. Independent predictors of index hospitalization CIED implantation included older age, diabetes, heart failure, nonelective index hospital admission and hospitalization at a privately owned hospital. Nonelective 30-day readmission rates among those who did and did not undergo CIED placement during their index hospitalization, were 6.8% and 7.9%, respectively (p = .53); median time to readmission was also similar between groups. CONCLUSIONS: One in four HCM patients undergoing ASA underwent CIED implantation during their index hospitalization; nearly 2/3rd during the first 48 h postprocedure. Private hospital ownership independently predicted CIED placement. More data are needed to better understand the unexpectedly high rates of CIED placement, earlier than anticipated timing of implantation and differential rates by hospital ownership.

Thirty-day readmissions after transcatheter versus surgical mitral valve repair in high-risk patients with mitral regurgitation: Analysis of the 2014-2015 Nationwide readmissions databases.

OBJECTIVE: Determine the rates, reasons, predictors, and costs of 30-day readmissions following transcatheter mitral valve repair (TMVR) versus surgical mitral valve repair (SMVR) in the United States. BACKGROUND: Data on 30-day readmissions after TMVR are limited. METHODS: High-risk patients with mitral regurgitation (MR) undergoing TMVR or SMVR were identified from the 2014-2015 Nationwide Readmissions Databases. Multivariable stepwise regression models were used to identify independent predictors of 30-day readmission. Risk of 30-day readmission was compared between the two groups using univariate and propensity score adjusted regression models. RESULTS: Among 8,912 patients undergoing mitral valve repair during 2014-2015 (national estimate 17,809), we identified 7,510 (84.7%) that underwent SMVR and 1,402 (15.3%) that underwent TMVR. Thirty-day readmission rates after SMVR and TMVR were 10.7% and 11.7%, respectively (unadjusted OR 1.11, 95% CI 0.89-1.39, p = .35). After propensity score adjustment, TMVR was associated with a lower risk of 30-day readmissions compared with SMVR (adjusted OR 0.70, 95% CI 0.51-0.95, p = .02). Heart failure and arrhythmias were the leading cardiac reasons for readmission. Anemia and fluid and electrolyte disorder were independent predictors of 30-day readmission after TMVR. Demographics, comorbidities, and length of stay were independent predictors of 30-day readmission after SMVR. CONCLUSIONS: One in 10 patients are readmitted within 30 days following TMVR or SMVR. Approximately half of the readmissions are for cardiac reasons. The predictors of 30-day readmission are different among patients undergoing TMVR and SMVR, but can be easily screened for to identify patients at highest risk for readmission.

Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial.

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI. Design, Setting, and Participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and Measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16). Conclusions and Relevance: Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial Registration: ClinicalTrials.gov Identifier: NCT01742117.

SimPEL: Simulation-based power estimation for sequencing studies of low-prevalence conditions.

Power estimations are important for optimizing genotype-phenotype association study designs. However, existing frameworks are designed for common disorders, and thus ill-suited for the inherent challenges of studies for low-prevalence conditions such as rare diseases and infrequent adverse drug reactions. These challenges include small sample sizes and the need to leverage genetic annotation resources in association analyses for the purpose of ranking potential causal genes. We present SimPEL, a simulation-based program providing power estimations for the design of low-prevalence condition studies. SimPEL integrates the usage of gene annotation resources for association analyses. Customizable parameters, including the penetrance of the putative causal allele and the employed pathogenic scoring system, allow SimPEL to realistically model a large range of study designs. To demonstrate the effects of various parameters on power, we estimated the power of several simulated designs using SimPEL and captured power trends in agreement with observations from current literature on low-frequency condition studies. SimPEL, as a tool, provides researchers studying low-frequency conditions with an intuitive and highly flexible avenue for statistical power estimation. The platform-independent "batteries included" executable and default input files are available at https://github.com/precisionomics/SimPEL.

Method and system for the centrifugal fabrication of low cost, polymeric, parabolic lenses.

A method for low-cost, rapid production of aspheric polymeric lenses using fluid rotation is presented. The system utilizes a cylindrical chamber to hold and cure a polymer while spinning. This system is capable of producing lenses with parabolic planar-concave, planar-convex, and meniscus geometries with tunable radii of curvature and focal lengths. Examples are demonstrated for lenses of 25 mm diameter. System models, performance, and components are described in detail, and lens variability is assessed for surface profile, surface roughness, radius of curvature, and single-lens resolution limit. Results show excellent RMS surface roughness for a low-cost lens production technique.

Grip Strength Is Associated with Longitudinal Health Maintenance and Improvement in Adolescents.

OBJECTIVE: To assess the effects of muscle strength, as determined by grip strength, on changes in health status in adolescents. STUDY DESIGN: Risk variables included excess body fat, elevated fasting glucose, high blood pressure, elevated serum triglycerides, and low high-density lipoprotein cholesterol. Multinomial logistic regression was used to quantify the odds of experiencing health maintenance (no risk factors identified at either time point) or health improvement (presence of ≥1 baseline risk factor and fewer or no risk factors at follow-up) over a 2-year period. The primary exposure variable was grip strength normalized by body mass (normalized grip strength [NGS]), and previous cut-offs were used to determine whether adolescents were weak or strong. RESULTS: Adolescents who had low NGSs had a significantly greater prevalence of health decline or poor health persistence as compared with those who were strong (boys: 60.2% vs 15.3%; girls: 51% vs 21.9%; all P < .001). Moreover, adolescents who were strong had an increased adjusted odds for health maintenance (OR 3.54; 95% CI 1.80-6.97) and health improvement (OR 1.30; 95% CI 1.05-1.60), even after we adjusted for baseline fat-free mass index, cardiorespiratory fitness, and objectively measured physical activity. CONCLUSIONS: Greater NGS is associated with longitudinal health maintenance and health improvements in adolescents. Low NGS could be used as a prognostic indicator of cardiometabolic risk and to identify adolescents who would benefit most from lifestyle interventions to improve muscular fitness.

High-Output Cardiac Failure and Coronary Steal With an Arteriovenous Fistula.

Creation of an arteriovenous access for hemodialysis can provoke a sequence of events that significantly affects cardiovascular hemodynamics. We present a 78-year-old man with end-stage renal disease and concomitant coronary artery disease previously requiring coronary artery bypass grafting including a left internal mammary graft to the left anterior descending artery, ischemic cardiomyopathy with left ventricular systolic dysfunction, and severe aortic stenosis who developed hypotension unresponsive to medical therapy after recent angioplasty of his ipsilateral arteriovenous fistula for high-grade outflow stenosis. This case highlights the long-term effects of dialysis access on the cardiovascular system, with special emphasis on complications such as high-output cardiac failure and coronary artery steal syndrome. Banding of the arteriovenous fistula provided symptomatic relief with a decrease in cardiac output. Avoidance of arteriovenous access creation on the ipsilateral upper extremity in patients with a left internal mammary artery bypass graft may prevent coronary artery steal syndrome.

Transcatheter aortic valve replacement in patients with severe aortic stenosis and heart failure.

Severe aortic stenosis (AS) and heart failure (HF) represent an important and high-risk group of patients who are often referred for transcatheter aortic valve replacement (TAVR) due to high risk for surgical intervention. Thus far, randomized controlled trials have shown comparable outcomes between TAVR and surgical aortic valve replacement in patients with severe AS and heart failure with reduced ejection fraction. In the current review, we will discuss (1) the pathophysiology of HF in patients with severe AS, (2) role of imaging modalities in management, (3) role of biomarkers of HF on prognosis, (4) impact of other valvular heart diseases, (5) evidence from the contemporary trials on the role of TAVR in patients with severe AS and HF, and (6) future directions and research.

Predictors of patient radiation exposure during transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) exposes patients to radiation. OBJECTIVES: We sought to identify factors associated with higher radiation exposure and to quantify their relative influence, which may inform reduction of this hazard. METHODS: All TAVR procedures at Rhode Island Hospital between March 20, 2012 and February 12, 2017 were included. Procedures were performed by two co-primary operators using a Siemens Artis Zeego system. Radiation metrics were generated by the imaging system. The primary metric was dose-area product (DAP, Gy*cm2 ), and secondary metrics were reference point air kerma (mGy) and fluoroscopy time (minutes). Data collected for the STS/ACC TVT Registry were utilized to develop a multivariable linear regression model predicting DAP. RESULTS: In 294 TAVRs, median DAP was 169 Gy*cm2 [interquartile range (IQR) 106-238]. The r2 values for the full 27-variable DAP model and reduced eight-variable model were 0.457 and 0.420, respectively. Valve area, aortic insufficiency, and procedure year (suggesting absence of a learning curve) were non-significant predictors in the full model, while increasing weight, cutdown transfemoral access, higher pre-procedure creatinine and hemoglobin, and vascular complications predicted higher DAP in both models. Results were unchanged when DAP was log-transformed. Secondary models for air kerma and fluoroscopy time revealed similar predictors. CONCLUSION: Factors associated with increased procedural complexity and duration as well as radiation attenuation and scatter predict increased patient radiation exposure during TAVR. Modification of procedural technique, especially using percutaneous femoral vascular access, may facilitate reduction in exposure.

The lifelong impact of fetal growth restriction on cardiac development.

BACKGROUND: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. METHODS: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. RESULTS: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR-FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR-FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR-FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. CONCLUSIONS: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development.