First Description of Novel End-Organ Effects by Speed Modulation Using the Aortix™ Device.

Aortix™ is a novel percutaneous mechanical circulatory support device designed to facilitate diuresis in patients with cardiorenal syndrome. We describe for the first time the development of end-organ hypoperfusion from excess blood acceleration at the nominal setting and demonstrate through temporal-perfusion marker curves, the potential for speed modulation to optimize results. This will inform future device development and investigation of patient-specific device titration.

Relationship between donor-derived cell-free DNA and tissue-based rejection-related transcripts in heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs, which may provide further insight into the pathophysiology of allograft rejection and injury. METHODS: This is a retrospective observational study of 156 EMB evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood before EMB (up to 9 days). Diagnostic agreement between traditional histopathology, MMDx, and dd-cfDNA (threshold of 0.20%) was compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated. RESULTS: MMDx characterized allograft tissue as no rejection (62.8%), antibody-mediated rejection (ABMR) (26.9%), T-cell-mediated rejection (TCMR) (5.8%), and mixed ABMR/TCMR (4.5%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (76.3% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters were correlated with dd-cfDNA scores, including DSAST, GRIT, HT1, QCMAT, and S4. For individual transcripts, tissue ROBO4 was significantly correlated with dd-cfDNA in both nonrejection and rejection as assessed by MMDx. CONCLUSIONS: Collectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA and expression of ROBO4 (a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of antibody-mediated rejection, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to acute cellular rejection.

Relationship between blood and tissue-based rejection-related transcripts in heart transplantation.

BACKGROUND: The purpose of the study is to investigate the relationship between blood and tissue-derived rejection-related transcripts from blood gene expression profiling (GEP) and molecular microscope in the setting of allograft rejection in heart transplant. METHODS: All heart transplant patients from August 2021 to May 2022 with both circulating blood GEP (AlloMap) and endomyocardial biopsy with molecular microscope diagnostic system (MMDx) within 4 weeks were included (N = 173 samples). We obtained individual blood GEP-based messenger RNA transcript expression levels of the 11 target genes from CareDx. Student's t-test was performed to compare blood GEP transcript expression levels between no rejection and rejection as assessed by MMDx. A Scatter plot with Spearman correlation analysis was performed to compare the relationship between transcript expression levels from AlloMap and MMDx, with and without allograft rejection. RESULTS: There were 52 samples (30.1%) with antibody-mediated rejection (ABMR) and 15 samples (8.7%) with T-cell-mediated rejection (TCMR), as assessed by MMDx. Expression of one of the blood ITGA4 (Integrin alpha 4) expression level was elevated in ABMR, compared to no ABMR (4,607.5 vs 4,217.5; p = 0.019). Most tissue rejection-associated transcript expression levels were elevated in ABMR, and tissue ROBO4 expression correlated with the blood ITGA4 expression with moderate or greater effect size in all samples (Spearman's R = 0.31; p < 0.001). There was also a positive correlation between blood ITGA4 and tissue ROBO4 expression in samples without ABMR (Spearman's R = 0.33; p < 0.001), but no correlation between blood ITGA4 and tissue ROBO4 expression in samples with ABMR (Spearman's R = 0.009; p = 0.513). CONCLUSIONS: Circulating blood ITGA4 expression is elevated in antibody-mediated rejection (AMR) and correlates with myocardial expression of ROBO4. The knowledge of individual transcript expression levels in blood and in tissue may provide insights into various disease processes in heart transplant patients. Taken together, the results of our study reveal an overlap between 2 objective post-heart transplant rejection surveillance methods, identify potential novel markers for ABMR, and reveal the need for a deeper understanding of molecular mechanisms underlying allograft rejection.

Safety and Performance of the Aortix Device in Acute Decompensated Heart Failure and Cardiorenal Syndrome.

BACKGROUND: Cardiorenal syndrome (CRS) complicates 33% of acute decompensated heart failure (ADHF) admissions, and patients with persistent congestion at discharge have high 30-day event rates. OBJECTIVES: The purpose of this study was to evaluate a novel catheter-deployed intra-aortic entrainment pump (IAEP) in patients with ADHF with CRS and persistent congestion. METHODS: A multicenter (n = 14), nonrandomized, single-arm, safety and feasibility study of IAEP therapy was conducted. Within patient changes (post-pre IAEP therapy) in fluid loss, hemodynamics, patient-reported dyspnea, and serum biomarkers were assessed using Wilcoxon signed-rank testing. RESULTS: Of 21 enrolled patients, 18 received Aortix therapy. Mean ± SD patient age was 60.3 ± 7.9 years. The median left ventricular ejection fraction was 22.5% (25th-75th percentile: 10.0%-53.5%); 27.8% had a left ventricular ejection fraction ≥50%. Pre-therapy, patients received 8.7 ± 4.1 days of loop diuretic agents and 44% were on inotropes. Pump therapy averaged 4.6 ± 1.6 days, yielding net fluid losses of 10.7 ± 6.5 L (P < 0.001) and significant (P < 0.01) reductions in central venous pressure (change from baseline: -8.5 mm Hg [25th-75th percentile: -3.5 to -10.0 mm Hg]), pulmonary capillary wedge pressure (-11.0 mm Hg [25th-75th percentile: -5.0 to -14.0 mm Hg]), and serum creatinine (-0.2 mg/dL [25th-75th percentile: -0.1 to -0.5 mg/dL]) with improved estimated glomerular filtration rate (+5.0 mL/min/1.73 m2 [25th-75th percentile: 2.0-9.0 mL/min/1.73 m2]) and patient-reported dyspnea score (+16 [25th-75th percentile: 3-37]). Dyspnea scores, natriuretic peptides, and renal function improvements persisted through 30 days. CONCLUSIONS: This pilot study of patients with ADHF, persistent congestion, and worsening renal function due to CRS supports the potential for safely achieving decongestion using IAEP therapy. These initial promising results provide the basis for future randomized clinical trials of this novel pump. (An Evaluation of the Safety and Performance of the Aortix System for Intra-Aortic Mechanical Circulatory Support in Patients with Cardiorenal Syndrome [The Aortix CRS Pilot Study]; NCT04145635).

A Case of Esmolol-Induced False-Positive Amphetamine Urine Drug Test.

False-positive urine drug screens can occur and lead to implicit bias. Confirmatory testing with gas chromatography/mass spectrometry can be performed. A morbidly obese patient with newly diagnosed atrial fibrillation spent multiple days in the cardiac intensive care unit (ICU) due to a false-positive test for methamphetamine. The patient was planned to undergo direct cardioversion with conscious-sedation anesthesia. His care was delayed because anesthesia was not comfortable administering sedatives in the setting of a positive urine drug screen for presumed methamphetamine use. Knowing that esmolol can cause a false positive on urine drug screen is imperative for delivering the best patient-centered care.

Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome.

BACKGROUND: Long QT syndrome (LQTS) is characterized by QT prolongation, syncope and sudden death. This study aims to explore the causes, clinical manifestations and therapeutic outcomes of Jervell and Lange-Nielsen syndrome (JLNS), a rare form of LQTS with congenital sensorineural deafness, in Chinese individuals. MATERIALS AND METHODS: Three JLNS kindreds from the Chinese National LQTS Registry were investigated. Mutational screening of KCNQ1 and KCNE1 genes was performed by polymerase chain reaction and direct DNA sequence analysis. LQTS phenotype and therapeutic outcomes were evaluated for all probands and family members. RESULTS: We identified 7 KCNQ1 mutations. c.1032_1117dup (p.Ser373TrpfsX10) and c.1319delT (p.Val440AlafsX26) were novel, causing JLNS in a 16-year-old boy with a QTc (QT interval corrected for heart rate) of 620 ms and recurrent syncope. c.605-2A>G and c.815G>A (p.Gly272Asp) caused JLNS in a 12-year-old girl and her 5-year-old brother, showing QTc of 590 to 600 ms and recurrent syncope. The fourth JLNS case, a 46-year-old man carrying c.1032G>A (p.Ala344Alasp) and c.569G>A (p.Arg190Gln) and with QTc of 460 ms, has been syncope-free since age 30. His 16-year-old daughter carries novel missense mutation c.574C>T (p.Arg192Cys) and c.1032G>A(p.Ala344Alasp) and displayed a severe phenotype of Romano-Ward syndrome (RWS) characterized by a QTc of 530 ms and recurrent syncope with normal hearing. Both the father and daughter also carried c.253G>A (p.Asp85Asn; rs1805128), a rare single nucleotide polymorphism (SNP) on KCNE1. Bizarre T waves were seen in 3/4 JLNS patients. Symptoms were improved and T wave abnormalities became less abnormal after appropriate treatment. CONCLUSION: This study broadens the mutation and phenotype spectrums of JLNS. Compound heterozygous KCNQ1 mutations can result in both JLNS and severe forms of RWS in Chinese individuals.

Transcranial imaging of functional cerebral hemodynamic changes in single blood vessels using in vivo photoacoustic microscopy.

Optical imaging of changes in total hemoglobin concentration (HbT), cerebral blood volume (CBV), and hemoglobin oxygen saturation (SO(2)) provides a means to investigate brain hemodynamic regulation. However, high-resolution transcranial imaging remains challenging. In this study, we applied a novel functional photoacoustic microscopy technique to probe the responses of single cortical vessels to left forepaw electrical stimulation in mice with intact skulls. Functional changes in HbT, CBV, and SO(2) in the superior sagittal sinus and different-sized arterioles from the anterior cerebral artery system were bilaterally imaged with unambiguous 36 × 65-µm(2) spatial resolution. In addition, an early decrease of SO(2) in single blood vessels during activation (i.e., 'the initial dip') was observed. Our results indicate that the initial dip occurred specifically in small arterioles of activated regions but not in large veins. This technique complements other existing imaging approaches for the investigation of the hemodynamic responses in single cerebral blood vessels.

Quantification and recognition of parkinsonian gait from monocular video imaging using kernel-based principal component analysis.

BACKGROUND: The computer-aided identification of specific gait patterns is an important issue in the assessment of Parkinson's disease (PD). In this study, a computer vision-based gait analysis approach is developed to assist the clinical assessments of PD with kernel-based principal component analysis (KPCA). METHOD: Twelve PD patients and twelve healthy adults with no neurological history or motor disorders within the past six months were recruited and separated according to their "Non-PD", "Drug-On", and "Drug-Off" states. The participants were asked to wear light-colored clothing and perform three walking trials through a corridor decorated with a navy curtain at their natural pace. The participants' gait performance during the steady-state walking period was captured by a digital camera for gait analysis. The collected walking image frames were then transformed into binary silhouettes for noise reduction and compression. Using the developed KPCA-based method, the features within the binary silhouettes can be extracted to quantitatively determine the gait cycle time, stride length, walking velocity, and cadence. RESULTS AND DISCUSSION: The KPCA-based method uses a feature-extraction approach, which was verified to be more effective than traditional image area and principal component analysis (PCA) approaches in classifying "Non-PD" controls and "Drug-Off/On" PD patients. Encouragingly, this method has a high accuracy rate, 80.51%, for recognizing different gaits. Quantitative gait parameters are obtained, and the power spectrums of the patients' gaits are analyzed. We show that that the slow and irregular actions of PD patients during walking tend to transfer some of the power from the main lobe frequency to a lower frequency band. Our results indicate the feasibility of using gait performance to evaluate the motor function of patients with PD. CONCLUSION: This KPCA-based method requires only a digital camera and a decorated corridor setup. The ease of use and installation of the current method provides clinicians and researchers a low cost solution to monitor the progression of and the treatment to PD. In summary, the proposed method provides an alternative to perform gait analysis for patients with PD.

Automatic spike sorting for extracellular electrophysiological recording using unsupervised single linkage clustering based on grey relational analysis.

Automatic spike sorting is a prerequisite for neuroscience research on multichannel extracellular recordings of neuronal activity. A novel spike sorting framework, combining efficient feature extraction and an unsupervised clustering method, is described here. Wavelet transform (WT) is adopted to extract features from each detected spike, and the Kolmogorov-Smirnov test (KS test) is utilized to select discriminative wavelet coefficients from the extracted features. Next, an unsupervised single linkage clustering method based on grey relational analysis (GSLC) is applied for spike clustering. The GSLC uses the grey relational grade as the similarity measure, instead of the Euclidean distance for distance calculation; the number of clusters is automatically determined by the elbow criterion in the threshold-cumulative distribution. Four simulated data sets with four noise levels and electrophysiological data recorded from the subthalamic nucleus of eight patients with Parkinson's disease during deep brain stimulation surgery are used to evaluate the performance of GSLC. Feature extraction results from the use of WT with the KS test indicate a reduced number of feature coefficients, as well as good noise rejection, despite similar spike waveforms. Accordingly, the use of GSLC for spike sorting achieves high classification accuracy in all simulated data sets. Moreover, J-measure results in the electrophysiological data indicating that the quality of spike sorting is adequate with the use of GSLC.