Comparison of admittance and cardiac magnetic resonance generated pressure-volume loops in a porcine model.

Objective. Pressure-volume loop analysis, traditionally performed by invasive pressure and volume measurements, is the optimal method for assessing ventricular function, while cardiac magnetic resonance (CMR) imaging is the gold standard for ventricular volume estimation. The aim of this study was to investigate the agreement between the assessment of end-systolic elastance (Ees) assessed with combined CMR and simultaneous pressure catheter measurements compared with admittance catheters in a porcine model.Approach. Seven healthy pigs underwent admittance-based pressure-volume loop evaluation followed by a second assessment with CMR during simultaneous pressure measurements.Main results. Admittance overestimated end-diastolic volume for both the left ventricle (LV) and the right ventricle (RV) compared with CMR. Further, there was an underestimation of RV end-systolic volume with admittance. For the RV, however, Ees was systematically higher when assessed with CMR plus simultaneous pressure measurements compared with admittance whereas there was no systematic difference in Ees but large differences between admittance and CMR-based methods for the LV.Significance. LV and RV Ees can be obtained from both admittance and CMR based techniques. There were discrepancies in volume estimates between admittance and CMR based methods, especially for the RV. RV Ees was higher when estimated by CMR with simultaneous pressure measurements compared with admittance.

Continuous-wave second-harmonic generation in the far-UVC pumped by a blue laser diode.

Far-UVC light in the wavelength range of 200-230 nm has attracted renewed interest because of its safety for human exposure and effectiveness in inactivating pathogens. Here we present a compact solid-state far-UVC laser source based on second-harmonic generation (SHG) using a low-cost commercially-available blue laser diode pump. Leveraging the high intensity of light in a nanophotonic waveguide and heterogeneous integration, our approach achieves Cherenkov phase-matching across a bonded interface consisting of a silicon nitride (SiN) waveguide and a beta barium borate (BBO) nonlinear crystal. Through systematic investigations of waveguide dimensions and pump power, we analyze the dependencies of Cherenkov emission angle, conversion efficiency, and output power. Experimental results confirm the feasibility of generating far-UVC, paving the way for mass production in a compact form factor. This solid-state far-UVC laser source shows significant potential for applications in human-safe disinfection, non-line-of-sight free-space communication, and deep-UV Raman spectroscopy.

Investigating the importance of left atrial compliance on fluid dynamics in a novel mock circulatory loop.

The left atrium (LA) hemodynamic indices hold prognostic value in various cardiac diseases and disorders. To understand the mechanisms of these conditions and to assess the performance of cardiac devices and interventions, in vitro models can be used to replicate the complex physiological interplay between the pulmonary veins, LA, and left ventricle. In this study, a comprehensive and adaptable in vitro model was created. The model includes a flexible LA made from silicone and allows distinct control over the systolic and diastolic functions of both the LA and left ventricle. The LA was mechanically matched with porcine LAs through expansion tests. Fluid dynamic measures were validated against the literature and pulmonary venous flows recorded on five healthy individuals using magnetic resonance flow imaging. Furthermore, the fluid dynamic measures were also used to construct LA pressure-volume loops. The in vitro pressure and flow recordings expressed a high resemblance to physiological waveforms. By decreasing the compliance of the LA, the model behaved realistically, elevating the a- and v-wave peaks of the LA pressure from 12 to 19 mmHg and 22 to 26 mmHg, respectively, while reducing the S/D ratio of the pulmonary venous flowrate from 1.5 to 0.3. This model provides a realistic platform and framework for developing and evaluating left heart procedures and interventions.

Novel Expansible Aortic Annuloplasty Ring Exhibits Similar Characteristics as the Dacron Ring-an In Vitro Evaluation.

An increasing body of research indicates that annular stability plays a key role for a successful aortic valve repair. The aim of this study was to evaluate and compare a novel open aortic annuloplasty ring (the A-ring) with the Dacron ring. Both rings were compared with native aortic roots in vitro. Eighteen aortic roots were included in the study and randomized into three groups: the native, Dacron, and A-ring group. The roots were evaluated in an in vitro physiologic pulsatile model simulating the left side of the heart. Aortic annulus diameters were significantly reduced both in the Dacron ring group (p = 0.003) and the A-ring group (p = 0.020) when compared with the native group. Both the Dacron ring and A-ring effectively downsized the aortic annulus diameter. The A-ring also displayed an ability to maintain aortic root distensibility during the cardiac cycle equally to the Dacron ring.

Comparison of aortic valve repair techniques with single- and double-ring annuloplasties.

OBJECTIVES: For patients with isolated aortic regurgitation, a double sub- and supravalvular annuloplasty has been shown to reduce recurrent aortic regurgitation after aortic valve repair compared with a single subvalvular annuloplasty. The objective of this study was to compare the geometrical and dynamic properties of single- and double-ring annuloplasties in an in vitro model. METHODS: Eighteen aortic roots from 80 kg pigs were randomized into a control, single-ring and double-ring group. Experiments were conducted in a pulsatile in vitro model. Hydrodynamics, radial force measurements at annular and sinotubular level and 2D echographic imaging were obtained. RESULTS: Both the single- and double-ring annuloplasties downsized the aortic annulus and sinotubular junction (STJ) significantly and increased the coaptation height. The double-ring annuloplasty showed an additional significant increase in coaptation height compared with the single ring [8.5 (0.9)-9.8 (0.8) mm, P < 0.01]. The single-ring annuloplasty reduced radial forces at both levels, whereas the double-ring annuloplasty showed the greatest force reduction of the STJ. CONCLUSIONS: By treating the whole functional aortic annulus, encompassing both the aortic annulus and the STJ, a greater force reduction is observed. A subvalvular annuloplasty alone is efficient in reducing aortic annulus diameter and increasing coaptation height, however, by treating the STJ as well, an additional effect is observed on coaptation height, creating a more efficient stabilization. Reduction of annular force-distensibility ratio with the double-ring annuloplasty compared with the native controls indicates a sustained stabilizing effect.

Personalized seizure detection using logistic regression machine learning based on wearable ECG-monitoring device.

PURPOSE: Wearable automated detection devices of focal epileptic seizures are needed to alert patients and caregivers and to optimize the medical treatment. Heart rate variability (HRV)-based seizure detection devices have presented good detection sensitivity. However, false alarm rates (FAR) are too high. METHODS: In this phase-2 study we pursued to decrease the FAR, by using patient-adaptive logistic regression machine learning (LRML) to improve the performance of a previously published HRV-based seizure detection algorithm. ECG-data were prospectively collected using a dedicated wearable electrocardiogram-device during long-term video-EEG monitoring. Sixty-two patients had 174 seizures during 4,614 h recording. The dataset was divided into training-, cross-validation-, and test-sets (chronological) in order to avoid overfitting. Patients with >50 beats/min change in heart rate during first recorded seizure were selected as responders. We compared 18 LRML-settings to find the optimal algorithm. RESULTS: The patient-adaptive LRML-classifier in combination with using only responders to train the initial decision boundary was superior to both the generic approach and including non-responders to train the LRML-classifier. Using the optimal setting of the LRML in responders in the test dataset yielded a sensitivity of 78.2% and FAR of 0.62/24 h. The FAR was reduced by 31% compared to the previous method, upholding similar sensitivity. CONCLUSION: The novel, patient-adaptive LRML seizure detection algorithm outperformed both the generic approach and the previously published patient-tailored method. The proposed method can be implemented in a wearable online HRV-based seizure detection system alerting patients and caregivers of seizures and improve seizure-count which may help optimizing the patient treatment.

A handsewn pericardial valved pulmonary conduit: pulsatile flow loop in vitro and acute porcine in vivo evaluation.

OBJECTIVES: Right ventricle to pulmonary artery anatomic discontinuity is common in complex congenital heart malformations. Handsewn conduits are a practised method of repair. In a proof-of-concept study, we evaluated pulmonary valve replacement with a handsewn pericardial valved pulmonary conduit in vitro and in vivo. METHODS: A pulsatile flow-loop model (in vitro) and an acute 60-kg porcine model (in vivo) were used. With echocardiography and pressure catheters, baseline geometry and fluid dynamics were measured. The pulmonary valve was replaced with a handsewn glutaraldehyde-treated pericardial valved pulmonary conduit corresponding to a 21-mm prosthetic valve, after which geometric measurements and fluid dynamics were reassessed. RESULTS: In vitro, 15 pulmonary trunks at 4 l/min and 13 trunks at 7 l/min, and in vivo, 11 animals were investigated. The valved pulmonary conduit was straightforward to produce at the operating table and easy to suture in place. All valves were clinically sufficient in vitro and in vivo. The mean transvalvular pressure gradient in the native valve and the conduit was 8 mmHg [standard deviation (SD): 2] and 7 mmHg (SD: 2) at 4 l/min in vitro, 19 mmHg (SD: 3) and 17 mmHg (SD: 4) at 7 l/min in vitro and 3 mmHg (SD: 2) and 6 mmHg (SD: 3) in vivo. CONCLUSIONS: Our proof-of-concept demonstrates no early evidence of structural damage to the conduit, and the fluid dynamic data were acceptable. The handsewn conduit can be produced at the operating table.

Trileaflet semilunar valve reconstruction: pulsatile in vitro evaluation.

OBJECTIVES: Residual regurgitation is common after congenital surgery for right ventricular outflow tract malformation. It is accepted as there is no competent valve solution in a growing child. We investigated a new surgical technique of trileaflet semilunar valve reconstruction possessing the potential of remaining sufficient and allowing for some growth with the child. In this proof-of-concept study, our aim was to evaluate if it is achievable as a functional pulmonary valve reconstruction in vitro. METHODS: Explanted pulmonary trunks from porcine hearts were evaluated in a pulsatile flow-loop model. First, the native pulmonary trunk was investigated, after which the native leaflets were explanted. Then, trileaflet semilunar valve reconstruction was performed and investigated. All valves were initially investigated at a flow output of 4 l/min and subsequently at 7 l/min. The characterization was based on hydrodynamic pressure and echocardiographic measurements. RESULTS: Eight pulmonary trunks were evaluated. All valves are competent on colour Doppler. There is no difference in mean pulmonary systolic artery pressure gradient at 4 l/min (P = 0.32) and at 7 l/min (P = 0.20). Coaptation length is increased in the neo-valve at 4 l/min (P < 0.001, P < 0.001, P = 0.008) and at 7 l/min (P < 0.001, P = 0.006, P = 0.006). A windmill shape is observed in all neo-valves. CONCLUSIONS: Trileaflet semilunar valve reconstruction is sufficient and non-stenotic. It resulted in an increased coaptation length and a windmill shape, which is speculated to decrease with the growth of the patient, yet remains sufficient as a transitional procedure until a long-term solution is feasible. Further in vivo investigations are warranted.

Tail Vein Transection Bleeding Model in Fully Anesthetized Hemophilia A Mice.

Tail bleeding models are important tools in hemophilia research, specifically for the assessment of procoagulant effects. The tail vein transection (TVT) survival model has been preferred in many settings due to sensitivity to clinically relevant doses of FVIII, whereas other established models, such as the tail clip model, require higher levels of procoagulant compounds. To avoid using survival as an endpoint, we developed a TVT model establishing blood loss and bleeding time as endpoints and full anesthesia during the entire experiment. Briefly, anesthetized mice are positioned with the tail submerged in temperate saline (37°C) and dosed with the test compound in the right lateral tail vein. After 5 min, the left lateral tail vein is transected using a template guide, the tail is returned to the saline, and all bleeding episodes are monitored and recorded for 40 min while collecting the blood. If no bleeding occurs at 10 min, 20 min, or 30 min post-injury, the clot is challenged gently by wiping the cut twice with a wet gauze swab. After 40 min, blood loss is quantified by the amount of hemoglobin bled into the saline. This fast and relatively simple procedure results in consistent and reproducible bleeds. Compared to the TVT survival model, it uses a more humane procedure without compromising sensitivity to pharmacological intervention. Furthermore, it is possible to use both genders, reducing the total number of animals that need to be bred, in adherence with the principles of 3R's. A potential limitation in bleeding models is the stochastic nature of hemostasis, which can reduce the reproducibility of the model. To counter this, manual clot disruption ensures that the clot is challenged during monitoring, preventing primary (platelet) hemostasis from stopping bleeding. This addition to the catalog of bleeding injury models provides an option to characterize procoagulant effects in a standardized and humane manner.

Left atrial appendage occlusion with the Amulet device: to tug or not to tug?

PURPOSE: Left atrial appendage occlusion (LAAO) involves a "tug test," in which implanters pull on the device delivery cable to ensure stable occluder placement. The aim of this study was to evaluate the recommendation to perform the tug test, by comparing forces exerted on the device during deployment and subsequent tug test. A secondary objective was to simulate forces experienced on left atrial appendage tissue by placement of a 20-mm device. METHODS: The AMPLATZER™ Amulet™ device was used for occlusion. A force transducer recorded forces in the delivery cable during deployment and tug test in 23 patients. Four patients were excluded due to improper transducer placement or technical errors in data collection. For a 20-mm device, the force imparted on the circumferential contact with left atrial appendage wall tissue was simulated in a computational model, using the measured externally applied forces as inputs. RESULTS: For devices < 25-mm in diameter, disc deployment force (mean ± standard deviation) was 1.72 ± 0.43 N, and tug force was 1.01 ± 0.59 N. For devices ≥ 25 mm in diameter, disc deployment force was 2.96 ± 0.57 N, and tug force was 1.04 ± 0.24 N. The increase in disc deployment force compared with tug test force was statistically significant for small devices (< 25 mm; p = 0.049) and large devices (≥ 25 mm; p < 0.001). CONCLUSIONS: Increased force applied on the AMPLATZER™ Amulet™ device during disc deployment compared with during tug test was statistically significant, suggesting that the tug test is redundant in most cases for checking device stability.

The importance of collagen composition and biomechanics for the porcine aortic root.

A thorough understanding of the aortic root structure and biomechanics is necessary when performing aortic valve-sparing procedures in patients with aortic root aneurysms. This study aimed to evaluate the amount of collagen and biomechanics at different levels and segments of the aortic root. Ten aortic roots from healthy pigs were excised including the aortic annulus, the sinuses of Valsalva, and the sinotubular junction (STJ). Specimens were further divided into three circumferential segments; left coronary (LC)-, right coronary (RC)-, and non-coronary (NC) sinus. Collagen was determined using hydroxyproline analysis and specimens were tested biomechanically for stress-strain relations. The annulus showed significantly larger average maximum stiffness (9.6 ± 4.5 N/mm) compared with the sinus (4.5 ± 2.0 N/mm) and STJ (4.8 ± 1.8 N/mm). The average collagen content was likewise higher in the annulus (4.0 ± 1.0 mg/ml) compared with the sinus (2.4 ± 0.6 mg/ml) and STJ (2.2 ± 0.5 mg/ml) for all three segments. The NC sinus segment exhibited a significantly larger maximum stiffness and stress under static conditions compared with the RC. These results suggest that the aortic root is heterogeneous in both structure and biomechanical properties and that it varies both in levels and segments of the aortic root. Future surgical approaches should consider enhanced strength parameters for specific areas of the aortic root to achieve the best results when performing aortic valve-sparing techniques. From this study, we conclude that the aortic annulus needs special attention to imitate normal physiologic properties during aortic valve-sparing surgery due to its higher maximum stiffness, stress, and load. Modified future surgical procedures could potentially prevent recurrent aneurysmal formation.

Seizure detection using heart rate variability: A prospective validation study.

Although several validated seizure detection algorithms are available for convulsive seizures, detection of nonconvulsive seizures remains challenging. In this phase 2 study, we have validated a predefined seizure detection algorithm based on heart rate variability (HRV) using patient-specific cutoff values. The validation data set was independent from the previously published data set. Electrocardiography (ECG) was recorded using a wearable device (ePatch) in prospectively recruited patients. The diagnostic gold standard was inferred from video-EEG monitoring. Because HRV-based seizure detection is suitable only for patients with marked ictal autonomic changes, we defined responders as the patients who had a>50 beats/min ictal change in heart rate. Eleven of the 19 included patients with seizures (57.9%) fulfilled this criterion. In this group, the algorithm detected 20 of the 23 seizures (sensitivity: 87.0%). The algorithm detected all but one of the 10 recorded convulsive seizures and all of the 8 focal impaired awareness seizures, and it missed 2 of the 4 focal aware seizures. The median sensitivity per patient was 100% (in nine patients all seizures were detected). The false alarm rate was 0.9/24 h (0.22/night). Our results suggest that HRV-based seizure detection has high performance in patients with marked autonomic changes.

Genetic diagnosis of trisomy 21 in chimpanzees (Pan troglodytes).

The most frequent chromosomal aneuploidy in humans, trisomy 21 (T21), has only been reported twice in the common chimpanzee (Pan troglodytes). In both cases, phenotypical traits were comparable to human T21 traits and were formally diagnosed through conventional techniques like chromosomal staining. Here, we present the first application of sequencing data as a diagnostic tool to compare chromosomal dosage imbalances in chimpanzees. By calculating the ratio of mapped reads on each chromosome between a case and a control, we observe a trisomic dosage imbalance on chromosome 21 in the case individual. While case numbers remain too low to be conclusive, evidence suggests that prevalence of T21 in chimpanzees could be lower than in humans. In future genetic testing of captive ape populations, the genetic diagnostic methods presented here will allow for a reliable and time-efficient assessment of the global prevalence of chromosomal dose imbalances in chimpanzees and other great apes.

Cell-Free Fetal DNA in the Early and Late First Trimester.

OBJECTIVE: The aim of this work was to investigate the association between maternal and fetal characteristics and the fetal fraction at 8-14 weeks' gestation, with emphasis on the change in the fetal fraction upon repeat sampling. METHOD: One sample for cell-free DNA (cfDNA) testing was collected at the same time as the biochemical markers for combined first trimester screening (visit 1) and another at the nuchal translucency scan (visit 2). Chromosome-selective cfDNA analysis was performed on frozen plasma. RESULTS: Overall, 321 women were included at visit 1, and 307 had a repeat blood sampling. A fetal fraction was obtained in 532 samples (238 samples with repeat fetal fraction). The fetal fraction decreased with maternal BMI (p < 0.001), was lower in Asian women (p = 0.03), and increased with ß-hCG levels (p < 0.001) and gestational age (p = 0.04). Before 10 weeks' gestation, the fetal fraction was lower (p = 0.02), as was the probability of a sufficient fetal fraction (p = 0.03) after adjustment for maternal BMI. Asian women had a higher increase in fetal fraction upon repeat sampling (p < 0.001). CONCLUSION: Before 10 weeks' gestation, the fetal fraction is significantly lower but seems to increase more rapidly compared to later gestations. Presently, combined first trimester screening with cfDNA testing should not include samples before 10 weeks' gestation.

Seizure detection based on heart rate variability using a wearable electrocardiography device.

OBJECTIVE: To assess the feasibility and accuracy of seizure detection based on heart rate variability (HRV) using a wearable electrocardiography (ECG) device. Noninvasive devices for detection of convulsive seizures (generalized tonic-clonic and focal to bilateral tonic-clonic seizures) have been validated in phase 2 and 3 studies. However, detection of nonconvulsive seizures still needs further research, since currently available methods have either low sensitivity or an extremely high false alarm rate (FAR). METHODS: In this phase 2 study, we prospectively recruited patients admitted to long-term video-EEG monitoring (LTM). ECG was recorded using a dedicated wearable device. Seizures were automatically detected using HRV parameters computed off-line, blinded to all other data. We compared the performance of 26 automated algorithms with the seizure time-points marked by experts who reviewed the LTM recording. Patients were classified as responders if >66% of their seizures were detected. RESULTS: We recruited 100 consecutive patients and analyzed 126 seizures (108 nonconvulsive and 18 convulsive) from 43 patients who had seizures during monitoring. The best-performing HRV algorithm combined a measure of sympathetic activity with a measure of how quickly HR changes occurred. The algorithm identified 53.5% of the patients with seizures as responders. Among responders, detection sensitivity was 93.1% (95% CI: 86.6%-99.6%) for all seizures and 90.5% (95% CI: 77.4%-97.3%) for nonconvulsive seizures. FAR was 1.0/24 h (0.11/night). Median seizure detection latency was 30 s. Typically, patients with prominent autonomic nervous system changes were responders: An ictal change of >50 heartbeats per minute predicted who would be responder with a positive predictive value of 87% and a negative predictive value of 90%. SIGNIFICANCE: The automated HRV algorithm, using ECG recorded with a wearable device, has high sensitivity for detecting seizures, including the nonconvulsive ones. FAR was low during the night. This approach is feasible in patients with prominent ictal autonomic changes.

Prophylactic administration of glycoPEGylated factor IX provides protection and joint outcome superior to recombinant factor IX after induced joint bleeding.

BACKGROUND: Following induced joint hemorrhage, hemophilia B results in the abnormal persistence of iron deposition, inflammation, and neovascularity of the synovial tissue, as well as deterioration of the bone articular surface and strength. Previously, we demonstrated that a factor IX (FIX) replacement protein with extended circulating FIX activity, glycoPEGylated FIX nonacog beta pegol (N9-GP), could improve synovial and osteochondral parameters in F9 knockout mice when administered after joint injury. OBJECTIVE: We explored the use of N9-GP prior to unilateral joint hemorrhage and compared to unmodified recombinant FIX (rFIX). METHODS: Pharmacodynamics, histology, and microcomputed tomography were used to assess the effects of prophylactic administration of glycoPEGylated FIX. RESULTS: In comparison to rFIX, N9-GP significantly improved soft tissue histological parameters, as well as bone outcome at 2 weeks post injury, while performing equally in reduction of blood present in the joint space assessed 1 day after injury. CONCLUSIONS: These results indicate that, in comparison to rFIX, the prophylactic use of extended half-life FIX provides superior protection from bleeding-induced joint damage, manifested by improved correction of histologic parameters.

In-vitro and in-vivo evaluation of a novel bioprosthetic pulmonary valve for use in congenital heart surgery.

BACKGROUND: Management of congenital malformations of the pulmonary artery and valve can be challenging. The severity often demands early intervention, which is rarely definitive due to the natural growth and multiple surgeries may be required. An artificial valve made entirely from biodegradable materials that will serve as a bioscaffold for host recellularization would be an attractive solution for these patients. Such valves have been experimentally evaluated with various results. In this study, a simple valve design supported by an absorbable proximal stabilization ring is evaluated both in-vitro and in-vivo. METHODS: From a 6.7 × 5.0 cm sheet of CorMatrix® tissue we created the valve as an inverted tubegraft with three sutured commissures. A non-closed ring of LactoSorb® basally supported the valve. The commissure height was 2 cm. Inserted as an interposition graft the valve was tested in an in-vitro model and an acute porcine model. Right ventricular and pulmonary artery pressures were recorded. RESULTS: The in-vitro testing indicated a proper opening and closure function of valve at physiological simulated hemodynamic conditions. The in-vivo evaluation showed a peak right ventricular pressure of 38 mmHg and a peak pulmonary artery pressure of 27 mmHg and thereby a peak valve gradient of 11 mmHg. The pulmonary pressure wave demonstrated a dicrotic notch indicating competence of the valve. CONCLUSION: This new pulmonary valve made entirely from biodegradable tissue worked in an acute setting and displayed a good hemodynamic profile. The valve gradient observed is equal to or superior of today's surgical treatment options.