Transcatheter aortic valve implantation in patients with high-risk symptomatic native aortic regurgitation (ALIGN-AR): a prospective, multicentre, single-arm study.

BACKGROUND: Surgery remains the only recommended intervention for patients with native aortic regurgitation. A transcatheter therapy to treat patients at high risk for mortality and complications with surgical aortic valve replacement represents an unmet need. Commercial transcatheter heart valves in pure aortic regurgitation are hampered by unacceptable rates of embolisation and paravalvular regurgitation. The Trilogy transcatheter heart valve (JenaValve Technology, Irvine, CA, USA) provides a treatment option for these patients. We report outcomes with transfemoral transcatheter aortic valve implantation (TAVI) in patients with pure aortic regurgitation using this dedicated transcatheter heart valve. METHODS: The ALIGN-AR trial is a prospective, multicentre, single-arm study. We recruited symptomatic patients (aged ≥18 years) with moderate-to-severe or severe aortic regurgitation at high risk for mortality and complications after surgical aortic valve replacement at 20 US sites for treatment with the Trilogy transcatheter heart valve. The 30-day composite primary safety endpoint was compared for non-inferiority with a prespecified performance goal of 40·5%. The primary efficacy endpoint was 1-year all-cause mortality compared for non-inferiority with a performance goal of 25%. This trial is registered with ClinicalTrials.gov, NCT04415047, and is ongoing. FINDINGS: Between June 8, 2018, and Aug 29, 2022, we screened 346 patients. We excluded 166 (48%) patients and enrolled 180 (52%) patients with symptomatic aortic regurgitation deemed high risk by the heart team and independent screening committee assessments. The mean age of the study population was 75·5 years (SD 10·8), and 85 (47%) were female, 95 (53%) were male, and 131 (73%) were White. Technical success was achieved in 171 (95%) patients. At 30 days, four (2%) deaths, two (1%) disabling strokes, and two (1%) non-disabling strokes occurred. Using standard Valve Academic Research Consortium-2 definitions, the primary safety endpoint was achieved, with events occurring in 48 (27% [97·5% CI 19·2-34·0]) patients (pnon-inferiority<0·0001), with new pacemaker implantation in 36 (24%) patients. The primary efficacy endpoint was achieved, with mortality in 14 (7·8% [3·3-12·3]) patients at 1 year (pnon-inferiority<0·0001). INTERPRETATION: This study shows the safety and effectiveness of treating native aortic regurgitation using a dedicated transcatheter heart valve to treat patients with symptomatic moderate-to-severe or severe aortic regurgitation who are at high risk for mortality or complications after surgical aortic valve replacement. The observed short-term clinical and haemodynamic outcomes are promising as are signs of left ventricular remodelling, but long-term follow-up is necessary. FUNDING: JenaValve Technology.

Explaining and predicting the increased thorax injury in aged females: age and subject-specific thorax geometry coupled with improved bone constitutive models and age-specific material properties evaluated in side impact conditions.

Predicting and understanding thorax injury is fundamental for the assessment and development of safety systems to mitigate injury risk to the increasing and vulnerable aged population. While computational human models have contributed to the understanding of injury biomechanics, contemporary human body models have struggled to predict rib fractures and explain the increased incidence of injury in the aged population. The present study enhanced young and aged human body models (HBMs) by integrating a biofidelic cortical bone constitutive model and population-based bone material properties. The HBMs were evaluated using side impact sled tests assessed using chest compression and number of rib fractures. The increase in thoracic kyphosis and the associated change in rib angle with increasing age, led to increased rib torsional moment increasing the rib shear stress. Coupled with and improved cortical bone constitutive model and aged material properties, the higher resulting shear stress led to an increased number of rib fractures in the aged model. The importance of shear stress resulting from torsional load was further investigated using an isolated rib model. In contrast, HBM chest compression, a common thorax injury-associated metric, was insensitive to the aging factors studied. This study proposes an explanation for the increased incidence of thorax injury with increasing age reported in epidemiological data, and provides an enhanced understanding of human rib mechanics that will benefit assessment and design of future safety systems.

Modern Trends in Microelectronics Packaging Reliability Testing.

In this review, recent trends in microelectronics packaging reliability are summarized. We review the technology from early packaging concepts, including wire bond and BGA, to advanced techniques used in HI schemes such as 3D stacking, interposers, fan-out packaging, and more recently developed silicon interconnect fabric integration. This review includes approaches for both design modification studies and packaged device validation. Methods are explored for compatibility in new complex packaging assemblies. Suggestions are proposed for optimizations of the testing practices to account for the challenges anticipated in upcoming HI packaging schemes.

Assessment of brain response in operators subject to recoil force from firing long-range rifles.

Mild traumatic brain injury (mTBI) may be caused by occupational hazards military personnel encounter, such as falls, shocks, exposure to blast overpressure events, and recoil from weapon firing. While it is important to protect against injurious head impacts, the repeated exposure of Canadian Armed Forces (CAF) service members to sub-concussive events during the course of their service may lead to a significant reduction in quality of life. Symptoms may include headaches, difficulty concentrating, and noise sensitivity, impacting how personnel complete their duties and causing chronic health issues. This study investigates how the exposure to the recoil force of long-range rifles results in head motion and brain deformation. Direct measurements of head kinematics of a controlled population of military personnel during firing events were obtained using instrumented mouthguards. The experimentally measured head kinematics were then used as inputs to a finite element (FE) head model to quantify the brain strains observed during each firing event. The efficacy of a concept recoil mitigation system (RMS), designed to mitigate loads applied to the operators was quantified, and the RMS resulted in lower loading to the operators. The outcomes of this study provide valuable insights into the magnitudes of head kinematics observed when firing long-range rifles, and a methodology to quantify effects, which in turn will help craft exposure guidelines, guide training to mitigate the risk of injury, and improve the quality of lives of current and future CAF service members and veterans.

Brain Material Properties and Integration of Arachnoid Complex for Biofidelic Impact Response for Human Head Finite Element Model.

Finite element head models offer great potential to study brain-related injuries; however, at present may be limited by geometric and material property simplifications required for continuum-level human body models. Specifically, the mechanical properties of the brain tissues are often represented with simplified linear viscoelastic models, or the material properties have been optimized to specific impact cases. In addition, anatomical structures such as the arachnoid complex have been omitted or implemented in a simple lumped manner. Recent material test data for four brain regions at three strain rates in three modes of loading (tension, compression, and shear) was used to fit material parameters for a hyper-viscoelastic constitutive model. The material model was implemented in a contemporary detailed head finite element model. A detailed representation of the arachnoid trabeculae was implemented with mechanical properties based on experimental data. The enhanced head model was assessed by re-creating 11 ex vivo head impact scenarios and comparing the simulation results with experimental data. The hyper-viscoelastic model faithfully captured mechanical properties of the brain tissue in three modes of loading and multiple strain rates. The enhanced head model showed a high level of biofidelity in all re-created impacts in part due to the improved brain-skull interface associated with implementation of the arachnoid trabeculae. The enhanced head model provides an improved predictive capability with material properties based on tissue level data and is positioned to investigate head injury and tissue damage in the future.

Impact Location Dependence of Behind Armor Blunt Trauma Injury Assessed Using a Human Body Finite Element Model.

Behind armor blunt trauma (BABT), resulting from dynamic deformation of protective ballistic armor into the thorax, is currently assessed assuming a constant threshold of maximum backface deformation (BFDs) (44 mm). Although assessed for multiple impacts on the same armor, testing is focused on armor performance (shot-to-edge and shot-to-shot) without consideration of the underlying location on the thorax. Previous studies identified the importance of impacts on organs of animal surrogates wearing soft armor. However, the effect of impact location was not quantified outside the threshold of 44 mm. In the present study, a validated biofidelic advanced human thorax model (50th percentile male) was utilized to assess the BABT outcome from varying impact location. The thorax model was dynamically loaded using a method developed for recreating BABT impacts, and BABT events within the range of real-world impact severities and locations were simulated. It was found that thorax injury depended on impact location for the same BFDs. Generally, impacts over high compliance locations (anterolateral rib cage) yielded increased thoracic compression and loading on the lungs leading to pulmonary lung contusion (PLC). Impacts at low compliance locations (top of sternum) yielded hard tissue fractures. Injuries to the sternum, ribs, and lungs were predicted at BFDs lower than 44 mm for low compliance locations. Location-based injury risk curves demonstrated greater accuracy in injury prediction. This study quantifies the importance of impact location on BABT injury severity and demonstrates the need for consideration of location in future armor design and assessment.

Quantifying the Importance of Active Muscle Repositioning a Finite Element Neck Model in Flexion Using Kinematic, Kinetic, and Tissue-Level Responses.

PURPOSE: Non-neutral neck positions are important initial conditions in impact scenarios, associated with a higher incidence of injury. Repositioning in finite element (FE) neck models is often achieved by applying external boundary conditions (BCs) to the head while constraining the first thoracic vertebra (T1). However, in vivo, neck muscles contract to achieve a desired head and neck position generating initial loads and deformations in the tissues. In the present study, a new muscle-based repositioning method was compared to traditional applied BCs using a contemporary FE neck model for forward head flexion of 30°. METHODS: For the BC method, an external moment (2.6 Nm) was applied to the head with T1 fixed, while for the muscle-based method, the flexors and extensors were co-contracted under gravity loading to achieve the target flexion. RESULTS: The kinematic response from muscle contraction was within 10% of the in vivo experimental data, while the BC method differed by 18%. The intervertebral disc forces from muscle contraction were agreeable with the literature (167 N compression, 12 N shear), while the BC methodology underpredicted the disc forces owing to the lack of spine compression. Correspondingly, the strains in the annulus fibrosus increased by an average of 60% across all levels due to muscle contraction compared to BC method. CONCLUSION: The muscle repositioning method enhanced the kinetic response and subsequently led to differences in tissue-level responses compared to the conventional BC method. The improved kinematics and kinetics quantify the importance of repositioning FE neck models using active muscles to achieve non-neutral neck positions.

Primary results of the SAVAL randomized trial of a paclitaxel-eluting nitinol stent versus percutaneous transluminal angioplasty in infrapopliteal arteries.

BACKGROUND: Effective and durable options for infrapopliteal artery revascularization for patients with chronic limb-threatening ischemia (CLTI) are limited. METHODS: The SAVAL trial is a prospective, multicenter, randomized trial of patients with CLTI and infrapopliteal artery lesions with total lesion length ⩽ 140 mm, stenosis ⩾ 70%, and Rutherford category 4-5 assigned 2:1 to treatment with the SAVAL self-expandable paclitaxel drug-eluting stent (DES) or percutaneous transluminal angioplasty (PTA) with an uncoated balloon. The primary effectiveness endpoint was primary vessel patency (i.e., core lab-adjudicated duplex ultrasound-based flow at 12 months in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesion). The primary safety endpoint was the 12-month major adverse event (MAE)-free rate; MAEs were defined as a composite of above-ankle index limb amputation, major reintervention, and 30-day mortality. The endpoints were prespecified for superiority (effectiveness) and noninferiority (safety) at a one-sided significance level of 2.5%. RESULTS: A total of 201 patients were enrolled and randomly assigned to treatment (N = 130 DES, N = 71 PTA). Target lesion length was 68.1 ± 35.2 mm for the DES group and 68.7 ± 49.2 mm for the PTA group, and 31.0% and 27.6% of patients, respectively, had occlusions. The 12-month primary patency rates were 68.0% for the DES group and 76.0% for the PTA group (Psuperiority = 0.8552). The MAE-free rates were 91.6% and 95.3%, respectively (Pnoninferiority = 0.0433). CONCLUSION: The SAVAL trial did not show benefit related to effectiveness and safety with the nitinol DES compared with PTA in infrapopliteal artery lesions up to 140 mm in length. Continued innovation to provide optimal treatments for CLTI is needed. (ClinicalTrials.gov Identifier: NCT03551496).

Griddient: a microfluidic array to generate reconfigurable gradients on-demand for spatial biology applications.

Biological tissues are highly organized structures where spatial-temporal gradients (e.g., nutrients, hypoxia, cytokines) modulate multiple physiological and pathological processes including inflammation, tissue regeneration, embryogenesis, and cancer progression. Current in vitro technologies struggle to capture the complexity of these transient microenvironmental gradients, do not provide dynamic control over the gradient profile, are complex and poorly suited for high throughput applications. Therefore, we have designed Griddent, a user-friendly platform with the capability of generating controllable and reversible gradients in a 3D microenvironment. Our platform consists of an array of 32 microfluidic chambers connected to a 384 well-array through a diffusion port at the bottom of each reservoir well. The diffusion ports are optimized to ensure gradient stability and facilitate manual micropipette loading. This platform is compatible with molecular and functional spatial biology as well as optical and fluorescence microscopy. In this work, we have used this platform to study cancer progression.

Effect of muscle pre-tension and pre-impact neck posture on the kinematic response of the cervical spine in simulated low-speed rear impacts.

Computational human body models (HBMs) can identify potential injury pathways not easily accessible through experimental studies, such as whiplash induced injuries. However, previous computational studies investigating neck response to simulated impact conditions have neglected the effect of pre-impact neck posture and muscle pre-tension on the intervertebral kinematics and tissue-level response. The purpose of the present study was addressing this knowledge gap using a detailed neck model subjected to simulated low-acceleration rear impact conditions, towards improved intervertebral kinematics and soft tissue response for injury assessment. An improved muscle path implementation in the model enabled the modeling of muscle pre-tension using experimental muscle pre-stretch data determined from previous cadaver studies. Cadaveric neck impact tests and human volunteer tests with the corresponding cervical spine posture were simulated using a detailed neck model with the reported boundary conditions and no muscle activation. Computed intervertebral kinematics of the model with pre-tension achieved, for the first time, the S-shape behavior of the neck observed in low severity rear impacts of both cadaver and volunteer studies. The maximum first principal strain in the muscles for the model with pre-tension was 27% higher than that without pre-tension. Although, the pre-impact neck posture was updated to match the average posture reported in the experimental tests, the change in posture was generally small with only small changes in vertebral kinematics and muscle strain. This study provides a method to incorporate muscle pre-tension in HBM and quantifies the importance of pre-tension in calculating tissue-level distractions.

Microfluidic device with reconfigurable spatial temporal gradients reveals plastic astrocyte response to stroke and reperfusion.

As a leading cause of mortality and morbidity, stroke constitutes a significant global health burden. Ischemic stroke accounts for 80% of cases and occurs due to an arterial thrombus, which impedes cerebral blood flow and rapidly leads to cell death. As the most abundant cell type within the central nervous system, astrocytes play a critical role within the injured brain. We developed a novel microphysiological platform that permits the induction of spatiotemporally controlled nutrient gradients, allowing us to study astrocytic response during and after transient nutrient deprivation. Within 24 h of inducing starvation in the platform, nutrient deprivation led to multiple changes in astrocyte response, from metabolic perturbations to gene expression changes, and cell viability. Furthermore, we observed that nutrient restoration did not reverse the functional changes in astrocyte metabolism, which mirrors reperfusion injury observed in vivo. We also identified alterations in numerous glucose metabolism-associated genes, many of which remained upregulated or downregulated even after restoration of the nutrient supply. Together, these findings suggest that astrocyte activation during and after nutrient starvation induces plastic changes that may underpin persistent stroke-induced functional impairment. Overall, our innovative device presents interesting potential to be used in the development of new therapies to improve tissue repair and even cognitive recovery after stroke.

Inference of process variations in silicon photonics from characterization measurements.

Understanding process variations and their impact in silicon photonics remains challenging. To achieve high-yield manufacturing, a key step is to extract the magnitude and spatial distribution of process variations in the actual fabrication, which is usually based on measurements of replicated test structures. In this paper, we develop a Bayesian-based method to infer the distribution of systematic geometric variations in silicon photonics, without requiring replication of identical test structures. We apply this method to characterization data from multiple silicon nitride ring resonators with different design parameters. We extract distributions with standard deviation of 28 nm, 0.8 nm, and 3.8 nm for the width, thickness, and partial etch depth, respectively, as well as the spatial maps of these variations. Our results show that this characterization and extraction approach can serve as an efficient method to study process variation in silicon photonics, facilitating the design of high-yield silicon photonic circuits in the future.

Trends in Cardiogenic Shock-Related Mortality in Patients With Acute Myocardial Infarction in the United States, 1999 to 2019.

Data on mortality trends in patients with acute myocardial infarction (AMI) with cardiogenic shock (CS) are scant. This study aimed to assess the trends in CS-AMI-related mortality in United States (US) subjects over the latest 21 years. Mortality data of US subjects with AMI listed as the underlying cause of death and CS as contributing cause were obtained from the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) dataset from January 1999 to December 2019. CS-AMI-related age-adjusted mortality rates (AAMRs) per 100,000 US population were stratified by gender, race and ethnicity, geographic areas, and urbanicity. Nationwide annual trends were assessed as annual percent change (APC) and average APC with relative 95% confidence intervals (CIs). Between 1999 and 2019, CS-AMI was listed as the underlying cause of death in 209,642 patients, (AAMR of 3.01 per 100,000 people [95% CI 2.99 to 3.02]). AAMR from CS-AMI remained stable from 1999 to 2007 (APC -0.2%, [95% CI -2.0 to 0.5], p = 0.22) and then significantly increased (APC 3.1% [95% CI 2.6 to 3.6], p <0.0001), especially in male patients. Starting in 2009, the AAMR increase was more pronounced in those <65 years, Black Americans, and residents of rural areas. The higher AAMRs were clustered in the South (average APC 4.5%, [95% CI 4.4 to 4.6]) of the country. In conclusion, CS-AMI-related mortality in US patients increased from 2009 to 2019. Targeted health policy measures are needed to address the rising burden of CS-AMI in US subjects.

Impact of process variations on splitter-tree-based integrated optical phased arrays.

We consider the impact of intra-wafer systematic spatial variation, pattern density mismatch, and line edge roughness on splitter-tree-based integrated optical phased arrays. These variations can substantially affect the emitted beam profile in the array dimension. We study the effect on different architecture parameters, and the analysis is shown to be consistent with experimental results.

Percutaneous Management of High-Risk Pulmonary Embolism.

Acute pulmonary embolism (PE) leads to an abrupt increase in pulmonary vascular resistance and right ventricular afterload, and when significant enough, can result in hemodynamic instability. High-risk PE is a dire cardiovascular emergency and portends a poor prognosis. Traditional therapeutic options to rapidly reduce thrombus burden like systemic thrombolysis and surgical pulmonary endarterectomy have limitations, both with regards to appropriate candidates and efficacy, and have limited data demonstrating their benefit in high-risk PE. There are growing percutaneous treatment options for acute PE that include both localized thrombolysis and mechanical embolectomy. Data for such therapies with high-risk PE are currently limited. However, given the limitations, there is an opportunity to improve outcomes, with percutaneous treatments options offering new mechanisms for clot reduction with a possible improved safety profile compared with systemic thrombolysis. Additionally, mechanical circulatory support options allow for complementary treatment for patients with persistent instability, allowing for a bridge to more definitive treatment options. As more data develop, a shift toward a percutaneous approach with mechanical circulatory support may become a preferred option for the management of high-risk PE at tertiary care centers.

Sustained Mechanical Aspiration Thrombectomy for High Thrombus Burden Coronary Vessel Occlusion: The Multicenter CHEETAH Study.

BACKGROUND: Poor myocardial reperfusion due to distal embolization and microvascular obstruction after percutaneous coronary intervention is associated with increased risk of morbidity and mortality. Prior trials have not shown a clear benefit of routine manual aspiration thrombectomy. Sustained mechanical aspiration may mitigate this risk and improve outcomes. The objective of this study is to evaluate sustained mechanical aspiration thrombectomy before percutaneous coronary intervention in high thrombus burden acute coronary syndrome patients. METHODS: This prospective study evaluated the Indigo CAT RX Aspiration System (Penumbra Inc, Alameda CA) for sustained mechanical aspiration thrombectomy before percutaneous coronary intervention at 25 hospitals across the USA. Adults presenting within 12 hours of symptom onset with high thrombus burden and target lesion(s) located in a native coronary artery were eligible. The primary end point was a composite of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or new or worsening New York Heart Association class IV heart failure within 30 days. Secondary end points included Thrombolysis in Myocardial Infarction thrombus grade, Thrombolysis in Myocardial Infarction flow, myocardial blush grade, stroke, and device-related serious adverse events. RESULTS: From August 2019 through December 2020, a total of 400 patients were enrolled (mean age 60.4 years, 76.25% male). The primary composite end point rate was 3.60% (14/389 [95% CI, 2.0-6.0%]). Rate of stroke within 30 days was 0.77%. Final rates of Thrombolysis in Myocardial Infarction thrombus grade 0, Thrombolysis in Myocardial Infarction flow 3, and myocardial blush grade 3 were 99.50%, 97.50%, and 99.75%, respectively. No device-related serious adverse events occurred. CONCLUSIONS: Sustained mechanical aspiration before percutaneous coronary intervention in high thrombus burden acute coronary syndrome patients was safe and was associated with high rates of thrombus removal, flow restoration, and normal myocardial perfusion on final angiography.

Characterizing In-Situ Metatarsal Fracture Risk During Simulated Workplace Impact Loading.

Metatarsal fractures represent the most common traumatic foot injury; however, metatarsal fracture thresholds remain poorly characterized, which affects performance targets for protective footwear. This experimental study investigated impact energies, forces, and deformations to characterize metatarsal fracture risk for simulated in situ workplace impact loading. A drop tower setup conforming to ASTM specifications for testing impact resistance of metatarsal protective footwear applied a target impact load (22-55 J) to 10 cadaveric feet. Prior to impact, each foot was axially loaded through the tibia with a specimen-specific bodyweight load to replicate a natural weight-bearing stance. Successive iterations of impact tests were performed until a fracture was observed with X-ray imaging. Descriptive statistics were computed for force, deformation, and impact energy. Correlational analysis was conducted on donor age, BMI, deformation, force, and impact energy. A survival analysis was used to generate injury risk curves (IRC) using impact energy and force. All 10 specimens fractured with the second metatarsal being the most common fracture location. The mean peak energy, force, and deformation during fracture were 46.6 J, 4640 N, 28.9 mm, respectively. Survival analyses revealed a 50% fracture probability was associated with 35.8 J and 3562 N of impact. Foot deformation was not significantly correlated (p = 0.47) with impact force, thus deformation is not recommended to predict metatarsal fracture risk. The results from this study can be used to improve test standards for metatarsal protection, provide performance targets for protective footwear developers, and demonstrate a methodological framework for future metatarsal fracture research.

Enhancing the Biofidelity of an Upper Cervical Spine Finite Element Model Within the Physiologic Range of Motion and Its Effect on the Full Ligamentous Neck Model Response.

Contemporary finite element (FE) neck models are developed in a neutral posture; however, evaluation of injury risk for out-of-position impacts requires neck model repositioning to non-neutral postures, with much of the motion occurring in the upper cervical spine (UCS). Current neck models demonstrate a limitation in predicting the intervertebral motions within the UCS within the range of motion, while recent studies have highlighted the importance of including the tissue strains resulting from repositioning FE neck models to predict injury risk. In the current study, the ligamentous cervical spine from a contemporary neck model (GHBMC M50 v4.5) was evaluated in flexion, extension, and axial rotation by applying moments from 0 to 1.5 N·m in 0.5 N·m increments, as reported in experimental studies and corresponding to the physiologic loading of the UCS. Enhancements to the UCS model were identified, including the C0-C1 joint-space and alar ligament orientation. Following geometric enhancements, an analysis was undertaken to determine the UCS ligament laxities, using a sensitivity study followed by an optimization study. The ligament laxities were optimized to UCS-level experimental data from the literature. The mean percent difference between UCS model response and experimental data improved from 55% to 23% with enhancements. The enhanced UCS model was integrated with a ligamentous cervical spine (LS) model and assessed with independent experimental data. The mean percent difference between the LS model and the experimental data improved from 46% to 35% with the integration of the enhanced UCS model.