Autonomous precision resuscitation during ground and air transport of an animal hemorrhagic shock model.

We tested the ability of a physiologically driven minimally invasive closed-loop algorithm, called Resuscitation based on Functional Hemodynamic Monitoring (ReFit), to stabilize for up to 3 h a porcine model of noncompressible hemorrhage induced by severe liver injury and do so during both ground and air transport. Twelve animals were resuscitated using ReFit to drive fluid and vasopressor infusion to a mean arterial pressure (MAP) > 60 mmHg and heart rate < 110 min-1 30 min after MAP < 40 mmHg following liver injury. ReFit was initially validated in 8 animals in the laboratory, then in 4 animals during air (23nm and 35nm) and ground (9 mi) to air (9.5nm and 83m) transport returning to the laboratory. The ReFit algorithm kept all animals stable for ~ 3 h. Thus, ReFit algorithm can diagnose and treat ongoing hemorrhagic shock independent to the site of care or during transport. These results have implications for treatment of critically ill patients in remote, austere and contested environments and during transport to a higher level of care.

Altered Gene Expression Within the Renin-Angiotensin System in Normal Aging and Dementia.

The renin-angiotensin system (RAS) is dysregulated in Alzheimer's disease (AD). In this study, we have explored the hypothesis that an -age--related imbalance in brain RAS is a trigger for RAS dysregulation in AD. We characterized RAS gene expression in the frontal cortex from (i) a cohort of normal aging (n = 99, age range = 19-96 years) and (ii) a case-control cohort (n = 209) including AD (n = 66), mixed dementia (VaD + AD; n = 50), pure vascular dementia (VaD; n = 42), and age-matched controls (n = 51). The AD, mixed dementia, and age-matched controls were further stratified by Braak tangle stage (BS): BS0-II (n = 48), BSIII-IV (n = 44), and BSV-VI (n = 85). Gene expression was calculated by quantitative PCR (qPCR) for ACE1, AGTR1, AGTR2, ACE2, LNPEP, and MAS1 using the 2-∆∆Cq method, after adjustment for reference genes (RPL13 and UBE2D2) and cell-specific calibrator genes (NEUN, GFAP, PECAM). ACE1 and AGTR1, markers of classical RAS signaling, and AGTR2 gene expression were elevated in normal aging and gene expression in markers of protective downstream regulatory RAS signaling, including ACE2, MAS1, and LNPEP, were unchanged. In AD and mixed dementia, AGTR1 and AGTR2 gene expression were elevated in BSIII-IV and BSV-VI, respectively. MAS1 gene expression was reduced at BSV-VI and was inversely related to parenchymal Aß and tau load. LNPEP gene expression was specifically elevated in VaD. These data provide novel insights into RAS signaling in normal aging and dementia.

Elevated late-life blood pressure may maintain brain oxygenation and slow amyloid-ß accumulation at the expense of cerebral vascular damage.

Hypertension in midlife contributes to cognitive decline and is a modifiable risk factor for dementia. The relationship between late-life hypertension and dementia is less clear. We have investigated the relationship of blood pressure and hypertensive status during late life (after 65 years) to post-mortem markers of Alzheimer's disease (amyloid-ß and tau loads); arteriolosclerosis and cerebral amyloid angiopathy; and to biochemical measures of ante-mortem cerebral oxygenation (the myelin-associated glycoprotein:proteolipid protein-1 ratio, which is reduced in chronically hypoperfused brain tissue, and the level of vascular endothelial growth factor-A, which is upregulated by tissue hypoxia); blood-brain barrier damage (indicated by an increase in parenchymal fibrinogen); and pericyte content (platelet-derived growth factor receptor ß, which declines with pericyte loss), in Alzheimer's disease (n = 75), vascular (n = 20) and mixed dementia (n = 31) cohorts. Systolic and diastolic blood pressure measurements were obtained retrospectively from clinical records. Non-amyloid small vessel disease and cerebral amyloid angiopathy were scored semiquantitatively. Amyloid-ß and tau loads were assessed by field fraction measurement in immunolabelled sections of frontal and parietal lobes. Homogenates of frozen tissue from the contralateral frontal and parietal lobes (cortex and white matter) were used to measure markers of vascular function by enzyme-linked immunosorbent assay. Diastolic (but not systolic) blood pressure was associated with the preservation of cerebral oxygenation, correlating positively with the ratio of myelin-associated glycoprotein to proteolipid protein-1 and negatively with vascular endothelial growth factor-A in both the frontal and parietal cortices. Diastolic blood pressure correlated negatively with parenchymal amyloid-ß in the parietal cortex. In dementia cases, elevated late-life diastolic blood pressure was associated with more severe arteriolosclerosis and cerebral amyloid angiopathy, and diastolic blood pressure correlated positively with parenchymal fibrinogen, indicating blood-brain barrier breakdown in both regions of the cortex. Systolic blood pressure was related to lower platelet-derived growth factor receptor ß in controls in the frontal cortex and in dementia cases in the superficial white matter. We found no association between blood pressure and tau. Our findings demonstrate a complex relationship between late-life blood pressure, disease pathology and vascular function in dementia. We suggest that hypertension helps to reduce cerebral ischaemia (and may slow amyloid-ß accumulation) in the face of increasing cerebral vascular resistance, but exacerbates vascular pathology.

Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer's disease pathology in mouse models of Alzheimer's disease.

An imbalance in the circulatory and organ-specific renin-angiotensin system (RAS) pathways is associated with age-related dysfunction and disease including cardiovascular burden and more recently Alzheimer's disease (AD). It is currently unclear whether an age-associated imbalance in components of the RAS within the brain precedes the onset of AD or whether a RAS imbalance is associated with the onset of disease pathology and cognitive decline. Angiotensin-converting enzyme-1 (ACE-1) and -2 (ACE-2) protein (ELISA) and enzyme activity (FRET assay), markers of the classical and counter-regulatory RAS axis respectively, and Ang-II and Ang-(1-7) peptide levels (ELISA), were measured in the left cortex across four transgenic AD mouse models of amyloid pathology (5xFAD - 2, 6, and 12 months of age; Apd9 - 3-4, 12, and 18 months of age; Tg2576 - 3-4 and 24 months of age; and PDAPP - 3-4, 7, 11, 15, and 18 months of age) and littermate wild-type (WT) controls. ACE-1 level, and enzyme activity, was unaltered in relation to age in WT mice and across all four models. In contrast, ACE-2 level and enzyme activity, was reduced and Ang-II increased with ageing in both WT animals and disease models. The changes in ACE-2 and Ang-II in AD models mirrored WT mice, except for the 5xFAD model, when the reduction in ACE-2 (and elevated Ang-II) was observed at a younger age. These data indicate an age-related dysregulation of brain RAS is likely to be driven by a reduction in ACE-2. The reduction in ACE-2 occurs at a young age, coinciding with early pathological changes and the initial deposition of Aß, and preceding neuronal loss and cognitive decline, in the transgenic AD models. However, the age-related loss was mirrored in WT mice suggesting that the change was independent of pathological Aß deposition.

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer's Disease.

An imbalance in the renin-angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer's disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n = 121; 19-95 years age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, United Kingdom, and AD and age-matched controls (n = 60) from the South West Dementia Brain Bank, University of Bristol, United Kingdom, stratified according to Braak tangle stage (BS): 0-II, III-IV (intermediate disease), and V-VI (end-stage disease). ACE-1 and ACE-2 enzyme activity were measured using fluorogenic peptide activity assays. ACE-1, ACE-2, and Ang-II protein level were measured by enzyme-linked immunosorbent assay (ELISA). In both regions, ACE-1 protein and Ang-II levels correlated positively with age whereas ACE-1 enzyme activity was inversely related to age. ACE-1 protein correlated positively with Ang-II, whilst ACE-1 activity correlated inversely with Ang-II in normal aging. ACE-1 enzyme activity was elevated at an early/intermediate stage, BS III-IV compared to BS 0-II in the temporal cortex in AD. ACE-2 protein and enzyme activity were unchanged with aging and in AD. In conclusion, ACE-1 activity is induced in the early stages of AD independently from normal physiological age-related changes in ACE-1 protein.

Real-time vessel segmentation and reconstruction for virtual fixtures for an active handheld microneurosurgical instrument.

PURPOSE: Complications related to vascular damage such as intra-operative bleeding may be avoided during neurosurgical procedures such as petroclival meningioma surgery. To address this and improve the patient's safety, we designed a real-time blood vessel avoidance strategy that enables operation on deformable tissue during petroclival meningioma surgery using Micron, a handheld surgical robotic tool. METHODS: We integrated real-time intra-operative blood vessel segmentation of brain vasculature using deep learning, with a 3D reconstruction algorithm to obtain the vessel point cloud in real time. We then implemented a virtual-fixture-based strategy that prevented Micron's tooltip from entering a forbidden region around the vessel, thus avoiding damage to it. RESULTS: We achieved a median Dice similarity coefficient of 0.97, 0.86, 0.87 and 0.77 on datasets of phantom blood vessels, petrosal vein, internal carotid artery and superficial vessels, respectively. We conducted trials with deformable clay vessel phantoms, keeping the forbidden region 400 [Formula: see text]m outside and 400 [Formula: see text]m inside the vessel. Micron's tip entered the forbidden region with a median penetration of just 8.84 [Formula: see text]m and 9.63 [Formula: see text]m, compared to 148.74 [Formula: see text]m and 117.17 [Formula: see text]m without our strategy, for the former and latter trials, respectively. CONCLUSION: Real-time control of Micron was achieved at 33.3 fps. We achieved improvements in real-time segmentation of brain vasculature from intra-operative images and showed that our approach works even on non-stationary vessel phantoms. The results suggest that by enabling precise, real-time control, we are one step closer to using Micron in real neurosurgical procedures.

Variability in Reassessment of Left Ventricular Ejection Fraction After Myocardial Infarction in the Acute Myocardial Infarction Quality Assurance Canada Study.

Importance: Persistently depressed left ventricular ejection fraction (LVEF) after myocardial infarction (MI) is associated with adverse prognosis and directs the use of evidence-based treatments to prevent sudden cardiac death and/or progressive heart failure. Objective: To assess adherence with guideline-recommended LVEF reassessment and to study the evolution of LVEF over 6 months of follow-up. Design, Setting, and Participants: This was a multicenter cohort study at Canadian academic and community hospitals with on-site cardiac catheterization services. Patients with type 1 acute MI and LVEF less than or equal to 45% during the index hospitalization were enrolled between January 2018 and August 2019 and were followed-up for 6 months. Data analysis was performed from May 2020 to September 2021. Exposures: Baseline clinical factors, in-hospital care and LVEF, and site-specific features. Main Outcomes and Measures: The main outcomes were receipt of repeat LVEF assessment by 6 months and the presence of a persistent LVEF reduction at 2 thresholds: LVEF less than or equal to 40%, prompting consideration of additional medical therapy for heart failure, or LVEF less than or equal to 35%, prompting referral for implanted cardioverter defibrillator in addition to medical therapy. Results: This study included 501 patients (mean [SD] age, 63.3 [13.0] years; 113 women [22.6%]). Overall, 370 patients (73.4%) presented with STEMI, and 454 (90.6%) had in-hospital revascularization. The median (IQR) baseline LVEF was 40% (34%-43%). Of 458 patients (91.4%) who completed the 6-month follow-up, 303 (66.2%; 95% CI, 61.7%-70.5%) had LVEF reassessment, with a range of 46.7% to 90.0% across sites (χ213 = 19.6; P = .11). Participants from community hospitals were more likely than those from academic hospitals to undergo LVEF reassessment (73.6% vs 63.2%; χ21 = 4.50; P = .03), as were those with worse LVEF at baseline. Follow-up LVEF improved by an absolute median (IQR) of 8% (3%-15%). However, 103 patients (34.1%) met the definitions of clinically relevant LVEF reduction, including 52 patients (17.2%) with LVEF less than or equal to 35% and 51 patients (16.9%) with LVEF of 35.1% to 40.0%. Conclusions and Relevance: In this cohort study, approximately 1 in 3 patients with at least mild LVEF reduction after acute MI did not undergo indicated LVEF reassessment within 6 months, suggesting that programs to improve the quality of post-MI care should include measures to ensure that indicated repeat cardiac imaging is performed. In those with follow-up imaging, clinically relevant persistent LVEF reduction was identified in more than one-third of patients.

Monocular Vision-Based Retinal Membrane Peeling With a Handheld Robot.

Retinal membrane peeling requires delicate manipulation. The presence of the surgeon's physiological tremor, the high variability and often low quality of the ophthalmic image, and excessive forces make the tasks more challenging. Preventing unintended movement caused by tremor and unintentional forces can reduce membrane injury. With the use of an actively stabilized handheld robot, we employ a monocular camera-based surface reconstruction method to estimate the retinal plane and we propose the use of a virtual fixture with the application of a hard stop and motion scaling to improve control of the tool tip during delaminating in a laboratory simulation of retinal membrane peeling. A hard stop helps to limit downward force exerted on the surface. Motion scaling also improves the user's control of contact force when delaminating. We demonstrate a reduction of maximum force and maximum surface-penetration distance from the estimated retinal plane using the proposed technique.

Toward Monocular Camera-Guided Retinal Vein Cannulation with an Actively Stabilized Handheld Robot.

In this paper we describe work towards retinal vessel cannulation using an actively stabilized handheld robot, guided by monocular vision. We employ a previously developed monocular camera based surface reconstruction method using automated laser beam scanning over the retina. We use the reconstructed plane to find a coordinate transform between the 2D image plane coordinate system and the global 3D frame. Within a hemispherical region around the target, we use motion scaling for higher precision. The contribution of this work is the homography matrix estimation using monocular vision and application of the previously developed laser surface reconstruction to Micron guided vein cannulation. Experiments are conducted in a wet eye phantom to show the higher accuracy of the surface reconstruction as compared to standard stereo reconstruction. Further, experiments to show the increased surgical accuracy due to motion scaling are also carried out.

Multirate Kalman Filter Rejects Impulse Noise in Frequency-Domain-Multiplexed Tracker Measurements.

Frequency domain multiplexing (FDM) is a useful for making multiple measurements simultaneously, such as in optical and electromagnetic position trackers. Much interference is periodic (e.g., AC power harmonics), and is rejected well by FDM, but impulse disturbances are also common. Impulses corrupt the entire spectrum for a short period, and are better rejected in the time domain. Nonlinear blanking is a simple way to suppress impulses, but cannot be easily realized when the required dynamic range is large, and problematic noise may be far smaller than the signal. The described multi-rate Kalman filter upsamples the prediction to the input rate so that impulse departures from the predicted signal are easily detected and blanked out. Also, noise levels in unused adjacent channels are used to estimate measurement noise so that the Kalman filter adapts more slowly when noise is high, keeping output noise roughly constant even in the presence of longer noise bursts.

Comparative Evaluation of Handheld Robot-Aided Intraocular Laser Surgery.

This paper presents robot-aided intraocular laser surgery using a handheld robot known as Micron. The micromanipulator incorporated in Micron enables visual servoing of a laser probe, while maintaining a constant distance of the tool tip from the retinal surface. The comparative study was conducted with various control methods for evaluation of robot-aided intraocular laser surgery.

Hybrid position/force control of an active handheld micromanipulator for membrane peeling.

BACKGROUND: Peeling procedures in retinal surgery require micron-scale manipulation and control of sub-tactile forces. METHODS: Hybrid position/force control of an actuated handheld microsurgical instrument is presented as a means for simultaneously improving positioning accuracy and reducing forces to prevent avoidable trauma to tissue. The system response was evaluated, and membrane-peeling trials were performed by four test subjects in both artificial and animal models. RESULTS: Maximum force was reduced by 56% in both models compared with position control. No statistically significant effect on procedure duration was observed. CONCLUSIONS: A hybrid position/force control system has been implemented that successfully attenuates forces and minimizes unwanted excursions during microsurgical procedures such as membrane peeling. Results also suggest that improvements in safety using this technique may be attained without increasing the duration of the procedure.

Electromagnetic Tracker for Active Handheld Robotic Systems.

We describe the development of the In-Loop Electromagnetic Tracker (ILEMT), designed to meet the demanding latency and resolution requirements for active stabilization of hand motion during precision manipulations such as microsurgery. The prototype surpasses the fastest commercial EM trackers by > 4× in root bandwidth/resolution and 2× in latency. The use of two widely spaced carrier frequencies (e.g., 300 Hz and 10 kHz) enables a particularly simple way of reducing the eddy-current interference caused by nonferrous metals present in the workspace. Previously, metal compatibility has only been achieved at a large cost to measurement speed.

Manipulator Design and Operation for a Six-Degree-of-Freedom Handheld Tremor-Canceling Microsurgical Instrument.

This paper presents the design and actuation of a six-degree-of-freedom (6-DOF) manipulator for a handheld instrument, known as "Micron," which performs active tremor compensation during microsurgery. The design incorporates a Gough-Stewart platform based on piezoelectric linear motor, with a specified minimum workspace of a cylinder 4 mm long and 4 mm in diameter at the end-effector. Given the stall force of the motors and the loading typically encountered in vitreoretinal microsurgery, the dimensions of the manipulator are optimized to tolerate a transverse load of 0.2 N on a remote center of motion near the midpoint of the tool shaft. The optimization yields a base diameter of 23 mm and a height of 37 mm. The fully handheld instrument includes a custom-built optical tracking system for control feedback, and an ergonomic housing to serve as a handle. The manipulation performance was investigated in both clamped and handheld conditions. In positioning experiments with varying side loads, the manipulator tolerates side load up to 0.25 N while tracking a sinusoidal target trajectory with less than 20 µm error. Physiological hand tremor is reduced by about 90% in a pointing task, and error less than 25 µm is achieved in handheld circle-tracing.

Toward Hybrid Position/Force Control for an Active Handheld Micromanipulator.

Vitreoretinal microsurgery requires precise hand-eye coordination to manipulate delicate structures within the eye on the order of tens of microns. To achieve these tasks, surgeons use tools of diameter 0.9 mm or less to access the eye's interior structures. The level of force required during these manipulations is often below the human tactile threshold, requiring the surgeon to rely on subtle visual cues or to apply larger forces above the tactile threshold for feedback. However, both of these methods can lead to tissue damage. Excursions can be made into tissues which are not felt by the surgeon, while larger forces have a higher chance of damaging tissue within the eye. To prevent damage to the retina and other anatomy, we present the implementation of hybrid position/force control operating in the sub-tactile force range for a handheld robotic system. This approach resulted in a 42% reduction in the mean force and 52% reduction in maximum force during peeling tasks.

Toward Automated Intraocular Laser Surgery Using a Handheld Micromanipulator.

This paper presents a technique for automated intraocular laser surgery using a handheld micromanipulator known as Micron. The novel handheld manipulator enables the automated scanning of a laser probe within a cylinder of 4 mm long and 4 mm in diameter. For the automation, the surface of the retina is reconstructed using a stereomicroscope, and then preplanned targets are placed on the surface. The laser probe is precisely located on the target via visual servoing of the aiming beam, while maintaining a specific distance above the surface. In addition, the system is capable of tracking the surface of the eye in order to compensate for any eye movement introduced during the operation. We compared the performance of the automated scanning using various control thresholds, in order to find the most effective threshold in terms of accuracy and speed. Given the selected threshold, we conducted the handheld operation above a fixed target surface. The average error and execution time are reduced by 63.6% and 28.5%, respectively, compared to the unaided trials. Finally, the automated laser photocoagulation was demonstrated also in an eye phantom, including compensation for the eye movement.

Performance of a 6-degree-of-freedom active microsurgical manipulator in handheld tasks.

This paper presents the first experimental results from human users of a new 6-degree-of-freedom handheld micromanipulator. This is the latest prototype of a fully-handheld system, known as "Micron," which performs active compensation of hand tremor for microsurgery. The manipulator is a miniature Gough-Stewart platform incorporating linear ultrasonic motors that provide a cylindrical workspace 4 mm long and 4 mm wide. In addition, the platform allows the possibility of imposing a remote center of motion for controlling motion not only at the tip but also at the entry point in the sclera of the eye. We demonstrate hand tremor reduction in both static and dynamic micromanipulation tasks on a rubber pad. The handheld performance is also evaluated in an artificial eye model while imposing a remote center of motion. In all cases, hand tremor is significantly reduced.

Improvement of optical coherence tomography using active handheld micromanipulator in vitreoretinal surgery.

An active handheld micromanipulator has been developed to cancel hand tremor during microsurgery. The micromanipulator is also applicable in optical coherence tomography to improve the quality of scanning and minimize surgical risks during the scans. The manipulator can maneuver the tool tip with six degrees of freedom within a cylindrical workspace 4 mm in diameter and 4 mm high. The imaging system is equipped with a 25-gauge Fourier-domain common-path OCT probe. This paper introduces the handheld OCT imaging system and techniques involved and presents stabilized OCT images of A-mode and M-mode scans in air and live rabbit eyes. We show the first demonstration of OCT imaging using the active handheld micromanipulator in vivo.

Comparison of Baseline Tremor Under Various Microsurgical Conditions.

This paper presents the characterization and comparison of physiological tremor for pointing tasks in multiple environments, as a baseline for performance evaluation of microsurgical robotics. Previous studies have examined the characteristics of physiological tremor under laboratory settings as well as different operating conditions. However, different test methods make the comparison of results across trials and conditions difficult. Two vitroretinal microsurgeons were evaluated while performing a pointing task with no entry-point constraint, constrained by an artificial eye model, and constrained by a rabbit eye in vivo. For the three respective conditions the 3D RMS positioning error was 144 µm, 258 µm, and 285 µm, and maximum 3D error was 349 µm, 647 µm, and 696 µm. A spectral analysis was also performed, confirming a distinct peak near in the 6-12 Hz frequency range, characteristic of hand tremor during tasks in all three environments.