Microvascular plasticity in mouse stroke model recovery: Anatomy statistics, dynamics measured by longitudinal in vivo two-photon angiography, network vectorization.

This manuscript quantitatively investigates remodeling dynamics of the cortical microvascular network (thousands of connected capillaries) following photothrombotic ischemia (cubic millimeter volume, imaged weekly) using a novel in vivo two-photon angiography and high throughput vascular vectorization method. The results suggest distinct temporal patterns of cerebrovascular plasticity, with acute remodeling peaking at one week post-stroke. The network architecture then gradually stabilizes, returning to a new steady state after four weeks. These findings align with previous literature on neuronal plasticity, highlighting the correlation between neuronal and neurovascular remodeling. Quantitative analysis of neurovascular networks using length- and strand-based statistical measures reveals intricate changes in network anatomy and topology. The distance and strand-length statistics show significant alterations, with a peak of plasticity observed at one week post-stroke, followed by a gradual return to baseline. The orientation statistic plasticity peaks at two weeks, gradually approaching the (conserved across subjects) stroke signature. The underlying mechanism of the vascular response (angiogenesis vs. tissue deformation), however, is yet unexplored. Overall, the combination of chronic two-photon angiography, vascular vectorization, reconstruction/visualization, and statistical analysis enables both qualitative and quantitative assessments of neurovascular remodeling dynamics, demonstrating a method for investigating cortical microvascular network disorders and the therapeutic modes of action thereof.

12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction and Microthrombi after Subarachnoid Hemorrhage in Mice.

Background and Purpose: Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus 12/15-LOX is an important target to prevent delayed cerebral ischemia. Methods: SAH was induced in C57BL/6 and 12/15-LOX-/- mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro. C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day five to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and for development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. Results: In SAH mice, 12/15-LOX was upregulated in brain vascular cells and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Conclusions: Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.

Dynamic Light Scattering in Biomedical Applications: feature issue introduction.

The feature Issue on "Dynamic Light Scattering in Biomedical Applications" presents a compilation of research breakthroughs and technological advancements that have shaped the field of biophotonics, particularly in the non-invasive exploration of biological tissues. Highlighting the significance of dynamic light scattering (DLS) alongside techniques like laser Doppler flowmetry (LDF), diffusing wave spectroscopy (DWS), and laser speckle contrast imaging (LSCI), this issue underscores the versatile applications of these methods in capturing the intricate dynamics of microcirculatory blood flow across various tissues. Contributions explore developments in fluorescence tomography, the integration of machine learning for data processing, enhancements in microscopy for cancer detection, and novel approaches in optical biophysics, among others. Innovations featured include a high-resolution speckle contrast tomography system for deep blood flow imaging, a rapid estimation technique for real-time tissue perfusion imaging, and the use of convolutional neural networks for efficient blood flow mapping. Additionally, studies delve into the impact of skin strain on spectral reflectance, the sensitivity of cerebral blood flow measurement techniques, and the potential of photobiomodulation for enhancing brain function. This issue not only showcases the latest theoretical and experimental strides in DLS-based imaging but also anticipates the continued evolution of these modalities for groundbreaking applications in disease detection, diagnosis, and monitoring, marking a pivotal contribution to the field of biomedical optics.

Laser speckle contrast imaging versus microvascular Doppler sonography in aneurysm surgery: A prospective study.

Objective: This study aimed to compare microvascular Doppler sonography (MDS) and laser speckle contrast imaging (LSCI) for assessing vessel patency and aneurysm occlusion during microsurgical clipping of intracranial aneurysms. Methods: MDS and LSCI were used after clip placement during six neurovascular procedures including six patients, and agreement between the two techniques was assessed. LSCI was performed in parallel or right after MDS evaluation. The Doppler response was assessed through listening while flow in the LSCI videos was evaluated by three blinded neurovascular surgeons after the surgery. Statistical analysis determined the agreement between the techniques in assessing flow in 18 regions of interest (ROIs). Results: Agreement between MDS and LSCI in assessing vessel patency was observed in 87 % of the ROIs. LSCI accurately identified flow in 93.3 % of assessable ROIs, with no false positive or negative measurements. Three ROIs were not assessable with LSCI due to motion artifacts or poor image quality. No complications were observed. Conclusions: LSCI demonstrated high agreement with MDS in assessing vessel patency during microsurgical clipping of intracranial aneurysms. It provided continuous, real-time, full-field imaging with high spatial resolution and temporal resolution. While MDS allowed evaluation of deep vascular regions, LSCI complemented it by offering unlimited assessment of surrounding vessels.

In older patients with AF and frailty, switching from VKA to NOAC therapy increased a composite of major or CRNM bleeding at 12 mo.

SOURCE CITATION: Joosten LP, van Doorn S, van de Ven PM, et al. Safety of switching from a vitamin K antagonist to a non-vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation: results of the FRAIL-AF randomized controlled trial. Circulation. 2024;149:279-289. 37634130.

Management of loperamide-related opioid use disorder with buprenorphine within an Australian context: A case report.

Loperamide is an over-the-counter peripheral mu-opioid agonist commonly used to manage diarrhoea. When taken in an excessive dose, loperamide's penetration of the central nervous system increases, leading to euphoria, respiratory depression and other opioid effects. A health warning was released in the United States in 2016 with increased reports of excessive loperamide use leading to cardiac conduction abnormalities such as ventricular tachycardia, prolonged QTc and Torsades des Pointes. The growing number of cases is likely due to the increased restrictions on other opioids. Loperamide use disorder has been managed effectively in the United States and the United Kingdom using buprenorphine. In Australia, there have been recent opioid restrictions limiting easy access to opioids. We describe the case of a 28-year-old male who was admitted to hospital on multiple occasions with symptoms relating to loperamide use disorder. Buprenorphine was used to manage withdrawal symptoms in the hospital and maintain abstinence from loperamide in the community through an opioid agonist treatment program. To our knowledge, this is the first case study to describe the successful management of loperamide use disorder with buprenorphine within Australia. Our findings suggest that buprenorphine can be used to manage patients with loperamide associated withdrawal and help them remain abstinent upon discharge. Extramedical use of over-the-counter opioid medication may be becoming an emerging trend in Australia, and increased monitoring is warranted to prevent detrimental health outcomes.

Wide-field intensity fluctuation imaging.

The temporal intensity fluctuations contain important information about the light source and light-medium interaction and are typically characterized by the intensity autocorrelation function, g2(τ). The measurement of g2(τ) is a central topic in many optical sensing applications, ranging from stellar intensity interferometer in astrophysics, to fluorescence correlation spectroscopy in biomedical sciences and blood flow measurement with dynamic light scattering. Currently, g2(τ) at a single point is readily accessible through high-frequency sampling of the intensity signal. However, two-dimensional wide-field imaging of g2(τ) is still limited by the cameras' frame rate. We propose and demonstrate a 2-pulse within-exposure modulation approach to break through the camera frame rate limit and obtain the quasi g2(τ) map in wide field with cameras of only ordinary frame rates.

A Deep Learning Approach for Improving Two-Photon Vascular Imaging Speeds.

A potential method for tracking neurovascular disease progression over time in preclinical models is multiphoton fluorescence microscopy (MPM), which can image cerebral vasculature with capillary-level resolution. However, obtaining high-quality, three-dimensional images with traditional point scanning MPM is time-consuming and limits sample sizes for chronic studies. Here, we present a convolutional neural network-based (PSSR Res-U-Net architecture) algorithm for fast upscaling of low-resolution or sparsely sampled images and combine it with a segmentation-less vectorization process for 3D reconstruction and statistical analysis of vascular network structure. In doing so, we also demonstrate that the use of semi-synthetic training data can replace the expensive and arduous process of acquiring low- and high-resolution training pairs without compromising vectorization outcomes, and thus open the possibility of utilizing such approaches for other MPM tasks where collecting training data is challenging. We applied our approach to images with large fields of view from a mouse model and show that our method generalizes across imaging depths, disease states and other differences in neurovasculature. Our pretrained models and lightweight architecture can be used to reduce MPM imaging time by up to fourfold without any changes in underlying hardware, thereby enabling deployability across a range of settings.

Cortical perfusion measurements with laser speckle contrast imaging during adenosine induced cardiac arrest for aneurysm clipping: a case report.

Adenosine induced cardiac arrest (AiCA) is one of the methods used to facilitate microsurgical aneurysm clipping by providing more visibility and less pressure in the aneurysmal sac and neighboring vessels. We report the use of laser speckle contrast imaging (LSCI) during AiCA to monitor the changes in pulsation and perfusion on the cortical surface during adenosine induced cardiac arrest for aneurysm clipping surgery. Application of this technology for perfusion monitoring may improve workflow and surgical guidance and provide valuable feedback continuously throughout the procedure. ClinicalTrials.gov identifier: NCT0502840.

Non-Degenerate Two-Photon Imaging of Deep Rodent Cortex using Indocyanine Green in the water absorption window.

We present a novel approach for deep vascular imaging in rodent cortex at excitation wavelengths susceptible to water absorption using two-photon microscopy with photons of dissimilar wavelengths. We demonstrate that non-degenerate two-photon excitation (ND-2PE) enables imaging in the water absorption window from 1400-1550 nm using two synchronized excitation sources at 1300 nm and 1600 nm that straddle the absorption window. We explore the brightness spectra of indocyanine green (ICG) and assess its suitability for imaging in the water absorption window. Further, we demonstrate in vivo imaging of the rodent cortex vascular structure up to 1.2 mm using ND-2PE. Lastly, a comparative analysis of ND-2PE at 1435 nm and single-wavelength, two-photon imaging at 1300 nm and 1435 nm is presented. Our work extends the excitation range for fluorescent dyes to include water absorption regimes and underscores the feasibility of deep two-photon imaging at these wavelengths.

Fixed-Dose Phenobarbital Versus As-Needed Benzodiazepines for the Management of Alcohol Withdrawal in Acute Care General Internal Medicine.

OBJECTIVES: The management of patients at risk of severe alcohol withdrawal is challenging because conventional treatment with as-needed benzodiazepines may be ineffective. We created a fixed-dose phenobarbital protocol and compared patient outcomes using this protocol with an as-needed benzodiazepine protocol. METHODS: Patients admitted from the emergency department (ED) to General Medicine from January 1 to June 30, 2022 and treated for alcohol withdrawal with a novel phenobarbital protocol were compared with all of the patients admitted from the ED to General Medicine from January 1 to June 30, 2018, and treated with as-needed benzodiazepines. The primary outcome was a composite of intensive care unit (ICU) transfer or mortality. Secondary outcomes included mortality, ICU transfer, seizure, length of stay, excess sedation, delirium, against medical advice discharge, 30-day re-admission, 30-day ED reevaluation, and antipsychotic use. RESULTS: There were 54 patients in the phenobarbital group and 197 in the benzodiazepine group. The phenobarbital group was less medically complex but had more risk factors for severe withdrawal. There was no difference in the primary outcome, although there was a trend toward benefit in the phenobarbital group (3.7 vs 8.1%, P = 0.26), and there was a lower incidence of delirium in the phenobarbital cohort (0 vs 8.6%, P = 0.03). Secondary outcome trends favored phenobarbital, with lower mortality, ICU transfer, seizure, oversedation, against medical advice discharge, and 30-day re-admissions. A subgroup analysis accounting for differences in patient populations in the primary analysis found similar results. CONCLUSIONS: Phenobarbital is as safe and effective as benzodiazepine-based protocols for the treatment of high-risk alcohol withdrawal, with lower rates of delirium.

Continuous hemodynamics monitoring during arteriovenous malformation microsurgical resection with laser speckle contrast imaging: case report.

AVM surgery is challenging due to progressive and often unforeseeable flow changes during its resection which involve both the AVM and the surrounding brain tissue. Hence, accurate monitoring of blood flow is crucial to minimize complications and improve outcomes. The following case report illustrates the usefulness of complimentary non-invasive tools that can provide real time blood flow assessment. We present a case demonstrating the application of laser speckle contrast imaging (LSCI) in evaluating vessel flow dynamics during AVM surgery. A 30-year-old female presented with sudden headaches, nausea, vomiting, and vertigo. Emergency imaging revealed a ruptured cerebellar AVM necessitating surgical intervention. LSCI was integrated into the surgical workflow, providing continuous visualization of relative cerebral blood flow (rCBF) of vessels surrounding the AVM. Before AVM resection, LSCI measurements revealed the arterialized vasculature supplying the AVM nidus; measurements after AVM resection showed significant hemodynamic changes including normal flow in the initially arterialized AVM draining veins and adjacent arterial branches. LSCI also detected blood flow alterations during temporary occlusion, enabling assessment of downstream vascular regions. In conclusion, we provide an example supporting the utility of LSCI for real-time hemodynamic monitoring during AVM resection surgery. LSCI offers non-invasive, continuous, and immediate blood flow information, complementing conventional imaging methods like indocyanine green angiography. Additionally, our findings suggest that LSCI has the potential to provide a non-invasive means of identifying the specific superficial vessel branches or cortical areas that receive blood supply from a particular vessel.

Perioperative management of antithrombotic therapy: an American college of chest physicians clinical practice guideline

The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug. Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines. A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures. Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management