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.

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.

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.

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.

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.

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.

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.

Sedation with dexmedetomidine decreases skin perfusion in cats.

OBJECTIVE: To evaluate skin perfusion in cats receiving dexmedetomidine compared to a placebo. ANIMALS: 9 healthy adult research cats. METHODS: A randomized, blinded, placebo-controlled study design was used. Two sites, the dorsal metatarsus (site: limb) and lateral flank (site: flank), were evaluated with laser speckle contrast imaging (LSCI) at baseline and following administration of dexmedetomidine (1, 3, or 5 mcg/kg, IV) or a placebo (0.9% saline, IV). Mean speckle contrast (MSC), a surrogate for perfusion, was obtained from LSCI and compared between treatments. Heart rate, sedation score, and body temperature were recorded. Skin perfusion to the flank and limb, reported as MSC, was assessed via LSCI at baseline and at 5, 10, and 15 minutes posttreatment. RESULTS: There was a significant decrease in heart rate (P < .001) in cats receiving 1, 3, and 5 mcg/kg dexmedetomidine compared to placebo. There was a significant increase in median sedation score at all time points postsedation compared to baseline (P < .018). Changes in MSC for the metatarsus were not significantly different between treatments at any time point (P = .12). For the flank, MSC was significantly higher for cats treated with dexmedetomidine compared to baseline (P ≤ .01). Skin perfusion to the flank decreased as early as 5 minutes posttreatment with dexmedetomidine and persisted for at least 15 minutes, regardless of dexmedetomidine dose. CLINICAL RELEVANCE: Dexmedetomidine decreased skin perfusion in cats, even at low doses. Veterinarians may elect for an alternative sedative medication when decreased skin perfusion is a concern.

Pulse train gating to improve signal generation for in vivo two-photon fluorescence microscopy.

Significance: Two-photon microscopy is used routinely for in vivo imaging of neural and vascular structures and functions in rodents with a high resolution. Image quality, however, often degrades in deeper portions of the cerebral cortex. Strategies to improve deep imaging are therefore needed. We introduce such a strategy using the gating of high repetition rate ultrafast pulse trains to increase the signal level. Aim: We investigate how the signal generation, signal-to-noise ratio (SNR), and signal-to-background ratio (SBR) improve with pulse gating while imaging in vivo mouse cerebral vasculature. Approach: An electro-optic modulator with a high-power (6 W) 80 MHz repetition rate ytterbium fiber amplifier is used to create gates of pulses at a 1 MHz repetition rate. We first measure signal generation from a Texas Red solution in a cuvette to characterize the system with no gating and at a 50%, 25%, and 12.5% duty cycle. We then compare the signal generation, SNR, and SBR when imaging Texas Red-labeled vasculature using these conditions. Results: We find up to a 6.73-fold increase in fluorescent signal from a cuvette when using a 12.5% duty cycle pulse gating excitation pattern as opposed to a constant 80 MHz pulse train at the same average power. We verify similar increases for in vivo imaging to that observed in cuvette testing. For deep imaging, we find that pulse gating results in a 2.95-fold increase in the SNR and a 1.37-fold increase in the SBR on average when imaging mouse cortical vasculature at depths ranging from 950 to 1050 µm. Conclusions: We demonstrate that a pulse gating strategy can either be used to limit heating when imaging superficial brain regions or used to increase signal generation in deep regions. These findings should encourage others to adopt similar pulse gating excitation schemes for imaging neural structures through two-photon microscopy.

Intraoperative Laser Speckle Contrast Imaging to Assess Vessel Flow in Neurosurgery: A Pilot Study.

BACKGROUND AND OBJECTIVES: Laser speckle contrast imaging (LSCI) has emerged as a promising tool for assessment of vessel flow during neurosurgery. We aimed to investigate the feasibility of visualizing vessel flow in the macrocirculation with a new fully microscope-integrated LSCI system and assess the validity and objectivity of findings compared with fluorescence angiography (FA). METHODS: This is a single-center prospective observational study enrolling adult patients requiring microsurgical treatment for brain vascular pathologies or brain tumors. Three independent raters, blinded toward findings of FA, reviewed regions of interest (ROIs) placed in exposed vessels and target structures. The primary end point was the validity of LSCI for assessment of vessel flow as measured by the agreement with FA. The secondary end point was objectivity, measured as the inter-rater agreement of LSCI findings. RESULTS: During 18 surgical procedures, 23 observations using FA and LSCI were captured simultaneously. Using LSCI, vessel flow was assessable in 62 (86.1%) and not assessable in 10 (13.9%) ROIs. The agreement between LSCI and FA was 86.1%, with an agreement coefficient of 0.85 (95% CI: 0.75-0.94). Disagreement between LSCI and FA was observed in the 10 ROIs that were not assessable. The agreement between ROIs that were assessable using LSCI and FA was 100%. The inter-rater agreement of LSCI findings was 87.9%, with an agreement coefficient of 0.86 (95% CI: 0.79-0.94). CONCLUSION: Fully microscope-integrated LSCI is feasible and has a high potential for clinical utility. Because of its characteristics, LSCI can be viewed as a full-field visual micro-Doppler that can be used as a complementary method to FA for assessing vessel flow during neurosurgery. Despite technical limitations related to the early development phase of the fully microscope-integrated system, we demonstrated reasonable validity and objectivity of findings compared with FA. Further research and refinement of the system may enhance its value in neurosurgical applications.

Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke.

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.

Outpatient Treatment of Confirmed COVID-19: Living, Rapid Practice Points From the American College of Physicians (Version 2).

DESCRIPTION: Evidence for the use of outpatient treatments in adults with confirmed COVID-19 continues to evolve with new data. This is version 2 of the American College of Physicians (ACP) living, rapid practice points focusing on 22 outpatient treatments for COVID-19, specifically addressing the dominant SARS-CoV-2 Omicron variant. METHODS: The Population Health and Medical Science Committee (formerly the Scientific Medical Policy Committee) developed this version of the living, rapid practice points on the basis of a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems). This topic will be maintained as living and rapid by continually monitoring and assessing the impact of new evidence. PRACTICE POINT 1: Consider molnupiravir to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. PRACTICE POINT 2: Consider nirmatrelvir-ritonavir combination therapy to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. PRACTICE POINT 3: Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 4: Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.

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 measurement of g2(τ) is still limited by camera frame rates. 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.

Eccrine Porocarcinoma of the Vulva With Sarcomatoid Transformation, a New Human Papillomavirus-associated Malignancy? Case Report and Review of the Literature.

Eccrine porocarcinoma is a rare cutaneous neoplasm, and rarer still in the anogenital region. In the vulva, the most common carcinoma by far is squamous cell carcinoma; however, eccrine porocarcinoma can arise at this site. As the distinction between porocarcinoma and squamous cell carcinoma has important prognostic implications at other cutaneous sites, it stands to reason that it may have these same implications in the vulva. We present a case of an eccrine porocarcinoma in the vulva of a 70-year-old woman that, in addition, showed sarcomatoid transformation. This tumor harbored human papillomavirus-18 DNA and mRNA, raising the question of the role of the oncogenic virus in sweat gland neoplasms of the vulva.

Qualitative Assessment of Implementation of a Discharge Prediction Tool Using RE-AIM Framework.

The implementation process in the routine clinical care of a new predictive tool based on machine learning algorithms has been investigated using the RE-AIM framework. Semi-structured qualitative interviews have been conducted with a broad range of clinicians to elucidate potential barriers and facilitators of the implementation process across five major domains: Reach, Efficacy, Adoption, Implementation, and Maintenance. The analysis of 23 clinician interviews demonstrated a limited reach and adoption of the new tool and identified areas for improvement in implementation and maintenance. Future implementation efforts of machine learning tools should support the proactive engagement of a wide range of clinical users since the very initiation of the predictive analytics project, provide higher transparency of the underlying algorithms, employ broader onboarding of all potential users on a periodic basis, and collect feedback from clinicians on an ongoing basis.

Analysing Monday discharges to identify lost opportunities for weekend discharge.

Lower rates of hospital discharge occur on weekends compared with weekdays. The authors performed a retrospective chart review of Monday discharges from the Hospital Medicine service at an academic hospital over a 3-month period to identify reasons for delayed discharge despite medical stability. Of 202 eligible patients, 81 (40%) had documentation indicating stability for earlier discharge. Common causes included bed availability or insurance authorisation at a skilled nursing facility, home care services and patient/family disagreement with discharge.

Pulse train gating to improve signal generation for in vivo two-photon fluorescence microscopy.

Significance: Two-photon microscopy is used routinely for in vivo imaging of neural and vascular structure and function in rodents with a high resolution. Image quality, however, often degrades in deeper portions of the cerebral cortex. Strategies to improve deep imaging are therefore needed. We introduce such a strategy using gates of high repetition rate ultrafast pulse trains to increase signal level. Aim: We investigate how signal generation, signal-to-noise ratio (SNR), and signal-to-background ratio (SBR) improve with pulse gating while imaging in vivo mouse cerebral vasculature. Approach: An electro-optic modulator is used with a high-power (6 W) 80 MHz repetition rate ytterbium fiber amplifier to create gates of pulses at a 1 MHz repetition rate. We first measure signal generation from a Texas Red solution in a cuvette to characterize the system with no gating and at a 50%, 25%, and 12.5% duty cycle. We then compare signal generation, SNR, and SBR when imaging Texas Red-labeled vasculature using these conditions. Results: We find up to a 6.73-fold increase in fluorescent signal from a cuvette when using a 12.5% duty cycle pulse gating excitation pattern as opposed to a constant 80 MHz pulse train. We verify similar increases for in vivo imaging to that observed in cuvette testing. For deep imaging we find pulse gating to result in a 2.95-fold increase in SNR and a 1.37-fold increase in SBR on average when imaging mouse cortical vasculature at depths ranging from 950 µm to 1050 µm. Conclusions: We demonstrate that a pulse gating strategy can either be used to limit heating when imaging superficial brain regions or used to increase signal generation in deep regions. These findings should encourage others to adopt similar pulse gating excitation schemes for imaging neural structure through two-photon microscopy.