The synergy between alkylating agents and ERCC1-XPF inhibitors is p53 dependent.

Background: DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA-targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting.

Development and Implementation of a Multicenter Registry for Resuscitation-Focused Transesophageal Echocardiography.

Study Objective: To evaluate the clinical effect, safety, and clinical outcomes of focused transesophageal echocardiography (TEE) in the evaluation of critically ill patients in the emergency department (ED) and ICUs.

Methods: We established a prospective, multicenter, observational registry involving adult critically ill patients in whom focused TEE was performed for evaluation of out-of-hospital cardiac arrest (OHCA), inhospital cardiac arrest, evaluation of undifferentiated shock, hemodynamic monitoring, and/or procedural guidance in the ED, ICU, or operating room setting. The primary objective of the current investigation was to evaluate the clinical influence and safety of focused, point-of-care TEE in critically ill patients.

Maternal supplementation of egg yolk modulates brain functional organization and functional outcomes of offspring.

Maternal nutrition during the perinatal stage is critical to offspring brain development. Egg yolks are a balanced and nutrient-dense food that is rich in bioactive components crucial to optimal neurodevelopment early in life. Egg consumption is often recommended to pregnant women to enhance both maternal and fetal health.

Recommendations for Cardiac Point-of-Care Ultrasound Nomenclature.

Point-of-care ultrasound (POCUS) involves the acquisition, interpretation, and immediate clinical integration of ultrasonographic imaging performed by a treating clinician. The current state of cardiac POCUS terminology is heterogeneous and ambiguous, in part because it evolved through siloed specialty practices. In particular, the medical literature and colloquial medical conversation contain a wide variety of terms that equate to cardiac POCUS.

Human-Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Limits Tissue Damage and Promotes Tissue Regeneration and Functional Recovery in a Pediatric Piglet Traumatic-Brain-Injury Model.

Traumatic brain injury (TBI) is a leading cause of death and disability in pediatric patients and often results in delayed neural development and altered connectivity, leading to lifelong learning, memory, behavior, and motor function deficits. Induced pluripotent stem cell-derived neural stem cells (iNSCs) may serve as a novel multimodal therapeutic as iNSCs possess neuroprotective, regenerative, and cell-replacement capabilities post-TBI. In this study, we evaluated the effects of iNSC treatment on cellular, tissue, and functional recovery in a translational controlled cortical impact TBI piglet model.

PEERLESS II: A Randomized Controlled Trial of Large-Bore Thrombectomy Versus Anticoagulation in Intermediate-Risk Pulmonary Embolism.

Background: Anticoagulation (AC) is the guideline-recommended treatment for intermediate-risk pulmonary embolism (PE); however, it remains unclear whether mechanical thrombectomy provides benefit over AC alone. The PEERLESS II study aims to evaluate outcomes in intermediate-risk PE patients randomized to treatment with large-bore mechanical thrombectomy and AC vs AC alone.

Methods: PEERLESS II is an international randomized controlled trial enrolling up to 1200 patients with intermediate-risk PE and additional clinical risk factors from up to 100 sites.

Evaluation of Brain Function Recovery After Traumatic Brain Injury Treatment in a Porcine Model by Cross-Group Temporal-Spatial Correlation Analysis.

Traumatic brain injury (TBI), a significant global health issue, is affecting ∼69 million annually. To better understand TBI's impact on brain function and assess the efficacy of treatments, this study uses a novel temporal-spatial cross-group approach with a porcine model, integrating resting-state functional magnetic resonance imaging (rs-fMRI) for temporal and arterial spin labeling for spatial information. Our research used 18 four-week-old pigs divided into three groups: TBI treated with saline (SLN, = 6), TBI treated with fecal microbial transplant (FMT, = 6), and a sham group (sham, = 6) with only craniectomy surgery as the baseline.

Utilization of qPCR to Determine Duration and Environmental Drivers Contributing to the Persistence of Human DNA in Soil.

Little is known about the underlying mechanisms that contribute to the persistence and degradation of DNA within soil. The goals of this study are to determine the duration of mitochondrial DNA (mtDNA) and nuclear DNA (nuDNA) persistence in soils enriched by surface-level human decomposition and to better understand the contribution of environmental factors. The surface-level decomposition of three human cadavers was documented over 11 weeks.

The Pan-Canadian Chemical Library: A Mechanism to Open Academic Chemistry to High-Throughput Virtual Screening.

Computationally screening chemical libraries to discover molecules with desired properties is a common technique used in early-stage drug discovery. Recent progress in the field now enables the efficient exploration of billions of molecules within days or hours, but this exploration remains confined within the boundaries of the accessible chemistry space. While the number of commercially available compounds grows rapidly, it remains a limited subset of all druglike small molecules that could be synthesized.

Structure-Based Discovery of Allosteric Inhibitors Targeting a New Druggable Site in the Respiratory Syncytial Virus Polymerase.

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infections for which effective treatment options remain limited. Herein, we employed a computational structure-based design strategy aimed at identifying potential targets for a new class of allosteric inhibitors. Our investigation led to the discovery of a previously undisclosed allosteric binding site within the RSV polymerase, the large (L) protein.

Clinical, Functional, and Quality-of-Life Outcomes after Computer Assisted Vacuum Thrombectomy for Pulmonary Embolism: Interim Analysis of the STRIKE-PE Study.

Purpose: To report the first interim analysis of the STRIKE-PE study, evaluating the safety and effectiveness of computer assisted vaccum thrombectomy (CAVT) for the treatment of acute pulmonary embolism (PE).

Materials And Methods: This prospective, international, multicenter study will enroll 600 adult patients with acute PE of ≤14 days and a right ventricle (RV)-to-left ventricle (LV) ratio of ≥0.9 who receive first-line endovascular treatment with CAVT using the Indigo Aspiration System (Penumbra, Alameda, California).

Best Practices for Point of Care Ultrasound: An Interdisciplinary Expert Consensus.

Despite the growing use of point of care ultrasound (POCUS) in contemporary medical practice and the existence of clinical guidelines addressing its specific applications, there remains a lack of standardization and agreement on optimal practices for several areas of POCUS use. The Society of Point of Care Ultrasound (SPOCUS) formed a working group in 2022 to establish a set of recommended best practices for POCUS, applicable to clinicians regardless of their training, specialty, resource setting, or scope of practice. Using a three-round modified Delphi process, a multi-disciplinary panel of 22 POCUS experts based in the United States reached consensus on 57 statements in domains including: (1) The definition and clinical role of POCUS; (2) Training pathways; (3) Credentialing; (4) Cleaning and maintenance of POCUS devices; (5) Consent and education; (6) Security, storage, and sharing of POCUS studies; (7) Uploading, archiving, and reviewing POCUS studies; and (8) Documenting POCUS studies.

Affinity of structural white matter tracts between infant and adult pig.

Background: The piglet brain has been increasingly used as an excellent surrogate for investigation of pediatric neurodevelopment, nutrition, and traumatic brain injuries. This study intends to establish a piglet brain's structural connectivity model and compare it with the adult pig, enhancing its application for structurally guided functional analysis.

Methods: In this study, diffusion-weighted (DW)-MRI data from piglets (n=11, 3-week-old) was used to establish piglet model and compare with adult pigs.

White Matter Integrity and Motor Function Disruption Due to Traumatic Brain Injury in Piglets: Impacts on Motor-Related Brain Fibers.

Pediatric traumatic brain injury (TBI) often induces significant disability in patients, including long-term motor deficits. Early detection of injury severity is key in determining a prognosis and creating appropriate intervention and rehabilitation plans. However, conventional magnetic resonance imaging (MRI) scans, such as T2 Weighted (T2W) sequences, do not reliably assess the extent of microstructural white matter injury.

A case of transfusion-transmission Anaplasma phagocytophilum from leukoreduced red blood cells.

Background: Anaplasma phagocytophilum is a tick-borne bacterium and the cause of human granulocytic anaplasmosis (HGA). Here, we report a case of transfusion-transmitted (TT)-HGA involving a leukoreduced (LR) red blood cell (RBC) unit.

Case Report: A 64-year-old woman with gastric adenocarcinoma and multiple myeloma who received weekly blood transfusions developed persistent fevers, hypotension, and shortness of breath 1 week after receiving an RBC transfusion.

Sparse multiway canonical correlation analysis for multimodal stroke recovery data.

Conventional canonical correlation analysis (CCA) measures the association between two datasets and identifies relevant contributors. However, it encounters issues with execution and interpretation when the sample size is smaller than the number of variables or there are more than two datasets. Our motivating example is a stroke-related clinical study on pigs.

Probing amino acid side chains of the integral membrane protein PagP by solution NMR: Side chain immobilization facilitates association of secondary structures.

Solution NMR spectroscopy of large protein systems is hampered by rapid signal decay, so most multidimensional studies focus on long-lived H-C magnetization in methyl groups and/or backbone amide H-N magnetization in an otherwise perdeuterated environment. Herein we demonstrate that it is possible to biosynthetically incorporate additional H-C groups that possess long-lived magnetization using cost-effective partially deuterated or unlabeled amino acid precursors added to Escherichia coli growth media. This approach is applied to the outer membrane enzyme PagP in membrane-mimetic dodecylphosphocholine micelles.

Can Untrained Patients Perform Their Own Skin and Soft Tissue Ultrasound Examination by Teleguidance?

This pilot study aims to determine if patients untrained in performing ultrasound can self-scan to obtain images under remote clinician teleguidance during a simulated telehealth encounter. This study also seeks to describe the patients' comfort level and barriers to performing an ultrasound examination on themselves using a handheld ultrasound device. This was a single center prospective observational cohort study conducted over a 4-month period in 2021.

Resuscitative transesophageal echocardiography in emergency departments in the United States and Canada: A cross-sectional survey.

Introduction: Over the past two decades, transesophageal echocardiography (TEE) has been used with increasing frequency to evaluate critically ill patients outside of traditional settings. The purpose of this study was to characterize the number of programs, users, practice characteristics, training and competency requirements and barriers for the current use of resuscitative transesophageal echocardiography (TEE) in Emergency Departments (EDs) in the United States and Canada.

Methods: A closed internet-based, cross-sectional, point-prevalence survey was administered via email to 120 program directors of emergency ultrasound fellowships (EUSF) and 43 physicians from EDs without EUSF from the United States and Canada.

Proof of concept: Pull down assay using bovine serum albumin and an immunomodulator small molecule.

In the past decade, there has been increasing interest in use of small molecules for immunomodulation. The affinity-based pull-down purification is an essential tool for target identification of small molecules and drug discovery. This study presents our recent efforts to investigate the cellular target(s) of Compound A, a small molecule with demonstrated immunomodulatory properties in human peripheral blood mononuclear cells (PBMCs).

Induced pluripotent stem cells derived from patients carrying mitochondrial mutations exhibit altered bioenergetics and aberrant differentiation potential.

Background: Human mitochondrial DNA mutations are associated with common to rare mitochondrial disorders, which are multisystemic with complex clinical pathologies. The pathologies of these diseases are poorly understood and have no FDA-approved treatments leading to symptom management. Leigh syndrome (LS) is a pediatric mitochondrial disorder that affects the central nervous system during early development and causes death in infancy.

Fecal microbial transplantation limits neural injury severity and functional deficits in a pediatric piglet traumatic brain injury model.

Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Due to bidirectional communication between the brain and gut microbial population, introduction of key gut bacteria may mitigate critical TBI-induced secondary injury cascades, thus lessening neural damage and improving functional outcomes. The objective of this study was to determine the efficacy of a daily fecal microbial transplant (FMT) to alleviate neural injury severity, prevent gut dysbiosis, and improve functional recovery post TBI in a translational pediatric piglet model.

Stereoselective Intramolecular [2+2] Trapping of 1,2-Cyclohexadienes: a Route to Rigid, Angularly Fused Tricyclic Scaffolds.

1,2-Cyclohexadienes generated under mild fluoride-mediated desilylative conditions undergo efficient intramolecular [2+2] trapping, providing tricyclic alkylidene cyclobutanes with complete diastereoselectivity for the cis-fused products. Pendent styrenes or electron-deficient olefins can trap simple 1,2-cyclohexadienes or their oxygenated counterparts, with 14 substrates being disclosed. Reactions proceed at ambient temperature using just cesium fluoride in up to 91 % yield, and the necessary precursors are easily accessed from substituted 2-bromocyclohexenones.

Cost-effective selective deuteration of aromatic amino acid residues produces long-lived solution H NMR magnetization in proteins.

Solution NMR studies of large proteins are hampered by rapid signal decay due to short-range dipolar H-H and H-C interactions. These are attenuated by rapid rotation in methyl groups and by deuteration (H), so selective H,C-isotope labelling of methyl groups in otherwise perdeuterated proteins, combined with methyl transverse relaxation optimized spectroscopy (methyl-TROSY), is now standard for solution NMR of large protein systems > 25 kDa. For non-methyl positions, long-lived magnetization can be introduced as isolated H-C groups.