Delayed Pressure Urticaria Associated With Altitude Chamber Training Responsive to Cyclosporine and Omalizumab.

Delayed pressure urticaria (DPU) is a subset of chronic inducible urticaria. It is characterized by the formation of wheals anytime between 30 minutes and 24 hours after stimulus exposure of localized pressure application. In this case report, we discuss a military flight crew member with no significant past medical history who developed DPU following rapid decompression in an altitude chamber. The chamber training included an uneventful ascent to 45,000 feet, higher than he had been previously, and a rapid decompression. About 16 hours later, he developed pruritic swelling of his hands and feet, along with diffuse deep nodular swelling, erythematous plaques, and erythematous nodules. His DPU was refractory to monotherapy treatment with antihistamines, and he continued to develop lesions in weight-bearing areas. Control of symptoms was achieved through combination treatment of a second-generation antihistamine, a leukotriene receptor antagonist, and an immunosuppressant (cyclosporine). His waiver to return to flight status was denied while on cyclosporine. He was transitioned to a monoclonal antibody that binds free immunoglobin E (omalizumab) with resolution of symptoms and was cleared to return to active duty.

Dispersal history of SARS-CoV-2 in Galicia, Spain.

The dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission are influenced by a variety of factors, including social restrictions and the emergence of distinct variants. In this study, we delve into the origins and dissemination of the Alpha, Delta, and Omicron-BA.1 variants of concern in Galicia, northwest Spain. For this, we leveraged genomic data collected by the EPICOVIGAL Consortium and from the GISAID database, along with mobility information from other Spanish regions and foreign countries. Our analysis indicates that initial introductions during the Alpha phase were predominantly from other Spanish regions and France. However, as the pandemic progressed, introductions from Portugal and the United States became increasingly significant. The number of detected introductions varied from 96 and 101 for Alpha and Delta to 39 for Omicron-BA.1. Most of these introductions left a low number of descendants (<10), suggesting a limited impact on the evolution of the pandemic in Galicia. Notably, Galicia's major coastal cities emerged as critical hubs for viral transmission, highlighting their role in sustaining and spreading the virus. This research emphasizes the critical role of regional connectivity in the spread of SARS-CoV-2 and offers essential insights for enhancing public health strategies and surveillance measures.

Nanoparticle delivery of Tat synergizes with classical latency reversal agents to express HIV antigen targets.

Limited cellular levels of the HIV transcriptional activator Tat are one contributor to proviral latency that might be targeted in HIV cure strategies. We recently demonstrated that lipid nanoparticles containing HIV tat mRNA induce HIV expression in primary CD4 T cells. Here, we sought to further characterize tat mRNA in the context of several benchmark latency reversal agents (LRAs), including inhibitor of apoptosis protein antagonists (IAPi), bromodomain and extra-Terminal motif inhibitors (BETi), and histone deacetylase inhibitors (HDACi). tat mRNA reversed latency across several different cell line models of HIV latency, an effect dependent on the TAR hairpin loop. Synergistic enhancement of tat mRNA activity was observed with IAPi, HDACi, and BETi, albeit to variable degrees. In primary CD4 T cells from durably suppressed people with HIV, tat mRNA profoundly increased the frequencies of elongated, multiply-spliced, and polyadenylated HIV transcripts, while having a lesser impact on TAR transcript frequencies. tat mRNAs alone resulted in variable HIV p24 protein induction across donors. However, tat mRNA in combination with IAPi, BETi, or HDACi markedly enhanced HIV RNA and protein expression without overt cytotoxicity or cellular activation. Notably, combination regimens approached or in some cases exceeded the latency reversal activity of maximal mitogenic T cell stimulation. Higher levels of tat mRNA-driven HIV p24 induction were observed in donors with larger mitogen-inducible HIV reservoirs, and expression increased with prolonged exposure time. Combination LRA strategies employing both small molecule inhibitors and Tat delivered to CD4 T cells are a promising approach to effectively target the HIV reservoir.

PD-L1 Immunohistochemistry in Gastric Cancer: Comparison of Combined Positive Score and Tumor Area Positivity Across 28-8, 22C3, and SP263 Assays.

PURPOSE: The clinical application of PD-L1 immunohistochemistry (IHC) testing is complicated by the availability of multiple IHC assays, scoring algorithms, and cutoffs. This study assessed the analytical comparability of three commercially available PD-L1 assays and two scoring algorithms used to assess PD-L1 status in gastric cancer (GC) samples. METHODS: Serial sections of 100 resected GC samples, with PD-L1 expression levels across the dynamic range, were stained with three in vitro diagnostic-grade PD-L1 assays (28-8, 22C3, and SP263). Three trained pathologists blindly and independently scored slides using combined positive score (CPS) and tumor area positivity (TAP) algorithms. Comprehensive statistical analyses were performed to evaluate analytical concordance. Digital image analysis (DIA) was used to objectively compare the technical performance of each assay by simulating CPS and TAP. RESULTS: Comparable staining patterns were observed with these three PD-L1 assays. Despite discernible variation in staining intensity, reproducible evaluations of PD-L1 positivity were observed. Inter- and intra-assay assessments of all three assays, using either CPS or TAP and the same PD-L1 cutoffs, demonstrated moderate to almost-perfect (interassay Cohen's kappa [κ] range, 0.47-0.83) and substantial to almost-perfect (intra-assay κ range, 0.77-1.00) agreement. Interpathologist assessment exhibited a significant level of concordance (intraclass correlation coefficient ≥0.92). No difference in technical performance was observed using DIA. CONCLUSION: This study highlights analytical concordance in PD-L1 testing between three major PD-L1 assays when TAP and CPS are applied. Comparability of the technical assay performance was further supported by independent DIA. These observations support cross-application flexibility of the different PD-L1 assays and scoring algorithms to characterize PD-L1 expression in GC.

Assistive tools for classifying neurological disorders using fMRI and deep learning: A guide and example.

BACKGROUND: Deep-learning (DL) methods are rapidly changing the way researchers classify neurological disorders. For example, combining functional magnetic resonance imaging (fMRI) and DL has helped researchers identify functional biomarkers of neurological disorders (e.g., brain activation and connectivity) and pilot innovative diagnostic models. However, the knowledge required to perform DL analyses is often domain-specific and is not widely taught in the brain sciences (e.g., psychology, neuroscience, and cognitive science). Conversely, neurological diagnoses and neuroimaging training (e.g., fMRI) are largely restricted to the brain and medical sciences. In turn, these disciplinary knowledge barriers and distinct specializations can act as hurdles that prevent the combination of fMRI and DL pipelines. The complexity of fMRI and DL methods also hinders their clinical adoption and generalization to real-world diagnoses. For example, most current models are not designed for clinical settings or use by nonspecialized populations such as students, clinicians, and healthcare workers. Accordingly, there is a growing area of assistive tools (e.g., software and programming packages) that aim to streamline and increase the accessibility of fMRI and DL pipelines for the diagnoses of neurological disorders. OBJECTIVES AND METHODS: In this study, we present an introductory guide to some popular DL and fMRI assistive tools. We also create an example autism spectrum disorder (ASD) classification model using assistive tools (e.g., Optuna, GIFT, and the ABIDE preprocessed repository), fMRI, and a convolutional neural network. RESULTS: In turn, we provide researchers with a guide to assistive tools and give an example of a streamlined fMRI and DL pipeline. CONCLUSIONS: We are confident that this study can help more researchers enter the field and create accessible fMRI and deep-learning diagnostic models for neurological disorders.

An examination of acute physiological and perceptual responses following blood flow restriction exercise using a traditional research device or novel, automated system.

Objective. To compare the acute physiological and perceptual responses to blood flow restriction (BFR) exercise using a traditional research device or novel, automated system.Methods. Forty-four resistance trained individuals performed four sets of unilateral elbow flexion exercise (30% one-repetition maximum) to volitional failure using two distinct restrictive devices [SmartCuffs PRO BFR Model (SMARTCUFF), Hokanson E20 Rapid Inflation device (HOKANSON)] and with two levels of BFR [40% limb occlusion pressure (LOP), 80% LOP]. Blood pressure (BP), muscle thickness (MT), and isometric strength (ISO) were assessed prior to and following exercise. Perceptual responses [ratings of perceived exertion (RPE), discomfort] were assessed prior to exercise and following each exercise set.Main results. Data are displayed as means (SD). Immediately following exercise with 40% LOP, there were no statistical differences between devices for BP, MT, and ISO. However, only following Set 1 of exercise, RPE was greater with SMARTCUFF compared to HOKANSON (p< 0.05). In addition, only following Set 2 of exercise, discomfort was greater with HOKANSON compared to SMARTCUFF (p< 0.001). Immediately following exercise with 80% LOP, there were no statistical differences between devices for BP, MT, and ISO. However, only following Set 4 of exercise, RPE was greater with HOKANSON compared to SMARTCUFF (p< 0.05). In addition, following all exercise sets, discomfort was greater with HOKANSON compared to SMARTCUFF (p< 0.001). For repetitions completed with 40% LOP there were no statistical differences between SMARTCUFF and HOKANSON across any exercise sets. For repetitions completed with 80% LOP there were no statistical differences between SMARTCUFF and HOKANSON across Set 1 of exercise (p= 0.34), however, for Sets 2-4 of exercise, significantly greater number of repetitions were completed during SMARTCUFF than HOKANSON.Significance. The present study provides valuable insight into the efficacy of a novel, automated BFR system (SMARTCUFF) eliciting comparable acute physiological responses to BFR exercise and in some cases favorable perceptual responses when compared to a traditional research device (HOKANSON).

spread.gl: visualising pathogen dispersal in a high-performance browser application.

Phylogeographic analyses are able to exploit the location data associated with sampled molecular sequences to reconstruct the spatio-temporal dispersal history of a pathogen. Visualisation software is commonly used to facilitate the interpretation of the accompanying estimation results, as these are not always easily interpretable. spread.gl is a powerful, open-source and feature-rich browser application that enables smooth, intuitive and user-friendly visualisation of both discrete and continuous phylogeographic inference results, enabling the animation of pathogen geographic dispersal through time. spread.gl can render and combine the visualisation of several data layers, including a geographic layer (e.g., a world map), multiple layers that contain information extracted from the input phylogeny, and different types of layers that represent environmental data. As such, users can explore which environmental data may have shaped pathogen dispersal patterns, that can subsequently be formally tested through more principled statistical analyses. We showcase the visualisation features of spread.gl on several representative pathogen dispersal examples, including the smooth animation of a phylogeny encompassing over 17,000 genomic sequences resulting from a large-scale SARS-CoV-2 analysis.

Protocol to study CCT-mediated folding of Gß5 by single-particle cryo-EM.

The chaperonin CCT mediates folding of many cytosolic proteins, including G protein ß subunits (Gßs). Here, we present a protocol for isolating Gß5 bound to CCT and its co-chaperone PhLP1 and determining the CCT-mediated folding trajectory of Gß5 using single-particle cryoelectron microscopy (cryo-EM) techniques. We describe steps for purifying CCT-Gß5-PhLP1 from human cells, stabilizing the closed CCT conformation, preparing and imaging cryo-EM specimens, and processing data to recover multiple Gß5 folding intermediates. This protocol permits visualization of protein folding by CCT. For complete details on the use and execution of this protocol, please refer to Sass et al.1.

Efficacy of the bumped kinase inhibitor BKI-1708 against the cyst-forming apicomplexan parasites Toxoplasma gondii and Neospora caninum in vitro and in experimentally infected mice.

Toxoplasma gondii and Neospora caninum are major worldwide morbidity-causing pathogens. Bumped kinase inhibitors (BKIs) are a compound class that has been optimized to target the apicomplexan calcium-dependent protein kinase 1 (CDPK1) - and several members of this class have proven to be safe and highly active in vitro and in vivo. BKI-1708 is based on a 5-aminopyrazole-4-carboxamide scaffold, and exhibited in vitro IC50 values of 120 nM for T. gondii and 480 nM for N. caninum ß-galactosidase expressing strains, and did not affect human foreskin fibroblast (HFF) viability at concentrations up to 25 µM. Electron microscopy established that exposure of tachyzoite-infected fibroblasts to 2.5 µM BKI-1708 in vitro induced the formation of multinucleated schizont-like complexes (MNCs), characterized by continued nuclear division and harboring newly formed intracellular zoites that lack the outer plasma membrane. These zoites were unable to finalize cytokinesis to form infective tachyzoites. BKI-1708 did not affect zebrafish (Danio rerio) embryo development during the first 96 h following egg hatching at concentrations up to 2 µM. Treatments of mice with BKI-1708 at 20 mg/kg/day during five consecutive days resulted in drug plasma levels ranging from 0.14 to 4.95 µM. In vivo efficacy of BKI-1708 was evaluated by oral application of 20 mg/kg/day from day 9-13 of pregnancy in mice experimentally infected with N. caninum (NcSpain-7) tachyzoites or T. gondii (TgShSp1) oocysts. This resulted in significantly decreased cerebral parasite loads and reduced vertical transmission in both models without drug-induced pregnancy interference.

Making sense of artificial intelligence and large language models-including ChatGPT-in pediatric hematology/oncology.

ChatGPT and other artificial intelligence (AI) systems have captivated the attention of healthcare providers and researchers for their potential to improve care processes and outcomes. While these technologies hold promise to automate processes, increase efficiency, and reduce cognitive burden, their use also carries risks. In this commentary, we review basic concepts of AI, outline some of the capabilities and limitations of currently available tools, discuss current and future applications in pediatric hematology/oncology, and provide an evaluation and implementation framework that can be used by pediatric hematologist/oncologists considering the use of AI in clinical practice.

Varied prevalence of antimalarial drug resistance markers in different populations of newly arrived refugees in Uganda.

Newly arrived refugees offer insights into malaria epidemiology in their countries of origin. We evaluated asymptomatic refugee children within 7 days of arrival in Uganda from South Sudan and the Democratic Republic of Congo (DRC) in 2022 for parasitemia, parasite species, and Plasmodium falciparum drug resistance markers. Asymptomatic P. falciparum infections were common in both populations. Co-infection with P. malariae was more common in DRC refugees. Prevalences of markers of aminoquinoline resistance (PfCRT K76T, PfMDR1 N86Y) were much higher in South Sudan refugees, of antifolate resistance (PfDHFR C59R and I164L, PfDHPS A437G and K540E) much higher in DRC refugees, and of artemisinin partial resistance (ART-R; PfK13 C469Y and A675V) moderate in both populations. Prevalences of most mutations differed from those seen in Ugandans attending health centers near the refugee centers. Refugee evaluations yielded insights into varied malaria epidemiology and identified markers of ART-R in two previously little-studied countries.

Association between continuous glucose monitoring metrics and clinical outcomes in adults with type 1 diabetes in a real-world setting.

AIMS: Continuous glucose monitoring (CGM) metrics can assist diabetes management. Consensus statements recommend > 70 % time in range (TIR) and ≤ 36 % glucose coefficient of variation (CV). However, how these targets perform in clinical practice is unknown. This retrospective, longitudinal cohort study analyzed relationships between TIR, CV, glycated hemoglobin (HbA1c), and hypoglycemia in a real-world setting. METHODS: Data of 542 adults with type 1 diabetes who used CGM (January 2014-July 2020) were analyzed. Associations between TIR and HbA1c at the same and subsequent visits, incidence rate ratios (IRRs) for hypoglycemia at different CVs, and number of hypoglycemic events at cross-sections of HbA1c and CV were estimated by regression. RESULTS: TIR was inversely related to HbA1c; for every 10 % increase in TIR, HbA1c was significantly reduced by 0.34 % (4 mmol/mol) and 0.20 % (2 mmol/mol) at the same and subsequent visits, respectively. Level 2 hypoglycemia was significantly reduced at CV < 30 %, 30-33 %, 33.1-36 %, and 36.1-40 %: adjusted IRRs vs CV ≥ 40.1 % of 0.14, 0.28, 0.32, and 0.50, respectively. Hypoglycemic events were reduced at lower CV across HbA1c levels and at higher HbA1c across CV levels. CONCLUSION: This study quantifies HbA1c improvements with increased TIR and hypoglycemia reductions with improved CV in clinical practice.

Tackling antimicrobial resistance in sub-Saharan Africa: challenges and opportunities for implementing the new people-centered WHO guidelines.

INTRODUCTION: Antimicrobial drugs form an essential component of medical treatment in human and animal health. Resistance associated with their use has posed a global public health threat. Multiple efforts have been made at the global level directed by the World Health Organization and associated partners to develop policies aimed at combatting antimicrobial resistance. AREAS COVERED: Whilst the Global Action Plan on antimicrobial resistance and people-centered framework aim to guide countries in implementing successful antimicrobial resistance policies, their adoption and success depend on different implementation contexts. Therefore, this paper highlights the challenges and opportunities for implementing the World Health Organization's people-centered approach in sub-Saharan Africa, whilst recognizing antimicrobial resistance as a multifaceted problem rooted in 'complex systems.' EXPERT OPINION: The people-centered approach provides a solid framework for combating antimicrobial resistance. Countries should build sustainable national action plans, adopt the One Health approach, limit over-the-counter antibiotic consumption, and educate communities on rational antibiotic use. They should also promote inter-country collaborations and innovative solutions, strengthen drug regulatory capacities, invest in infection control, water sanitation, hygiene, diagnostics, and surveillance tools, and promote vaccine uptake to prevent drug-resistant infections.

Ultraflexible electrodes for recording neural activity in the mouse spinal cord during motor behavior.

Implantable electrode arrays are powerful tools for directly interrogating neural circuitry in the brain, but implementing this technology in the spinal cord in behaving animals has been challenging due to the spinal cord's significant motion with respect to the vertebral column during behavior. Consequently, the individual and ensemble activity of spinal neurons processing motor commands remains poorly understood. Here, we demonstrate that custom ultraflexible 1-µm-thick polyimide nanoelectronic threads can conduct laminar recordings of many neuronal units within the lumbar spinal cord of unrestrained, freely moving mice. The extracellular action potentials have high signal-to-noise ratio, exhibit well-isolated feature clusters, and reveal diverse patterns of activity during locomotion. Furthermore, chronic recordings demonstrate the stable tracking of single units and their functional tuning over multiple days. This technology provides a path for elucidating how spinal circuits compute motor actions.

Fossil marine vertebrates (Chondrichthyes, Actinopterygii, Reptilia) from the Upper Cretaceous of Akkermanovka (Orenburg Oblast, Southern Urals, Russia).

Upper Cretaceous coastal marine deposits are widespread in the Southern Urals with a number of marine vertebrates previously reported from this region. However, previous studies on the vertebrate faunas in this region often lack detailed taxonomic descriptions and illustrations, rendering comparisons to other faunal assemblages difficult. A new diverse vertebrate assemblage comprising cartilaginous and bony fishes, as well as marine reptiles, is described here from the Orenburg region near Akkermanovka (Southern Urals, Russia). Thirty five taxa are identified, including three holocephalans (Elasmodus sp., Ischyodus yanschini, Chimaeroid indet.), two hybodontiform sharks (Meristodonoides sp., cf. Polyacrodus sp.), 17 neoselachians (Paraorthacodus cf. andersoni, Paraorthacodus sp., Synechodus sp., Cederstroemia nilsi, Acrolamna acuminata, Archaeolamna ex gr. kopingensis, Cretalamna sarcoportheta, Cretoxyrhina mantelli, Eostriatolamia segedini, E. venusta, Hispidaspis horridus, H. cf. gigas, Pseudocorax laevis, Pseudoscapanorhynchus compressidens, Scapanorhynchus rhaphiodon, Squalicorax kaupi, Ptychodus rugosus), a holostean (Lepisosteidae indet.), nine teleosts (Protosphyraena sp., Saurodontidae indet., cf. Pachyrhizodus sp., Pachyrhizodontidae indet., Enchodus petrosus, E. ferox, E. cf. gladiolus, E. spp., Alepisauroidei indet.), two plesiosaurs (Polycotylidae indet., Plesiosauria indet.), and one mosasaurid (Tylosaurinae indet.). Based on the faunal assemblage, a Santonian-?early Campanian age is proposed. Lamniform sharks are the best represented group in terms of taxic diversity and relative abundance, probably reflecting the peak in diversity this group experienced following the Cenomanian radiation in the Late Cretaceous. The faunal assemblage of Akkermanovka exhibits significant taxonomic overlaps with assemblages reported from Asia and North America, but not from Southern Hemisphere continents, indicating east-west dispersal of several marine taxa during the Late Cretaceous.

Deep-Learning Models for Abdominal CT Organ Segmentation in Children: Development and Validation in Internal and Heterogeneous Public Datasets.

Background: Deep-learning abdominal organ segmentation algorithms have shown excellent results in adults; validation in children is sparse. Objective: To develop and validate deep-learning models for liver, spleen, and pancreas segmentation on pediatric CT examinations. Methods: This retrospective study developed and validated deep-learning models for liver, spleen, and pancreas segmentation using 1731 CT examinations (1504 training, 221 testing), derived from three internal institutional pediatric (age ≤18) datasets (n=483) and three public datasets comprising pediatric and adult examinations with various pathologies (n=1248). Three deep-learning model architectures (SegResNet, DynUNet, and SwinUNETR) from the Medical Open Network for AI (MONAI) framework underwent training using native training (NT), relying solely on institutional datasets, and transfer learning (TL), incorporating pre-training on public datasets. For comparison, TotalSegmentator (TS), a publicly available segmentation model, was applied to test data without further training. Segmentation performance was evaluated using mean Dice similarity coefficient (DSC), with manual segmentations as reference. Results: For internal pediatric data, DSC for normal liver was 0.953 (TS), 0.964-0.965 (NT models), and 0.965-0.966 (TL models); normal spleen, 0.914 (TS), 0.942-0.945 (NT models), and 0.937-0.945 (TL models); normal pancreas, 0.733 (TS), 0.774-0.785 (NT models), and 0.775-0.786 (TL models); pancreas with pancreatitis, 0.703 (TS), 0.590-0.640 (NT models), and 0.667-0.711 (TL models). For public pediatric data, DSC for liver was 0.952 (TS), 0.876-0.908 (NT models), and 0.941-0.946 (TL models); spleen, 0.905 (TS), 0.771-0.827 (NT models), and 0.897-0.926 (TL models); pancreas, 0.700 (TS), 0.577-0.648 (NT models), and 0.693-0.736 (TL models). For public primarily adult data, DSC for liver was 0.991 (TS), 0.633-0.750 (NT models), and 0.926-0.952 (TL models); spleen, 0.983 (TS), 0.569-0.604 (NT models), and 0.923-0.947 (TL models); pancreas, 0.909 (TS), 0.148-0.241 (NT models), and 0.699-0.775 (TL models). DynUNet-TL was selected as the best-performing NT or TL model and was made available as an opensource MONAI bundle (https://github.com/cchmc-dll/pediatric_abdominal_segmentation_bundle.git). Conclusion: TL models trained on heterogeneous public datasets and fine-tuned using institutional pediatric data outperformed internal NT models and TotalSegmentator across internal and external pediatric test data. Segmentation performance was better in liver and spleen than in pancreas. Clinical Impact: The selected model may be used for various volumetry applications in pediatric imaging.

High freezing sensitivity of legumes relative to other herbaceous species in northern temperate plant communities.

BACKGROUND AND AIMS: Reduced snow cover and increased air temperature variability are predicted to expose overwintering herbaceous plants to more severe freezing in some northern temperate regions. Legumes are a key functional group that may exhibit lower freezing tolerance than other species these regions, but this trend only has been observed for non-native legumes. Our aim was to confirm if this trend is restricted to non-native legumes or whether native legumes in these regions also exhibit low freezing tolerance. METHODS: First, we transplanted legumes (five non-native species and four native species) into either an old field (non-native) or a prairie (native) and used snow removal to expose the plots to increased soil freezing. Second, we grew plants in mesocosms (old field) and pots (prairie species) and exposed them in controlled environment chambers to a range of freezing treatments (control, 0, -5 or -10 °C) in winter or spring. We assessed freezing responses by comparing differences in biomass, cover and nodulation between freezing (or snow removal) treatments and controls. KEY RESULTS: Among legume species, lower freezing tolerance was positively correlated with a lower proportion of nodulated plants and active nodules, and under controlled conditions, freezing-induced reductions in aboveground biomass were lower on average in native legumes than in non-native legumes. Nevertheless, both non-native and native legume (except Desmodium canadense) exhibited greater reductions in biomass in response to increased freezing than their non-leguminous neighbors, both in controlled environments and in the field. CONCLUSIONS: These results demonstrate that both native and non-native legumes exhibit low freezing tolerance relative to other herbaceous species in northern temperate plant communities. By reducing legume biomass and nodulation, increased soil freezing could reduce N inputs into these systems.

Unzipping hBN with ultrashort mid-infrared pulses.

Manipulating the nanostructure of materials is critical for numerous applications in electronics, magnetics, and photonics. However, conventional methods such as lithography and laser writing require cleanroom facilities or leave residue. We describe an approach to creating atomically sharp line defects in hexagonal boron nitride (hBN) at room temperature by direct optical phonon excitation with a mid-infrared pulsed laser from free space. We term this phenomenon "unzipping" to describe the rapid formation and growth of a crack tens of nanometers wide from a point within the laser-driven region. Formation of these features is attributed to the large atomic displacement and high local bond strain produced by strongly driving the crystal at a natural resonance. This process occurs only via coherent phonon excitation and is highly sensitive to the relative orientation of the crystal axes and the laser polarization. Its cleanliness, directionality, and sharpness enable applications such as polariton cavities, phonon-wave coupling, and in situ flake cleaving.

An Ovine Model Yields Histology and Gene Expression Changes Consistent with Laryngotracheal Stenosis.

OBJECTIVES: Animal models for laryngotracheal stenosis (LTS) are critical to understand underlying mechanisms and study new therapies. Current animal models for LTS are limited by small airway sizes compared to human. The objective of this study was to develop and validate a novel, large animal ovine model for LTS. METHODS: Sheep underwent either bleomycin-coated polypropylene brush injury to the subglottis (n = 6) or airway stent placement (n = 2) via suspension microlaryngoscopy. Laryngotracheal complexes were harvested 4 weeks following injury or stent placement. For the airway injury group, biopsies (n = 3 at each site) were collected of tracheal scar and distal normal regions, and analyzed for fibrotic gene expression. Lamina propria (LP) thickness was compared between injured and normal areas of trachea. RESULTS: No mortality occurred in sheep undergoing airway injury or stent placement. There was no migration of tracheal stents. After protocol optimization, LP thickness was significantly increased in injured trachea (Sheep #3: 529.0 vs. 850.8 um; Sheep #4: 933.0 vs. 1693.2 um; Sheep #5: 743.7 vs. 1378.4 um; Sheep #6: 305.7 vs. 2257.6 um). A significant 62-fold, 20-fold, 16-fold, 16-fold, and 9-fold change of COL1, COL3, COL5, FN1, and TGFB1 was observed in injured scar specimen relative to unaffected airway, respectively. CONCLUSION: An ovine LTS model produces histologic and transcriptional changes consistent with fibrosis seen in human LTS. Airway stent placement in this model is safe and feasible. This large airway model is a reliable and reproducible method to assess the efficacy of novel LTS therapies prior to clinical translation. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

Nonadiabatic dynamics of molecules interacting with metal surfaces: A quantum-classical approach based on Langevin dynamics and the hierarchical equations of motion.

A novel mixed quantum-classical approach to simulating nonadiabatic dynamics of molecules at metal surfaces is presented. The method combines the numerically exact hierarchical equations of motion approach for the quantum electronic degrees of freedom with Langevin dynamics for the classical degrees of freedom, namely, low-frequency vibrational modes within the molecule. The approach extends previous mixed quantum-classical methods based on Langevin equations to models containing strong electron-electron or quantum electronic-vibrational interactions, while maintaining a nonperturbative and non-Markovian treatment of the molecule-metal coupling. To demonstrate the approach, nonequilibrium transport observables are calculated for a molecular nanojunction containing strong interactions.